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

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 α_1/2-adrenoceptors, 5-HT ₁, 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-adreno-ceptors. Since α_1/2-adrenoceptors mediate vasopressor and vasoconstrictor responses in the cardiovascular system, this study was designed to identify the α-adrenoceptor subtypes (α_1A, α_1B, α_1D, α_2A, α_2B and α_2C) 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 α_1/2-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 (α_1A, 100 and 300 μg/kg), L-765,314 (α_1B, 100 and 300 μg/kg), BMY 7378 (α_1D, 100 and 300 μg/kg), BRL44408 (α_2A, 300 and 1000 μg/kg) and JP-1302 (α_2C, 300 μg/kg), significantly blocked the vasopressor responses to ergotamine, whereas imiloxan (α_2B, 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 α_1A-, α_1B-, α_1D-, α_2A- and α_2C-adrenoceptors and may explain its adverse/therapeutic effects.