Pain: A Need for Paradigm Change

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ANTICANCER RESEARCH 7: 971-990 (1987)

Pain: A Need for Paradigm Change

F. BATMANGHELIDJ 

The Foundation for the Simple in Medicine, Lancaster, PA, U.S.A.
(Guest Lecture)

This paper was presented at the 1st International Workshop New Perspectives in Cancer Research, 15th~18th October 1987, Chalkis, Greece.

Reprint requests to: Dr. F. Batmanghelidj, 
Foundation for the Simple in Medicine, 
111 Centerville Road, Lancaster, 
PA 17603, or P.O. Box 3270, McLean, 
VA. 22103-3270, U.S.A.

Key Words: Pain, thirst, peptic ulcer, histamine, 
serotonin, renin-angiotensin, hypertension, 
diabetes, cholesterol, kinins, tryptophan, 
free water, cation pumps, neoplasia.

Abstract. 
From November 1979 to May 1982, I had the
"honor" of serving time at Evin political prison,
Teheran, Iran. Evin is the historical prison which 
has set the pace of revolution in the country. At 
Evin it was discovered that increased regular 
intake of water improved the clinical picture of 
peptic ulcer disease. One of the main 
components of this picture was pain of varying 
severity, sometimes very severe indeed.
Theoretical research to find the physiological 
reasons for the observed effect of water, in a 
condition currently classified as disease, has 
revealed a neurotransmitter, an osmoregulator, 
a water intake promoter status and a role for 
histamine. The action of histamine seems to be 
coupled to the efficient function of the cation 
pumps. Histamine and serotonin are involved in 
the regulation of the body's water balance.
Cellular "free water" insufficiency produces a 
disturbance of tryptophan metabolism; it is this 
disturbance and induced functional deficiency 
altering the homeostatic balance that produces 
pain and eventually tissue transformation and/or 
damage. This pain is being introduced as a 
signal system denoting free water deficiency of 
the cell and, therefore, it should be classified as 
thirst pain. Histamine and the renin-angiotensin
system also coordinate the water intake and
sodium balance of the body. With the induction 
of renin-angiotensin system for increase in water 
intake, threshold rates for water intake and the 
threshold rates for raising blood pressure seem 
close.

Treatment of clinically diagnosed peptic ulcer 
disease with increased regular intake of water at 
Evin prison has been reported (1,2). The prison 
diet consisted mainly of starch and pulses (such 
as beans, peas, lentils, a great amount of broad 
beans), low in animal protein or fat. In this 
report, observations on water induced relief of 
abdominal pain, which could not have been 
clearly associated with peptic ulcer disease, 
were also recorded. Accordingly, there was the 
indication that, as well-as the symptoms and 
signs of the clinically diagnosed peptic ulcer
disease under the existing, yet constant 
environmental factors, being transformed with 
increased water intake, other types of pain also 
responded to "water test". A number of patients 
with hematemesis, apart from blood transfusion, 
were for the first 36-48 hours given a regular 
drink of a strong sugar solution, followed by 
regular water intake (1,2,25).

In the older age group, in the same environment, 
the main clinical manifestation of stress was 
hypertension of varying severity. On a few 
occasions, individuals without a history of 
hypertension registered a systolic pressure of 
well over 200 mm. mercury. One patient's 
systolic pressure reached 300 mm. mercury. 
These patients were also advised to increase 
their water intake in addition to the medication
they were receiving.

The clinical observations made at Evin required
scientific explanation. In the laboratory we record
our observations on laboratory animals; here, 
observations were made on human beings. If 
water was producing the recorded responses in 
conditions that are normally classified as 
disease, then either the classifications are wrong 
or the physiological effect of the substance we 
recognize as water has not received due attention.
A very extensive theoretical search has produced 
the following concepts. It now seems that the 
scope of the regulatory physiological effect of
water has not received sufficient attention when
evaluating disease processes, and that the body's
response and reaction to simple water deficiency
has led to confused trends in medicine. In the
hope of generating interest, the following 
thoughts on the involvement and possible role of 
disturbances in water metabolism responsible for
disease production are presented. This course has
become necessary, since there are no means of 
comparing water with any other substance in 
order to discover its effect. One can only rely on 
the body's response to regulated water 
supplementation, and this means simple clinical
evaluation of the patient and his complaint 
before, during and after adequate hydration: 
this is exactly what took place at Evin.

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THE BASIC PARAMETERS

Assuming that man is one type of space satellite
of the initial "replicators" from the "primeval
soup" and that he has brought his salt water 
dependence with him, in the same way as man 
takes his capsule into space with him; again 
assuming that sub-disciplines of the science of 
biology are to be viewed according to the 
Darwinian concept of evolution, the law of the 
"survival of the stable" (3) would continue to 
apply to the descendants of the first cellular
creation of the earlier creative replicators. On 
the basis of this paradigm, man, the ultimate 
"survival machine" of the first replicator cell (3),
would also have to cope with the osmotic forces 
of the solutes in its cell environment. We see that 
it has retained the power to equilibrate 
effectively the osmotic balance of the cells by 
sending sodium ions out of the cell and returning 
potassium ions inside the cells. This mechanism 
has developed into a very complex pump system 
called the cation pump or sodium potassium 
adenosine triphosphatase pump. Coupled to this 
pump action is the activation of the energy 
transforming enzyme phosphatase. For the
transport of three mol. of sodium and two mol. 
of potassium, one mol of ATP is hydrolyzed (4). 
The same pump mechanism is developed around 
the hydrogen ion, calcium ion and possibly the 
magnesium ion, to activate the ATPase (4,5,6,7 ).
Even the shift of the dominant cellular 
polyvalent ions, such as magnesium and 
phosphorus, seem to be coupled together
with the shift of potassium into the cell. 
According to Cronin, there is a close relationship 
between the movement of magnesium. and 
potassium in the cells of the body. In general, a 
change in the serum level of one ion causes the 
other to deviate in the same direction. Calcium 
ion movement, absorption and its bone tissue 
metabolism seems also, in turn, to be coupled to 
magnesium turnover (7). According to Hesketh 
(99), evidence has accumulated indicating that 
cations play important roles within the cell in
controlling metabolism. In particular it is
now established that changes in the intracellular 
concentration of calcium regulate not only 
contraction in the muscle, but conduction in 
nerve; coupling of secretion to stimulus in cells 
such as platelets and mast cells, the initiation of 
development in fertilized eggs and, possibly, the 
activation of growth in normal cells. A second 
Ca++ transport across the cell membrane, other 
than Mg ion dependent movement, seems to be 
coupled to Na+ movement; this Na+/Ca++ 
exchange action is dependent on the 
transmembrane Na+ gradient maintained by 
Na -K activated ATPase. Current evidence 
suggests a stoichiometry of 3Na+:lCa++ and that 
the exchange protein functions independently of 
ATP, although, in the presence of ATP, the ionic 
affinity of the system increases. Again, 
according to Hesketh, the electrogenic Na+/K+ 
exchange catalysed by the Na+-K+ ATPase, may 
in turn be coupled to an electrically silent Na+H+
protein. In some cells this latter protein appears 
to regulate intracellular pH, whereas in others 
Cl- /HCO3- is the predominant mechanism.
The mast cell secretion activation depends on free
calcium ion in the celL It seems that, of the total 
calcium content of the cells, 0.01 % exists in the 
free ionised form and, of the rest, 40-60% is 
sequestrated in the mitochondria, either ionised, 
bound or precipitated as the carbonate or 
phosphate salt, 20% occurs in the endoplasmic 
reticulum and the remainder is either 
accumulated in secretory granule or the nucleus, 
or bound to macromolecules. It should be borne 
in mind that the activity of the plasma membrane 
cation pumps, in conjunction with the leakage 
across the membrane determines the steady-state 
concentration of free ions within the cytosol 
(99,100). According to Edelman and Hiatt, 
biosynthesis and regulation of Na+/K+ pump 
protein is thyroid dependent; this augmentation 
of the transport system accounts for 50-75% of 
the thermogenic action of the thyroid hormone. 
An equally important function of the Na+/K+ 
pump is the regulation and maintenance of the 
cell volume (100). The existence of linked passive
transport of Na+/Ca++ , K+/Ca++ and Na+/H+ 
exchange that are coupled to the action of the 
Na+-K+ pump is also noted. There are other 
co-transport systems for glucose and amino acids 
that are coupled to Na+ exchange because, active
transport of organic solutes by animal cells is 
sodium dependent, without exception (141). 
Also, pH gradient across membranes appear to 
be determined by the action of the H+/Na+ 
transport (l00). According to Kaufmann and 
Silman (101), it seems that the appearance of ion 
channels is pH regulated. In reconstituted 
membranes, significant opening and closing of 
ion channels takes place at pH range 2.5 to 3 and
no appearance of channels is observed at below 
pH 2 (101). 

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Today, medical research has forced the conclusion
that many disease conditions need to be 
controlled through purposeful limitation of 
sodium intake, or its encouraged expulsion from 
the body. The drugs most used are synthetically 
modified carbonic anhydrase inhibitors (8).

[Note: What is the role of carbonic anhydrase in
the kidneys?
Renal carbonic anhydrase. Carbonic anhydrase 
is a zinc metalloenzyme widely distributed 
throughout the tissues of the body. This enzyme 
exists in a number of isozymic forms in most 
mammalian species. ... In the kidney, this 
enzyme is thought to play a pivotal role in 
urinary acidification and bicarbonate reabsorption.]

