Pharmacological profile of the inhibition by dihydroergotamine and methysergide on the cardioaccelerator sympathetic outflow in pithed rats

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Abstract

The present study set out to analyse the pharmacological profile of the inhibitory responses induced by the antimigraine agents dihydroergotamine (DHE) and methysergide on the tachycardic responses to preganglionic sympathetic stimulation in pithed rats. For this purpose, 132 male Wistar normotensive rats were pithed and prepared to: (i) selectively stimulate the preganglionic (C7–T1) cardiac sympathetic outflow; or (ii) receive intravenous (i.v.) bolus injections of exogenous noradrenaline. Electrical sympathetic stimulation or exogenous noradrenaline produced, respectively, frequency-dependent and dose-dependent tachycardic responses. Moreover, i.v. continuous infusions of DHE (1.8, 3.1 and 5.6 μg/kg.min) or methysergide (100, 300 and 1000 μg/kg.min) dose-dependently inhibited the tachycardic responses to sympathetic stimulation, but not those to exogenous noradrenaline. Using physiological saline or antagonists (given as i.v. bolus injections), the cardiac sympatho-inhibition induced by either DHE (3.1 μg/kg.min) or methysergide (300 μg/kg.min) was: (1) unaffected by saline (1 ml/kg); (2) partially blocked by the antagonists rauwolscine (300 μg/kg; α2) or N-[4-methoxy-3-(4-methyl-1-piperazinyl) phenyl]-2'-methyl-4'-(5-methyl-1,2,4-oxadiazol-3-yl) [1,1,-biphenyl]-4-carboxamide hydrochloride monohydrate (GR127935, 300 μg/kg; 5-HT1B/1D); and (3) completely antagonised by the combination rauwolscine plus GR127935. These antagonists, at doses high enough to completely block their respective receptors, failed to modify the sympathetically-induced tachycardic responses per se. The above results, taken together, suggest that the cardiac sympatho-inhibition induced by DHE (3.1 μg/kg.min) and methysergide (300 μg/kg.min) may be mainly mediated by stimulation of both α2-adrenoceptors and 5-HT1B/1D receptors.

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