MINERALOCORTICOID REGULATION OF ION CONDUCTIVE PATHWAYS OF THE CORTICAL COLLECTING DUCT

Mineralocorticoids (DOCA) are known to increase Na(\u27+) absorption and K(\u27+) secretion in the rabbit cortical collecting duct (CCD). However, the mechanism of regulation of the apical and basolateral cell membranes and tight junction ion conductive pathways (G(\u27a), G(\u27b), and G(\u27tj), respectively) by mineralocorticoids are only partially understood. Using electrophysiological techniques and microelectrodes it was demonstrated that the apical cell membrane contained a dominant Ba(\u272+) sensitive K(\u27+) conductive pathway, G(,K)(\u27a), and an amiloride sensitive Na(\u27+) conductive pathway, G(,Na)(\u27a). The basolateral membrane contained a dominant Cl(\u27-) conductive pathway, G(,Cl)(\u27b), and a significant Ba(\u272+) sensitive K(\u27+) conductive pathway, G(,K)(\u27b). Upon elevating the mineralocorticoid levels of rabbits with intact adrenal glands it was found that V(\u27te) was significantly increased after 1 day with a further increase after 13-16 days. These results indicated both primary and secondary effects of mineralocorticoid elevation. After 1 day of DOCA treatment, G(,Na)(\u27a), I(,Na)(\u27a) and I(,K)(\u27a) increased by more than 2-fold and were maintained at high levels after 13-16 days of DOCA treatment. Secondary (chronic) effects of mineralocorticoids were evident after 4 days or more of DOCA treatment. These included a significant increase in G(,K)(\u27a) from 4.0 to 10.2 mS.cm(\u27-2) and a hyperpolarization of V(\u27b) by -20 mV after 4 days of treatment. After 13-16 days of DOCA treatment V(\u27b) remained hyperpolarized at -98.1 mV and G(\u27tj) decreased from 5.6 to 4.2 mS.cm(\u27-2). The hyperpolarization of V(\u27b) was due to an increase in electrogenic Na(\u27+) pump activity as the pump current, I(,act)(\u27b), increased significantly from 35.7 to 195.2 (mu)A.cm(\u27-2). Whereas net passive K(\u27+) current across the basolateral membrane, I(,K)(\u27b), was near zero in the control group of animals, i.e., K(\u27+) near equilibrium, I(,K)(\u27b) was approximately -40 (mu)A.cm(\u27-2) in chronic DOCA treated animals. These results demonstrate that the initial effect of mineralocorticoid elevation is to increase G(,Na)(\u27a). The ensuing depolarization of the apical membrane increases the driving force for K(\u27+) exit into the lumen. Between 1 and 4 days of elevation, G(,K)(\u27a) more than doubles in magnitude and at the same time the electrogenic activity of the Na(\u27+) pump increases. This results in a hyperpolarization of V(\u27b) which increases the driving force for K(\u27+) uptake from the bath to the cell through a basolateral membrane conductive pathway. After 13-16 days G(\u27tj) decreases thereby serving to maintain high electrochemical gradients across the epithelium. Therefore, the long term effects of mineralocorticoid elevation on the CCD appear to be adaptive mechanisms that serve to maintain high levels of K(\u27+) secretion and Na(\u27+) absorption.