According to Wiggins. it seems that the 
mechanism that controls, or brings about the 
effective function of the said cation pumps 
utilizes an energy transforming property of 
water, the solvent of its environment. The source 
of energy for cation transport or for ATP 
synthesis lies in increases in chemical potential 
with increasing hydration of small cations and 
polyphosphate anions in the highly structured 
interfacial aqueous phase of the two 
phosphorylated intermediates (6). Efficient
operation of the (Na+-K+)-ATPase seems to 
require that the chemical potential of K+ 
decreases in the highly ordered phase. The 
properties of the water must then be such that 
lightly hydrated solutes (large univalent cations 
and anions and small non-electrolytes) decrease 
in chemical potential when the phase change 
occurs (61).

Water in the cells of the body, according to
Hempling, is considered to be utilized for two 
different functions: water which is osmotically 
active and, by difference, that volume of cell 
water which is not active osmotically. "The 
key points were that the percentage 
of water in the cells remained 
constant but the fraction which 
was osmotically active decreased 
as the cell progressed through the 
cell cycle" (9).

In light of the above, the efficiency of the
function of the cation pumps and energy
transformation would then be contingent upon the
proportionate or quantitative presence of "free 
water" in the area of "demand"; be this demand 
within the brain and the spinal cord, renal tissue, 
the gastrointestinal tract, or for that matter any 
other tissue or organ of the body.

In the aquatic or amphibian species, except for 
the marine mammals such as the whale or the 
seal that cannot easily utilize the sea water (10), 
the fluid environment would present a uniform 
consistency, enabling the species concerned to 
adapt and maintain a uniform fluid intake. In 
terrestrial animals that have to adapt to a 
non-uniform and changing environment, what 
would happen if water intake is not 
sufficiently regular to maintain a 
uniform, let alone an upgraded 
demand on the cation pumps?

  Histamine is now being recognized to be a
neurotransmitter (11,12). By the presence of 
L-amino acid decarboxylase and the specific 
L-histidine decarboxylase, found in very high 
activity in catecholaminergic and serotonergic 
neurones, histamine is being considered to be a 
neurotransmitter, with also a specific neuronal 
system of its own, particularly in the proximal 
part of the duodenum (11,102,103). The 
basophil, the mast cell, the enterochromaffin-like
cells, as well as the neuronal tissue that contain 
histamine (13), particularly the neuronal tissue 
and the mast cell, demonstrate differing
mechanisms for the release of their amine 
granules (11). A highly significant characteristic 
is the effect of potassium ion induced 
depolarization; histamine of the neurones and the
synaptosomes is released when depolarization 
takes place. whereas histamine granules of the 
mast cell are not released (11). Mast cell 
degranulator, compound 48/80, whilst it 
effectively and proportionately degranulates
the mast cell it has no effect on the release of
neuronal or the synaptosomal histamine (l1). 
ACTH also invokes a proportionate release of 
histamine and serotonin from mast cells; the 
release process is very rapid and up to 90% of 
HA. and 5-Ht of rat mast cells is released by 
ACTH, and the response to ACTH being 
enhanced in the presence of Ca++ (104).
Another significant phenomenon is the mooe of
recovery of the amine; the synaptosomes need to 
be hypo-osmotically treated before the granules 
can be recovered intact in the synaptic vesicles 
(l1,12,14)

The histaminergic receptors are stated to belong
to either H1, H2 or H3 sub-class. H1-receptor 
mediated responses include glycogenolysis, 
stimulation of cyclic GMP formation, 
potentiation of cyclic AMP formation,
possibly linked to phosphatidylinositol
breakdown and mobilization of Ca++ from its 
endoplamic reticulum stores involving Ca++
-calmodulin complex. H2-receptors seem to be 
directly linked to an adenylate cyclase, and their 
stimulation results in enhanced
electrophysiologically recorded response to
excitatory agents. H1 and H2-receptors jointly 
seem to stimulate activation of protein kinase C,
resulting in phosphorylation of a protein
regulating the H2-receptor-linked adenylate 
cyclase (105). H3- receptors are auto-receptors 
mediating inhibition of histamine release from 
and biosynthesis in histaminergic nerve 
terminals in the CNS. In vitro experiments have 
shown the inhibitory action of H3-receptors to 
be concentration dependent with a maximal 
inhibition of up to 60% (105). H3-receptors
are presynaptic and modulate production and
release of histamine as a result of feedback from 
stimulus coupled H1 or H2 receptors' response (106).

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  When histamine is introduced into the lateral
hypothalamus of rats it induces drinking even in
satiated animals. 

Gerald and Maickel have shown that 80 
micrograms of histamine, when injected in the 
hypothalamus, produced a three-fold increase in 
water intake even in rats that were satiated. 
They suggest that central histaminergic functions 
may be involved in thirst-induced consumption 
of fluids(15). Leibowitz has shown that when 
small dosages of about 50ng. are injected into the 
different parts of the hypothalamus, histamine 
can elicit water consumption in water-satiated 
rats; with the statement that this action of 
histamine is a centrally and not a peripherally
mediated phenomenon (16). According to Kraly, 
histamine is also involved in the induction of 
drinking by food intake (17). In another paper, 
Kraly and associates demonstrate a 
histaminergic mechanism for drinking elicited 
by insulin in the rat (18). 



Gebhardt N. et al. showed that vagus nerve stimulation promotes neurogenesis in the dentate gyrus of animals after 48 hours of treatment.



Kraly further demonstrates a pre-absorptive 
pregastric vagally mediated histaminergic 
component of drinking elicited by eating in the 
rat (19.20); selective gastric vagotomy abolishes 
drinking response to low doses of histamine in 
the rat, while the combination of vagotomy with 
angiotensin convening enzyme inhibitor 
(captopril) abolishes drinking elicited by higher 
doses of subcutaneous histamine (107). 
According to Goldstein and Halperin, histamine 
is the mast cell amine involved in the triggering 
of the drinking response induced by a hypetonic 
load through the activation of an H2 receptor. 
They propose that the mast cell has certain 
characteristics one would expect to see in an 
osmotic receptor (21). Goldstein and associates, 
in another paper, further demonstrate a firm 
association of histamine and water metabolism
of the terrestrial vertebrates; the mast cell of the 
fish and the amphibians differ from those of 
higher vertebrates by being devoid of histamine; 
on the other hand. in the reptilians, the first truly 
terrestrial vertebrates, tissue histamine is mainly 
stored in mast cell (reported from Reite). They 
further report, also in the reptilians, as stressed 
by Kaufman and Fitzsimons, that a new 
dimension of water balance appears, namely the 
ability to drink water when the need arises. With 
water deprivation and food intake, they 
demonstrate an increase in the mast cell number 
in the rat mesentery* (22). 


[* Mesentery: In general, a fold of tissue that 
attaches organs to the body wall. The word 
mesentery usually refers to the small bowel 
mesentery, which anchors the small intestines 
to the back of the abdominal wall. Blood 
vessels, nerves, and lymphatics branch through 
the mesentery to supply the intestine.]

Hiroshi Izumi and associates have demonstrated
that compound 48/80 and histamine stimulate
water intake by different mechanisms, 
peripherally through stimulation of the renin-
angiotensin system and centrally mediated by its 
direct action on the brain. They also report a 
change in plasma Na+ and K+ levels after 
administration of compound 48/80, histamine 
and isoproterenol (23).

  Humes also expands on the different aspects of 
the thirst mechanism involving the renin-
angiotensin system, first demonstrated by 
Fitzsimmons (108), indicating that the 
subfornical organ is the only site for the 
dipsogenic receptors for angiotensin II in the 
entire brain. Beta-adrenergic agents stimulate
drinking, but their action appear to be mediated 
via the renin-angiotensin system, quoting Houpt 
and Epstein. Hume also states that, "since 
extracellular fluid volume is determined by Na+ 
balance, the major determinants of intracellular 
fluid and extracellular fluid volume homeostasis 
are clearly separate: sodium balance 
regulates extracellular fluid volume;
water balance regulates intracellular 
fluid volume. (24), It seems that, in any water 
loss, approximately 66% comes from 
intracellular fluid volume, 26% from interstitial 
fluid volume and only 8% from intravascular 
fluid volume (24), Thus, hypovolemic shock is 
rare in pure or "free water" loss or deficiency (24).

  On the basis of the above information - namely
that hypo-osmotic treatment stabilized the 
histamine granules within its vesicle, and that 
the effect of the K+ by itself, enhanced by the 
presence of Ca++,which degranulate the 
synaptosomes of its histamine; the indication 
that histamine and the sympathomimetic amine 
isoproterenol affect plasma Na+ and K+ levels 
and that H2 receptor stimulation enhances
electrophysiologically recorded responses to
excitatory agents: the indication that the cation 
pumps are "driven" by water it is proposed (25) 
that: histamine is a neurotransmitter amine that
demonstrates a mechanism of production and
release that is extremely sensitive to the 
inefficient function of the cation pump; that 
histamine is reproduced and released when there 
is a K+ build up around the site of action or 
increased activity forced on the tissue. The tissue 
most susceptible to such fluctuation would, of 
necessity, be the nervous system and its 
transmission mechanism.

It has also been proposed that certain
neurotransmitters, histamine in particular, 
demonstrate certain properties that would make 
them candidates to be classified as responsible 
for the efficient operation of the cation pumps; 
whilst promoting water intake by the body, in the
interim, they act as an emergency substitute for 
water with respect to bringing about the cation 
pump drive (25), as well as promoting post 
receptor energy release (26,105) for this function.

