Chemistry, Biology, and Medicine of Neurohypophyseal Hormones and their Analogs. The Peptides Analysis, Synthesis, Biology, Vol. 8

369 Pages·1987·25.494 MB·English

by  Sidney Udenfriend, Johannes Meienhofer and Clark W. Smith (Eds.)

THE PEPTIDES
Analysis, Synthesis, Biology
Treatise Editors
S. UDENFRIEND AND J. MEIENHOFER
Volume 1
Major Methods ofPeptide Bond Formation
Volume 2
Special Methods in Peptide Synthesis, Part A
Volume 3
Protection ofFunctional Groups in Peptide Synthesis
Volume 4
Modern Techniques ofConformational, Structural,
and Configurational Analysis
Volume 5
Special Methods in Peptide Synthesis, Part B
Volume 6
Opioid Peptides: Biology, Chemistry, and Genetics
Volume 7
Edited by Victor J. Hruby
Conformation in Biology and Drug Design
Volume 8
Edited by Clark W. Smith
Chemistry, Biology, and Medicine ofNeurohypophyseal
Hormones and Their Analogs
T he
Peptides
Analysis, Synthesis, Biology
Edited by
SIDNEY UDENFRIEND JOHANNES MEIENHOFER
Roche Institute of Molecular Biology Berlex Laboratories, Inc.
Nutley, New Jersey Cedar Knolls, New Jersey
VOLUME 8 Chemistry, Biology, and Medicine
of Neurohypophyseal Hormones
and Their Analogs
Edited by
CLARK W. SMITH
Biopolymer Chemistry
The Upjohn Company
Kalamazoo, Michigan
1987
ACADEMIC PRESS, INC.
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Library of Congress Cataloging in Publication Data
(Revised forvol. 8)
The Peptides : analysis, synthesis, biology.
Vol. 6- edited by Sidney Udenfriend and others.
Includes bibliographies and indexes.
Contents: v. 1. Maior methods of peptide bond
formation.-V. 2. Special methods in peptide synthesis,
part A.-[etc.] -v. 8. Chemistry, biology, and
medicine of neurohypophyseal hormones and their
analogs.
1. Peptides-Collected works. 2. Peptides.
I. Gross, Erhard.
QP552.P4P47 574.Γ92456 78-31958
ISBN 0-12-304208-9 (v. 8: alk. paper)
PRINTED IN THH UNITtD STATKS OF AMERICA
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Preface
The last treatise that covered the chemistry, biology, and medicine of neu­
rohypophyseal hormones was the excellent work edited by B. Berde in Volume
23 of the "Handbook of Experimental Pharmacology" in 1968. During tνie
interim there have been a number of reviews that covered specific aspects of the
chemistry or the biology or the medicine of neurohypophyseal hormones. In
Volume 8 of *'The Peptides" I have attempted again to bring together many of
the advances in our knowledge about this important class of peptides in all three
disciplines into one volume.
The emphasis of Volume 8 is certainly different from that of the "Handbook"
and reflects the advances in methods to study peptide hormone action at the
molecular level. Powerful new methods in physical chemistry and biophysics
have allowed the study of specific conformational features to be related to bio­
logical activity. Recombinant molecular biology has allowed the elucidation of
the biosynthetic pathway of neurohypophyseal hormones. New methods in cell
biology have advanced our knowledge of peptide hormone-receptor interactions
and the role of the second messenger molecules. New techniques in protein
biochemistry have even made it necessary to expand our definition of neurohypo­
physeal peptides.
Because the neurohypophyseal peptides have been used for so many basic
studies in the chemistry, biophysics, biology, and medicine of peptide hor­
mones, these reviews are intended as a reference for the specialist in neu­
rohypophyseal peptides and as a guide for the novice investigator interested more
generally in peptide hormone research.
The order of the chapters in this volume begins with studies on the neu­
rohypophysis, proceeds through the chemistry of the peptides, and finishes with
the biological effects of the hormones at their target tissues. In Chapter 1 by Alan
G. Robinson and Joseph G. Verbalis the anatomy, physiology, and clinical
disorders of the neurohypophysis are discussed. In Chapter 2 by Thomas L.
