The involvement of central cholinergic system in the pressor effect of intracerebroventricularly injected U-46619, a thromboxane A2 analog, in conscious normotensive rats

The aim of this study was to determine the involvement of the central cholinergic system in the rise in blood pressure evoked by the thromboxane A2 (TxA2) analog, U-46619, given centrally. Intracerebroventricular (i.c.v.) injections of U-46619 (0.5, 1.0 and 2.0 μg) caused dose- and time-related increases in blood pressure and decreased heart rate in awake rats. U-46619 (1 μg; i.c.v.) also produced an approximately 65% increase in posterior hypothalamic extracellular acetylcholine and choline levels. Pretreatment with SQ-29548 (8 μg; i.c.v.), selective TxA2 receptor antagonist, completely inhibited both the cardiovascular responses and the increase in acetylcholine and choline levels to subsequent injection of U-46619 (1 μg; i.c.v.). Atropine (10 μg; i.c.v.), nonselective muscarinic receptor antagonist, pretreatment did not affect the cardiovascular responses observed after U-46619 (1 μg; i.c.v.). Pretreatment with the nonselective nicotinic receptor antagonist, mecamylamine (50 μg; i.c.v.) attenuated the pressor effect of U-46619 (1 μg; i.c.v.). Higher doses of mecamylamine (75 and 100 μg; i.c.v.) pretreatments did not change the magnitude of the blockade of pressor response to U-46619; however, they abolished the bradycardic effect of U-46619 dose-dependently. Interestingly, pretreatment of rats with methyllycaconitine (10 μg; i.c.v.) or α-bungarotoxin (10 μg; i.c.v.), selective antagonists of α7 subtype of nicotinic acetylcholine receptors (α7nAChRs), partially abolished the pressor response to i.c.v. injection of U-46619 (1 μg). Similar to the mecamylamine data, the use of higher doses of methyllycaconitine (25 and 50 μg; i.c.v.) produced the same magnitude of blockade that was observed after the 10 μg methyllycaconitine pretreatment, but it completely abolished the bradycardic effect of U-46619 (1 μg; i.c.v.) at the dose of 25 μg. The present results show that central administration of U-46619 produces pressor and bradycardic effect and increase in hypothalamic acetylcholine and choline levels by activating central TxA2 receptors. The activation of central nicotinic receptors, predominantly α7nAChRs, partially mediates the cardiovascular responses to i.c.v. injection of U-46619.