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In light of this and other information on the 
apparent involvement of histamine in the water
intake of the body and its functional role as a 
neurotransmitter and an osmoregulator, in order 
for cation pumps to revert to their natural mode
of function, histamine, it seems, has become a 
messenger in the loop that promotes water intake 
by the "animal". It seems that the prominent 
serotonergic neuromodulating neuronal system is
another major water intake promoting part of the 
loop. According to Holstein, the dipsogenic 
effect seen in the absence of intestinal perfusion 
indicates that 5-HT may be involved also in the 
regulation of drinking (27). Serotonin seems to 
be involved in regulation of the gastrointestinal 
tract function: it promotes water intake, inhibits 
acid production; inhibits acid production by 
histamine at 33% salt water perfusion of cod 
intestine; while, with 67% salt water perfusion 
of the intestine, the action of histamine is not 
inhibited by serotonin (27). Serotonin also 
promotes mucus production making the gastric 
effluence more viscous. Despite inhibition of 
acid secretion, volume outflow increases during 
i.m. water support, not during intestinal 
perfusion (27). Accordingly, 5-HT is dipsogcnic 
in the cod and, as with all, the dipsogenic
response is suppressed by an intestinal satiety
mechanism, the latter probably activated by 
intestinal distension (27). Serotonin inhibits acid
production in the rat stomach. As shown, 5-HT 
on the serosal* side caused significant inhibition 
of the acid secretory response to histamine 
(Canfield and Spencer 28). 
[*NOTE: A serous membrane (also referred to 
as a serosa) is one of the thin membranes that 
cover the walls and some organs of the thoracic 
and abdominopelvic cavities. Serous 
membranes have two layers. The parietal layers 
of the membranes line the walls of the body 
cavity (pariet- refers to a cavity wall).]


According to Kraly, histamine and serotonin 
independently elicit drinking in the rat, possibly
through the peripheral action of renin- 
angiotensin stimula[ion when they arc released 
from the mast cells (109). Laczi and associates 
demonstrate presence of a strong stimulatory 
effect on the release of arginine-8-vasopressin 
by histamine in man (115). Panula and 
associates (116) report that the distribution of
histamine resembles the distribution of 
serotonin; that histamine participates in the 
physiological regulation of pituitary hormones, 
for example, ACTH, perhaps by releasing 
vasopressin, which has corticotropin releasing 
hormone activity. Shenker and associates(119)
postulate the presence of a direct central
stimulatory effect of serotonin on secretion of 
aldosterone .

When a satiety mechanism is being anticipated, 
it is interesting to note that, according to 
Christofides and associates, water intake 
promotes a volume dependent sustained 
secretion of hormone motilin (29). Yet hormone 
motilin itself has been isolated in the EC cells 
(30); and its serotonin-like characteristics are
being postulated; it is likely that the serotonin 
and motilin granules of density 1.20 in this study 
are identical and thus represent EC2 granules" 
(Bryant and associates, 3D). Motilin Granules Density

According to Fernstrom, growth hormone 
secretion, blood pressure, pain, sleep and 
appetite seem to be strongly affected by the 
serotonergic neuronal system of the brain (31). 
Blood pressure is reduced, the pain threshold is 
raised, and appetite for carbohydrates is reduced,
whilst protein intake is not affected. According 
to Costa and associates, the more confirmed 
hypothesis is that the decrease of serotonergic 
function in the brain or spinal cord causes an 
increase of sensitivity and reactivity to noxious
stimuli, whereas an increase of serotonergic
neurotransmission is correlated to analgesia (32).
Seltzer and associates, on the subject of chronic
maxillofacial pain tolerance, Slate that manipula·
tion of diet to favor tryptophan and therefore a
rise in brain serotonin, results in a significant
reduction in pain intensity (33). Pollack and
associates also state, a high tryptophan diet can
alter chronic pain sensitivity (34). It seems that
even morphia induced analgesia is produced 
through the serotonergic neuronal system in 
the raphe nuclei of the brain, particularly raphe 
magnus. The activation of this nucleus can even 
produce depolarization of cutaneous afferent 
terminals of mechanoceptors as well as 
nocioceptors (35).



According to Katchalski- Katzir(36), three to ten
amino acid residues are highly flexible in 
solutions of low viscosity; as the viscosity of the 
medium increases, conformational changes slow 
down. In solutions of high viscosity, the peptide 
chains become completely frozen in their 
conformation. Their data reveals that, 
conformational flexibility of peptides or
nucleotide oligomers enables them not only to 
recognize the biological receptors but also to 
fold into the specific three-dimensional 
receptor structure. It is further stated that this 
requirement applies to endorphins, enkephalins, 
ACTH and growth hormone. In the same vein, 
it is stated. that globular proteins "breathe", 
allowing oxygen consumption and opening of 
channels to release their fanned products. This 
same efficiency of function, as a result of 
conformational change acceleration, also appltes
to immunoglobulins and side chains to proteins, 
The implications of this aspect of hydration are 
vast. It seems that the aromatic amino acids 
within proteins also continue to breathe or force 
their inherent characteristics on the constituted 
protein(36). Munro and associates have 
calculated the conformational change for 
tryptophan, At 5℃ it has practically no rotational
freedom, whereas at 43℃ it rotates with a
'correlation time of 0.14 nano-seconds, 
indicating

↑Page 975 ANTICANCER RESEARCH 7: 971-990 (1987)
↓Page 6 of 19.

that it arises from rotation of tryptophan with the
whole protein or a large domain of it. At 43℃ 
this tryptophan residue acquires rotational 
freedom independent of the whole protein (37). 
This rotational property of tryptophan must also 
apply to its loose binding to albumin.

Tryptophan has to be carried through the blood 
brain barrier (as well as through cell membrane 
in the gastrointestinal tract or the cells dependent
on its metabolism) competing with the other 
large neutral amino acids - leucine, isoleucine, 
valine tyrosine and phenylalanine - that share the
same carrier mechanism. Insulin, secreted as a 
response to carbohydrates in the diet, alters 
the odds in favor of tryptophan against 
the competing large neutral amino acids for its 
transport across the blood brain barrier, by 
stimulating the entry of the branched-chain 
amino acids into muscle tissue (38,39).

This increase in tryptophan conformational
change, with increased enthalpy*, (*Enthalpy is 
a measurement of energy in a thermodynamic 
system. It is equal to the internal energy of the 
system plus the product of pressure and volume.)
, will favor its easier release from its albumin 
binding site and make a faster lock into the 
transporter protein possible; it will give it still 
one more advantage at the antiluminal side of 
the brain capillaries, where the mitochondria of 
the capillaries and the cation pumps are situated 
(40). This heat excitability of tryptophan must 
be involved in the "shaving" mechanism
attributed to the brain capillaries for their uptake 
of tryptophan from albumin. The heat produced 
by the cation pump has been calculated by 
George and associates (6), and Hempling also 
talks of "high heats of activation" (9). There 
seems to be substantial evidence that "free 
water", as the driving force of the cation pump 
and also essential in the initial phase of fat and 
protein breakdown in gluconeogenesis, is 
actually bringing about energy transformation 
and enthalpy of activation and, therefore, is 
indirectly upgrading the rotational properties
of proteins and polypeptides as well as the amino
acids. tryptophan in particular. Accordingly,
it effectively becomes responsible for the 
efficiency of conformational change of 
tryptophan and carrier or transporter proteins 
enabling them to keep up with the demand for 
their very diverse functions in' the body (42,43,
44). In the case of axonal transport, kinesin
class of transporter proteins have been identified 
(41,112), the assumption is that a similar 
mechanism and type of protein transporter 
systems involving microtubule activated ATPase 
exist within other cells (113, 114,110 )
Theoretically, gluconeogenesis,"free water' loss 
and the need for free water if continued, can 
bring and, is thus responsible for inefficient 
protein and enzyme function, as a result of 
increased microviscosity of the cytosol, further 
embarrassing the transport systems within the 
cell, be it the axonal transport or blood brain 
barrier transport systems. Particularly, a novel 
hypothesis forwarded by Weiss and Gross, 
predicts (a) the force for cell transport to be 
non-specific in character, (b) the transport to be 
micro stream born, i.e., a hydrodynamic
phenomenon (111).


  Histamine produces a capillary dilation of the
blood brain barrier, an H2 receptor phenomenon
(45,46). On the other hand, K+ turnover seems 
to regulate capillary dilation or local circulation 
in the brain (47,48) and presumably in 
capillaries elsewhere. The two-way transport 
system through the blood brain barrier places a 
great demand on the efficiency of the local or 
general circulation of the brain tissue,
particularly as some transport systems have rate 
limitations per unit surface area of the capillary.
Therefore, the efficient operation of the cation
pump has to be in place to cope with thc demand
by increasing the microcirculation of the brain 
tissue in particular.


  The hormone receptor coupling depends on the 
three dimensional fit of the hormone into the 
receptor site. Rimon and associates state, that 
when the hormone or the neurotransmitter bind 
to the receptor, the catalytic unit of the cyclase is
activated and produces cyclic AMP at the inner
surface of the membrane. Membrane fluidity 
affects the catalytic unit directly, as the maximal 
activity of the enzyme increases as a function of 
membrane fluidity. It is apparent that the 
adenosine dependent activity, the adrenaline 
dependent activity and the Na-stimulated activity 
increases as a function of membrane fluidity. 
Ca++-ATPase, Na+-K+" ATPase and the 
Betagalactoside transport system were also found 
to depend on the membrane fluidity. They 
postulate, "Either the receptor and the enzyme 
are mobile and float in the membrane, or the 
receptor and the enzyme are permanently coupled
to each other" (49). It seems that the adenylate 
cyclase , [*Adenylyl cyclase (EC 4.6.1.1, also 
commonly known as adenyl cyclase and 
adenylate cyclase, abbreviated AC) is an enzyme 
with key regulatory roles in essentially all cells.] 
activation is a diffusion-controlled process. 
Increase in membrane fluidity also causes a
maximal threefold increase in the adenylate 
cyclase activity, based on the assumption that the 
bet-adrenergic receptor and the cyclase are 
separate units and diffuse freely in the membrane 
(50). Ross and Gilman, also quoting Livitzki and 
co-workers, state that increase in the rate 
constant for activation of GPP(NH)p plus 
epinephrine is inversely related to the 
"microviscosity" of the bilayer. They are of the 
opinion that the floating receptor model for 
regulation of the adenylate cyclase is essentially 
accurate (51).

