Differential effects of U46619 on renal regional hemodynamics in the rat: involvement of endothelin.

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 microg/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 F2alpha, a TxA2 mimetic, produced similar effects as U46619. SQ29548 ([1S-[1alpha,2alpha(Z), 3alpha,4alpha]]-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-gamma-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.