Vasopressin receptor renal actions

Vasopressin and desmopressin are used in the treatment of central diabetes insipidus. They are discussed in Chapter 37. Their renal action appears to be mediated primarily via V2 receptors although Vla receptors may also be involved. 

Conivaptan hydrochloride (1) represents the first FDA-approved agent for the treatment of hyponatremia to modulate electrolyte-free water reabsorption in the renal collecting ducts by antagonizing the action of AVP on vasopressin receptors. As such, 1 represents a novel approach toward the treatment of hyponatremia that could significantly affect the pharmacotherapy of a range of diseases characterized by abnormal water retention. 

Due to the dual renal and vascular action of AVP, scientists at Yamanouchi Pharmaceuticals became interested in the identification of dual Vla/V2 vasopressin receptor antagonists, particularly because such agents were anticipated to be of unique utility in the treatment of congestive heart failure (CHF), where aberrant AVP secretion appeared responsible for both the onset of hypervolemic hyponatremia and deleterious increases in vascular resistance.14 The resulting drug discovery program ultimately lead to the identification of conivaptan HCl (1). 

RENAL ACTIONS OF VASOPRESSIN Several actions of vasopressin in the kidney involve both Vj and receptors. Vj receptors mediate contraction of mesangial cells in the glomerulus and vascular smooth muscle cells in the vasa recta and efferent arteriole. Indeed, Vj-receptor-mediated reduction of inner medullary blood flow contributes to the maximum concentrating capacity of the kidney (Figure 29-4). Vj receptors also stimulate prostaglandin synthesis by... 

Desmopressin f/V-deamino-8-D-arginine vasopressin, dDAVP) is a longer acting analogue of vasopressin. It has very little vasoactive effect but is antidiuretic by an action on vasopressin V2 receptors in the renal tubule and is used to treat central diabetes insipidus and nocturnal enuresis. 

Desmopressin has little vasoconstrictor effect but has potent antidiuretic action, through renal vasopressin V2 receptors, and at high doses hemostatic properties, by increasing concentrations of factor VIII and von Willebrand factor in the blood. 

Reduction of portal pressure. Vasopressin (anti-duiretic hormone, see p. 711), in addition to its action on the renal collecting ducts (through receptors), constricts smooth muscle (Vj receptors) in the cardiovascular system (hence its name), and particularly in splanchnic blood vessels, so reducing blood flow in the portal venous system. Unfortunately, coronary vasoconstriction can also occur, and treatment has to be withdrawn from 20% of patients because of myocardial ischaemia. Glyceryl trinitrate (transdermally, sublingually, or intravenously) reduces the cardiac risk and, advantageously, further reduces portal venous resistance and pressure. 

Arginine vasopressin (AVP) is a potent vasoconstrictor that preferentially reduces renal medullary blood flow through the stimulation of the vasopressin Via receptor (VlaR). Studies have also shown that the vasopressin V2 receptor (V2R) may modulate AVP-mediated vasoconstriction. The transcriptional and translational sites of the VlaR and V2R in micro-dissected intrarenal vascular segments from both the cortex and medulla was studied [154]. The results indicate that VlaR mRNA and proteins are present in the isolated cortical or medullary vasculature, but the V2R mRNA and proteins were not found. This study suggests that the vasoconstrictor action of AVP within the renal medulla is mediated through the VlaR and that the modulatory V2R- mediated vasodilation is probably through the release of paracrine hormones found within the renal interstitial or tubular cells. 

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