↑Page 976
↓Page 7 of 19.

It seems that the rate of lateral diffusion of the 
enzyme unit of the bound receptor within the 
bi-layer membrane of the cell determines the 
effectiveness of the hormone receptor function; 
and this lateral diffusion in the bilayer membrane 
is inversely proportional to the microviscosity 
within the bi-layer.

We have all, at one time or another, seen the 
lipid-globular protein mosaic model of a cell 
membrane depicting a bi-layer structure, with 
"tuning fork" like projections into the bilayer 
from both sides. We have been told that the 
external surfaces are hydrophilic and the 
projections into the bilayer are hydrophobic. 
Some may wrongly assume that the 
"hydrophobic" property means that water does 
not get into the bilayer membrane. 



Rand and Parsegian have shown that water 
separates the bilayer structure of lipids to either 
a fixed distance of 20-30 A in the case of
an electrically neutral bilayer or to indefinitely 
large separation of up to 100 A in the case of a 
charged bilayer(52). A lateral diffusion pressure 
is also developed with the introduction of water 
in the bi-layer. The above information permits 
the thought that these hydrophobic "tuning-fork-
like" projections may act as mixers or stirrers in 
the bilayer membrane, by being responsible for a 
build-up of the lateral" diffusion pressure 
between the fork-like projections: they may bring 
about a more efficient "hormone-receptor-
enzyme" action within the bilayer membrane 
(for the receptor types that stimulate function 
within the bilayer), the microviscosity of the 
space having also been adjusted, when free water 
diffuses through the phospholipid membrane.
Because the inherent property of the cell 
membrane is to be a barrier for ions and most 
polar molecules, whilst permitting water through 
the lipid membrane by the process of diffusion. 
The permeability coefficient (cm/sec) for water 
is 10 to the power of negative 3 (0.001 cm/sec)
and for sodium and potassium, it is 10 to the 
power of negative 12 (53). The diffusion rate 
through the membrane is ultimately dependent 
on the composition of the membrane, cholesterol 
contents of the membrane being the determining 
factor in the rigidity, and thus in the comparative 
impermeability of the membrane (53,54,55). 
These concepts indicate the importance of water 
in fine regulation of the interlocking hormones, 
neurotransmitters and neuro-modulators' action 
in the body. This concept may seem important to 
the function of neuromodulators or neuro-
endocrine systems that regulate themselves on
the basis of a feedback mechanisms. This could 
also include the short loop negative feedback 
that seems to exist between renin production and 
angiotensin II inhibition of renin production 
(56), and also the fast and delayed feedback 
mechanisms that regulate corticosteroid 
inhibition of adrenocorticotropin release from 
anterior pituitary gland (117).

Kinins are involved in renin release from the
glomeruli (57). It should be noted that sodium
deprivation promotes kinin production and 
release into the circulation through production 
of kallikreins in the glands (salivary. sweat, 
pancreatic, kidney and digestive tract), 
particularly submandibular gland (58); kinins 
regulate renin production, when all the time the 
renin-angiotensin mechanism is involved in
thirst production and water regulation; sodium
seems 10 be involved in cell pH regulation 
through the action of Na+·H+ pump (59,60.99), 
when pH changes can convert prekallikrein to 
kallikrein, with the resultant formation of 
bradykinin or kallidin from kininogens, kinins, 
capable of causing pain (61), as well as the other 
functions they perform.

  The serotonergic system in the brain and the
periphery is another such complex network of a
neuronal system that seems to be affected when 
there is a deficiency of hydration. The 
serotonergic system in the brain has three types 
of receptors: S1, S2 and S3. The receptor 
classified as S2 is an auto-receptor; it is
presynaptic and mediates collateral inhibition, or
it may have a direct inhibitory action. The S3 
receptor is found in many parts of the brain: it 
too has an inhibitory function. S1 receptor is 
found in post-synaptic locations, its function is 
neuro-modulatory (62). Sub-types D and M are 
reported in the muscle and the skin , with type 
M being further divided into three subtypes, one 
of which is involved with pain registration (63). 
Skin serotonergic receptors are also involved in 
the themoregulation of the body. Histamine
receptors will similarly be influenced by the 
efficiency of the feedback mechanism, 
particularly since H3 receptors have a major 
role in HI-H2 inhibition.


  In the discipline of gastroenterology, the
epigastric pain not associated with the presence 
of an ulcer crater or with a definable pathology, 
such as cholecystitis or pancreatitis is not 
considered important, in most cases, it also 
shows equal response to antacids, cimetidine 
or placebo" (64). When, with a similar pain, a 
macroscopic ulcer crater is seen. the treatment 
of choice then becomes H2 receptor blocking
agents. Between that initial nondescript pain and
the final visual stage, the "same characteristic
pain" with some local mucosal change. is 
classified as gastritis. duodenitis, esophagitis 
and so on. At times, an autoimmune state is 
postulated. Is separation of these stages as 
different conditions accurate? If the ultimate 
stage is to be treated with an H2 blocking agent, 
then we are interfering with a neurotransmisssion

↑Page 977 ANTICANCER RESEARCH 7: 971-990 (1987)

↓Page 8 of 19.

mechanism that is involved in the water intake of
the body, and possibly substituting for the 
function of water for the cation pump drive, until 
the deficiency is replenished. It seems reasonable 
to assume that in such circumstances the inter-
locking control mechanism may possibly not be 
operative until full hydration takes place. The 
parietal cell uses up vast quantities of water; full 
function of the parietal cell requires transport of 
large volumes of water from the circulation (13). 
It requires water in order to operate the 
H+-K+ ATPase pump (6). When this normal 
physiology is not efficient, histamine takes over, 
since the capillary circulation of the stomach has 
H2 receptors (65). Histamine will continue to 
maintain the integrity of the local circulation, at 
the same time producing a central pain alarm; 
low pH conversion of kininogens to kinins may 
be the pain inducing mechanism (61).

According to my clinical observations and the 
exposed theoretical reasons, the abdominal pain, 
when other local pathology such as cholecystitis 
or other definable conditions are not suspected, 
should be considered to be a "thirst pain"; in 
fact, a glass of water can serve as a diagnostic 
tool (1,2,25). This initial pain is the important
signal representing the malfunction of a water 
regulated system, because, when insufficient
hydration that has caused pain continues, a
physiological state inducive to tissue 
transformation and/or tissue damage is then 
created. Depending on the duration of the body 
protein and enzymes' lower rate of production 
and functional down-regulation, which could 
include the class of body proteins known as 
"receptors" be they interferon receptors,
cholesterol receptors, insulin receptors, sex 
steroid receptors, or any other class of receptors 
the different stages of disease conditions will be 
seen. This question about the rationale of 
separation of pain and the different stages of' 
tissue damage in peptic ulcer disease has been 
voiced by Spiro (66).

  Unfortunately, in "stress", assumed to be 
induced by cellular free water depletion, the 
amino acid tryptophan - which determines the 
level of activity of the serotonergic neuronal 
system and possibly other indoleaminergic 
activity, that among other functions raise or shift 
the pain threshold (31,35), as well as regulating 
all aspects of the pituitary-adrenal functions (67,
68,69) - will be one of the more important 
elements that will become quantitatively depleted
as a result of its over metabolism by the liver, and
the tryptophan that remains is rendered less 
effective by the decrease in its rotational 
properties. One of the events, that seems to take 
place is a change in the ratio of free to bound 
tryptophan in circulation(70).  If the level' for 
free tryptophan reaches to more than twenty 
percent, the liver will metabolize the excess(71) 
by induction of the enzyme tryptophan
oxygenase; also as a result of increased free 
tryptophan in circulation, the enterochromaffin 
cells increase serotonin production which will be 
taken up by the platelets (133) and mast cells 
(22); whereas in tissues other than the liver, 
tryptophan metabolism occurs through induction 
of the enzyme indolamine dioxygenase and 
production of superoxides (72,73). It seems that, 
through induction by cortisone, the liver 
enzymes, tyrosine aminotransferase as well as 
tryptophan oxygenase are activated, with the 
possibility of eventual depletion of the body's 
pool of tyrosine and tryptophan (Bender 72).
Depending on the ratio of the intake (animal 
protein, meat, has very low tryptophan content 
compared to its transport competitors, 31), to the 
over metabolization by the liver (71,72), causing 
an induced tryptophan insufficiency (74), and 
altered route of metabolism, signs as well as 
symptoms will then be produced. It is important 
to note that when a combination of protein and 
fat is exposed to oxygen, oxidation of fatty acids 
and the release of free radicals results in some 
essential amino acid's deterioration, among them 
tryptophan, lysine and methionine; lysine loss 
can be high and methionine loss can be total (74).
This information is particularly important since 
lysine, in conjunction with tryptophan, acts as an 
enzyme system for recognition and repair of 
damaged DNA (75). Meat, when exposed for 
marketing, could be a candidate for this 
deterioration.

  Under such circumstances, tissue damage or its
transformation will involve more than just the 
tract and its gastric or duodenal disorder.

  Tryptophan, is possibly involved in the 
antiviral tissue defense mechanisms by 
production of superoxide of anion and hydrogen 
peroxide. It seems that interferon stimulates the 
synthesis of prostaglandins in the cells, which in 
turn bring about induction of indoleamine 
dioxygenase (73), It is important to consider this 
link in the chain when conditions of apparent
deterioration in the body's immune system are 
being investigated, even if we are searching for
a viral depressant of the immune system because,
in certain circumstances, a plasma borne tissue
-CRF, with extreme potency and prolonged 
course of action, "intestinal stress" induced, can 
be transferable through blood or plasma (124,
128,142).

