SEQUENTIAL AGONIST ACTIVATION AND SITE-SPECIFIC MEDIATION OF ACUTE CYCLOSPORINE CONSTRICTION IN RAT RENAL ARTERIOLES

Evidence suggests that acute and chronic cyclosporine (CsA) nephropath y may be related to its renal vasoconstrictor effects. While the mecha nism of CsA-induced renal vasoconstriction is uncertain, several studi es indicate that endogenous constrictor agonists including endothelins (ET), platelet activating factor (PAF), and thromboxane A(2) (TXA(2)) play a mediating role. In this study, two possible mechanisms explain ing the participation of multiple constrictor agonists in CsA vasocons triction were investigated: sequential activation of agonists initiate d by CsA and site-specific mediation of CsA constriction by different agonists. The acute constrictor effects of CsA were examined in isolat ed rat renal afferent (AA) and efferent arterioles (EA) without and wi th specific receptor antagonists of ET(A) (BQ123, 10(-7) M), PAF (L-65 9,989, 10(-7) M), and TXA(2)/PGH(2) (SQ29,548, 10(-7) M) in the bathin g media. Both BQ123 and L-659,989 completely inhibited CsA, constricti on in AA, but had no significant inhibiting effect in EA. Constriction to ET-1 was also blocked by the PAF antagonist L-659,989 in AA, but n ot EA. There was no effect of SQ29,548 on CsA constriction in AA-howev er, there was partial attenuation of CsA constriction in EA Based on t hese results in isolated rat renal arterioles, it is suggested that Cs A-induced constriction in AA is likely mediated by sequential activati on of ET and PAF. However, CsA constriction of EA involves a different mechanism or mediator that, in part, may involve TXA(2)/PGH(2) stimul ation.