Pharmacological analysis of the mechanisms involved in the tachycardic and vasopressor responses to the antimigraine agent, isometheptene, in pithed rats

The present study set out to investigate the pharmacological profile of the cardiovascular responses induced by the antimigraine agent, isometheptene, in pithed rats. For this purpose, intravenous (i.v.) administration of blocking doses of the antagonists prazosin (alpha1; 100 microg/kg), rauwolscine (alpha2; 300 microg/kg), the combination of prazosin (100 microg/kg) plus rauwolscine (300 microg/kg), propranolol (beta; 1000 microg/kg), ritanserin (5-HT2; 100 microg/kg) or equivalent volumes of saline (1 ml/kg) were used. Isometheptene (0.03, 0.1, 0.3, 1 and 3 mg/kg, i.v.) produced dose-dependent increases in heart rate and diastolic blood pressure which were highly reproducible as they remained unaltered after saline. These tachycardic responses to isometheptene remained unaffected after prazosin, rauwolscine, ritanserin or the combination prazosin plus rauwolscine, but were abolished after propranolol. In contrast, the isometheptene-induced vasopressor responses were not significantly modified after the above doses of rauwolscine, ritanserin or propranolol, but were markedly blocked after prazosin or the combination of prazosin plus rauwolscine; the latter blockade did not significantly differ from that produced by prazosin alone. Interestingly, in rats pretreated intraperitoneally (i.p.) with reserpine (5 mg/kg; -24 h), isometheptene-induced tachycardic responses were abolished whereas the corresponding vasopressor responses were markedly attenuated and subsequently blocked by prazosin. It is concluded that isometheptene-induced tachycardic responses seem to involve only an indirect (tyramine-like action) mechanism mediated by beta-adrenoceptors, whilst the corresponding vasopressor responses are mediated by a predominantly indirect (tyramine-like action), as well as a minor direct (alpha1-adrenoceptors), sympathomimetic mechanism.