Pharmacological profile of the mechanisms involved in the external carotid vascular effects of the antimigraine agent isometheptene in anaesthetised dogs
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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 (α2A) and MK912 (α2C) markedly attenuated this response, while imiloxan (α2B) was ineffective. The involvement of 5-HT1B and 5-HT1D receptors seems highly unlikely since antagonists at 5-HT1B (SB224289) and 5-HT1D (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 αA- and α2C-adrenoceptors, while the involvement of α1-adrenoceptors seems rather limited.
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