Cyclosporine A and control of vascular tone in the human forearm

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Abstract
The use of cyclosporine A after organ transplantation is associated with a high incidence of hypertension, but the underlying mechanisms for this process are not clear. We investigated the effects of blockade of basal release of endothelial nitric oxide and the effects of endothelium-independent and -dependent vasodilators and vasoconstrictors in patients treated with cyclosporine A after heart transplantation. We measured blood pressure and forearm blood flow responses to brachial artery infusions of NG-monomethyl-L-arginine (L-NMMA), sodium nitroprusside, acetylcholine, norepinephrine and vasodilating and vasoconstricting doses of endothelin-1 in eight patients early (< 3 months) and in 11 patients late (> 18 months) after transplantation. Diastolic blood pressure was higher late after transplantation, but calculated forearm vascular resistance was lower (P < 0.01). Thus, increased forearm vascular resistance does not contribute to the increase in blood pressure. The vasoconstrictor response to L-NMMA was similar in both groups but a reduced endothelium-dependent vasodilator response to acetylcholine was seen late after transplantation. However, impaired smooth muscle responsiveness to nitric oxide may have contributed to this finding, since the response to sodium nitroprusside tended to be reduced. Vasoconstrictor responses to norepinephrine and endothelin-1 were comparable but no vasodilation was seen with low doses of endothelin-1 late compared with early after transplantation (P < 0.05). The findings in the forearm circulation question the concept of generalized increases in vasoconstrictor responses or a disturbance of tonic, basal release nitric oxide in the pathogenesis of cyclosporine-A-induced hypertension. Although the forearm vasodilator responses to the stimulation of endothelial nitric oxide production and release by acetylcholine, and to low doses of endothelin-1, were impaired, these findings could be explained by the increase in blood pressure rather than cyclosporine A itself.