Protective effects of nicotinamide against nitric oxide-mediated delayed vascular failure in endotoxic shock: potential involvement of polyADP ribosyl synthetase.
Nitric oxide (NO) produced by the inducible isoform of nitric oxide synthase contributes to the hypotension and vascular hyporeactivity in shock. Nicotinamide is protective against the cytotoxic effects of exogenous and endogenous NO in vitro. We investigated the effect of nicotinamide on the cellular energetic and vascular failure in a rat model of endotoxin shock. Administration of nicotinamide to rats, starting at 1 h bacterial lipopolysaccharide, maintained higher blood pressure levels, without affecting induction of nitric oxide synthase. Nicotinamide treatment prevented the lipopolysaccharide-induced decrease in mitochondrial respiration and intracellular NAD+ levels in peritoneal macrophages and improved the contractility of the thoracic aorta ex vivo. Thus, nicotinamide protects against the delayed, NO-mediated vascular failure in endotoxic shock. Its actions are unrelated to inhibition of NO biosynthesis but may be related to inhibition of the NO-mediated activation of an energy-consuming DNA repair cycle triggered by polyADP ribose synthetase.
Zingarelli
B
B
Children's Hospital Medical Center, Division of Critical Care, Cincinnati, Ohio 45229, USA.
Salzman
A L
AL
Szabó
C
C
D036002:ADP Ribose Transferases / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004734:Energy Metabolism / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D009536:Niacinamide / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012772:Shock, Septic / Q000188:drug therapy* / Q000473:pathology; D014655:Vascular Resistance / Q000187:drug effects
D008070:Lipopolysaccharides; D009243:NAD; D009536:Niacinamide; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D036002:ADP Ribose Transferases; D009638:Norepinephrine