The role of α(1)- and α(2)-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-HT(1/2) receptors and α(1)/α(2)-adrenoceptors. Since activation of vascular α(1)/α(2)-adrenoceptors results in systemic vasopressor responses, the purpose of this study was to investigate the specific role of α(1)- and α(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 μg/kg; to exclude the 5-HT(2) 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 α(1)/α(2)-adrenoceptor antagonists. RESULTS: In control animals (without ritanserin pretreatment), the vasopressor responses to DHE were: (i) unaffected after prazosin (α(1); 30 μg/kg); (ii) slightly, but significantly, blocked after rauwolscine (α(2); 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 (α(1); 10 and 30 μg/kg) or rauwolscine (α(2); 100 and 300 μg/kg); (ii) markedly blocked after prazosin (30 μg/kg) plus rauwolscine (300 μg/kg); (iii) attenuated after 5-methylurapidil (α(1A); 30–100 μg/kg), L-765,314 (α(1B); 100 μg/kg), BMY 7378 (α(1D); 30–100 μg/kg), BRL44408 (α(2A); 100–300 μg/kg), imiloxan (α(2B); 1000–3000 μg/kg) or JP-1302 (α(2C); 1000 μg/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 α(1)- (probably α(1A), α(1B) and α(1D)) and α(2)- (probably α(2A), α(2B) and α(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.