BENEFICIAL-EFFECTS OF DANTROLENE ON LIPOPOLYSACCHARIDE-INDUCED HEMODYNAMIC-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 anaes thetised rat and on survival in a murine model of severe endotoxaemia. Injection of lipopolysaccharide (i) induced biphasic changes of recta l 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 f rom 115 +/- 3 mmHg (time 0) to 83 +/- 6 mmHg at 360 min, (iii) resulte d in a substantial hyporeactivity to noradrenaline (1 mu g/kg i.v.), ( iv) raised plasma nitrate (an indicator of NO formation) in a time-dep endent manner, (v) elicited a significant increase in NO synthase II a ctivity in the lung and (vi) caused a 80% lethality (in mice). Pretrea tment of animals with dantrolene not only attenuated the delayed circu latory failure, but also prevented the overproduction of NO and the in duction of NO synthase II caused by lipopolysaccharide in the rat, and improved survival in a murine model of severe endotoxaemia. Thus, dan trolene 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.