O'Donohue and Joszef Z. Kiss we are introduced to "the other neu­
rohypophyseal peptides." In Chapter 3 by Dietmar Richter the biosynthesis of
neurohypophyseal peptides is presented. In Chapter 4 by Victor J. Hruby and
Clark W. Smith the structure-activity relationships of neurohypophyseal pep-
ix
÷ Preface
tides are discussed with an emphasis on the role of conformational features.
Except for puφoses of continuity of discussion, the extensive tables in this
chapter do not include those analogs already listed in the earlier "Handbook of
Experimental Pharmacology." In Chapter 5 Judith C. Hempel presents confor­
mational studies of neurohypophyseal hormones by physical chemical techniques
such as X-ray crystallography, NMR, and other spectroscopic methods. In Chap­
ter 6 by Paula Hoffman some of the central nervous system effects of neu­
rohypophyseal peptides are given. The effects on memory and learning by neu­
rohypophyseal hormones have been an entirely new area of study since the last
treatise. Effects on one of the major target tissues of neurohypophyseal hor­
mones, the kidney, are presented by S. Ishikawa, J. K. Kim, and R. W. Schrier
in Chapter 7. An integrated discussion of the effects of neurohypophyseal hor­
mones on the cardiovascular systems, including clinical implications, is clearly
presented in the final chapter by P. G. Schmid and K. P. Patel.
I am greatly indebted to Johannes Meienhofer for his constant encouragement
and everlasting patience with me during the creation of this volume. We are all
indebted to Vincent du Vigneaud and Roderich Walter for their many insights
upon which much of the work presented here was built.
Clark W. Smith
1
Chapter
Clinical Disorders of the Neurohypophysis
ALAN G. ROBINSON, JOSEPH G. VERBALIS
Department of Medicine
School of Medicine
University of Pittsburgh
Pittsburgh, Pennsylvania 15261
I. ANATOMY
The peptide hormones of the posterior pituitary, oxytocin and vasopressin, are
synthesized in specialized magnocellular neurons of the hypothalamus (9, 103).
The magnocellular neurons are grouped into two major nuclei, the supraoptic
nucleus (SON) and the paraventricular nucleus (PVN) (102, 103). In most spe­
cies, both hormones are synthesized in both nuclei, although there is frequently a
predominance of vasopressin in the supraoptic nucleus {20, 102-104). Each
hormone is synthesized together with its neurophysin (56) in individual neurons,
which are hormone-specific {104). The vasopressinergic and oxytocinergic neu­
rons are clustered into rather discrete areas within each nucleus {20, 103), and
there is, in addition, some suggestion that the clustering within the nucleus is on
the basis of the ultimate projection of the neurons {20, 55, 76, 83, 101). For
example, vasopressinergic neurons that project to the spinal cord may be clus­
tered in an area separate from vasopressinergic neurons that project to the pos­
terior pituitary. The major projection of both nuclei is to the posterior pituitary
via the supraopticohypophyseal tract. In the posterior pituitary there is a large
store of vasopressin, oxytocin, and their associated neurophysins in neu­
rosecretory granules within the axon terminals.
The first clear demonstration that neurohypophyseal neurons projected to areas
other than the posterior pituitary was the description of neurophysin terminals in
the zona externa of the median eminence {50, 78, 100). Since the terminals in the
median eminence ended on capillaries of the hypothalamohypophyseal portal
system, it was concluded that the vasopressin was secreted into the pituitary
THE PEPTIDES, VOLUME 8
Copyright © 1987 by Academic Press, Inc.
All rights of reproduction in any form reserved.
