INTERACTIONS OF CAMP-MEDIATED VASODILATORS WITH ANGIOTENSIN-II IN RAT-KIDNEY DURING HYPERTENSION

In previous studies [C. Chatziantoniou and W. J. Arendshorst. Arm J. P hysiol. 263 (Renal Fluid Electrolyte Physiol. 32): F573-F580, 1992], w e reported that vasodilator prostaglandins (PGs) are defective in buff ering the angiotensin II (ANG II)-induced vasoconstriction in the rena l vasculature of spontaneously hypertensive rats (SHR). The purpose of the present study was to determine whether this defect in SHR kidneys is specific to PGs or generalized to the action of vasodilators and t o pin insight into which intracellular signal(s) mediates this abnorma lity. Renal blood flow (RBF; electromagnetic flowmetry) was measured i n 7 wk-old anesthetized, euvolemic SHR and normotensive Wistar-Kyoto ( WKY) rats pretreated with indomethacin to avoid interactions with endo genous PGs. ANG II (2 ng) was injected into the renal artery before an d during continuous intrarenal infusion of fenoldopam [DA1 receptor ag onist and G protein-dependent stimulator of adenosine 3',5'-cyclic mon ophosphate (cAMP)], forskolin (G protein-independent stimulator of cAM P), dibutyryl-cAMP (soluble cAMP), and acetylcholine (cGMP stimulator) . Each vasodilator was infused at a low dose that did not affect basel ine arterial pressure or RBF. In the control period, ANG H reduced RBF by 50% in both strains. Infusion of fenoldopam significantly blunted the ANG II-induced vasoconstriction in WKY, but not in SHR. In contras t, forskolin, dibutyryl-cAMP, and acetylcholine effectively buffered t he vasoconstriction due to ANG II in both SHR and WKY. These results s uggest that renal vasodilators acting through receptor binding to stim ulate the cAMP signaling pathway are ineffective in counteracting the ANG II-induced vasoconstriction in SHR kidneys. The cause of this abno rmality may be related to a defective coupling of the receptors of the se vasodilators to G proteins and could play an important role in the development of hypertension.