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

704
SECTION III
MODULATION OF CARDIOVASCULAR FUNCTION
Plasma vasopressin
pg/ml
10
8
6
4
2
Hypovolemia or
hypotension
-20
-15
-10
Hypervolemia or
hypertension
0
260 270 280 290 300 310 320 330 340
Plasma osmolality
mOsm/kg
Figure 25–18. Interactions between osmolality and hypovolemia/hypotension.
Numbers in circles refer to percentage
increase (+) or decrease (−) in blood volume or arterial blood
pressure. N indicates normal blood volume/blood pressure.
(Reprinted by permission from Macmillan Publishers Ltd:
Robertson GL, Shelton RL, Athar S: The osmoregulation of
vasopressin. Kidney Internat 10:25, 1976. Copyright © 1976.)
known, and the vasopressin response to hypovolemia or hypotension
serves as a mechanism to stave off cardiovascular collapse
during periods of severe blood loss and/or hypotension.
Hemodynamic regulation of vasopressin secretion does not disrupt
osmotic regulation; rather, hypovolemia/hypotension alters
the set point and slope of the plasma osmolality-plasma vasopressin
relationship (Figure 25–18).
Neuronal pathways that mediate hemodynamic regulation of
vasopressin release are different from those involved in osmoregulation.
Baroreceptors in left atrium, left ventricle, and pulmonary
veins sense blood volume (filling pressures), and baroreceptors in
carotid sinus and aorta monitor arterial blood pressure. Nerve
impulses reach brainstem nuclei predominantly through the vagal
trunk and glossopharyngeal nerve; these signals are relayed to the
solitary tract nucleus, then to the A 1
-noradrenergic cell group in the
caudal ventrolateral medulla, and finally to the SON and PVN.
Hormones and Neurotransmitters. Vasopressin-synthesizing magnocellular
neurons have a large array of receptors on both perikarya
and nerve terminals; therefore, vasopressin release can be accentuated
or attenuated by chemical agents acting at both ends of the magnocellular
neuron. Also, hormones and neurotransmitters can
modulate vasopressin secretion by stimulating or inhibiting neurons
in nuclei that project, either directly or indirectly, to the SON and
PVN. Because of these complexities, results of any given investigation
may depend critically on route of administration of the agent
and on the experimental paradigm. In many cases, the precise mechanism
by which a given agent modulates vasopressin secretion is
either unknown or controversial, and the physiological relevance of
the modulation of vasopressin secretion by most hormones and neurotransmitters
is unclear.
Nonetheless, several agents are known to stimulate vasopressin
secretion, including acetylcholine (by nicotinic receptors),
histamine (by H 1
receptors), dopamine (by both D 1
and D 2
receptors),
N
+10
+15
+20
glutamine, aspartate, cholecystokinin, neuropeptide Y, substance P,
vasoactive intestinal polypeptide, prostaglandins, and angiotensin II
(AngII). Inhibitors of vasopressin secretion include atrial natriuretic
peptide, γ-aminobutyric acid, and opioids (particularly dynorphin
via κ receptors). The affects of AngII have received the most attention.
AngII, applied directly to magnocellular neurons in the SON
and PVN, increases neuronal excitability; when applied to the
MnPO, AngII indirectly stimulates magnocellular neurons in the
SON and PVN. In addition, AngII stimulates angiotensin-sensitive neurons
in the OVLT and SFO (circumventricular nuclei lacking a
blood-brain barrier) that project to the SON/PVN. Thus, AngII synthesized
in the brain and circulating AngII may stimulate vasopressin
release. Inhibition of the conversion of AngII to AngIII blocks AngIIinduced
vasopressin release, suggesting that AngIII is the main effector
peptide of the brain renin-angiotensin system controlling
vasopressin release (Reaux et al., 2001).
Pharmacological Agents. A number of drugs alter urine osmolality
by stimulating or inhibiting vasopressin secretion. In some cases the
mechanism by which a drug alters vasopressin secretion involves
direct effects on one or more CNS structures that regulate vasopressin
secretion. In other cases vasopressin secretion is altered indirectly
by the effects of a drug on blood volume, arterial blood
pressure, pain, or nausea. In most cases the mechanism is not known.
Stimulators of vasopressin secretion include vincristine, cyclophosphamide,
tricyclic antidepressants, nicotine, epinephrine, and high
doses of morphine. Lithium, which inhibits the renal effects of vasopressin,
also enhances vasopressin secretion. Inhibitors of vasopressin
secretion include ethanol, phenytoin, low doses of morphine,
glucocorticoids, fluphenazine, haloperidol, promethazine, oxilorphan,
and butorphanol. Carbamazepine has a renal action to produce
antidiuresis in patients with central diabetes insipidus but actually
inhibits vasopressin secretion by a central action.
BASIC PHARMACOLOGY
OF VASOPRESSIN
Vasopressin Receptors. Cellular vasopressin effects are
mediated mainly by interactions of the hormone with the
three types of receptors, V 1a
, V 1b
, and V 2
. The V 1a
receptor
is the most widespread subtype of vasopressin receptor;
it is found in vascular smooth muscle, adrenal gland,
myometrium, bladder, adipocytes, hepatocytes, platelets,
renal medullary interstitial cells, vasa recta in the renal
microcirculation, epithelial cells in the renal cortical collecting-duct,
spleen, testis, and many CNS structures. V 1b
receptors have a more limited distribution and are found
in the anterior pituitary, several brain regions, pancreas,
and adrenal medulla. V 2
receptors are located predominantly
in principal cells of the renal collecting-duct system
but also are present on epithelial cells in thick
ascending limb and on vascular endothelial cells.
Although originally defined by pharmacological criteria,
vasopressin receptors now are defined by their primary
amino acid sequences. The cloned vasopressin receptors