The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

The role of α1- and α2-adrenoceptor subtypes in the vasopressor responses induced by dihydroergotamine in ritanserin-pretreated pithed rats

The Journal of Headache and Pain, October 2017

29022279

Eduardo Rivera-Mancilla, Victor H. Avilés-Rosas, Guadalupe Manrique-Maldonado, Alain H. Altamirano-Espinoza, Belinda Villanueva-Castillo, Antoinette MaassenVanDenBrink, Carlos M. Villalón

Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D2-like receptors, serotonin 5-HT1/2 receptors and α1/α2-adrenoceptors. Since activation of vascular α1/α2-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α1- and α2-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 μg/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1-3100 μg/kg, given cumulatively) were determined after i.v. administration of some α1/α2-adrenoceptor antagonists. In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α1; 30 μg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α2; 300 μg/kg); and (iii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (α1; 10 and 30 μg/kg) or rauwolscine (α2; 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α1A; 30-100 μg/kg), L-765,314 (α1B; 100 μg/kg), BMY 7378 (α1D; 30-100 μg/kg), BRL44408 (α2A; 100-300 μg/kg), imiloxan (α2B; 1000-3000 μg/kg) or JP-1302 (α2C; 1000 μg/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by α1- (probably α1A, α1B and α1D) and α2- (probably α2A, α2B and α2C) adrenoceptors. These findings could shed light on the pharmacological profile of the vascular side effects (i.e. systemic vasoconstriction) produced by DHE and may lead to the development of more selective antimigraine drugs devoid vascular side effects.