Antidiuretic Hormone

ANTIDIURETIC HORMONE

It is a nonapeptide secreted by posterior pituitary (neurohypophysis) along with oxytocin (see Ch. No. 23). It is synthesized in the hypothalamic (supraoptic and paraventricular) nerve cell bodies as a large precursor peptide along with its binding protein ‘neurophysin’, and is transported down the axons to nerve endings in the median eminence and pars nervosa. Osmoreceptors present in hypothalamus and volume receptors present in left atrium, ventricles and pulmonary veins primarily regulate the rate of ADH release governed by body hydration. Impulses from baroreceptors and higher centres also impinge on the nuclei synthesizing ADH and affect its release. The two main physiological stimuli for ADH release are rise in plasma osmolarity and contraction of e.c.f. volume.

ADH secretion is enhanced by angiotensin II, prostaglandins (PGs), histamine, neuropeptide Y and ACh. It is inhibited by GABA and atrial natriuretic peptide (ANP). Opioids have agentspecific action: while morphine stimulates ADH secretion, endogenous opioid peptides are mostly inhibitory. These humoral mediators may play a role in the modulation of ADH secretion.

The mammalian ADH is 8argininevasopressin (AVP); 8-lysinevasopressin (lypressin) is found in swine and has been synthetically prepared. Other more potent and longer acting peptide analogues of ADH having agonistic as well as antagonistic action have been prepared.

ADH (Vasopressin) Receptors

These are G protein coupled cell membrane receptors; two subtypes V₁ and V₂ have been identified, cloned and structurally characterized.

V₁ Receptors

All vasopressin receptors except those on renal CD cells and some blood vessels are of the V₁ type. These are further divided into:

V_1a present on vascular and other smooth muscles, platelets, liver, etc. and V_1b localized to the anterior pituitary.

The V₁ receptors function mainly through the phospholipase C–IP₃/DAG pathway—release Ca2+ from intracellular stores—causing vasoconstriction, visceral smooth muscle contraction, glycogenolysis, platelet aggregation, ACTH release, etc. These actions are augmented by enhanced influx of Ca2+ through Ca2+ channels as well as by DAG mediated protein kinase C activation which phosphorylates relevant proteins. V₁ receptors, in addition, activate phospholipase A2—release arachidonic acid resulting in generation of PGs and other eicosanoids which contribute to many of the V₁ mediated effects. Persistent V₁ receptor stimulation activates protooncogenes (possibly through IP ₃/DAG pathway) resulting in growth of vascular smooth muscle and other responsive cells.

V₂ Receptors

These are located primarily on the collecting duct (CD) cells in the kidney—regulate their water permeability through cAMP production. Vasodilatory V₂ receptors are present in blood vessels.

The V₂ receptors are more sensitive (respond at lower concentrations) to ADH than are V₁ receptors.

Selective peptide agonists and antagonists of the subtypes of vasopressin receptors are:

Some orally active nonpeptide V_1a and V₂ receptor antagonists have been produced and are under clinical trial.

Actions

Kidney

AVP acts on the collecting duct (CD) cells to increase their water permeability—water from the lumen diffuses to the interstitium by equilibrating with the hyperosmolar renal medulla (see Fig. IX.1). In man, maximal osmolarity of urine that can be attained is 4 times higher than plasma. When ADH is absent, CD cells remain impermeable to water → dilute urine (produced by the diluting segment) is passed as suCh. No. Graded effect occurs at lower concentration of ADH: urine volume closely balances fluid intake.

Mechanism Of Action

The V₂ subtype of ADH receptors are present on the basolateral side of CD cell membrane. Activation of these receptors increases cAMP formation intracellularly → activation of cAMP dependent protein kinase A → phosphorylation of relevant proteins which promote exocytosis of ‘aquaporin2’ water channel containing vesicles (WCVs) through the apical membrane → more aqueous channels get inserted into the apical membrane. The rate of endocytosis and degradation of WCVs is concurrently reduced. The water permeability of CD cells is increased in proportion to the population of aquaporin2 channels in the apical membrane at any given time. Continued V₂ receptor stimulation (during chronic water deprivation) in addition upregulates aquaporin2 synthesis through cAMP response element of the gene encoding aquaporin2.

Other aquaporins like aquaporin1 (in PT) and aquaporin3,4 (on basolateral membrane of CD cells) also participate in water transport at these sites.

To achieve maximum concentration of urine, activation of V₂ receptors increases urea permeability of terminal part of CDs by stimulating a vasopressin regulated urea transporter (VRUT or UT1)—which in turn augments medullary hypertonicity. Recently, V₂ receptor mediated actions of AVP on AscLH have been demonstrated which further reinforce medullary hypertonicity by activating the Na+K+2Cl¯ cotransporter in the shortterm and increasing its synthesis in the long-term.

The V ₁ receptors also participate in the renal response to ADH. While V_1a receptor activation constricts vasa recta to diminish blood flow to inner medulla which will help in maintaining high osmolarity in this region and thus contribute to antidiuresis; other V₁ actions augmenting PG production from interstitial cells and directly diminishing responsiveness of CD cells to V₂ receptor stimulation tend to restrain V₂ mediated water permeability. Since V₂ action is produced at much lower concentration of AVP, physiologically V₁ renal actions may serve to restrict V₂ effect when blood levels of AVP are very high.

Lithium and demeclocycline partially antagonize ADH action (probably by limiting cAMP formation), reduce the urine concentrating ability of the kidney, produce polyuria and polydipsia. They have been used in patients with inappropriate ADH secretion. On the other hand NSAIDs (especially indomethacin) augment AVP induced antidiuresis by inhibiting renal PG synthesis. Carbamazepine and chlorpropamide also potentiate AVP.

Blood Vessels

AVP constricts blood vessels through V₁ receptors and can raise BP (hence the name vasopressin), but much higher concentration is needed than for maximal antidiuresis. The cutaneous, mesenteric, skeletal muscle, fat depot, thyroid, and coronary beds are particularly constricted. Though vasoconstrictor action of AVP does not appear to be physiologically important, some recent studies indicate that it may play a role in CHF, haemorrhage, hypotensive states, etc. Prolonged exposure to AVP causes vascular smooth muscle hypertrophy.

The V₂ receptor mediated vasodilatation can be unmasked when AVP is administered in the presence of a V₁ antagonist. It can also be demonstrated by the use of selective V₂ agonist desmopressin, and appears to be EDRF (NO) mediated.

Other Actions

Most visceral smooth muscles contract. Increased peristalsis in gut (especially large bowel), evacuation and expulsion of gases may occur.

Uterus is contracted by AVP acting on oxytocin receptors. In the nonpregnant and early pregnancy uterus, AVP is equipotent to oxytocin. Only at term sensitivity to oxytocin increases selectively.

CNS Exogenously administered AVP does not penetrate blood-brain barrier. However, it is now recognized as a peptide neurotransmitter in many areas of brain and spinal cord: may be involved in regulation of temperature, circulation, ACTH release, and in learning of tasks.

AVP induces platelet aggregation and hepatic glycogenolysis. It releases coagulation factor VIII and von Willebrand’s factor from vascular endothelium through V₂ receptors.

Pharmacokinetics

AVP is inactive orally because it is destroyed by trypsin. It can be administered by any parenteral route or by intranasal application. The peptide chain of AVP is rapidly cleaved enzymatically in many organs, especially in liver and kidney; plasma t½ is short~25 min. However, the action of aqueous vasopressin lasts 3– 4 hours.

Aqueous vasopressin (AVP) inj: POSTACTON 10 U inj; for i.v., i.m. or s.c. administration.