  Tryptophan is involved in protein synthesis and
in tissue repair, especially in high turnover 
tissues such as the stomach and the intestines, 
when protein synthesis and the regeneration of 
cells need tryptophan in particular, According to 
Majumdar, force feeding of L-tryptophan 
stimulates amino acid incorporation into albumin,
fibrinogen, transferrin and ferritin; by its effect 
on protein synthesis in the gastric mucosa, there 
is indication that dietary tryptophan plays a 
significant role in maintaining the structural and 
functional properties of the gastric mucosa (76) 
and, undoubtedly, other tissues of the body.

↑Page 987.
↓Page 9 of 19.

  Even at the level of damaged DNA, it is 
postulated that tryptophan, in conjunction with 
lysine (and glycine), acts as an enzyme system 
for the recognition of a damaged site and for its 
repair(75). Also, according to Seymour Zigman, 
among the photooxidation by-products of 
tryptophan, the sub-groups PPI and PT2 
demonstrate cell division antagonism, and also 
act as enzyme and protein inhibitors, since they 
mimic the action of organic peroxides. PT2 
appears to be a better macromolecule synthesis 
inhibitor than other tryptophan oxidation
products (77). Whether photooxidised or 
indoleamine dioxygenase induced, it appears that 
by-products of tryptophan metabolism have 
marked influence on the defense and regulation 
of cell function when the function of the cation 
pump is adequately maintained.


  It is worthy of note that, even when H2 blocking
agents are used to "repair the ulcer", the repair 
time depends on a natural healing rate; according 
to Gregory, even with the "tissue" covering the 
ulcer crater, morphologically the site of damage 
is not considered normal or fully repaired (78). It 
seems that the H2 blocking agents, among them 
the tricyclic antidepressant drugs being very 
potent H2 blocking agents (79), influence the 
serotonergic neuronal system (80). In view of the 
fact that the cerebral capillary system has H2 
receptors for dilation and increased circulation,
the question arises: when these drugs are used, is 
the brain tissue being forced into a functional
hypoxic down-regulation, to heal the ulcer, or to 
treat depression?

  Having discovered that the renin-angiotensin 
system is histamine induced (23), and being
armed also with the knowledge that the renin-
angiotensin system is the operative peripheral 
drive for water intake by the body (23,24), it 
becomes equally very important to know that the 
threshold rates for water intake and the threshold 
rates for raising the blood pressure seem to be 
very close (81). In the dog and rat these rates are 
antidiuretic and antinatriuretic (81), possibly
because angiotensin III, a septapeptide 
metabolite of angiotensin II, has a direct 
aldosterone secreting property (118), It is 
understandable, since the blood circulation 
operates within a closed system, that any volume 
change has to be compensated for immediately, 
otherwise a "gas lock" could develop, causing a 
malfunction of the system. This compensation 
seems to be secured primarily by "borrowing"
water from the other two compartments to the 
extent of 92% (24), while the other 8% is made 
up by closing the system proportionately, If 
through inadequate intake of water, the body 
continues to run on a deficit (82,83,84), then, by 
manipulation of the osmotic forces through salt 
retention (or glucose threshold manipulation and 
possibly retention of uric acid), it will continue 
to borrow water from the other compartments in 
order to maintain a comparative integrity of its 
blood circulation and, therefore, brain cell 
volume. It is interesting to note that, with salt 
deprivation, there is a higher turnover of
glandular kallikrein in the glands of the body, 
apparently as an agent for induction of 
vasodilation to maintain circulation (58). This 
sodium retention could have a much more 
important functional role than merely being 
needed for maintaining the extracellular' fluid
volumes. Since membranes are functionally 
asymmetric, particularly with respect to the ionic 
pumps (53), and the primer of these pumps is a 
build up of the particular ion on the "intake side" 
of the pump, and since the function of all cells 
has an inherent property of continuously 
buffering its energy charge as well as its pH 
change (53), this sodium retention may be a very 
delicate balancing component of the cell pH 
buffering system in some cells (99). Selvaggio
and associates, expanding on the work of Rindler
and associates, have demonstrated the existence 
of a Na+-H+ pump (59). Livne and associates 
also propose Na+ to be involved in the pH 
buffering system of the body (60). It is assumed 
that this pump also operates in a similar way to 
the other cation pumps, namely that "free water" 
is responsible for driving it. According
to Cooke, sodium uptake by the enterocytes may 
be affected by the level of tryptophan made 
available to the tissue (rabbit jejunum); 
"tryptophan increases electrogenic sodium 
absorption, followed by inhibition of the active 
sodium absorption." This regulation between 
inhibition and stimulation of absorption depends 
on the quantity of the amino acid made available
to the tissue (85), when serotonergic neuronal
system directly and indirectly, through 
aldosterone secretion, also promotes sodium 
retention (119). In light of the above, 
malregulation of the cell pH may be the cause of 
pain in tissues other than those of the 
gastrointestinal tract, in the same way as was 
proposed for the abdominal pain, particularly as, 
according to Goldstein and associates,

Page 979 ANTICANCER RESEARCH 7: 971-990 (1987)

generation of endogenous kininogen splitting 
enzyme(s) responsible for bradykinin production 
is/are inaccessible to exogenous or circulating 
substrates (121).

↓Page 10 of 19

It is interesting to note that procaryotes regulate
the fluidity of their membrane by varying the 
number of double bonds and the length of their 
fatty acid chain to alter the fluidity of their 
membrane; as a process of adaptation to 
environmental change, they take this course in 
order to survive. This has been shown in E.coli 
(53). In eucaryores, cholesterol is the important 
regulator of membrane fluidity. Thus cholesterol 
moderates the fluidity of the membrane (53). 
This phenomenon seems to demonstrate itself in 
the tracheal epithelial cell apical membrane. 
According to Wonnan and associates, increases 
in fluidity correlate with increases in water
permeability of these membranes. At a transition
temperature of between 28-26℃, cholesterol 
significantly decreases water permeability above
phase transition temperature of planar lipid 
bilayer, and increases it below the transition 
temperature (54). If water permeability through 
the cell membrane commands such fine 
regulation as even to dictate a membrane's 
structural change, and if in chronic water loss the 
cellular water content becomes depleted, and if 
each cell in the body, to a lesser or greater 
extent, has an individual power of adaptation 
very much like that of E. coli, then should we not
expect a "cholesterol" adaptation phenomenon? 
If these adapting cells are exposed to the osmotic 
forces of the blood, drawing their water directly, 
would there not be a logical regional defensive 
build up of cholesterol within the cell membrane, 
to bring about a form of protective adaptation, 
in order to survive?·

DISCUSSION

Up to now, we in the medical profession have
taken the water consumption of the body for 
granted. We have considered it to be a self-
regulating mechanism that will take care of itself.
 We have relied on the sensation of thirst as an 
everlasting quality of the body. It is true that 
whenever we treat a sick patient in hospital, we 
fuss about water intake and the electrolytes, but 
by and large our other patients are not controlled 
for their fluid intake (not drying agents, such as 
coffee, tea and alcohol, the latter through 
inhibiting the secretion of anti-diuretic hormone 
(140,24). We must assume that all sensations of 
the body lose their edge with the passage of time, 
including the thirst sensation. Sliding Meyer has 
shown that from the age of twenty onwards the 
brain capillaries gradually lose their 
responsiveness to breathing 100% oxygen, and 
increased CO2 tension (86). We must assume that
if the receptors involved in evaluation and 
compensatory adaptation to fluctuations of
oxygen and carbon dioxide tension lose their 
edge, from the age of twenty onward, then the 
same probability applies to the ability to evaluate 
the water content of the body to the point of 
inducing thirst mechanism as a finely adjusting 
sensation, in order to keep protein and enzyme 
function at the optimum for that body (25). 
Bruce and associates have also demonstrated a 
definite predisposition of a lasting change in the 
body water composition with age. The ratio of 
extracellular water content to intracellular
water content change from an approximate 0.8 to 
almost 1.1 between the ages of 20 to 70 - a very 
drastic change in composition (87). We are more 
and more coming to realize that older people are 
chronically dehydrated, losing the capacity to 
re-hydrate their body, even though obviously 
dehydrated (82,83,84) with a predisposition to 
hypothermia, yet we do not make a strong effort 
to compensate for this problem over a longer 
period of time before their "ailment" is treated, 
sometimes very drastically, as for example with
vascular surgery for intermittent claudication*, 
or allow anginal pain to proceed to its logical 
conclusion. [*Claudication is pain caused by too 
little blood flow, usually during exercise. 
Sometimes called intermittent claudication, this 
condition generally affects the blood vessels in 
the legs, but claudication can affect the arms, 
too.]

We must reevaluate the concept of dry mouth as 
a safe sign of thirst, first proposed by Haller and 
ardently supported by Cannon; we must accept 
and explore Schiff's original evaluation of thirst 
as a general sensation of the body (108). It is 
taken for granted that, coupled with the process
of aging, the body gradually loses its reserve 
capacity; protein and enzyme functions are 
trimmed to the basic day-to-day requirement. 
Yet, at any age a form of homeostatic balance is 
established for that body and its norm of activity. 
To optimize the protein and enzyme functions for
this period of life, maximum activity of the cation
pumps and the energy transforming enzymes 
should be assured through increased hydration. 
It is also in this group of people that pain, as a 
signal system of the inefficient operation of the 
cation pumps, develops significance and importance.

  At this point, Medawar's opinion finds 
significance. Dawkins (3) considers that the body 
is just a survival machine for the genes we have 
inherited. He is of the opinion that every function 
of the body is genetically determined, even 
predetermined. He expands on Medawar's 
opinion that there are late acting semi-lethal and 
lethal genes. It is said that senile decay is the 
result of the activity of these genes, when the 
"good" genes have given way. 

