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

¹Department of Pharmacology, Jichi Medical School, Tochigi, Japan; and ²Department of Pediatrics, University of Rochester School of Medicine, Rochester, New York

Submitted 25 January 2006 ; accepted in final form 10 May 2006

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 -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 ET_B receptor antagonist BQ-788, as well as the NO synthase inhibitor, N^G-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 ET_A receptor 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 ET_B receptor regulates the adaptation of the CCD to metabolic acidosis and that the NO guanylate cyclase component of ET_B receptor signaling mediates downregulation of Cl^–/HCO₃^– exchange and HCO₃^– secretion.

tubule microperfusion; endothelin receptor antagonist; nitric oxide synthase inhibitor; cyclic GMP; cyclic GMP-dependent protein kinase