CYCLOSPORINE-A INCREASES NITRIC-OXIDE ACTIVITY IN-VIVO

The use of cyclosporine is complicated by its vasoconstrictive actions . In vitro cyclosporine has been associated with both decreased endoth elium-dependent vasodilatation and increased nitric oxide activity. We studied the interaction between cyclosporine and endothelium-derived nitric oxide in seven healthy volunteers. Using venous-occlusion pleth ysmography, we measured forearm blood flow during intra-arterial infus ion of serotonin, which in the concentrations used is a selective agon ist of endothelial nitric oxide release, or N-G-monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase, during coinfusion of s aline or cyclosporine (75 mu g/min), respectively.During coinfusion of cyclosporine, forearm blood flow increased on maximal serotonin infus ion from 2.9 (SE, 0.2) to 8.1 (0.9) mL/100 mL per minute in forearm ti ssue, which was significantly higher than the increase during saline c oinfusion (3.0 [0.3] to 6.0 [0.5]; P<.05). Cyclosporine infusion durin g a ''free'' nitric oxide system had no effect on basal forearm blood how, but it significantly decreased forearm blood flow (21.7 [2.8]%; P <.05) during fixed nitric oxide activity. These data suggest that acut e administration of cyclosporine enhances both basal and receptor-stim ulated nitric oxide activity. The mechanism is not clear but may inclu de cyclosporine-induced shear stress as well as direct effects of cycl osporine. The latter was supported by our observation that gene expres sion of the enzyme nitric oxide synthase III was enhanced by approxima tely 50% after coincubation with cyclosporine. In conclusion, the pres ent observation demonstrates that nitric oxide constitutes an importan t regulating mechanism that protects against cyclosporine-associated v asoconstriction in vivo.