DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

708 antidiuretic response to vasopressin. Since prostaglandins
attenuate antidiuretic responses to vasopressin and
NSAIDs inhibit prostaglandin synthesis, reduced
prostaglandin production probably accounts for potentiation
of vasopressin’s antidiuretic response. Carbamazepine
and chlorpropamide also enhance antidiuretic effects of
vasopressin by unknown mechanisms. In rare instances,
chlorpropamide can induce water intoxication.
A number of drugs inhibit the antidiuretic actions
of vasopressin. Lithium is of particular importance
because of its use in the treatment of manic-depressive
disorders. Acutely, Li + appears to reduce V 2
-receptormediated
stimulation of adenylyl cyclase. Also, Li +
increases plasma levels of parathyroid hormone, a partial
antagonist to vasopressin. In most patients, the
antibiotic demeclocycline attenuates the antidiuretic
effects of vasopressin, probably owing to decreased
accumulation and action of cyclic AMP.
Nonrenal Actions of Vasopressin. Vasopressin and related peptides
are ancient hormones in evolutionary terms, and they are found in
species that do not concentrate urine. Thus, it is not surprising that
vasopressin has nonrenal actions in mammals.
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Cardiovascular System. The cardiovascular effects of vasopressin
are complex, and vasopressin’s role in physiological situations is
ill-defined. Vasopressin is a potent vasoconstrictor (V 1
receptormediated),
and resistance vessels throughout the circulation may
be affected. Vascular smooth muscle in the skin, skeletal muscle,
fat, pancreas, and thyroid gland appear most sensitive, with significant
vasoconstriction also occurring in GI tract, coronary vessels,
and brain. Despite the potency of vasopressin as a direct
vasoconstrictor, vasopressin-induced pressor responses in vivo
are minimal and occur only with vasopressin concentrations significantly
higher than those required for maximal antidiuresis. To
a large extent, this is due to circulating vasopressin actions on V 1
receptors to inhibit sympathetic efferents and potentiate baroreflexes.
In addition, V 2
receptors cause vasodilation in some blood
vessels.
A large body of data supports the conclusion that vasopressin
helps to maintain arterial blood pressure during episodes of severe
hypovolemia/hypotension. At present, there is no convincing evidence
for a role of vasopressin in essential hypertension in humans
(Kawano et al., 1997).
The effects of vasopressin on heart (reduced cardiac output and
heart rate) are largely indirect and result from coronary vasoconstriction,
decreased coronary blood flow, and alterations in vagal and sympathetic
tone. In humans, vasopressin effects on coronary blood flow
can be demonstrated easily, especially if large doses are employed.
The cardiac actions of the hormone are of more than academic interest.
Some patients with coronary insufficiency experience angina even
in response to the relatively small amounts of vasopressin required to
control diabetes insipidus, and vasopressin-induced myocardial
ischemia has led to severe reactions and even death.
CNS. It is likely that vasopressin plays a role as a neurotransmitter
and/or neuromodulator. Vasopressin may participate in the acquisition
of certain learned behaviors, in the development of some complex
social processes, and in the pathogenesis of specific psychiatric
diseases such as depression. However, the physiological/ pathophysiological
relevance of these findings is controversial, and some
actions of vasopressin on memory and learned behavior may be
due to visceral autonomic effects. Many studies support a physiological
role for vasopressin as a naturally occurring antipyretic factor.
Although vasopressin can modulate CNS autonomic systems
controlling heart rate, arterial blood pressure, respiration rate, and
sleep patterns, the physiological significance of these actions is
unclear. Finally, ACTH secretion is enhanced by vasopressin
released from parvicellular neurons in the PVN and secreted into
pituitary portal capillaries from axon terminals in the median eminence.
Although vasopressin is not the principal corticotropinreleasing
factor, vasopressin may provide for sustained activation
of the hypothalamic-pituitary-adrenal axis during chronic stress.
CNS effects of vasopressin appear to be mediated predominantly
by V 1
receptors.
Blood Coagulation. Activation of V 2
receptors by desmopressin or
vasopressin increases circulating levels of procoagulant factor VIII
and of von Willebrand factor. These effects are mediated by
extrarenal V 2
receptors (Bernat et al., 1997). Presumably, vasopressin
stimulates secretion of von Willebrand factor and of factor VIII from
storage sites in vascular endothelium. However, since release of von
Willebrand factor does not occur when desmopressin is applied
directly to cultured endothelial cells or to isolated blood vessels,
intermediate factors are likely to be involved.
Other Nonrenal Effects of Vasopressin. At high concentrations, vasopressin
stimulates smooth muscle contraction in uterus (by oxytocin
receptors) and GI tract (by V 1
receptors). Vasopressin is stored in
platelets, and activation of V 1
receptors stimulates platelet aggregation.
Also, activation of V 1
receptors on hepatocytes stimulates
glycogenolysis. The physiological significance of these effects of
vasopressin in not known.
VASOPRESSIN RECEPTOR AGONISTS
AND ANTAGONISTS
A number of vasopressin-like peptides occur naturally
(Table 25–8). All are nonapeptides, contain cysteine
residues in positions 1 and 6, have an intramolecular
disulfide bridge between the two cysteine residues
(essential for agonist activity), have additional conserved
amino acids in positions 5, 7, and 9 (asparagine,
proline, and glycine, respectively), contain a basic
amino acid in position 8, and are amidated on the carboxyl
terminus. In all mammals except swine, the neurohypophyseal
peptide is 8-arginine vasopressin, and
the terms vasopressin, arginine vasopressin (AVP), and
antidiuretic hormone (ADH) are used interchangeably.
The chemical structure of oxytocin is closely
related to that of vasopressin: oxytocin is [Ile 3 ,
Leu 8 ]AVP. Oxytocin binds to specific oxytocin receptors
on myoepithelial cells in mammary gland and on