Cyclosporin effect on rat aorta alpha(1)-adrenoceptors and their transduction mechanisms.

A possible explanation for cyclosporin-induced arterial hypertension may be its action on the adrenergic system. In spite of the controversial results reported in literature, it seems that cyclosporin changes the vascular response to noradrenaline. Therefore, after observation that two cyclosporin doses increase rat blood pressure and vascular reactivity in response to noradrenaline, the aim of this work was to study the cellular mechanisms beside the cyclosporin-induced changes in response to noradrenaline. Therefore, the cyclosporin influence on alpha(1)-adrenoceptors as well as on their transduction mechanism in smooth muscle cells was studied. Through Scatchard analysis of specific [(3)H]-prazosin binding, the alpha(1)-adrenoceptor number and related affinity were studied, before and after cyclosporin exposure. The cyclosporin influence on alpha1-adrenoceptor transduction mechanisms was also evaluated by the quantification of intracellular free calcium contents [Ca2+]i and inositol phosphate (InsP) turnover. All in vitro experiments were performed in rat aortic smooth muscle cells in culture. Results showed that both cyclosporin concentrations (10(-6) and 10(-7) M) changed alpha1-adrenoceptor number but only 10(-7) M cyclosporin increased its affinity for [(3)H]-prazosin. Compared with control cells, only 10(-7) M cyclosporin increased InsP levels. Stimulation by noradrenaline increased InsP in 10(-7) M cyclosporin-treated cells but decreased InsP in the presence of 10(-6) M cyclosporin. Both cyclosporin concentrations increased [Ca2+]i in basal conditions and after noradrenaline stimulation. The results suggest that after noradrenaline stimulation cyclosporin increases [Ca2+]i, probably through different mechanisms, depending on the cyclosporin concentration used. However, 10(-7) M cyclosporin increases alpha1-adrenoceptor affinity and their related transduction mechanisms. The higher cyclosporin concentration (10(-6) M) seems to induce downregulation of alpha1-adrenoceptors, probably by activation of protein kinase C.