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

Background: Dihydroergotamine (DHE) is an acute antimigraine agent that displays affinity for dopamine D-2-like receptors, serotonin 5-HT1/2 receptors and alpha(1)/alpha(2)-adrenoceptors. Since activation of vascular alpha(1)/alpha(2)-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of alpha(1)-and alpha(2)-adrenoceptors mediating DHE-induced vasopressor responses using several antagonists for these receptors. Methods: For this purpose, 135 male Wistar rats were pithed and divided into 35 control and 100 pretreated i.v. with ritanserin (100 mu g/kg; to exclude the 5-HT2 receptor-mediated systemic vasoconstriction). Then, the vasopressor responses to i.v. DHE (1-3100 mu g/kg, given cumulatively) were determined after i.v. administration of some alpha(1)/alpha(2)-adrenoceptor antagonists. Results: In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (alpha(1); 30 mu g/kg); (ii) slightly, but significantly, blocked after rauwolscine (alpha(2); 300 mu g/kg); and (iii) markedly blocked after prazosin (30 mu g/kg) plus rauwolscine (300 mu g/kg). In contrast, after pretreatment with ritanserin, the vasopressor responses to DHE were: (i) attenuated after prazosin (alpha(1); 10 and 30 mu g/kg) or rauwolscine (alpha(2); 100 and 300 mu g/kg); (ii) markedly blocked after prazosin (30 mu g/kg) plus rauwolscine (300 mu g/kg); (iii) attenuated after 5-methylurapidil (alpha(1A); 30-100 mu g/kg), L-765,314 (alpha(1B); 100 mu g/kg), BMY 7378 (alpha(1D); 30-100 mu g/kg), BRL44408 (alpha(2A); 100-300 mu g/kg), imiloxan (alpha(2B); 1000-3000 mu g/kg) or JP-1302 (alpha(2C); 1000 mu g/kg); and (iv) unaffected after the corresponding vehicles (1 ml/kg). Conclusion: These results suggest that the DHE-induced vasopressor responses in ritanserin-pretreated pithed rats are mediated by alpha(1)-(probably alpha(1A), alpha(1B) and alpha(1D)) and alpha(2)-(probably alpha(2A), alpha(2B) and alpha(2C)) 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.