Cardiovascular effect of peripheral injected melittin in normotensive conscious rats: Mediation of the central cholinergic system

Recently we demonstrated that centrally administrated melittin, a phospholipase A2 (PLA2) activator, caused the pressor effect in normotensive, conscious rats. In the present study, we aimed to determine the cardiovascular effect of peripherally injected melittin and the involvement of the central cholinergic system on these effects in the normotensive conscious rats. For this reason, 250, 500 or 1000 μg/kg doses of melittin were injected intraperitoneally to normotensive male Sprague Dawley rats. Melittin produced dose- and time-dependent increases in mean arterial pressure (MAP) and heart rate (HR). Both peripheral (5 mg/kg; i.p.) and central (500 μg; i.c.v.) pretreatment with indomethacin, nonselective inhibitor of cyclooxygenase (COX) 1 and 2, totally abolished cardiovascular effect of melittin. Intraperitoneal (i.p.) pretreatment with propranolol, a nonselective β-adrenergic receptor blocker, completely abolished the tachycardic response to melittin. Also, the pressor effect of melittin was partially attenuated in these rats. In order to test the mediation of the central cholinergic system on the pressor and tachycardic effects of melittin, the rats were pretreated with atropine sulfate (10 μg; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, mecamylamine (50 μg; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, methyllycaconitine (10 μg; i.c.v.) or α-bungarotoxin (10 μg; i.c.v.), selective antagonists of α7 subtype nicotinic acetylcholine receptors (α7nAChRs) 15 min prior to melittin (500 μg/kg; i.p.) injection. Pretreatment with mecamylamine, methyllycaconitine or α-bungarotoxin partially diminished the pressor and tachycardic response to melittin in the normotensive conscious rats whereas pretreatment with atropine sulfate had no effect.In conclusion, our data demonstrate that peripherally administered melittin exerts a clear pressor and tachycardic effect by activating COX pathway. The activation of central cholinergic nicotinic receptors, predominantly α7nAChRs, appears to be involved in the pressor and tachycardic effects of the drug.