Stein CM, He H, Pincus T, Wood AJJ
Cyclosporine impairs vasodilatation without increased sympathetic activity in humans

Hypertension (Oct) 26:705-710 1995

Two potential mechanisms for cyclosporine induced hypertension include enhanced sympathetic tone (Scherrer et al, NEJM 323:693, 1990) and enhanced vasoconstriction. Here 12 patients with rheumatoid arthritis receiving cyclosporine were studied, once on and once off the drug. Venodilatation was assessed using a dorsal hand vein method, measuring changes in vein diameter in response to infusion of vasoconstricting or vasodilating agents. Cyclosporine had no effect on the constricting effect of phenylephrine. Venodilation in response to isoproterenol and PGE-1 was markedly impaired when the patients were on cyclosporine, whereas the dilatory response to nitroglycerine was similar. Interestingly, response to isoproterenol was still impaired in 5 patients (who had received cyclosporine for 6-12 months) after being off the drug for 1 month. This points to a potential prolonged effect of cyclosporine on the vasculature. Sympathetic activity was measured by the spillover technique. Tritiated NEPI is infused and the venous blood is analyzed for rate of norepinephrine release into plasma. Cyclosporine had no effect on NEPI spillover.

Comment: The Scherrer study measured sympathetic activation directly, by peroneal nerve microneurography. Thus this paper does not negate the Scherrer data (in cardiac transplant recipients) that cyclosporine may induce sympathetic activation. However, the data suggesting a "direct" vascular effect are interesting.Daugirdas

Additional comments by J.G. Umans: Mechanisms for the frequent and difficult to control hypertension which often occurs in patients receiving cyclosporine A remains obscure. Species differences and limited ability to extrapolate from many in vitro models have limited mechanistic insights. This study suggests some defect in vasodilation following cyclosporine, but provides little mechanistic insight as to how vasodilation may be impaired. Indeed, we learn neither the cells nor mediators which might be involved. As well, one must be circumspect in extrapolating from the reactivity of a small subset of capacitance vessels to those small arterial vessels which may contribute to systemic resistance or to the renal regulation of blood pressure. This in vivo human study provides yet another insight to our still-limited understanding of this particular drug-induced blood pressure disorder. (Umans)

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