Human Physiology, Vol. 31, No. 5, 2005, pp. 566572. Translated from Fiziologiya Cheloveka, Vol. 31, No.

5, 2005, pp. 8087.

Original Russian Text Copyright 2005 by Natochin.

Clinical Physiology: Role in Studying Basic Problems

of the Regulation of Renal Functions in Humans
Yu. V. Natochin
Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences,
St. Petersburg, 194223 Russia
e-mail: natochin@iephb.ru
Received May 26, 2005

AbstractClinical physiology is described as a unique branch of human physiology that allows basic regula-
tory mechanisms of renal functions to be revealed. The analysis of physiological mechanisms that change the
renal functions under the influence of endogenous or exogenous factors made it possible to detect new aspects
of the regulatory system involved. The following problems are discussed: (1) the role of autacoids in the regu-
lation of ion and water transport in the kidney; (2) the significance of functional loading tests for assessing the
main components of the regulatory system of water and electrolyte balance; (3) the variety of sources of human
blood hormones; and (4) the intranephron redistribution of water and electrolyte flows, which does not change
their excretion by the kidney but affects the regulation of the totality of body functions.

In many cases, man is an object of physiological
studies. Physiological branches that investigate human
functions include the physiology of individual organs
and systems (in particular, the physiology of respira-
tion, circulation, the heart, and the kidney), ecological
physiology, labor physiology, space physiology, sports
physiology, and extreme state physiology. In these
cases, studies focus on the functions of a healthy human
body. The efforts of pathophysiologists are concen-
trated on the study of the vital activities of the body in
a state of disease [1, 2]: pathophysiology studies the
most general features of functional disorders in cells,
organs, and the whole body in disease ([3], p. 18). Phys-
iology must comprehend the mechanisms of functions
in the body as a whole, and data from each of the above
branches of physiology can contribute to the solution of
the basic problems of physiology, which is a prerequi-
site for the solution of applied problems and is essential
for medicine and for the optimization of approaches to
human adaptation to varying environmental conditions.
In addition to normal and pathological physiology,
progress is being made in the area of clinical physiol-
ogy, a field of science whose purpose is to investigate
the role and character of changes in physiological pro-
cesses under premorbid and morbid conditions of the
body ([4], p. 186). Clinical physiology must character-
ize the physiological processes that occur during the
development of morbid conditions ([5], p. 3), elucidate
the mechanisms whereby the disturbed functions are
compensated ([5], p. 4), and describe the functions in
the presence of a given disease and under changing
environmental conditions. However, it seems important
to focus attention on an aspect of clinical physiology
that the present author failed to find in the literature,
and it is with this aspect that the present paper will
mainly be concerned. This aspect renders clinical phys-
iology the one and only approach to the solution of the
fundamental problems of human physiology and gen-
eral physiology. This approach is unique because man
is the object of study and the test procedure is deter-
mined by a complex of factors influencing man rather
than designed by a physiologist. These factors com-
prise previous life conditions or inborn defects result-
ing in the deviation of functions from normal. This con-
cept includes innumerable states when the bodys via-
bility is retained but the physiological systems are
unable to provide for compensation even under minor
changes in environmental conditions.
The present work was designed to study the potenti-
alities of clinical physiology for the detection of new
aspects in the physiological regulation of renal func-
tions in humans, namely, the aspects that are inaccessi-
ble to other branches of physiology.
METHODS
Description of the subjects, including their age and
conditions of blood and urine sampling, was presented
in the works mentioned in the text. In all cases, blood
samples were taken after fasting from the antecubital
vein before 9:30 a.m. Urine samples were collected
upon voluntary urination, and the sampling time was
accurately recorded. Diuresis (ml/min) was calculated
for a body surface area of 1.73 m2. The osmolalities of
urine and blood serum were determined with an MT-4
osmometer; creatinine was established by Poppers
method with an SF-16 spectrophotometer; Na and K
were assayed with a Corning 410 flame photometer;
and Mg was quantitated with a Hitachi 508 spectropho-
tometer.

0362-1197/05/3105-0566 2005 MAIK Nauka /Interperiodica

 CLINICAL PHYSIOLOGY: ROLE IN STUDYING BASIC PROBLEMS
Table 1. Diuresis types and their mechanisms in humans
Diuresis type Acting factor
Water diuresis Hyposmia of blood plasma
Osmotic diuresis Unreabsorbed osmotically active substance
Saluresis Furosemide, prostaglandin E2
Antidiuresis Vasopressin
RESULTS AND DISCUSSION
Autacoids in the regulation of renal functions.
