Vol. 281, Issue 1, 48-53, 1997

Alpha-2a/d Adrenoceptor Subtype Stimulation by Guanfacine Increases Osmolar Clearance¹

H. D. Intengan² and D. D. Smyth³

Departments of Pharmacology and Therapeutics (H.D.I., D.D.S.) and Internal Medicine (D.D.S.), University of Manitoba, Winnipeg, Manitoba, Canada R3E 0W3

We have previously demonstrated that the osmolar and free water responses to an intrarenal infusion of clonidine could be dissociated pharmacologically into naltrexone-sensitive and prazosin-sensitive responses, respectively. These results supported the notion that two distinct alpha-2 adrenoceptor sites were mediating the effects of clonidine. The ability of prazosin to selectively block the increase in free water clearance suggested the involvement of the alpha-2b subtype. Based on the identification by others of only the alpha-2a/d and alpha-2b subtypes in the rat kidney, the osmolar response was, by deduction only, speculated but not proven to involve the alpha-2a/d subtype. To provide evidence that the alpha-2a/d subtype mediated osmolar clearance, we investigated the effects of intrarenal infusion of the selective alpha-2a/d adrenoceptor agonist guanfacine. Studies were conducted in anesthetized Sprague-Dawley rats that were unilaterally nephrectomized 7 to 10 days before the experiment. The infusion of guanfacine (3.0 nmol/kg/min) into the remaining renal artery increased urine flow without altering blood pressure or creatinine clearance. The increase in urine flow was associated with an increase in osmolar clearance but no increase in free water clearance. The effects of the alpha-2a/d adrenoceptor selective antagonist, RX-821002, on the renal actions of guanfacine were determined. RX-821002 (3.0 mg/kg) attenuated the ability of guanfacine to increase urine flow rate and osmolar clearance. Similarly to the increase in osmolar clearance observed with clonidine, the guanfacine-induced increase in osmolar clearance was attenuated by naltrexone (3.0 mg/kg) and unaltered by prazosin (0.15 mg/kg) pretreatment (i.e., naltrexone-sensitive and prazosin-insensitive). These results were consistent with the alpha-2a/d adrenoceptor subtype in the rat kidney which mediated an increase in osmolar clearance. A physiological function of this alpha-2a/d adrenoceptor subtype may therefore involve regulation of solute/sodium excretion.