Vol. 281, Issue 1, 62-69, 1997

Dexmedetomidine Inhibits Osmotic Water Permeability in the Rat Cortical Collecting Duct¹

Alexander J. Rouch, Lúcia H. Kudo² and Connie Hébert

Oklahoma State University College of Osteopathic Medicine, Tulsa, Oklahoma (A.J.R., C.H.), and Department of Medicine, University of Sao Paulo, Sao Paulo, Brazil (L.H.K.)

The purpose of this study was to determine whether the selective alpha-2 agonist dexmedetomidine inhibits basic transport properties in the rat cortical collecting duct (CCD). Sprague-Dawley rat CCDs were isolated and perfused to allow measurement of osmotic water permeability (P_f), transepithelial voltage (V_t) and resistance (R_t). Arginine vasopressin (AVP) increases P_f, hyperpolarizes V_t and decreases R_t in the CCD via stimulation of adenylyl cyclase. Dexmedetomidine at 100 nM added to the basolateral side of the CCD reduced AVP-stimulated P_f by 95% to 100%, and the alpha-2 antagonist atipamezole reversed the inhibition. In the presence of the protein kinase C inhibitor staurosporine, dexmedetomidine reduced AVP-stimulated P_f by 70% to 75% compared with the complete inhibition without staurosporine. When P_f was increased by the use of the nonhydrolyzable analog of cAMP, 8-chlorophenylthio-cAMP, in lieu of AVP, dexmedetomidine inhibited P_f by ~35%. This demonstrated alpha-2-mediated inhibition of P_f despite the presence of constant cellular cAMP levels. Dexmedetomidine reversed AVP-induced effects on V_t and R_t, indicating inhibition of Na⁺ transport. Results confirm an alpha-2-mediated mechanism that reduces Na⁺ and water transport in the CCD and suggest that a cellular messenger other than cAMP is involved. This messenger could be protein kinase C.