Potentiation of the natriuretic effect of clonidine following indomethacin in the rat.
Previous studies have demonstrated a diuretic effect of clonidine at low intrarenal infusion rates with a natriuretic effect being observed at high infusion rates (greater than or equal to 3 micrograms.kg-1.min-1). The natriuresis at high infusion rates may have been secondary to increased renal prostaglandin production. We therefore evaluated the effects of indomethacin (a cyclooxygenase inhibitor) on the response to clonidine in the anesthetized rat. Intrarenal infusions of saline (vehicle) or clonidine (0.1, 0.3, 1, and 3 micrograms.kg-1.min-1) were examined both in the presence and absence of pretreatment with indomethacin (5 mg/kg, i.p.). Clonidine produced a dose-related increase in urine volume and free water clearance at 0.3, 1, and 3 micrograms.kg-1.min-1 as compared with the vehicle group. Sodium excretion and osmolar excretion were increased only at the highest infusion rate investigated. Following indomethacin pretreatment, clonidine produced a greater increase in urine volume at each infusion rate investigated. The indomethacin pretreatment also resulted in a potentiation of the natriuretic effect of clonidine at all infusion rates. Interestingly, this was associated with an increase in osmolar clearance but not free water clearance. These effects of indomethacin were reversed by infusion of prostaglandin E2. An infusion of prostaglandin E2 attenuated the indomethacin-induced increase in both urine flow rate and sodium excretion, indicating that the effects of indomethacin were mediated by prostaglandin inhibition. These results suggest that endogenous prostaglandin production attenuates the renal effects of clonidine, and as well, that in the presence of alpha 2-adrenoceptor stimulation, prostaglandin E2 mediates an antidiuretic and antinatriuretic effect.
Blandford
D E
DE
Department of Pharmacology, University of Manitoba, Winnipeg, Canada.
Smyth
D D
DD
D000818:Animals; D003000:Clonidine / Q000008:administration & dosage / Q000494:pharmacology*; D015232:Dinoprostone / Q000008:administration & dosage; D004357:Drug Synergism; D007213:Indomethacin / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D009318:Natriuresis; D011188:Potassium / Q000652:urine; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000652:urine
D012964:Sodium; D015232:Dinoprostone; D003000:Clonidine; D011188:Potassium; D007213:Indomethacin