According to classical concepts, renal functions are
regulated by efferent nerves [6, 7] and various hor-
mones [810]. The function of the kidney depends on
its adequate blood supply, because all processes result-
ing in uropoiesis are more or less associated with the
blood supply of the kidney. Blood supply determines
not only the volume of filtered fluid but also the
amounts of reabsorbed and secreted substances. Physi-
cochemical features of blood plasma, its osmolality, ion
and protein concentrations, and pH also determine the
functional state of renal cells.
Characteristics of the regulation of renal function
usually concern only the effects of efferent nerves and
hormones as factors responsible for the regulation of
uropoiesis. However, the human regulatory system has
at least one other level, which determines paracrine reg-
ulation (intercellular interactions) and exerts an auto-
crine effect (influences functions of the cell that
secretes the corresponding factor). In total, some types
of changes in the volume and osmolality of the pro-
duced urine and various physiological factors are
important for changes in diuresis (Table 1).
Consider the data on the mechanism regulating
human renal functions with the involvement of auta-
coids. It is known that uropoiesis at night decreases in
children older than three or four years: they sleep
soundly without waking for urination. The situation is
different in children with nocturnal enuresis. In this
case, the volume of urine produced at night is sharply
increased [11], but the child sleeps soundly without
waking in response to the filling of the urinary bladder,
and involuntary urination occurs. The night excess was
attributed either to a perverted rhythm in the secretion
of Arg-vasopressin (the antidiuretic hormone) by the
neurohypophysis [12] and a resulting decrease in the
reabsorption of solute-free water or to a neurological
defect in the regulation of the urinary bladder functions
[11]. In the first case, a normal elevation of vasopressin
secretion at night does not occur and diuresis increases.
Introduction of the vasopressin analog desmopressin is
effective, which confirms that a deficit of vasopressin
underlies the development of the disease [12, 13].
Studies in the lab of the present author yielded unex-
pected results, which initially were difficult to explain.
In some children, the kidney response exactly corre-
sponded to that expected in the case of an insufficient
HUMAN PHYSIOLOGY Vol. 31 No. 5 2005
567
UOsm /POsm Mechanism of realization
<1 Elimination of aquaporin 2
>1 Decrease in proximal reabsorption
>1 Decrease in ion reabsorption in Henle's loop

1 Incorporation of aquaporin 2
secretion of vasopressin: indeed, nocturnal polyuria
was accompanied by an increase in the volume of urine
with a decreased osmolality, a decrease in the reabsorp-
tion of solute-free water, and its increased excretion
[13], as expected for a decreased secretion of vaso-
pressin. However, in other children with similar poly-
uria, the reabsorption of solute-free water was not
decreased, but even increased. It seemed that the
increase in diuresis at the same rate of glomerular filtra-
tion but with an increased reabsorption of solute-free
water is either an artifact or a physiological paradox
calling for a solution. The problem was solved not only
for the case of nocturnal enuresis in children but also as
the more general problem of the physiological regula-
tion of renal functions in humans. An increase in the
renal excretion of autacoids was found [14]. This
increase correlated with an increase both in the excre-
tion of osmotically active substances, in particular,
sodium ions, and in the reabsorption of solute-free
water. In this case, prostaglandin 2 was one of the
autacoids [14]. Prostaglandin E2 is known to inhibit the
effect of vasopressin, and its increased secretion can be
expected to decrease the reabsorption of solute-free
water. Yet this effect did not occur in these children:
rather, the renal excretion of sodium and magnesium
ions increased, along with an increased (!) reabsorption
C
of solute-free water ( T H2 O ) [13].
Such a complicated picture may be explained as fol-
lows. The synthesis of prostaglandin 2 increases in the
thick ascending limb of Henles loop to cause a local
decrease in the reabsorption of sodium, chloride, mag-
nesium, and potassium ions. As a result, unreabsorbed
fluid enters the distal convoluted tubule of the nephron
and the collecting tubes. At the same blood concentra-
tion of vasopressin and the same effect on collecting
tubule cells, water reabsorption increases. Because of
the large volume of fluid flowing through the tubule, at
the same osmotic permeability, absorption increases
and a greater amount of water is returned into blood by
osmotic gradient.
