Induction of contraction in isolated rat aorta by cyclosporine

Cyclosporine (CsA) is a new immunosuppressive agent that has adverse effects of nephrotoxicity and de novo appearance of hypertension. It has been hypothesized that the mechanism of the contrary effects is through an action of CsA on vascular smooth muscle. To test this hypothesis, thoracic aortas were isolated from Wistar Kyoto rats and ring segments prepared for measurement of tension. CsA (5 X 10(-6) M) induced a slow increase in tone of the isolated rings with a response at 3 hr of 0.70 +/- 0.17 N/m2 X 10(4). This contraction was significantly inhibited by the Ca2+ channel blocker verapamil (0.30 +/- 0.08 N/m2 X 10(4) after 3 hr, P less than 0.05) and by the noncompetitive alpha-antagonist phenoxybenzamine (0.06 +/- 0.07 N/m2 X 10(4) after 3 hr, P less than 0.05). The competitive alpha-antagonist phentolamine had mixed effects. CsA does not irreversibly alter vascular smooth muscle contractile ability since a 3 hr exposure to the agent had no effect on either the maximal contractile response or sensitivity to KCl. We conclude that CsA can directly induce contraction in vascular smooth muscle, perhaps by inducing a release of norepinephrine from adrenergic nerve terminals. The data are consistent with the hypothesis that CsA induces nephrotoxicity and de novo hypertension through a contractile effect on vascular smooth muscle.