Triple signal transduction model for the mechanism of PGE 2 actions in rabbit cortical collecting duct

Abstract

As the final segment of the nephron, the collecting duct is the ultimate regulator of renal salt and water excretion. Balance between intake and renal excretion of salt and water is fine-tuned by the action of several hormones targeted to the collecting duct. Vasopressin is, perhaps, the prototypical example of such a hormone. As total body water decreases and plasma osmolality rises, vasopressin secretion from the posterior pituitary increases (1). Picomolar concentrations of circulating vasopressin lead to increased water permeability of the apical collecting duct cell resulting in increased water reabsorption and increased total body water (2, 3). There is abundant evidence demonstrating vasopressin’s effects on water reabsorption in the collecting duct are mediated through the classic second messanger, CAMP (3). V2 selective receptors are linked via a G protein, to stimulation of plasma membrane adenylyl cyclase, resulting in increased cell cyclic AMP levels (4, 5). The increased cyclic AMP then leads to augmented water permeability of the apical membrane. (6, 7). As one might expect with such an important biologic process, other hormones and autocoids provide a counter-regulatory influence to modulate vasopressin mediated increases in osmotic water permeability. There is good evidence that the arachidonate acid metabolite PGEz plays a critical physiologic and pathophysiologic role in inhibiting vasopressin action in the collecting duct (8, 9). Not only is the collecting duct the major renal site of synthesis for this cyclooxygenase product of arachidonic acid but PGE2 production is stimulated by vasopressin itself (10, 11, 12). PGE:! infusion significantly blunts vasopressin induced water reabsorption and cyclooxygenase inhibition augments vasopressin antidiuresis (9, 13). Thus, there is good evidence that the autocoid PGE;, plays an important role in regulating vasopressin stimulated osmotic water flow.