Thus, data of clinical physiology allowed us to
reveal another mechanism regulating renal functions
[15]. This mechanism includes the following compo-
nents: (1) secretion of autacoids; (2) a redistribution of
the flows of fluid and absorbed substances in different
parts of the distal nephron and collecting tubules; and
(3) different effects of autacoids on closely located
parts of the nephron or a dependence of their effect on
568 NATOCHIN
the locus of their secretion and action. In the one case,
the effect can be realized from inside the nephron when
autacoids are secreted into the lumen and appropriate
receptors are present on the cell membranes. In the
other case, an autocrine effect can occur.
It is still unknown what factors (in addition to local
ones) affect the secretion of autacoids, i.e., whether
they are released by cells only under the influence of
endogenous stimuli or there are systemic factors influ-
encing the secretion of autacoids.
Sources of human blood hormones. The title of
this section seems to be self-evident. Endocrine glands
are sources of hormones present in human blood [10,
1618]. However, there are situations when the normal,
standard schemethat described in guidebooks and
manualsis inadequate. Pediatricians have noticed
that, in spite of fever, children with acute pneumonia
are not thirsty and refuse to drink water. Concurrently,
there are obvious signs of a fluid deficit in the body.
Physiological analysis has revealed a paradoxical pic-
ture. The absence of thirst under conditions of intense
extrarenal losses of fluid (high temperature, tachipnea)
is adequate and develops against the background of
hyposmia (the blood serum osmolality is within the
lower normal limit, <280 mosmol/kg 2 [19]).
Therefore, it has been suggested that the extrahypophy-
seal secretion of vasopressin is activated in children
with acute pneumonia [20]. This activation is accompa-
nied by an increase in the reabsorption of solute-free
water in the kidney, with a resulting decrease in the
blood plasma osmolality and the development of an
adequate reaction by the regulatory system, i.e., the
refusal to drink. Thus, it is reasonable to elucidate the
mechanisms and pathways leading to the activation of
the extrahypophyseal secretion of vasopressin or a sim-
ilar nonapeptide with an antidiuretic effect.
In healthy humans, the absorption of intact, physio-
logically active nonapeptides in the gastrointestinal
tract can be another source of this hormone. According
to current concepts, organic polymers (proteins, carbo-
hydrates, lipids) taken with food are enzymatically
cleaved in the gastrointestinal tract to monomers, which
are absorbed from the intestine into blood [21]. It is pre-
cisely this system that seems mainly to function, but
new findings show that the above scheme is incomplete.
Experiments with animals have shown that Arg-vaso-
pressin can be absorbed in vivo without a loss of its
physiological activity. Its absorption was shown with
an isolated small intestine by means of both the Thiri-
Wella technique [22] and in vitro. Studies with volun-
teers have also shown that desmopressin (a nonapeptide
analog of vasopressin) is absorbed in the gastrointesti-
nal tract [23, 24]. It might be supposed that absorption
is possible for desmopressin but not for the natural non-
apeptide Arg-vasopressin, secreted in the human neuro-
hypophysis. To analyze this alternative, experiments
were performed with nonanesthetized rats upon intra-
gastric administration of Arg-vasopressin or desmo-
pressin. An antidiuretic effect was recorded, and
ELISA showed an increased blood concentration of the
hormone. Thus, not only amino acids but also polypep-
tides, in particular, functionally active nonapeptides
can normally be absorbed in the human gastrointestinal
tract. The absorption mechanism has been described for
amino acids and dipeptides [2527], but the transport of
larger molecules remains obscure. Our data suggest
that the peptide hormones contained in food present in
the intestinal lumen can be partly absorbed in the
unchanged form and released into blood, in addition to
their secretion by the endocrine gland. These results are
of importance for assessing the possible absorption of
intact natural peptide hormones in the intestine and
their influence on functions of the human body. The
possible absorption of physiologically active synthetic
polypeptides has also to be taken into account.
Functional loading tests. The functional organiza-
tion of human physiological systems is very similar to
that of other mammals but has some differences, in par-
ticular, in the functional state of body fluids. No doubt,
these are problems of clinical physiology, i.e., human
physiology. The upright posture of the body, compre-
hension of ones own functional state, and many other
human-specific features predetermine the necessity of
new approaches to studies with humans. For example,
consider the examination of the bodys functions with
loading tests.
