ROLE OF PROTEIN-KINASE-C IN ANGIOTENSIN-II-INDUCED RENAL VASOCONSTRICTION IN GENETICALLY HYPERTENSIVE RATS

The renal vasculature of young spontaneously hypertensive rats (SHR) r esponds to angiotensin II (ANG II) with exaggerated vasoconstriction, due in part to defective buffering by the adenosine 3',5'-cyclic monop hosphate (cAMP) pathway. In vitro studies suggest greater activation o f phospholipase C and protein kinase C (PKC) in cultured mesangial cel ls and vascular smooth muscle cells. The present studies evaluated the role of PKC activation in renal vascular responses to ANG II receptor activation and the relative contributions in SHR vs. Wistar-Kyoto con trol rats (WKY). Renal blood flow was measured in 8-wk-old anesthetize d SHR and WKY pretreated with indomethacin. ANG II (2 ng) injection in to the renal artery produced a transient 45-50% maximum reduction of r enal blood flow in both rat strains. Intrarenal infusion of either sta urosporine or chelerythrine into the renal artery effectively attenuat ed the vasoconstriction elicited by ANG II in a dose-dependent manner, with maximum inhibition of 60-70%. The PKC inhibitory effects were si gnificant and independent of strain. Coadministration of the PKC inhib itors produced maximal inhibition similar to that observed with one ag ent, suggesting action via a common pathway. In other studies, the lin kage of the PKC pathway to the AT(1) receptor was evaluated using sub and maximal doses of losartan to antagonize 50-80% of ANG II-induced v asoconstriction. The same degree of inhibition was observed when a PKC inhibitor was coadministered with losartan. These findings support th e views that the PKC system is a major intracellular signaling pathway coupled to the AT(1) receptor in renal resistance vessels and that PK C activation is involved to similar degrees in the renal vasoconstrict ion elicited by ANG II in young WKY and SHR. Exaggerated vascular reac tivity to vasoconstrictor agents in genetically hypertensive animals i s probably due to a defect in cAMP generation in the presence of a nor mally operating PKC pathway.