Vol. 299, Issue 1, 372-376, October 2001

Differential Effects of U46619 on Renal Regional Hemodynamics in the Rat: Involvement of Endothelin

Hercule Hantz, Ajayi Adesuyi and Oyekan Adebayo

Center for Cardiovascular Diseases, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas

Many vasoactive agents produce qualitatively similar effects on blood flow in the renal cortex and medulla, evoking reductions or increases in blood flow in both regions. We demonstrated previously that endothelin-1 (ET-1) is an exception because it evoked an increase in medullary perfusion despite a potent cortical vasoconstriction (Hercule and Oyekan, 2000). We report here that U46619 (11,9 epoxymethano-prostaglandin H₂), a selective agonist of prostaglandin H₂ (PGH₂)/thromboxane A₂ (TxA₂) (TP) receptor, evokes similar effects as ET-1. In the pentobarbital-anesthetized (60 mg/kg) rat, 1, 3, and 5 µg/kg U46619 dose dependently reduced mean arterial blood pressure by 2 ± 4, 8 ± 10, and 31 ± 10 mm Hg, respectively; renal cortical blood flow (CBF) by 50 ± 11, 174 ± 45, and 349 ± 43 perfusion units (PU), respectively; but increased medullary blood flow (MBF) by 42 ± 16, 51 ± 18, and 61 ± 21 PU, respectively. Prostaglandin F₂, a TxA₂ mimetic, produced similar effects as U46619. SQ29548 ([1S-[1,2(Z), 3,4]]-7-[3[[2-[(phenylamino)carbonyl[hydrazino] methyl]-7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid) (0.1 mg/kg), an antagonist of PGH₂/TxA₂ (TP), blunted U46619-induced hemodynamic changes without affecting that produced by phenylephrine. BMS182874 [5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyd)-1-naphthalene sulfonamide] (40 mg/kg), an ET_A-selective antagonist, blunted U46619-induced reduction in CBF by 54 ± 9% (p < 0.05) and the increase in MBF by 59 ± 18% (p < 0.05). Similarly, BQ788 (N-cis 2,6-dimethylpiperidinocarbonyl-L--methylleucyl-D-1-methoxycarbonyltryptophanyl-D-norleucine) (1 mg/kg), an ET_B-selective antagonist, blunted the effects of U46619 on CBF and MBF by 19 ± 3% (p < 0.05) and 48 ± 19% (p < 0.05), respectively. Combined administration of BMS182874 and BQ788 further attenuated U46619-induced reduction in CBF by 67 ± 8% (p < 0.05) and that on MBF by 61 ± 18% (p < 0.05). Phosphoramidon (10 mg/kg), an endothelin converting enzyme inhibitor, markedly blunted U46619-induced changes on CBF and MBF (p < 0.05). These findings are the first to demonstrate that U46619, through activation of ET_A and ET_B receptors, elicits renal cortical vasoconstriction and medullary vasodilation in the rat.