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Collecting duct-specific knockout of the endothelin A receptor alters renal vasopressin responsiveness, but not sodium excretion or blood pressure

¹Division of Nephrology, University of Utah Health Sciences Center, Salt Lake City; ³Salt Lake Veterans Affairs Medical Center, Salt Lake City, Utah; and ²Howard Hughes Medical Institute, University of Texas Southwestern, Dallas, Texas

Submitted 11 March 2005 ; accepted in final form 24 May 2005

Collecting duct (CD)-specific knockout (KO) of endothelin-1 (ET-1) causes hypertension, impaired ability to excrete a Na load, and enhanced CD sensitivity to the hydrosmotic effects of vasopressin (AVP). CD express the two known ET receptors, ET_A and ET_B; in the current study, the role of the CD ET_A receptor in mediating ET-1 actions on this nephron segment was evaluated. The ET_A receptor gene was selectively disrupted in CD (CD ET_A KO). CD ET_A KO mice had no differences in systemic blood pressure, Na or K excretion, and plasma aldosterone or renin activity in response to a normal- or a high-Na diet compared with controls. During normal water intake, urinary osmolality (Uosm), plasma Na concentration, and plasma osmolality were not affected, but plasma AVP concentration was increased in CD ET_A KO animals (0.57 ± 0.25 pg/ml in controls and 1.30 ± 0.29 pg/ml in CD ET_A KO mice). CD ET_A KO mice had a modestly enhanced ability to excrete an acute, but not a chronic, water load. DDAVP infusion increased Uosm similarly; however, CD ET_A KO mice had a more rapid subsequent fall in Uosm during sustained DDAVP administration. CD suspensions from CD ET_A KO mice had a 30–40% reduction in AVP- and forskolin-stimulated cAMP accumulation. These data indicate that CD ET_A KO decreases renal sensitivity to the urinary concentrating effects of AVP and suggest that activation of the ET_A receptor downregulates ET-1 inhibition of AVP actions in the CD. Furthermore, the CD ET_A receptor does not appear to be involved in modulation of systemic blood pressure or renal Na excretion under physiological conditions.

tubule; adenosine 3', 5'-cyclic monophosphate; inner medullary collecting duct

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