Nitric oxide supports atrial function in sepsis: relevance to side effects of inhibitors in shock.
The mechanisms underlying myocardial dysfunction in sepsis remain poorly understood. The theoretical benefits of nitric oxide synthase (NOS) inhibition in reversing the haemodynamic changes that characterise septic shock have not been supported by clinical trials, some of which have demonstrated detrimental myocardial effects. We have therefore assessed the effects of endotoxaemia on NOS enzyme expression as well as a number of functional responses of myocardial tissue from rats. Atrial tissue expressed high levels of mRNA for inducible (i) NOS and released increased levels of nitrite after animals were treated with endotoxin. In parallel, the inotropic response stimulated by isoprenaline was reduced in atria from endotoxin-treated animals, an effect that was reversed when endogenous release of NO was maximised. Our results suggest that myocardial contractility is maintained by NO production and that inhibitors may compromise cardiac output; this may explain the deleterious effects of NOS inhibition on cardiac function in clinical trials.
Price
Susanna
S
Unit of Critical Care Medicine, Imperial College School of Medicine, National Heart and Lung Institute, Dovehouse Street, London, SW3 6LY, UK.
Evans
Timothy W
TW
Mitchell
Jane A
JA
D000818:Animals; D009320:Atrial Natriuretic Factor / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004558:Electric Stimulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology*; D006325:Heart Atria / Q000187:drug effects; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000473:pathology; D009569:Nitric Oxide / Q000378:metabolism / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; D009924:Organ Culture Techniques; D051381:Rats; D012477:Salmonella enteritidis / Q000737:chemistry; D018805:Sepsis / Q000473:pathology / Q000503:physiopathology*; D012772:Shock, Septic / Q000473:pathology / Q000503:physiopathology*; D019323:omega-N-Methylarginine / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D009320:Atrial Natriuretic Factor; D007770:L-Lactate Dehydrogenase; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496318:Nos2 protein, rat; C496316:Nos3 protein, rat