ROLE OF THROMBOXANE AND ANGIOTENSIN IN CYCLOSPORINE-INDUCED RENAL VASOCONSTRICTION IN THE DOG

Cyclosporine is associated with renal insufficiency characterized by a reduction in glomerular filtration rate that may result from renal va soconstriction. Injection of cyclosporine in the isolated renal artery perfused at a constant flow induces a potent dose-dependent vasoconst riction of renal arterial vessels in the dog. The present study was de signed to investigate the role of thromboxane A2, angiotensin, and end othelial-dependent vasodilation in the cyclosporine-induced renal vaso constriction. A specific thromboxane A2-receptor antagonist (pinane-th romboxane A2), administered at a dose of 150 mug, significantly decrea sed the renal vasoconstriction response to cyclosporine from 103 +/- 2 6 min Hg to 45 +/- 11 mm Hg (p < 0.05), with cyclosporine serum levels at the end of injection averaging 382 +/- 105 and 421 +/- 150 nmol/L before and after injection of the antagonist. In contrast, pharmacolog ic blockade of angiotensin receptors by saralasin had no effect on the cyclosporine arterial vasoconstriction in the kidney. The endothelium -dependent vasodilation to acetylcholine was not modified during cyclo sporine injection. Thus cyclosporine renal vasoconstriction appears in dependent of the renin-angiotensin system and of endothelium-dependent vasodilation. It is at least partly mediated by thromboxane A2. Preve ntion of cyclosporine vasoconstriction by thromboxane A2-receptor anta gonist may likely be possible, with more potent agents having more aff inity to thromboxane A2 renal receptors.