1
2 Alan G. Robinson and Joseph G. Verbalis
portal circulation. Measurement of neurophysin and vasopression in pituitary
stalk blood of the monkey confirmed markedly elevated concentrations con­
sistent with direct secretion of vasopressin into portal blood (100). As it had long
been known that vasopressin could stimulate the release of adrenocorticotropic
hormone (ACTH), the content of neurophysin and vasopressin in the median
eminence was studied during a state of increased release of ACTH. The content
of vasopressin and neurophysin was determined by immunohistochemistry in the
zona externa after adrenalectomy (77). A marked increase in the neurophysin and
vasopressin at this level was noted, which could be specifically prevented by
pretreatment with glucocorticoid (50, 78). Subsequently, since the discovery of
corticotropin-releasing factor (CRF) (87), it has been amply demonstrated in
many species that vasopressin does potentiate CRF-mediated release of ACTH
(57, 88).
Interestingly, the vasopressinergic neurons that project to the median emi­
nence originate in the PVN (3), but in parvocellular rather than magnocellular
neurons (97). This is also the site of synthesis corticotropin-releasing factor.
Indeed, some reports have colocalized vasopressin and CRF within the same
neurons (10, 84). In addition to the projections to the median eminence, numer­
ous hypothalmic projections of both vasopressin and oxytocin neurons to the
spinal cord, brainstem, and forebrain have been described (76, 82, 83). Although
the function of these projections has not been elucidated, it is likely that vas­
opressin and oxytocin will be found to be involved in a variety of diverse central
nervous system (CNS) functions. Recent studies have confirmed that the para­
ventricular nucleus is the source of virtually all the extrahypothalamic projec­
tions of vasopressin, while the SON projects almost exclusively to the posterior
pituitary.
II. SYNAPTIC INPUT
It is now certain the response of the vasopressinergic neurons to changes in
osmolality is not due to osmoreceptivity of the magnocellular neurons them­
selves, but rather due to separate neurons that communicate synaptically with the
SON and PVN (74, 75). The osmoresponsive neurons are close to the SON and
PVN because hypothalamo-neurohypophyseal explants maintained in vitro in
organ culture continue to be responsive to osmotic stimulation (74). In these
explants, the osmotically stimulated release of vasopressin can be blocked by
nicotinic cholinergic antagonists, suggesting that acetylcholine is the main neu­
rotransmitter of the osmoreceptors (although angiotensin has also been impli­
cated) (74, 75). Lesion studies in several species have provided evidence that the
osmoregulation of vasopressin is disrupted by lesions in the anteroventral region
1 Clinical Disorders of the Neurohypophysis 3
of the third ventricle, either in the nucleus medianus (27, 38) and/or in the
Organum vasculosum terminalis (54).
A second major input to the vasopressinergic cells of the SON and PVN is
from the subfornical organ (42). The subfornical organ is thought to be important
as a central sensor of volume depletion, because destruction of the subfornical
organ will abolish the drinking response produced by infusion of angiotensin II
peripherally (53). This pathway provides a potential mechanism whereby volume
depletion can stimulate secretion of vasopressin via a humoral (angiotensin II)
stimulus independently of the classic brainstem-mediated volume-receptor
pathway.
The third major afferent input to the vasopressinergic neurons in the SON and
PVN is from the brainstem (82). These pathways are predominantly nor­
adrenergic or adrenergic and are probably responsible for the dense cate-
cholaminergic innervation that has been demonstrated in the SON and PVN (34).
Since catacholamines have generally been found to inhibit the secretion of vas­
opressin (4, 39), the brainstem input is thought to chronically inhibit the release
of vasopressin. Anything that interferes with the function of these inhibitory
pathways can potentially stimulate the release of vasopressin (5).
The fourth area of afferent input is from the limbic system, including the
lateral septum and amygdala (73, 86). This input is largely to the vasopres­
sinergic neurons of the PVN. Since glucocorticord receptors have been localized
in these areas (38), it is possible that this input is important in regulation of the
vasopressin and CRF neurons that project from the PVN to the median eminence.
