Pharmacological profile of the mechanisms involved in the external carotid vascular effects of the antimigraine agent isometheptene in anaesthetised dogs

Abstract.

The present study set out to investigate the external carotid vascular effects of isometheptene in vagosympathectomised dogs, anaesthetised with pentobarbital. One-minute intracarotid (intra-arterial; i.a.) infusions of isometheptene (10, 30, 100 and 300 µg/min) produced dose-dependent decreases in external carotid blood flow, without affecting blood pressure or heart rate. The vasoconstrictor responses to 100 µg/min and 300 µg/min of isometheptene were clearly attenuated in animals pretreated with reserpine (5000 µg/kg). Moreover, after prazosin (an α₁-adrenoceptor antagonist; 100 µg/kg), the responses to isometheptene remained unaltered in untreated as well as reserpine-pretreated dogs. In contrast, the responses to isometheptene were attenuated by rauwolscine (an α₂-adrenoceptor antagonist; 300 µg/kg) in untreated animals, and were practically abolished in reserpine-pretreated dogs. Further investigation into the specific α₂-adrenoceptor subtypes, using selective antagonists, showed that BRL44408 (α_2A) and MK912 (α_2C) markedly attenuated this response, while imiloxan (α_2B) was ineffective. The involvement of 5-HT_1B and 5-HT_1D receptors seems highly unlikely since antagonists at 5-HT_1B (SB224289) and 5-HT_1D (BRL15572) receptors (both at 300 µg/kg) were ineffective. On this basis, it is concluded that isometheptene-induced canine external carotid vasoconstriction is mediated by both indirect (a tyramine-like action) and direct (acting at receptors) mechanisms, which mainly involve α_A- and α_2C-adrenoceptors, while the involvement of α₁-adrenoceptors seems rather limited.