EFFECTS OF ANG-II, ET(A), AND TXA(2) RECEPTOR ANTAGONISTS ON CYCLOSPORINE-A RENAL VASOCONSTRICTION

The renin-angiotensin system, endothelin (ET), and vasoconstrictor pro staglandins have been reported in separate studies to mediate the rena l vasoconstrictor effect of cyclosporin A (CsA). However, direct compa rison of the relative importance of these potential mediators has not been performed. In this study, the attenuating effects of comparable a gonist-inhibiting doses of receptor antagonists for angiotensin II (AN G II), DuP-753 at 2.5 mg/kg, for ET(A), BQ-123 at 0.5 mg/kg, and for t hromboxane A(2) (TxA(2)), SQ-29,548 at 1.6 mg.kg(-1).h(-1), or saline vehicle on acute CsA (20 mg/kg) renal vasoconstriction were compared i n anesthetized Sprague-Dawley rats. All three receptor antagonists sig nificantly limited the CsA-induced increase in renal vascular resistan ce; however, BQ-123 and SQ-29,548 were more effective than DuP-753. Be cause all three receptor antagonists demonstrated at least some attenu ation of CsA-induced renal vasoconstriction, the potential role of acu te CsA-related nitric oxide synthase (NOS) inhibition and nonspecific heterologous effects of specific receptor antagonists on other agonist s were determined to exclude the possibilities that there was a genera l increased agonist sensitivity and that detection of a single or prim ary constrictor mediator was obscured by ''crossover'' receptor antago nist effects. CsA significantly reduced renal blood flow (39%) in the presence of the NOS inhibitor, N-omega-nitro-L-arginine methyl ester, and there was negligible indication that receptor antagonists had nons pecific effects. It is concluded that CsA-induced renal vasoconstricti on is complex and involves activation of multiple constrictor agonists independently or sequentially.