Type II nitric oxide synthase activity is cardio-protective in experimental sepsis.
Overproduction of nitric oxide (NO) via the induction of NO synthase (NOS) II is implicated in the pathogenesis of the refractory hypotension that characterizes septic shock. However, clinical trials of nonselective NOS inhibitors have failed to afford a mortality benefit in patients with sepsis, and in those with depressed left ventricular function, death rates were increased. Such observations have led to the suggestion that a selective inhibitor of NOSII would be more effective in treating septic shock, although precisely how NO modulates cardiac function in these circumstances remains unclear. We therefore used an isolated ejecting rodent heart model to study the effects of NO and experimental sepsis (endotoxin 20 mg kg i.p.) on cardiac functions. Coronary flow and cardiac output and ventricular functions were reduced by LPS, effects that were partially obviated by supplementation of perfusate with the NO substrate, L-arginine. These improvements were partially blocked by the selective NOSII inhibitor N-(3-(aminomethyl)benzyl)acetamidine (1400W) and further reduced by the combined NOSI, II and III inhibitor L-nitro L-arginine methyl ester (L-NAME). These findings suggest that NOSII is cardio-protective in the heart in sepsis and explain why its inhibition in man led to increased mortality in a subpopulation of patients.
Price
Suzanna
S
Unit of Critical Care Medicine, Imperial College School of Medicine, Royal Brompton Hospital, Dovehouse Street, London SW3 6LY, UK.
Mitchell
Jane A
JA
Anning
Peter B
PB
Evans
Timothy W
TW
D000578:Amidines / Q000494:pharmacology; D000818:Animals; D001596:Benzylamines / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000503:physiopathology*; D006334:Heart Function Tests; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009206:Myocardium / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D017208:Rats, Wistar; D018805:Sepsis / Q000201:enzymology / Q000503:physiopathology
D000578:Amidines; D001596:Benzylamines; D002316:Cardiotonic Agents; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; C104820:N-(3-(aminomethyl)benzyl)acetamidine; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D019331:NG-Nitroarginine Methyl Ester