↓Page 11 of 19.

It is being said that there are certain "cues" which
turn on the late-acting lethal genes. Let us expand
on this subject. Crowther, in his research on the 
effect of cations on the rheological properties of 
purified mucus glycoprotein gels, discovered that
Na+ reduced the gel elasticity, whilst the divalent 
cations generally increased the elasticity of 
mucus. He uses the interesting concept of "charge
shielding" by the monovalent cations (88). 
Thomas Record has proposed the existence of a 
specific control mechanism involving the direct 
effect of change in ion concentration on the 
interaction of proteins. and nucleic acids and on 
the stability of nucleoprotein complex (89). We 
understand that the cytoplasm of the cell is 
negatively charged. We understand that when
the three Na+ are exchanged for two K+, after the
initial electrogenically silent exchange of the H+ 
for Na+, the cation pumps are maintaining a pH 
and ionic equilibrium in this direction, 
particularly as the shift of the other polyvalent 
ions into the cell is in turn coupled to the shift of 
K+. In this way the possibility of the damaging 
effect of excess hydrogen ion and the effect of 
"charge shielding" of the monovalent cation on 
the glycoprotein structure of DNA is decreased. 
Is it possible that the inefficient operation of the 
cation pumps could predispose to "jumping 
genes" and creation of "selfish DNA'!" Are
"selfish DNAs" the "cues" for the action of the
"semi-lethal" or the "lethal" genes? If so, then, by
the same token it is possible that the maintained 
activity of tryptophan (through adequate balance 
in the free water content and a balanced diet with
least deterioration of the essential amino acids) 
could be more effective in the recognition and 
repair of the damaged DNA (75). According to 
Levinson, "there is compelling evidence that 
human cancer develops as a consequence of 
genetic damage (90). Dawkins ventures an 
opinion that viruses are genes that have broken 
loose (p.196,3). Green and Wyke indicate that 
recent advances in molecular biology have shown
that viral oncogenes of rapidly transfoming 
retroviruses were shown to be derived from and
represented a subset of host's cellular genes 
(cellular or proto-oncogenes) present in normal 
cell DNA. 

  Proto-oncogenes are now believed to play a 
vital role in cellular proliferation and/or 
differentiation. Cellular homeostasis exercises a 
regulatory action on the activity of these 
proto-oncogenes (138). Bishop proposes that 
retrovirus oncogenes characterized as of external
viral origin are possibly from the host's cellular
loci and not of external viral origin; this 
discovery is considered to be a very fortunate 
happenstance indicating that in carcinogenesis 
the enemy could be from within (135). Marx 
considers the two steps of immortalization of the 
tumor cell and its tumor formation are separate 
steps involving different genetic drives or 
possibly removal of the inhibitory phenomena in 
which the role of interferon is stressed (136). 
Weinberg is of the opinion that the environment
of the cell is of utmost importance in 
responsiveness to viral oncogenes and its spread 
(137).

  The relationship of these phenomena in 
conjunction with changes in the microviscosity 
of the body and the inefficient function of the 
cation pumps should be addressed. Because, if 
histamine is one of the sensor regulators of water 
balance in the body, it also acts as vasopressin 
secretion stimulant (l15). Vasopressin in turn acts 
as ACTH secretion stimulant, since it is being 
proposed that corticotropin releasing factor may 
be modulated vasopressin (122); therefore, as a 
potential CRF secretion stimulant, histamine is 
involved in beta endorphin and ACTH secretion, 
mediating the integration of body's response to 
stress (123). ACTH itself also acts as secretion 
stimulant for mast cell release of serotonin and 
histamine (104).

  According to Goldstein and associates, there
is also a direct thymus adrenal connection (I25), 
with the result that corticosteroids cause a 
thymic involution, T lymphocyte mitotic 
suppression, and inhibition of human leukocyte's 
phagocytic activity. Lower concentration of 
glucocorticoids would rave the reverse effect: 
enhanced thymocyte differentiation and increased
antibody formation in vitro. Thymus is also being
implicated in production and release of tissue-
CRF (125,124) with a delayed but prolonged 
duration of activity which is stress induced (128).
 Makman and associates have shown, in vitro, an 
inhibitory effect of cortisol on amino acid 
transport and nucleoside transport and/or 
phosphorylation in the thymocyte, through 
induction of synthesis of proteins with inhibitory
influence; they also report on Hechter and
associates' observation that there is a marked 
decrease in K+/Na+ ratio in thymus of 
adrenalectomised rats after repeated injection of 
cortisol (134). Makara also stipulates the role of 
vasopressin as a CRF in stress induced pituitary-
adrenal system stimulation. There is a weaker 
action of serotonin and angiotensin on ACTH 
release (124,126), from multiple sites of action 
(127). The role of serotonergic neuromodulation 
in the brain has to be separated from serotonin's 
short term peripheral action when evaluating 
isolated experimental results.


↓Page 12 of 19.

  At this point, reference to some other aspects 
of tryptophan metabolism becomes important.
According to Gerald Huether, serotonin is 
involved in the regulation of cell division
(cleavage, separation of mitotic centres), 
intracellular flow, cell shape, morphogenetic and 
pulsatory movements, primary invagination, 
neurulation; it is also involved in the control of 
transcription and translation of genetic 
information. Cell migration and synaptogenesis
in the developing brain are controlled by
serotonin. As for another tryptophan dependent
product, tryptamine is an 'phylogenetically old
modulator of intracellular communication, 
affecting the metabolic state and the function of 
developing cell. He is of the opinion that in 
nature, an increased availability of tryptophan to
individuals of a certain population would never 
occur, since several substrates and co-factors are 
involved. He further states that altered nutritional
supply of tryptophan during the development of 
an individual may cause various metabolic 
alterations. Such responses seem to last and to 
become continuously modified through several 
generations until a new steady state is finally 
reached (69).

  According to Kandel and associates, evaluating 
the effect of serotonin on modulation of Ca++ 
current during behavioral arousal, a depolarizing 
command pulse produces an inward current due 
to Na+ ,as well as Ca++ followed by an outward
current due to K+. With repeated commands, the 
peak inward current becomes less inward. 
Adding serotonin again now causes the transient 
current to become more inward. reduces leakage, 
and shifts the holding current inward. Identical 
effects are seen in the absence of the Na+ current 
(93). This manipulation of the calcium current by 
serotonin must be considered be its most 
important role in the physiology of the body.
It must be this effect that inhibits the histamine 
action in the experiment conducted by Canfield 
and Spencer, when serotonin from serosal point 
of contact inhibited the acid secretory effect of 
histamine, also showing a threshold phenomenon 
(28).

  According to Lippman there is an association 
between psychosocial factors and the hormonal 
regulation of tumor growth. He is of the opinion 
that emotional factors can profoundly regulate 
hypothalamico-pituitary hormones; 
neuroendocrine hormones in turn, directly or 
indirectly, regulate neoplastic cell growth or alter 
concentration or activation of other hormones 
that affect cancer cells (131).

  If, according to Dawkins, all actions of the body
are "genetically" determined, then, 
philosophically speaking, certain types of pain 
could be the "genes' cry" in "anticipation" of 
damage. particularly the recurring dyspeptic pain 
of peptic ulcer disease (regardless of the presence
of a macroscopic ulcer crater); and the tissue 
damage or its transformation phase is the result 
of not having recognized the meaning of that
pain signal, which now means both water 
deficiency and inadequacy and disturbance of 
tryptophan metabolism (25).Depending on the 
age of the person, the pain signal may well be an 
indication of a predisposition to the precipitation 
of a variety of disorders that will be determined 
by the role of tryptophan in the body. This pain 
may even herald a continued predisposition to 
disorders that may affect that person's offspring 
(69). This all encompassing role of tryptophan 
and its by-products of metabolism must be the 
determining factor in the genetic association
between a large variety of conditions and peptic
ulcer disease that Jerome Rotter lists (91). He is 
of the opinion that peptic ulcer is not a single 
disorder, but a host of disorders that share a 
common clinical finding: a hole in the lining of 
the gastrointestinal tract: similarly, heterogeneity 
is being recognized in gastric cancer.

  The significance of the role of serotonin and 
histamine in the regulation of body physiology,
through calcium turnover in the cell, is of 
paramount importance; since histamine through 
the combination of H1, H2 receptors activates 
protein kinase C, which catalyzes calmodulin-
dependent phosphorylation of a class of protein 
that has been identified for sarcoplasmic
reticulum of the cardiac muscle as 
phospholamban, producing a three-fold increase 
in Ca++ uptake and Ca++ATPase activity, a 
potential Ca++ translocator (5), and thus primes 
the cell growth process that is calcium
dependent and since through the manipulation of
Na+/K+ pump, which is a voltage inducing 
pump, generates ionic current and voltage 
gradient that according Jaffe (129), is essential 
for determination of cell growth, histamine may 
be considered to be a direct primer of growth 
within the cells. This idea could be further 
supported by the observation of Bender, who 
considers histidine one of the essential
amino acids for growth in children (72), by the 
way cimetidine reverses tumor growth 
enhancement of plasmacytoma tumors in mice 
(130), and by the fact that mast cells multiply 
with each degranulation of histamine. The 
presence of L-histidine decarboxylase, an 
indicator of histamine activity according to 
Beaven (13). is found in many tumour tissues,
including mastocytomas, gastric carcinoid
tumours, transplantable hepatomas and mast cell 
ascites tumour; in the rat tumour tissue, the 
enzyme is found to reach very high levels (13). 
The action of serotonin on stabilization of the 
calcium current, must be the balancing factor in 
this relationship. This physiological state must 
be considered a logical adaptation to life on land
, when the body is attempting gradually to 
become independent of constant need for water, 
very much like the reptilians; except that 
emotional, socio-economical, and environmental
factors disrupt integration of adaptation
to the needs of the total body, where upon the
natural drive for survival only manages to 
"liberate" some parts of the anatomy from 
environmental strains. The same will to survive 
must be the natural determining factor in 
remissions attributed to the "fighting spirit", a 
natural component of "fight or flight", when the 
body as a whole decides to survive.

