Cyclosporin A increases nitric oxide activity in vivo.
The use of cyclosporine is complicated by its vaso-constrictive actions. In vitro cyclosporine has been associated with both decreased endothelium-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 plethysmography, we measured forearm blood flow during intra-arterial infusion of serotonin, which in the concentrations used is a selective agonist of endothelial nitric oxide release, or NG-monomethyl-L-arginine, a specific inhibitor of nitric oxide synthase, during coinfusion of saline or cyclosporine (75 micrograms/min), respectively. During coinfusion of cyclosporine, forearm blood flow increased on maximal serotonin infusion from 2.9 (SE, 0.2) to 8.1 (0.9) mL/100 mL per minute in forearm tissue, which was significantly higher than the increase during saline coinfusion (3.0[0.3] to 6.0 [0.5]; P < .05). Cyclosporine infusion during a "free" nitric oxide system had no effect on basal forearm blood flow, but in significantly decreased forearm blood flow (21.7[2.8]%; P < .05) during fixed nitric oxide activity. These data suggest that acute administration of cyclosporine enhances both basal and receptor-stimulated nitric oxide activity. The mechanism is not clear but may include cyclosporine-induced shear stress as well as direct effects of cyclosporine. The latter was supported by our observation that gene expression of the enzyme nitric oxide synthase III was enhanced by approximately 50% after coincubation with cyclosporine. In conclusion, the present observation demonstrates that nitric oxide constitutes an important regulating mechanism that protects against cyclosporine-associated vasoconstriction in vivo.
Stroes
E S
ES
Department of Nephrology, University Hospital Utrecht, Netherlands.
Lüscher
T F
TF
de Groot
F G
FG
Koomans
H A
HA
Rabelink
T J
TJ
D000328:Adult; D002478:Cells, Cultured; D016572:Cyclosporine / Q000494:pharmacology*; D019332:Endothelin-1 / Q000378:metabolism; D004727:Endothelium / Q000187:drug effects; D005542:Forearm / Q000098:blood supply / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000187:drug effects / Q000235:genetics; D009599:Nitroprusside / Q000494:pharmacology; D012333:RNA, Messenger / Q000032:analysis; D012701:Serotonin / Q000494:pharmacology; D019323:omega-N-Methylarginine / Q000494:pharmacology
D019332:Endothelin-1; D012333:RNA, Messenger; D009599:Nitroprusside; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D012701:Serotonin; D016572:Cyclosporine; D019001:Nitric Oxide Synthase