Lewis B. Kinter

Water balance in the Brattleboro rat: considerations for hormone replacement therapy.

Brattleboro strain rats homozygous for diabetes insipidus (DI rats) lack detectable arginine vasopressin (AVP, antidiuretic hormone) and drink and excrete enormous quantities of water, as compared to vasopressin-replete Brattleboro heterozygotes (HZ) and Long-Evans (LE) strain controls (FIGURE 1) . Discovered in 1961, DI rats have become an increasingly popular experimental model of vasopressin insufficiency.l This chapter will summarize the mechanisms that permit net water balance to be achieved in both the presence and absence of antidiuretic hormone (ADH) , and describe the “water state” of the DI rat. Antidiuretic hormone replacement in DI rats will be discussed briefly in terms of integration of exogenously administered hormone with endogenous feedback-controlled mechanisms.

Flushing and haemodynamic responses to vasopressin peptides in the rhesus monkey

1 The mechanism of the flushing, hypotension and tachycardia associated with i.v. administration of desGlyd(CH2)5D‐Tyr(Et)VAVP (SK&F 101926; 25 μg kg−1) and the selective V2 antidiuretic agonist, desamino‐8‐D‐arginine vasopressin (dDAVP; 3 μg kg−1) was studied in ketamine‐anaesthetized rhesus monkeys. 2 The flushing associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer and by repeated administration of peptide (within 2–4 weeks). A similar desensitization to dDAVP‐associated flushing was observed on repeated administration. 3 Treatment with dDAVP also resulted in reduced SK&F 101926‐associated flushing. 4 The hypotension associated with SK&F 101926 was not affected by pretreatment with a mast cell stabilizer. A similar degree of hypotension was observed with repeated administration of either SK&F 101926 or dDAVP. 5 The tachycardia associated with SK&F 101926 was reduced by pretreatment with a mast cell stabilizer or repeated administration of SK&F 101926. Repeated administration of dDAVP, however, resulted in an enhanced tachycardia. 6 Indomethacin (5 mg kg−1 i.v.) did not alter the flushing or the hypotension associated with the administration of either SK&F 101926 or dDAVP, but resulted in an enhanced tachycardia to SK&F 101926. 7 Administration of a selective V1 vasopressor antagonist did not result in flushing, hypotension or tachycardia. 8 It was concluded that the flushing response to vasopressin‐like peptides in rhesus monkeys may be due to an action on mast cells, whereas the haemodynamic responses are not, but probably involve direct vasodilator actions.

Pharmacological characterization of vasopressin aggregation response of human platelets

Vasopressin has been reported to induce aggregation of human and dog platelets but not those of rabbit or pig (11. Vasopressin is generally recognized to have two distinct receptor subtypes associated with its respective vasoconstrictor (VII and antidiuretic (Vtl activities. In previous studies which used both platelet aggregation and binding studies in platelet membranes to characterize the vasopressin subtype pharmacologically, several groups have concluded it is of the V, subtype (2,3,5 and 61 while one group concluded the receptor subtype was Vf (41.

Chapter 10. Vasopressin Antagonists

Publisher Summary This chapter discusses the rationale for a therapeutic interest in vasopressin antagonists and describes the current status of animal models for the discovery of antagonists. The chapter describes the structural features present in antagonists. The identification of receptor-selective antagonists has furthered the characterization of the physiological and pathophysiological roles of vasopressin. Although vasopressin has been implicated in many biological processes, its principal physiological action is the regulation of body fluid tonicity and volume. The anti-diuretic or V 2 receptor is located on the basolateral membranes of renal collecting duct epithelia and is coupled to adenylate cyclase via stimulatory guanine nucleotide regulatory proteins. A second receptor subtype, the vasopressor or V 1 receptor, is located in the vasculature and liver and was recently identified in the adenohypophysis, the brain hippocampus, and seminal vesicles of mammals. V 1 receptors mediate the activation of phosphatidylinositol bisphosphate hydrolysis that, via the formation of inositol 1,4,5-trisphosphate, causes an increase in free cytosolic calcium. If the clinically observed agonism is the result of intrinsic agonist activity, the problem would be simplified if was possible to use the extensive structure–activity relationships (SAR) for V 2 receptor agonists to predict the residual intrinsic activity in antagonists. However, a number of reports have appeared that indicate that agonists and antagonists at the V 2 receptor have substantively different pharmacophores. The therapeutic utility of V 1 and V 1 /OT receptor antagonists has been evaluated in clinical studies. The therapeutic utility of V 2 receptor antagonists has not been tested because the only V 2 antagonist to be evaluated in man to date exhibited agonist activity.

The Vasopressin Antagonist SK&F 101926 is a Selective Aquaretic Agent in Dogs

The vasopressin analog desGly9d(CH2)5 1D-Tyr(Et)2Val4AVP (SK&F 101926) has previously been reported to be a potent vasopressin antagonist and aquaretic agent in anesthetized and conscious rats and in squirrel monkeys (1,2,3). In these studies we report the effects of SK&F 101926 on cardiovascular and renal hemodynamics and renal solute and water excretion in conscious dogs. The results show that SK&F 101926 selectively increases water excretion in dogs. The mechanism of action is antagonism of vasopressin at renal V-2 receptors. At diuretic doses, SK&F 101926 has no significant effects on blood pressure, heart rate, renal plasma flow, or glomerular filtration rate in conscious dogs. However, at these doses, SK&F 101926 blocks the pressor and bradycardic responses to exogenous vasopressin.

Vasopressin Antagonists: Model Aquaretic Agents

Drs. Manning and Sawyer and their colleagues were the first to report vasopressin analogs having intrinsic vasopressin-antagonist activities in anesthetized rats (1–5). We have previously shown that these and other diuretic vasopressin analogs have high affinity for renal vasopressin binding sites, and specifically antagonize renomedullary vasopressin-stimulated adenylate cyclase (6). The structures of some represented antagonists are shown in Figure 1.