Effect of direct injection of cyclosporine on the arterial vessels of the isolated hind limb in the dog.

: Cyclosporine's toxic side effects are widely recognized as a cause of major morbidity. Peripheral vasoconstriction has been suggested as the pathophysiological mechanism for hypertension and renal failure caused by cyclosporine. To study vascular effects on peripheral arterial circulation, cyclosporine was injected into isolated hind limbs perfused at constant flow in the dog. Pure powder cyclosporine was dissolved in a 10% fat emulsion and infused directly into the arterial inflow of the perfused hind limb (n = 7) at a concentration of 5 mg/kg body weight. Reactivity of the vascular bed was first shown by an average decrease of 72 +/- 4 mmHg (95% confidence interval 63 to 81, P less than 0.01) in hind limb perfusion pressure after infusion of 5 mg nitroglycerin. Infusion of fat emulsion did not cause any significant changes. The infusion of cyclosporine caused an average increase of 29 +/- 5 mmHg (95% confidence interval 17 to 41, P less than 0.01) in hind limb perfusion pressure after 4 mins' infusion. After cyclosporine infusion, the vascular bed still responded to nitroglycerin by an average decrease of 56 +/- 5 mmHg (95% confidence interval 42 to 69, P less than 0.01) in perfusion pressure. Blockade of alpha-receptors with phentolamine in five dogs and ipsilateral lumbar sympathectomy in four prevented the increase in perfusion pressure following cyclosporine injection. In conclusion, cyclosporine injected at high doses causes a small vasoconstriction of the peripheral arterial circulation in the hind limb through stimulation of alpha-adrenergic receptors mediated by the sympathetic nervous system. Since the response is completely abolished by sympathectomy, it is probably caused by reflex activation. A direct effect of cyclosporine on the arterial vessel walls of the limb can therefore be excluded.