The protective effects of a new, selective, plant-derived
platelet-activating factor (PAF) antagonist,
yangambin, on the cardiovascular alterations and mortality due to endotoxic
shock were investigated in anaesthetized rats. We also studied the involvement of PAF in the induction of the vascular and cardiac hyporesponsiveness to
adrenergic stimulation observed during endotoxaemia. The animals were sensitized to the lethal effects of Escherichia coli
lipopolysaccharide (LPS) with D(+)-
galactosamine (50 mg/kg, i.v.) 15 min before LPS injection. LPS (3 mg/kg, i.v.) induced a progressive and marked 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 that cardiovascular collapse resulted mainly from myocardial depression. The maximum pressor responses to
noradrenaline (0.3-3.0 microg/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 with
WEB 2086 (5 mg/kg, i.v.), a reference PAF receptor antagonist, completely prevented the LPS-induced cardiovascular collapse and abolished the sharp reductions of the arterial blood pressure and CO responses to
noradrenaline observed during endotoxaemia. Post-treatment with
yangambin 90 min after LPS administration did not reverse the arterial
hypotension,
cardiac failure or cardiovascular hyporesponsiveness to
catecholamines. Finally, the acute (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 long-term (7-day) survival also increased from 0% (LPS group) to 85% (
yangambin pre-treatment group). In conclusion, these data suggest a role for PAF in the pathogenesis of
endotoxin-induced vascular and cardiac hyporesponsiveness to
catecholamines and confirm its involvement in the complex cascade of multiple mediators released during endotoxic/
septic shock.
Yangambin proved to be an effective pharmacological agent against cardiovascular collapse and mortality in
endotoxin shock.