Beneficial effects of dantrolene on lipopolysaccharide-induced haemodynamic alterations in rats and mortality in mice.
We investigated the effect of dantrolene, an inhibitor of Ca2+ release from the sarcoplasmic reticulum, on the induction of nitric oxide (NO) synthase II by bacterial endotoxin (lipopolysaccharide) in the anaesthetised rat and on survival in a murine model of severe endotoxaemia. Injection of lipopolysaccharide (i) induced biphasic changes of rectal temperature and blood glucose: an initial increased phase (< 180 min after injection of lipopolysaccharide) followed by a decreased phase (at 240-360 min), (ii) caused a fall in mean arterial blood pressure from 115 +/- 3 mmHg (time 0) to 83 +/- 6 mmHg at 360 min, (iii) resulted in a substantial hyporeactivity to noradrenaline (1 microg/kg i.v.), (iv) raised plasma nitrate (an indicator of NO formation) in a time-dependent manner, (v) elicited a significant increase in NO synthase II activity in the lung and (vi) caused a 80% lethality (in mice). Pretreatment of animals with dantrolene not only attenuated the delayed circulatory failure, but also prevented the overproduction of NO and the induction of NO synthase II caused by lipopolysaccharide in the rat, and improved survival in a murine model of severe endotoxaemia. Thus, dantrolene has beneficial haemodynamic effects in animals with endotoxin shock. We propose that a decrease of free cytosolic Ca2+ levels plays an important role in the prevention of NO synthase II induction.
Wu
C C
CC
Department of Pharmacology, National Defense Medical Centre, Taipei, Taiwan.
Yen
M H
MH
D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D003620:Dantrolene / Q000494:pharmacology*; D006439:Hemodynamics / Q000187:drug effects*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000187:drug effects; D051381:Rats; D011921:Rats, Inbred WKY
D001786:Blood Glucose; D008070:Lipopolysaccharides; D009566:Nitrates; D019001:Nitric Oxide Synthase; D003620:Dantrolene; D002118:Calcium