Effect of L-canavanine, an Inhibitor of Inducible Nitric Oxide Synthase, on Myocardial Dysfunction During Septic Shock.

Overproduction of nitric oxide(NO)by inducible NO synthase(iNOS)plays ar ole in the pathophysiology of septic shock. The depression of cardiac contractilit yi n such situations is mediated by proinflammatory cytokines including interleukin‑1β(IL‑1β) and tumor necrosis factor‑α(TNF‑α) . The effects of two NOS inhibitors with different isoform selectivity were compared in isolated working rat hearts. The depression of contractility by IL‑1β and TNF‑α was prevented by administration of a nonselective nitric oxide synthase inhibitor N G ‑nitro‑L‑ arginine methyl ester (L‑NAME) or an inhibitor of inducible nitric oxide synthase L‑canavanine. In contrast when L‑NAME was administered in the absence of IL‑1β and TNF‑α it depressed contractility over the 2h perfusion period by significantly reducing coronary flow. These results support current thinking that the depression of myocardial funct ion by IL‑1β and TNF‑α is mediated at least in part by an intracardiac increase in inducible nitric oxide synthase and that in contrast to L‑NAME the decline in coronary conductance seen in cytokine‑treated is not prevented by L‑canavanine hearts. L‑canavanine shows selective inhibition of inducible nitric oxide synthase unlike the vasopressor action of L‑NAME in cytokine‑treated hearts. (J Nippon Med Sch 2002; 69: 13―18)