Dexmedetomidine inhibits osmotic water permeability in the rat cortical collecting duct

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.