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

All currently available diuretics perturb K + homeostasis.
However, studies in animals established that blockade of adenosine
A 1
receptors induces a brisk natriuresis without significantly
increasing urinary K + excretion (Kuan et al., 1993). Two clinical
studies with FK453, a highly selective A 1
-receptor antagonist, confirm
that blockade of A 1
receptors induces natriuresis in humans
with minimal effects on K + excretion (van Buren et al., 1993). The
natriuretic mechanism of this novel class of diuretics has been partially
elucidated (Takeda et al., 1993). Elevated intracellular cyclic
AMP reduces basolateral Na + -HCO 3–
symport in proximal tubular
cells. Endogenous adenosine normally acts on A 1
receptors in these
cells to inhibit adenylyl cyclase and reduce cyclic AMP accumulation.
Blockade of A 1
receptors removes this inhibition, permits cellular
cyclic AMP to rise, and results in reduced activity of the
Na + -HCO 3–
symporter. Because A 1
receptors are involved in TGF,
A 1
receptor antagonists uncouple increased distal Na + delivery
from activation of TGF. Other mechanisms, including an effect in
the collecting tubules, contribute to the natriuretic response to A 1
-
receptor antagonists; however, it is not known why this class of
diuretics has little effect on K + excretion. In some patients, loop
diuretics may compromise renal hemodynamics and actually
reduce GFR, a phenomenon known as diuretic intolerance.
Importantly, A 1
receptor antagonists tend to improve GFR in the
setting of diuretic intolerance. A 1
receptor antagonists such
as rolofylline are in clinical trials. However, the future utility of
this class of diuretics is doubtful: the large PROTECT trial showed in
2009 that rolofylline was not superior to placebo in patients with
acute heart failure; rolofylline also increased the incidence of
seizures, an expected side-effect of A 1
receptor antagonists.
WATER HOMEOSTASIS
Arginine vasopressin (the antidiuretic hormone in
humans) is the main hormone that regulates body
fluid osmolality. Many diseases of water homeostasis
and many pharmacological strategies for correcting
such disorders involve vasopressin. This section
of the chapter focuses on vasopressin, including (1)
chemistry of vasopressin agonists and vasopressin
antagonists; (2) physiology (anatomical considerations;
the synthesis, transport, and storage of vasopressin;
and regulation of vasopressin secretion); (3)
basic pharmacology (vasopressin receptors and their
signal-transduction pathways, renal actions of vasopressin,
pharmacological modification of the antidiuretic
response to vasopressin, and nonrenal actions
of vasopressin); (4) diseases affecting the vasopressin
system (diabetes insipidus, syndrome of inappropriate
secretion of antidiuretic hormone [SIADH], and
other water-retaining states); and (5) clinical pharmacology
of vasopressin peptides. A small number of
other drugs can be used to treat abnormalities of
water balance; a discussion of these agents is integrated
into the section on diseases affecting the vasopressin
system.
INTRODUCTION TO VASOPRESSIN
Genes encoding vasopressin-like peptides probably
evolved >700 million years ago. Immunoreactive vasopressin
occurs in neurons from organisms belonging to
the first animal phylum with a nervous system (e.g.,
Hydra attenuata), and vasopressin-like peptides have
been isolated and characterized from both mammalian
and nonmammalian vertebrates, as well as from invertebrates
(Table 25–8). With the emergence of life on
land, vasopressin became the mediator of a remarkable
regulatory system for water conservation. The hormone
is released by the posterior pituitary whenever water
deprivation causes an increased plasma osmolality or
whenever the cardiovascular system is challenged by
hypovolemia and/or hypotension. In amphibians, target
organs for vasopressin are skin and urinary bladder,
whereas in other vertebrates, including humans, vasopressin
acts primarily in the renal collecting duct. In
each of these target tissues, vasopressin increases the
water permeability of the cell membrane, thus permitting
water to move passively down an osmotic gradient
across skin, bladder, or collecting duct into the extracellular
compartment.
In view of the long evolutionary history of vasopressin,
it is not surprising that vasopressin acts at sites
in the nephron other than the collecting duct and on tissues
other than kidney. Vasopressin is a potent vasopressor;
indeed, its name was chosen originally in
recognition of this vasoconstrictor action. Vasopressin
is a neurotransmitter; among its actions in the CNS are
apparent roles in the secretion of adrenocorticotropic
hormone (ACTH) and in regulation of the cardiovascular
system, temperature, and other visceral functions.
Vasopressin also promotes release of coagulation factors
by vascular endothelium and increases platelet
aggregability.
PHYSIOLOGY OF VASOPRESSIN
Anatomy. The antidiuretic mechanism in mammals involves two
anatomical components: a CNS component for synthesis, transport,
storage, and release of vasopressin and a renal collecting-duct system
composed of epithelial cells that respond to vasopressin by
increasing their water permeability. The CNS component of the
antidiuretic mechanism is called the hypothalamiconeurohypophyseal
system and consists of neurosecretory neurons with perikarya
located predominantly in two specific hypothalamic nuclei, the
supraoptic nucleus (SON) and paraventricular nucleus (PVN). Long
axons of magnocellular neurons in SON and PVN transverse the
external zone of the median eminence to terminate in the neural lobe
of the posterior pituitary (neurohypophysis), where they release
vasopressin and oxytocin. In addition, axons of parvicellular neurons
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CHAPTER 25
REGULATION OF RENAL FUNCTION AND VASCULAR VOLUME