Activation of the central cholinergic system mediates the reversal of hypotension by centrally administrated U-46619, a thromboxane A2 analog, in hemorrhaged rats

Abstract

In the present study, we investigated the role of the central cholinergic system in mediating the pressor effect of intracerebroventricularly administrated U-46619, a thromboxane A2 (TxA2) analog, in hemorrhaged hypotensive rats. Hemorrhage was performed by withdrawing a total volume of 2.1 ml of blood per 100 g body weight over a period of 10 min. Intracerebroventricular (i.c.v.) injection of U-46619 (0.5, 1, 2 μg) produced a dose- and time-dependent increase in arterial pressure and reversed the hypotension of this condition. Hemorrhage caused small increases in extracellular hypothalamic acetylcholine and choline levels. Intracerebroventricular administration of U-46619 (1 μg) further increased the levels of extracellular acetylcholine and choline by 57% and 41%, respectively. Pretreatment with SQ-29548 (8 μg; i.c.v.), a selective TxA2 receptor antagonist, completely abrogated the effects of subsequent injection of U-46619 (1 μg; i.c.v.) on arterial pressure and extracellular acetylcholine and choline levels. Pretreatment with mecamylamine (50 μg; i.c.v.), a cholinergic nonselective nicotinic receptor antagonist, attenuated the pressor effect of U-46619 (1 μg, i.c.v.) in hemorrhaged rats whereas pretreatment with atropine (10 μg; i.c.v.), a cholinergic nonselective muscarinic receptor antagonist, had no effect. Interestingly, pretreatment of rats with methyllycaconitine (10 μg; i.c.v.) or α-bungarotoxin (10 μg; i.c.v.), selective antagonists of α-7 subtype nicotinic acetylcholine receptors (α7nAChRs), partially abolished the pressor effect of U-46619 (1 μg; i.c.v.) in the hypotensive condition. Pretreatment with a combination of mecamylamine plus methyllycaconitine or mecamylamine plus α-bungarotoxin attenuated the reversal effect of U-46619, but only to the same extent as pretreatment with either antagonist alone. In conclusion, i.c.v. administration of U-46619 restores arterial pressure and increases posterior hypothalamic acetylcholine and choline levels by activating central TxA2 receptors in hemorrhaged hypotensive rats. The activation of central nicotinic cholinergic receptors, predominantly α7nAChRs, partially acts as a mediator in the pressor responses to i.c.v. injection of U-46619 under these conditions.