DOSE-DEPENDENT EFFECT OF CYCLOSPORINE ON RENAL ARTERIAL RESISTANCE IN DOGS

Important side effects of cyclosporin (CSA) are renal insufficiency and hypertension. They might be related to a renal vasoconstrictive effect of CSA, and this vascular response might be due to a local mechanism. CSA was injected in isolated renal artery perfused at constant flow in dogs. Changes in renal perfusion pressure reflected variations in vascular resistance. Pure CSA was dissolved in autologous blood and injected at doses of 0.5, 1, 5, and 10 mg. The infusion of 0.5 and 1 mg caused averaged renal perfusion pressure increases of 8 +/- 4 mmHg and 15 +/- 8 mmHg. Renal venous CSA levels averaged 32 +/- 3 and 49 +/- 9 nmol/l, respectively, at the end of injections. Infusion of 5 and 10 mg of CSA caused averaged renal perfusion pressure increases of 32 +/- 12 mmHg and 81 +/- 21 mmHg. Renal venous CSA levels at the end of injections averaged 142 +/- 30 and 382 +/- 82 nmol/l, respectively. A positive correlation was found between the changes in renal perfusion pressure and renal venous CSA levels. Blockade of alpha-adrenergic receptors, surgical renal sympathectomy, administration of thromboxane receptor antagonist, and endothelial-dependent vasodilation by acetylcholine infusion did not affect the renal vasoconstriction effect of CSA; renal response to CSA was prevented by blockade of the Ca channels with diltiazem, and the plasma endothelin concentration in renal venous blood increased significantly after injection of CSA. A dose-dependent increase in renal arterial resistance occurs with therapeutic blood levels of CSA. Renal vasoconstriction is induced by a local effect at the arterial wall, which is independent of neurogenic, adrenergic, and prostaglandin mechanisms. However, the response appears to be at least partly mediated by endothelin release in the renal vessels and is prevented remarkably by Ca channel blockade.