Inhibition of Water Permeability in the Rat Collecting Duct: Effect of Imidazoline and Alpha-2 Compounds 2

Abstract

Abstract

Arginine vasopressin (AVP) increases water permeability in the collecting duct of the nephron via activation of adenylyl cyclase. Alpha-2 (α₂) agonists inhibit AVP-stimulated water permeability via binding to α₂ adrenoceptors that have been divided into 3 subtypes- α_2A, α_2B, and α_2C. Some biological effects mediated by α₂ agonists result from nonadrenergic imidazoline receptors that exist in the rat kidney. Thus, α₂-inhibition of AVP-stimulated water permeability in the rat collecting duct could be caused by imidazoline receptors. The purpose of this study was to test agonists and antagonists selective for α₂ and imidazoline receptors on AVP-stimulated water permeability in the rat inner medullary collecting duct (IMCD). Some experiments were conducted where water permeability was stimulated by a nonhydrolyzable analog of adenosine 3',5'-cyclic monophosphate (cAMP). Agonists included dexmedetomidine, clonidine, oxymetazoline, agmatine and rilmenidine. The latter two are selective imidazoline agonists. Antagonists included yohimbine, RX821002, atipamezole, prazosin, WB4101, idazoxan, and BU239. Prazosin and WB4101 demonstrate selectivity for the α_2B and α_2C subtypes, respectively, and oxymetazoline and RX821002 are selective for the α_2A subtype. BU239 is selective for imidazoline receptors. Wistar rat terminal IMCDs were isolated and perfused to determine the osmotic water permeability coefficient (P_f). All agonists except agmatine inhibited AVP-stimulated P_f. Inhibition by rilmenidine indicated a different mechanism of action from other agonists. Dose-response data show dexmedetomidine to be the most potent inhibitor. Oxymetazoline and clonidine inhibited cAMP-stimulated P_f indicating that the mechanism involves postcAMP cellular events. It was reported previously that dexmedetomidine inhibits cAMP-stimulated P_f (1). All antagonists except prazosin and WB4101 reversed α₂-inhibition of AVP-stimulated P_f. BU239 was effective at 1 μM but not at 100 nM. Results suggest that α_2A adrenoceptors modulate water permeability in the IMCD. The involvement of imidazoline receptors is inconclusive.