Studies in clinical physiology include analyses of
the functional capabilities of the kidneys and their reg-
ulatory system with loading tests. This problem was
already established in the early 20th century, and
F. Volhard proposed the use of urine dilution and con-
centration tests [28]. Patients had either to consume dry
food without water for two days, or, by contrast, to
drink 12 l of water, depending on body weight, and the
functional response of the kidney was determined. Sim-
ilar but milder functional tests were proposed by
S.S. Zimnitskii: urine samples should be collected
every 3 h over a duration of 24 h; according to S.D. Rei-
zelman, it was sufficient to compare samples of urine
collected during voluntary urinations. The loading tests
are functionally reasonable because the natural regimen
of food and water intake and of work and rest provides
a small but permanently changing functional load for
the system of water and electrolyte balance, and the
kidney response allows a researcher to assess the range
of functional capabilities of this system and the kidney
as it is. Tests analyzing the osmoregulatory system are
included in clinical practice for the functional diagnosis
of the state of the kidney. In 1963, when the first
manned space flights posed the problem of post-flight
adaptation, it was necessary to characterize the system
of water and electrolyte balance and the renal function
of cosmonauts. A program was developed for investi-
gating water and electrolyte balance and included stud-
ies of the osmoregulatory system and the state of the
kidney. The program included loading tests, in particu-
lar, a test with a water load and a short-time deprivation.
HUMAN PHYSIOLOGY Vol. 31 No. 5 2005
 CLINICAL PHYSIOLOGY: ROLE IN STUDYING BASIC PROBLEMS
This test was used on test pilots and then on cosmo-
nauts in 1964 during their flight aboard the spaceship
Voskhod [29].
Water load and dehydration tests were very success-
ful: they revealed that considerable changes were
caused by space flight, and these changes were ana-
lyzed physiologically. Moreover, these studies employ-
ing the methods of clinical physiology were very useful
for developing approaches to the prevention of the
effects of microgravitation and other flight factors on
the human body [3032]. Water and electrolyte balance
includes both the osmo- and ionoregulatory functions
of the kidney; therefore, the loading tests with salts of
potassium, calcium, and other ions were initially elab-
orated with animals [33] and only later applied in stud-
ies with humans [34]. These tests allowed for the inves-
tigation of humans by combining approaches of classi-
cal integrative physiology with methods of molecular
physiology, molecular biology, genetics, functional
morphology, and biochemistry. As a result, it was not
only the specific effects of microgravitation on the
human body that were elucidated, but also a complex of
precautions was developed to eliminate the unfavorable
effect of space flight factors on the human body [35].
This approach makes it possible to reconstruct a
complete picture of the functional state of the system
regulating water and electrolyte balance in humans:
from the motivation for thirst [36] and the first gulp of
water to transport of water molecules through aquapor-
ins, the water channels in the membranes of the cells of
renal tubules [37]. The analysis of this multicomponent
picture and of the data of clinical physiology reveal a
disturbed link in this regulatory system and outline
approaches for its correction. It is precisely this direc-
tion that is successfully taken in space physiology.
The physiological effect of diuretics lacking
a diuretic effect. In the treatment of essential hyperten-
sion, hypothiazide and indapamide are the diuretics of
choice [3840]. However, in some cases, drugs with a
considerably lower diuretic effect (compare furosemide
and hypothiazide, Table 2) produce a more pronounced
hypotensive effect. Clinical physiology provides a
rational explanation for these observations. Hypothiaz-
ide has a weaker but more prolonged natriuretic effect
than furosemide (Table 2) and inhibits the cotransporter
of Na+ and Cl in the membranes of tubule cells that are
located precisely in the zone of macula densa. The
luminal plasma membranes of these cells are sensitive
to changes in the concentration of Na+ and Cl in the
tubule lumen and transmit this information to the juxta-
glomerular apparatus, which determines the rate of
renin secretion into the blood. Secretion of renin is
determined, in particular, by the blood supply to the
kidney through the afferent arteriole and depends on the
concentrations of Na+ and Cl in the intratubular fluid.
The functional logic of this interrelationship is obvious.
