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.