III. PHYSIOLOGY
A. Oxytocin
The only recognized function for oxytocin is in women (13, 25), although the
levels of oxytocin in men may be similar in response to pharmacologic stimuli
(7). In women, oxytocin is released in response to suckling and is associated with
myocontraction of ducts within the breasts to cause milk letdown (13). Whether
oxytocin release at the time of nursing is essential for milk release is not known;
data in animals suggest that milk production and release can be ongoing in the
absence of oxytocin. At parturition, oxytocin can stimulate the uterus to cause
uterine contractions, and it is frequently used as a pharmacologic agent to stimu­
late uterine contractions and initiate labor (2, 12, 70). However, whether oxy­
tocin plays an important role in initiating labor in normal pregnancy is not
known. Stretching of the cervix that occurs during labor may be a stimulus to
cause increased release of oxytocin (24). Oxytocin levels have been reported to
4 Alan G. Robinson and Joseph G. Verbalis
be high at the time of parturition and immediately after delivery (27). Thus,
oxytocin may be more important for maintenance of uterine tone after expulsion
of the fetus than for initiation of labor. The fetus itself is also known to be a
source of oxytocin at parturition, but the importance of this secretion of oxytocin
is not known (14).
B. Vasopressin
As alluded to in the description of synaptic input, the two major regulatory
systems involved in the control of the release of arginine vasopressin (AVP) are
osmotic receptors and volume receptors (59). In recent years it has been recog­
nized that nausea (66), glucopenia (8, 95) and certain stresses (22) may also
stimulate the release of vasopressin (61, 64). As these various other inputs are
thought to be predominantly similar to volume receptor afferent pathways, the
concept of "volume" receptors has been expanded to include all "nonosmotic"
regulation of release of vasopressin.
7. Osmoreceptors
Secretion of vasopressin is exquisitely sensitive to changes in osmolality. A
1% increase in osmolality of the extracellular fluid will cause a measureable
increase in the secretion of vasopressin (59, 61). The relationship between plas­
ma osmolality and levels of vasopressin is illustrated in Fig. 1. The osmotic
I Thirst ^
I2H
if)
UJ
a. 8H
il
4H
CO
<
oH
I ' I · I ' I
270 280 290 300 310
PLASMA OSMOLALITY
mOsm/kg
Figure 1. The relationship between plasma vasopressin and plasma osmolality for normal
subjects. The thirst threshold is indicated at the top. [Reprinted with permission {64).]
1 Clinical Disorders of the Neurohypophysis 5
Ol 2 3 4 5 10 15
PLASMA AVP
pg/ml
Figure 2. The relationship between urine osmolality and the level of AVP in plasma for normal
subjects. [Reprinted with permission (64).]
threshold for release of vasopressin in normal subjects is approximately 280
mOsm/kg. While it is not possible to prove that no vasopressin is released below
this threshold, it is certain that release of vasopressin is sufficiently suppressed to
allow maximum water diuresis and no concentration of the urine. Between
osmolalities of 280 and 295-300 there is a linear increase in the level of vaso­
pressin with increases in osmolality. At a plasma osmolality of approximately
295-300, the level of vasopressin in plasma (5 pg/ml) is sufficient to cause
maximum antidiuresis. This is demonstrated in Fig. 2, in which the relationship
between plasma vasopressin and urine osmolality is illustrated. The entire phys­
iologic range from maximum water diuresis to maximum antidiuresis occurs with
vasopressin concentrations between 1 and 5 pg/ml (62, 63), While levels of
vasopressin in plasma may be much greater than 5 pg/ml, these levels will not
translate into further increases in antidiuresis. The sensitivity for the release of
vasopressin on the one hand and the sensitivity of the renal response on the other
is the explanation for the close correlation between plasma osmolality and urine
osmolality (Fig. 3) (41); shifts in plasma osmolality between 280 and 295-300
will cause corresponding changes in urine osmolality from less than 50 to greater
than 900 mOsm/kg.
In most situations, in the human the sensation of thirst is closely correlated
with urinary concentration (59). The osmoreceptors for thirst are in the same area
(or in fact may be localized in the same neurons) as those regulating the secretion
of vasopressin (80, 81). There are data showing that in humans the threshold for
thirst is somewhat higher than that for vasopressin, and that thirst is not stimu­
lated until reaching a plasma osmolality of as high as 295 (67). Therefore, most