By means of renin, the kidney contributes to the regu-
lation of volume and maintains the due volume of fluid
HUMAN PHYSIOLOGY Vol. 31 No. 5 2005
569
Table 2. Specific features of the physiological effect of di-
uretics
Diuretic EFNa, % Dose, mg Action time, h
Furosemide 2025 40 3
Hypothiazide 58 25 9
Amiloride 23 5 12
in the intravascular space. In response to a decrease in
the intravascular volume of fluid, the regulatory sys-
tems increase the secretion of vasoconstrictors to pro-
vide for a correspondence between the vascular capac-
ity and the volume of blood contained in it.
Another homeostatic function of the kidneys with
the involvement of the juxtaglomerular apparatus is to
prevent an excess loss of Na+ and Cl with urine. This
mechanism controls the composition of the tubular
fluid during uropoiesis when urine with a Na+ concen-
tration lower than in blood serum enters the distal seg-
ment of the nephron. Owing to its reabsorption in
Henles loop, Na+ is retained in the body with the
involvement of renin secretion and production of angio-
tensin and aldosterone. When Na+ and Cl concentra-
tions in the intratubular fluid increase in the macula
densa region, the juxtaglomerular apparatus responds
by a decrease in renin secretion, thereby decreasing the
renal blood flow, lowering the rate of glomerular filtra-
tion, and promoting the elimination of sodium and
chloride with urine. However, this process can be
accompanied by a systemic effecta decrease in blood
pressure. The clinical effect of diuretics is associated
with the removal of excess NaCl and the water osmoti-
cally bound with it. This seems to be one effect (but not
the only one) of diuretics that provides for the corre-
spondence of the intravascular fluid volume to the ves-
sel channel capacity.
Another effect is probably caused by the mainte-
nance of the concentrations of Na+ and Cl in the mac-
ula densa region at a level that is higher than is
observed in the given subject under usual conditions.
This hypothesis is supported by a number of findings.
The relative extents of the diuretic and natriuretic
effects of diuretics do not correlate with their hypoten-
sive effect, which correlates, in the one case, with the
diuretic effect and, in the other, with the time of effect
persistence. The correlation can depend on how long
the concentrations of sodium and chloride ions remain
increased just in the macula densa region rather than on
the amounts of excreted sodium and fluid (Table 2).
Diuretics exert a physiological, hypotensive effect,
but observant clinicians have recorded that this effect
does not always correlate with the diuretic effect and, in
some cases, is not accompanied by an increase in urina-
tion or excretion of sodium and chloride ions with
urine. This physiological paradox may be adequately
explained based on principles of clinical physiology.
Small amounts of hypothiazide (or another diuretic
570 NATOCHIN
lowering the reabsorption of sodium and chloride in
distal convoluted tubules) seem to induce a long-term
local increase in the concentrations of these ions to a
level sufficient to influence the secretion of renin. The
excess volume of fluid containing sodium and chloride
ions enters the connecting tubule of the nephron and
collecting tubule. However, the cells of these parts of
the nephron actively absorb these ions and water, and
the intranephronal redistribution of the reabsorption
intensity prevents changes in the final volume of the
renal excretion of water and ions. Thus, the antihyper-
tensive effect can occur without a noticeable increase in
the excretion of electrolytes and water by the kidney.
Physiological reasons for the combined application
of hypothiazide with amiloride or triamterene and with
-blockers will be discussed. Hypothiazide binds with
cotransporters of sodium and chloride ions; the binding
is associated not only with a decrease in their reabsorp-
tion but also with an increase in the secretion of potas-
sium into urine and the loss of these ions with urine. As
a result, there is a gradual development of hypokalemia.
Hypokalemia can be counteracted with sodium channel
blockers, such as amiloride or triamterene. The latter
act in the terminal regions of the nephron distal seg-
ment and collecting tubule and lower Na+ reabsorption,
the membrane potential, and, as a result, the secretion
of potassium [40]. This effect eliminates the unfavor-
able increase in the excretion of potassium and
hypokalemia, whereas the favorable functional effects
of hypothiazide are retained.
CONCLUSIONS
Studies on the physiological mechanisms of func-
tions in humans in order to understand whole-body reg-
ulation represent a classical experimental method.
