Pharmacological identification of α1- and α2-adrenoceptor subtypes involved in the vasopressor responses induced by ergotamine in pithed rats

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Abstract

Ergotamine has been used in clinical practice for the acute treatment of migraine for over 90 years. So far, it is known that ergotamine interacts with diverse receptors (including α1/2-adrenoceptors, 5-HT1, 5-HT2 and D2-like receptors) and that produces increases in mean blood pressure which are significantly blocked by yohimbine, a classical α2-adrenoceptor antagonist with a moderate affinity for α1-adrenoceptors. Since α1/2-adrenoceptors mediate vasopressor and vasoconstrictor responses in the cardiovascular system, this study was designed to identify the α-adrenoceptor subtypes (α1A, α1B, α1D, α2A, α2B and α2C) involved in ergotamine-induced vasopressor responses in pithed rats. In male Wistar pithed rats baseline heart rate and blood pressure were recorded. Then, the vasopressor responses to intravenous (i.v.) bolus injections of ergotamine were determined after administration of vehicle or several α1/2-adrenoceptor antagonists. I.v. administration of the antagonists prazosin (α1, 0.1–30 μg/kg), rauwolscine (α2, 0.3–300 μg/kg), prazosin (0.1 μg/kg) plus rauwolscine (0.3 μg/kg), 5-methylurapidil (α1A, 100 and 300 μg/kg), L-765,314 (α1B, 100 and 300 μg/kg), BMY 7378 (α1D, 100 and 300 μg/kg), BRL44408 (α2A, 300 and 1000 μg/kg) and JP-1302 (α2C, 300 μg/kg), significantly blocked the vasopressor responses to ergotamine, whereas imiloxan (α2B, 1000 and 3000 μg/kg), JP-1302 (100 μg/kg) or the corresponding vehicles (saline 0.9%, propylene glycol 20% or dimethyl sulfoxide 10%; 1 ml/kg) failed to modify the responses to ergotamine. The above results suggest that the vasopressor responses to ergotamine in pithed rats are mainly mediated by α1A-, α1B-, α1D-, α2A- and α2C-adrenoceptors and may explain its adverse/therapeutic effects.

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