↑982
↓Page 13 of 19.

It seems that, in stressful sedentary occupations, 
when the activity of large muscle mass in the 
body does not bring about the dominance of fat 
metabolism through activation of the hormone 
sensitive lipase, which seems to be time 
dependent (92), resulting in a net gain of water 
for the cells, and protein breakdown continues to
be a major component of gluconeogenesis; when
muscle metabolism does not adequately utilize 
the branched-chain amino acids, leucine 
isoleucine and valine (72), the blood brain 
barrier competitors to tryptophan, the actual
phenomenon of tissue damage and or tissue
transformation associated with stress will 
develop. A physiological translation of "fight or flight."

Pre-Conclusion
In any future drug trials, the curative effect of
waler has to be separated from the effect of the
chemical composition under investigation. This
can be done by hydrating the patient well for 
some time before and during the time that the 
trial is carried out. At the same time the 
idiosyncrasies of the metabolism of tryptophan 
should also be taken into account. It seems that 
tryptophan loosely binds to albumin and that 
free fatty acids compete for that binding site;
not all animal protein has a high tryptophan 
content, whilst more than one fifth of the 
weight of most meat consists of fat. The 
presence of unsaturated fatty acids, when also 
exposed to oxygen, could potentially bring about
the deterioration of some of the essential amino 
acids even before intake of food (74). It is 
interesting to note that a high content of
pulses in the diet could provide a reasonably
balanced protein intake, particularly of the amino
acid tryptophan; up to 90% of the 
"recommended" requirement of the body can be 
supplied from this source (74). Attention to the 
tryptophan content of food is most important. 
For, out of the total intake, only a small portion 
crosses the blood brain barrier, getting converted 
to the indispensable neurotransmitters as soon as
it reaches the serotonergic, tryptaminergic or 
melatonergic neurones. The role of these 
neurotransmitters in the maintenance of
homeostasis in the body is complex, and 
needs more attention. There seems to be a 
definite relationship between the water 
metabolism of the body and serotonergic 
neuronal function. If the regulatory role of the 
brain cells determines the state of the body 
physiology, then the role of serotonin in the 
maintenance of that regulation is important. If, 
according to Hume, in pure water loss, the brain 
cells adapt by increasing intracellular osmolality 
sugar, salt and "idiogenic solutes" are involved 
(24); if according to Fernstrom, 5HT synthesis is 
reduced in the diabetic brain, secondary to
brain tryptophan levels (96); if according to 
Ikeda and associate (97) and Hattori (98), 
xanthurenic acid can render insulin 
physiologically less effective, and we know that 
xanthurenic acid is a liver metabolite of 
tryptophan, what could be the role of disturbed
water regulation in pre-diabetes be a crisis state 
to brain cell volume reduction? Could nature be 
involved in resuscitating the brain in the same 
way as we use dextrose saline? Obviously, there 
is no "insulin barrier" to entry of glucose across 
the blood brain barrier, whereas, active transport 
of glucose across other cell membranes is 
dependent on the Na+-transport protein-glucose 
ternary complex formation with a stoichiometry 
of 1 Na: 1 glucose (141). Thus: thirst associated 
with a higher than normal blood glucose level 
may be a primary signal for water deficiency.

  We often see double blind randomised trials 
produce almost as good a result for placebo 
response as that produced by the medication 
under investigation (120). Often the placebo 
response is discarded as too good to be accurate. 
It must now be recognized that water taken with 
the pill, with all its regulatory properties, is 
responsible for the placebo effect. (2,25). 
Extensive observations need {be made on the 
response of raised systemic or so-called essential
hypertension to increased hydration (25), 
particularly as water by itself is the best natural 
diuretic(8). It seems that we must rethink our 
approach to the treatment of hypertensives by 
administration of chemical diuretics and sodium 
reduced diets. We may have to allow adequate 
water intake to adjust the cell volume, as well as 
the extracellular fluid volume. as a preventive 
measure before tissue damage takes place; 
because the natural drive of renin-angiotensin is
directed towards increased water intake (81), and
its hypertensive property is a compensatory
phenomenon. The dietary approach should be
directed towards an adequate supply of the 
essential amino acids because histidine turnover 
may cause a

Page 983↑ 

ANTICANCER RESEARCH 7: 971-990 (1987)


Page 14 of 19↓

body depletion of this essential amino acid. 
Particularly, as Holcslaw and associates have 
demonstrated a reduced histamine level in the 
wall of the aorta of the spontaneously 
hypenensive rats, although possessing an 
increased histidine uptake capability (132). I 
have seen very satisfactory results from 
treatment of essential hypertension with
increased water intake (25). It seems to me that
what we are seeing in hypertension is the body's
response to extracellular water loss through the
early loss of thirst sensation, and we are treating 
the hypertensive threshold and not the basic
physiological drive (25), for water, of all things, 
the most essential component of the body.

  When mast cells degranulate and serotonin and
histamine are released into the microcirculation,
serotonin. as well as histamine and bradykinin, 
has the property of compromising and breaking 
the wall and producing gaps in the wall of the 
capillary (44). This regional effect of histamine 
and serotonin may be a precipitating cause of 
local ulceration of the duodenal region that 
seems to have histaminergic nerve supply
(103). When the compromise of the capillary 
wall occurs in the blood brain barrier region, the 
resultant local inflammation and plaque 
formation can be accepted as a logical 
conclusion. The consequences of this 
phenomenon could become of catastrophic
dimension if a potentially higher aluminium 
concentration in blood is brought about with 
increased antacid intake (139) to relieve a thirst 
pain.

  Pain associated with decreased capillary 
circulation. such as anginal pain and pain of 
intermittent claudication needs to be investigated 
with increased hydration as a form of treatment 
prior to drug use (25).

  In order that actual or perceived, mental or 
emotional activity or emotional experiences 
should not produce adverse symptomatic or 
physiological response in the body precaution 
with increased hydration of the body should be 
taken, so that the blood brain barrier capillaries 
are optimally hydrated.

  Reassessment of the drug dependence of 
patients under medication is indicated after 
increased hydration. Drink water regularly, on 
time and enough quantity for the present body 
weight.


  Low back pain need be treated with increased 
water intake, as the efficiency of function of the 
discs also depends on their hydrolic property (25,94).


  According to Thomas Kuhn, quoted by Crue 
and associates under the subject of "continuing 
crisis in pain research" (95), when anomalies in 
the observations of science proliferate and 
cannot be reconciled within the rules, or the 
basic paradigm, then the significance of the 
crisis produced is the indication that an occasion 
for retooling has arrived. Crisis loosens the rules 
of normal puzzle  solving. When the anomaly 
appears to be more than just another puzzle of 
normal science, the transition to crisis and to 
extraordinary science has begun. Even former
standard solutions of solved problems can be 
called into question. According to Lakatos and 
Musgrave, no ordinary sense of the term 
"interpretation" can fit the flashes of "intuition" 
or "imaginative posits" through which a new 
paradigm is often born (95). The accepted 
paradigm on the metabolism of water is based on
the infallibility of the physico-chemical
properties of ions within the cells and assumes 
that it is this property which determines water 
regulation and the thirst mechanism. This view. 
whilst sound, does not take into account the 
"metering system." If the serotonergic neuronal 
system is considered to be the regulator of the 
homeostatic balance in the body - and according 
to Kandel and others it is even involved in the 
regulation of the ionic channels within the nerve 
cells - then what happens to this balance when 
the tryptophan reserves of the body become
depleted and its metabolism disturbed? If thirst 
sensation is gradually deteriorating. what are the 
consequences of under hydration and from what 
age do they begin? The above theoretical 
discussion, based on human observations. in a 
constantly stressful "laboratory" condition, 
where the level of stress and diet of pulse and 
starch were the constant factors, is intended
to expose the important lack of sufficient
knowledge of water metabolism in the human 
body; it is also intended to question some of the 
basic understandings of certain "disease" 
conditions.

CONCLUSION

When severe abdominal pain, often associated
with "peptic ulcer disease," is relieved with water
(and this phenomenon reveals a basic concept of
which a very brief form has been presented 
above), it seems that the time has come to 
reassess our approach to treatment in medicine. 
We must now recognize a pain signal to cellular 
free water deficiency of the body and also 
recognize the impending consequences of its 
misinterpretation. We must assume that
thirst sensation is no longer a reliable mechanism
for the regulation of the delicate balance of 
cellular hydration.

↑Page 984

↓Page 15 of 19.

We must encourage people to regulate water 
intake by establishing the habit of drinking
water. It seems that water intake before meals
should be encouraged to prevent 
hemoconcentration, and to bring about a 
separation of the sensation of thirst from hunger; 
confusion of these two sensations may be the 
causative factor in over-eating. It was found that 
an effective volume and timing for water intake, 
as a treatment procedure in clinically diagnosed 
peptic ulcer disease, was drink one full glass 
(250 ml) of water half an hour before a meal and 
another glass (250 ml) two and a half hours after 
a meal: that is six glasses of water, 
approximately one and one half liters, for three 
meals per day, (1,2,25). It was also found
that with regular intake of water, the thirst 
sensation becomes more pronounced and 
recognizable by the patients who did not 
acknowledge their thirst before. As a grass root 
phenomenon, and in view of presented new
perspectives, the role of free water deficiency in 
cancer transformation warrants investigation 
(25, unpublished theoretical research); and it 
certainly deserves application as a preventive 
measure. The final conclusion seems to be the 
importance of regular water intake regardless of 
thirst. The cell, it seems, is just like a city that 
runs on hydro-electric power, it needs the "water 
head" over the cation pumps of the membrane
barrier for generation of energy and its 
utilization, just like a "pump storage dam." After 
all, the initial progenitor cells used the same, 
physical laws when they lived in sea water.