Studies in the framework of the clinical physiology of
the kidneys do not solely concern the character of dis-
ease or approaches to treatment (although both prob-
lems are important): their main purpose is to grasp the
regulatory mechanism of renal functions. The solution
of this problem seems promising for understanding all
other problems. The examination of a child with noc-
turnal enuresis may be considered a natural experiment:
the researcher observes the functions without affecting
the subject and uninterruptedly analyzes the process
without interfering in it. Physiological analysis makes
it possible to understand the essence of disorders result-
ing in the dysfunction and to assess the possibility of a
return to the normal state. This approach is favorable
for the patient and allows for the verification of a phys-
iological hypothesis.
The above data explain the singularity of the clinical
physiologists position: he aspires to elucidate the
dynamics and succession of events in the body as well
as the mechanisms disturbing the normal course of
physiological processes. Clinical physiology is indis-
pensable for the physiological analysis of the regulation
of functions. The development of dysfunctions and the
great variety of their mechanisms are determined by the
multicomponent realization of every function, multiple
interrelations, and an unpredictable number of possible
compensatory reactions. To foretell the pathway by
which a process develops, one has, at least, to have an
idea concerning the existence of such reactions; but
there are innumerable examples of regulations that
were unknown only a few years ago, and many effects
and their mechanisms are still unknown.
In recent years, ionic channels, aquaporins, and
g-proteins have not only been discovered and described
in detail, but their possible chemical structures have
been established. Under conditions of their dysfunc-
tions caused by genetic defects, environmental factors,
and phenotypic changes, not only the degree of the
function deviation from the norm but also its mecha-
nism can be revealed in humans. A new, previously
unknown component of the system can be revealed
when a situation arises that promotes its manifestation:
an approach can then be invented to detect it and deter-
mine its significance. Not knowing such variants, it is
difficult to design experiments with animals. From all
the aforesaid, it is clear that progress in clinical physi-
ology is most important for the physiology of healthy
humans and for general physiology.
Physiological paradoxes and their solution by
methods of clinical physiology. Consider two examples.
The first one is the hypotensive effect of diuretics with-
out a diuretic effect, which was discussed in detail
above. This example requires commentary. Some
authors think that this effect is caused by the direct
influence of diuretics on vascular cells. This explana-
tion is unacceptable for the following reasons. Molecu-
lar mechanisms of the action of diuretics are well
known, and the effect of the majority of them
(amiloride, furosemide, hypothiazide, etc.) on the kid-
ney depends not only on the location of the chemical
receptor on the luminal membrane. After these agents,
acting in the distal segment of the nephron, are ultrafil-
tered into the lumen of the nephron, their concentration
increases owing to the absorption of water from the
lumen and to their secretion in the proximal segment of
the nephron into the lumen of the tubule [41]. There-
fore, even when chemical receptors are present on cells
of the vascular wall, the concentration of a diuretic in
blood and extracellular fluid is too low for its physio-
logical effect.
The second example is the increased reabsorption of
solute-free water in polyuria in adults with nocturia and
in children with nocturnal enuresis. In both nocturnal
enuresis and in nicturia, we have discriminated two
forms: one with an increased production of C H2 O and
C
the other with an increase in T H2 O. In other words, the
physiological mechanism is a decrease in the secretion
of vasopressin in one case and an increased local pro-
duction of autacoids in the other.
HUMAN PHYSIOLOGY Vol. 31 No. 5 2005
 CLINICAL PHYSIOLOGY: ROLE IN STUDYING BASIC PROBLEMS
Systemic factors in the development of a child: new
findings and new problems (a correlation of uropoiesis
and urination). A healthy adult and a normally develop-
ing child older than two or three years react to the filling
of the urinary bladder by adequate urination, indepen-
dently of the rate of uropoiesis. A different situation
exists in children with nocturnal enuresis: instead of the
harmonic correlation of these processes, the fluid accu-
mulation in the urinary bladder sometimes results in
involuntary urination. Based on the findings, it was sug-
gested that intersystemic relationships in the human
body and their regulation involve three systems: ner-
vous, endocrine, and autacoid. The coordination of
their interaction remains unclear, but changes in the
correlation between influences of the nervous system
and the secretion of hormones and autacoids affect the
bodys capability for adaptation to environmental con-
ditions.
ACKNOWLEDGMENTS
This work was supported by the Russian Foundation
for Basic Research (project no. 05-04-49836), the pro-
gram Leading Scientific Schools (grant no. NSh-
2106.2003.4) of the President of the Russian Federa-
tion, and the Division of Biological Sciences of the
Russian Academy of Sciences.
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