Protective effects of yangambin on cardiovascular hyporeactivity to catecholamines in rats with endotoxin-induced shock

The protective effects of a new, selective, plant-derived platelet-activati ng factor (PAF) antagonist, yangambin, on the cardiovascular alterations an d mortality due to endotoxic shock were investigated in anaesthetized rats. We also studied the involvement of PAF in the induction of the vascular an d cardiac hyporesponsiveness to adrenergic stimulation observed during endo toxaemia. The animals were sensitized to the lethal effects of Escherichia coli lipopolysaccharide (LPS) with D(+)-galactosamine (50 mg/kg, i.v.) 15 m in before LPS injection. LPS (3 mg/kg, i.v.) induced a progressive and mark ed decrease in mean arterial blood pressure from 85+/-4 to 30+/-3 mmHg and a reduction of cardiac output (CO) from 180+/-7 to 37+/-3 ml/min (120 min) accompanied by a maintenance of systemic vascular resistance, suggesting th at cardiovascular collapse resulted mainly from myocardial depression. The maximum presser responses to noradrenaline (0.3-3.0 mug/kg, i.v.) fell from 72+/-9 (control) to 5+/-1 mmHg (LPS) while the CO responses decreased from 81+/-5 to 8+/-3 ml/min. Pre-treatment with yangambin (30 mg/kg, i.v.) or w ith WEB 2086 (5 mg/kg, i.v.), a reference PAF receptor antagonist, complete ly prevented the LPS-induced cardiovascular collapse and abolished the shar p reductions of the arterial blood pressure and CO responses to noradrenali ne observed during endotoxaemia. Post-treatment with yangambin 90 min after LPS administration did not reverse the arterial hypotension, cardiac failu re or cardiovascular hyporesponsiveness to catecholamines. Finally, the acu te (150 min) survival rates of endotoxic shock increased from 0% (LPS group ) to 100% in the groups pretreated with either yangambin or WEB 2086. The l ong-term (7-day) survival also increased from 0% (LPS group) to 85% (yangam bin pre-treatment group). In conclusion, these data suggest a role for PAF in the pathogenesis of endotoxin-induced vascular and cardiac hyporesponsiv eness to catecholamines and confirm its involvement in the complex cascade of multiple mediators released during endotoxic/septic shock. Yangambin pro ved to be an effective pharmacological agent against cardiovascular collaps e and mortality in endotoxin shock.