Endothelin and nitric oxide mediate adaptation of the cortical collecting duct to metabolic acidosis

Abstract

Endothelin (ET) and nitric oxide (NO) modulate ion transport in the kidney. In this study, we defined the function of ET receptor subtypes and the NO guanylate cyclase signaling pathway in mediating the adaptation of the rabbit cortical collecting duct (CCD) to metabolic acidosis. CCDs were perfused in vitro and incubated for 3 h at pH 6.8, and bicarbonate transport or cell pH was measured before and after acid incubation. Luminal chloride was reversibly removed to isolate H+and HCO3−secretory fluxes and to raise the pH of β-intercalated cells. Acid incubation caused reversal of polarity of net HCO3−transport from secretion to absorption, comprised of a 40% increase in H+secretion and a 75% decrease in HCO3−secretion. The ETBreceptor antagonist BQ-788, as well as the NO synthase inhibitor, NG-nitro-l-arginine methyl ester (l-NAME), attenuated the adaptive decrease in HCO3−secretion by 40%, but only BQ-788 inhibited the adaptive increase in H+secretion. There was no effect of inactive d-NAME or the ETAreceptor antagonist BQ-123. Both BQ-788 and l-NAME inhibited the acid-induced inactivation (endocytosis) of the apical Cl−/HCO3−exchanger. The guanylate cyclase inhibitor LY-83583 and cGMP-dependent protein kinase inhibitor KT-5823 affected HCO3−transport similarly to l-NAME. These data indicate that signaling via the ETBreceptor regulates the adaptation of the CCD to metabolic acidosis and that the NO guanylate cyclase component of ETBreceptor signaling mediates downregulation of Cl−/HCO3−exchange and HCO3−secretion.