EFFECTS OF ENDOTHELIN RECEPTOR ANTAGONIST ON CYCLOSPORINE-INDUCED VASOCONSTRICTION IN ISOLATED RAT RENAL ARTERIOLES

Recent evidence suggests that the potent constrictor peptide, endothel in (ET) has a mediating role in cyclosporine A (CsA)-related renal vas oconstriction. However, the nature of the CsA-ET interaction and effec t on the renal vasculature is uncertain. The purpose of the present st udy was twofold: (a) to determine if CsA exposure caused direct local release of ET from the endothelium of the renal microvasculature and ( b) to determine if locally generated ET has paracrine effects on the u nderlying vascular smooth muscle to induce vasoconstriction. Experimen ts were performed in isolated rat renal arterioles. First it was deter mined that both afferent arteriole (AA) and efferent arteriole (EA) ex hibited concentration-dependent decreases in lumen diameter to increas ing molar concentrations of CsA. The AA was more sensitive to the vaso constrictive effects of CsA than the EA. Next, the blocking effect of a recently synthesized putative ET(A) receptor antagonist was verified in both the AA and EA, where it was found that the cyclic peptide cyc lo D-Asp-L-Pro-D-Val-L-Leu-D-Trp totally inhibited the vasoconstrictio n observed with ET addition. Finally, the role of locally stimulated E T in CsA-induced vasoconstriction was tested by determining the effect of the ET(A) receptor antagonist on CsA-induced AA and EA constrictio n. In the AA the vasoconstrictor effect of 10(-11) M CsA was completel y blocked by the ETA receptor antagonist. However, in contrast to AA, 10(-11) M CsA in EA in the presence of the ET(A) receptor antagonist d ecreased EA lumen diameter by a mean of 41% from baseline (4.80+/-0.75 mum vs 7.80+/-0.84 mum, P < 0.05). This change in lumen diameter was similar to that induced by CsA alone. These data suggest that CsA dire ctly constricts renal microvessels. This effect is mediated by ET in t he AA but not the EA.