Endothelin and nitric oxide mediate adaptation of the cortical collecting duct to metabolic acidosis.
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 HCO(3)(-) secretory fluxes and to raise the pH of beta-intercalated cells. Acid incubation caused reversal of polarity of net HCO(3)(-) transport from secretion to absorption, comprised of a 40% increase in H(+) secretion and a 75% decrease in HCO(3)(-) 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 HCO(3)(-) 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(-)/HCO(3)(-) exchanger. The guanylate cyclase inhibitor LY-83583 and cGMP-dependent protein kinase inhibitor KT-5823 affected HCO(3)(-) 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(-)/HCO(3)(-) exchange and HCO(3)(-) secretion.
Tsuruoka
Shuichi
S
Department of Pharmacology, Jichi Medical School, Tochigi, Japan.
Watanabe
Seiji
S
Purkerson
Jeffrey M
JM
Fujimura
Akio
A
Schwartz
George J
GJ
D000064:Acclimatization; D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D001639:Bicarbonates / Q000378:metabolism; D001692:Biological Transport; D016764:Cell Polarity / Q000187:drug effects / Q000502:physiology; D002712:Chlorides / Q000494:pharmacology; D004195:Disease Models, Animal; D016232:Endothelins / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007685:Kidney Tubules, Collecting / Q000187:drug effects / Q000502:physiology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011817:Rabbits
D001639:Bicarbonates; D002712:Chlorides; D016232:Endothelins; D009842:Oligopeptides; D010880:Piperidines; D009569:Nitric Oxide; C086539:BQ 788; D019331:NG-Nitroarginine Methyl Ester