CONTRIBUTION OF ENDOTHELIN RECEPTORS IN RENAL MICROVESSELS IN ACUTE CYCLOSPORINE-MEDIATED VASOCONSTRICTION IN RATS

Cyclosporine A (CsA), a widely used immunosuppressive agent, causes re nal vasoconstriction and systemic hypertension. Recent data suggest th at the renal ef:ect of CsA is possibly mediated by endothelin (ET). We investigated the effects of CsA on renal microvessels and the efficac y of ETA or ETA/ETB receptor antagonists in ameliorating CsA effects i n the hydronephrotic rat kidney. Infusion of CsA (30 mg . kg(-1)) indu ced a transient increase (20%) in mean arterial pressure (MAP) and a s ustained reduction (85%) in glomerular blood flow (GBF) due to prefere ntial constriction of the arcuate artery (39%) and the proximal segmen t of the interlobular artery (23%). Under basal conditions the ETA rec eptor antagonist BQ-123 had marginal effects consisting of reduction i n MAP, rise in GBF and dilation of preglomerular vessels. The Iron-sel ective ETA/ETB receptor antagonist PD 145065 also reduced MAP, but ten ded to decrease GBF and constrict large preglomerular vessels. The dif ference in effects of the two antagonists indicated that under basal c onditions ETB blockade constricts large preglomerular vessels and redu ces GBF. After BQ-123 or PD 145065,:he constriction of large preglomer ular vessels and reduction in GBF induced by CsA was attenuated by abo ut 50%: but the rise in MAP was not influenced. Our data indicate that a sizable parr of renal vasoconstriction due to CsA is mediated via E T production in large preglomerular arteries and can be avoided by the blockade of ETA receptors. Additional blockade of ETB receptors does not attenuate the CsA effects further, possibly because ETB receptors mediate both vasoconstriction and dilation.