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 a role in the pathophysiology of septic shock. The depression of cardiac contractility in such situations is mediated by proinflammatory cytokines, including interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha). The effects of two NOS inhibitors with different isoform selectivity were compared in isolated working rat hearts. The depression of contractility by IL-1beta and TNF-alpha 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-1beta and TNF-alpha, it depressed contractility over the 2h perfusion period by significantly reducing coronary flow. These results support current thinking that the depression of myocardial function by IL-1beta and TNF-alpha 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.
Suzuki
Norihito
N
Department of Anesthesiology, Nippon Medical School, Tokyo, Japan. norihito@nms.ac.jp
Sakamoto
Atsuhiro
A
Ogawa
Ryo
R
D000818:Animals; D002172:Canavanine / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects*; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D008297:Male; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017207:Rats, Sprague-Dawley; D012772:Shock, Septic / Q000503:physiopathology*
D002172:Canavanine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D019331:NG-Nitroarginine Methyl Ester