Acknowledgement.  
I thank The Almighty for His "light and fine 
detailed guidance" that has made this 
presentation in His name possible; through the 
pain and suffering of His creations He has tried 
to guide us yet again.

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51) ROSS. E.M. AND GILMAN, A.G,; BIOCHEMICAL PROPERTIES OF HORMONE- SENSITIVE ADENYLATE CYCLASE; ANN. REV. BIOCHEM. 49:533·64.1980.

52) RAND R.P. AND PARSEGIAN V.A.; 
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53) STRYER L.: INTRODUCTiON TO BIOLOGICAL
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54) WORMAN, H. J.: BRASITUS, T.A.: DUDEJA. P.K.; FOZZAKD. H.A. AND FIELD, M.; RELATIONSHIP BETWEEN LIPID FLUIDITY AND WATER PERMEABILITY OF BOVINE TRACHEAL EPITHELIAL CELL APICAL MEMBRANES: BIOCHEMISTRY. 25. PP. 1549- 1555.1986.

55) HAYDEN D.A.; WATER PERMEATION THROUGH 
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56) EISEN V.. MUNDAY. M.R. ANI) SLATER. J.D.H.; 
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57) BEIERWALTER, W. H.G, AND CARRETERO. O.A.:
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58) SETO, S.; RABITO, S.F.; MAITRA, S.R. WU. 
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59)SELVAGGIO. A.M.; SCHWARTL, J.H.; RENGELE 
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60) LIVNE A.; VEITCH.R.; GRlNSTElN.S.; BALFE. 
J.W.; MARQUEZ- JULIO,A.; ROTHSTEIN,A.; INCREASED PLATELET Na+·H+ EXCHANGE RATES IN ESSENTIAL HYPERTENSION: APPLICATION OF A NOVEL TEST; PP. 533-536. LANCET. MARCH 7, 1987.

61) DOUGLAS, W.W.; POLYPEPTIDES· ANGIOTENSIN. PLASMA KININS, AND OTHERS; GOODMAN AND GILMAN'S THE PHARMACOLOGICAL BASIS OF THERAPEUTICS, MACMILLAN. PP.647-667.1980.

62) AGHAGANlAN O.K.; THE MODULATORY ROLE OF
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63) RICHARDSON B.P.. ENGEL. G.: DONATSCH, P. 
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64) NYREN. O .. M.D.: ADAMI, H-A.. ~U).: 
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65) KOO, A.; INVIVO CHARACTERlZATI0N OF HISTAMINE H1 AND H2 - RECEPTORS IN THE RAT STOMACH MICROCIRCULATI0N; B.R.J. PHARMAC., 78.PP. 181-189. 1983.

66) SPIRO, HOWARD M.; VISCERAL VIEWPOINTS.
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67) VERNIKOS-DANELLIS J.; KELLAR, K.J.; KENT D.; GONZALES. C.; BERGER. P.A. AND BARCHAS. J.D.; SEROTONIN INVOLVEMENT IN PITUITARY , ADRENAL FUNCTION; ANNALS NEW YORK ACADEMY OF SCIENCES. 297: 518-26, 1977.

68) KREIGER, D. T. ; SEROTONIN REGULATION OF 
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69) HUETHER. G.; TIHE INFLUENCE OF INCREASED
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70) JOSEPH. M.H.; JOHNSON, J.A. AND KENNET, G.A.; INCREASED AVAILABILITY OF TRYPTOPHAN TO THE BRAIN IN STRESS IS NOT MEDIATED VIA CHANGES IN COMPETING AMINO ACIDS; PP.387-390, PROGRESS IN TRYPTOPHAN AND SEROTONIN RESEARCH. EDS. H.G. SCHLOSSBERGER, W. KOCHEN , A. L1NZEN AND H. STEINHART, DE GRUYTER.1984.

71) POGSON. C.I.; MUNOZ·CLARES, R.A.; COOK. 
J.S. AND SMITH. S.A.; TRYPTOPHAN METABOLISM AND  ITS CONTROL IN MAMMALIAN LIVER; PROGRESS IN TRYPTOPHAN AND SEROTONIN RESEARCH. EDS. H.G. SCHLOSSBERGER. W. KOCHEN,A. LlNZEN AND H. STErNHART. DE GRUYTER. PP.625·632. 1984

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75) HELENE. C. G.; MOLECULAR MECHANISM FOR THE RECOGNITION OF DAMAGED DNA REGIONS BY PEPTIDS AND PROTEINS; ADV. BIOPHYSICS. VOL.20, PP.177- 186,1985.

76) MAJUMDAR, A.P.N.; INFLUENCE OF 
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77) ZIGMAN. S.: THE ROLE OF TRYPTOPHAN OXIDATION INOCULAR TISSUE DAMAGE; PP.449-467. PROGRESS IN TRYPTOPHAN AND SEROTONIN RESEARCH, EDS. H.G. SCHLOSSBERGER, W. KOCHEN. B. L1NZEN AND H. STEINHART, DE GRUYTER.1984.

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79) REIS, R.K.• M.D.; GILBERT. D.A.• M.D.; KATON. W.• M.D. ; TRICYCLIC ANTIDEPRESSANT THERAPY FOR PEPTIC ULCER DISEASE; ARCH. INTER. MED.· VOL. 144, PP.566-569. MARCH 1984.

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85) COOKE. H.J.; TRYPTOPHAN AND INTESTINAL SECRETION: PP. 563-566. PROGRESS IN TRYPTOPHAN AND SEROTONIN RESEARCH, EDS. 
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87) BRUCE,A.; ANDERSON, M.; ARVIDSSON, B. AND
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89) RECORD, M.T. JR.; ANDERSON, C.F.; MILLS, P.; MOSSSING,M. AND ROE, J- H.: IONS AS REGULATORS OF PROTEIN NUCLEIC ACID INTERACTIONS IN VITRO AND IN VIVO; PP. 109-I35. ADV. BIOPHYS.• VOL. 20. 1985.

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90) LEVINSON, A. D,; NORMAL AND ACTIVATED RAS ONCOGENES AND THEIR ENCODE PRODUCTS: REVIEWS, TRENDS IN GENETlCS. PP. 81-85, MARCH 1986.

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93) KANDEL, E.R.: KLEIN, M.; RAILEY, C.H.; HAWKINS, R.D.; CASTELLUCCI. V,F.; LURIT, B.W.; 
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96) FERNSTROM. J.D..PH.D.; TRYPTOPHAN AVAILABILITY AND SEROTONIN SYNTHESIS IN RAT BRAIN: EFFECT OF EXPERIMENTAL DIABETES; 
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97) IKEDA. S. AND KOTAKE. Y.; URINARY 
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98) HATTORI. M.; STUDIES OF THE URINARY 
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99) HESKETH. R.; INTRACELLULAR CALCIUM REGULATION AND THE MEASUREMENT OF FREE CALCIUM IN 2H3 CELLS AND SYNAPTOSOMES: BR. J. PHARMAC.. 20. 2215-23I5, 1985

100) EDELMAN. I.S. AND HIAIT. A.: STRUCTURE 
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101) KAUFMAN. K. AND SILMAN. I.: ION CHANNELS 
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102) POLLARD. H, PACHOT, I. AND SCHWART. J.C.:
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104) IRMAN·FLORJANC. T. AND ERJAVEC. F.; THE 
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106) AARANG. J.-M.: GARBARG. M. AND SCWARTL 
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107) KRALY. F.SCOTT; HISTAMINE A ROLE IN 
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108) FITZSIMONS, J.T.: THE PHYSIOLOGY OF 
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109) KRALY, F.SCOTT: SIMANSKY. K.1.: COOGAN, 
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112) VALE. R.D.: REESE. TS. AND SHEETZ, M.P.; 
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113) COLLINS, C.A. AND VALLEE. R.B.:A MICROTUBULE:ACTIVATED ATPase FROM 
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114) PORTER. M.E.: SCHOLEY. 1.M.: STEMPLE. 
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115) LACZI. F.: IVANYI. T; JULESZ. J.; JANAKY. T. 
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116) PANULA. P.: KAARTINEN. M.: MACKLIN. M. 
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117) MAHMOUD. S.N.: SCACCIANOCE. S.; 
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118) FROHLICH. E.D.; ANTI-HYPERTENSIVE 
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122) GILUES, G. AND LOWERY, P.; CORTICOTROPIN RELEASING FACTOR MAY BE MODULATED VASOPRESSIN, NATURE, VOL. 278, PP.463-464, 29 MARCH 1979.

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124) MAKARA, G.; MECHANISM BY WHICH 
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130) GORCZYNSKI, R.M.; KENNEDY, M. AND CIAMPI, 
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131) LIPPMAN, M.E.: PSYCHOSOCIAL FACTORS AND HORMONAL REGULATION OF TUMOR GROWTH; 
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132) HOLCSLOW. Y.L.: NlC:HOLS, G. AND WILSON, C: STUDIES ON UPTAKE AND CATABOLISM OF VASCULAR HISTAMINE IN SPONTANEOUSLY HYPERTENSIVE RATS; THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS; VOL. 233, NO.2, PP.352-360. 1985.

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Received August 11, 1987
Accepted September 9, 1987

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