The systemic cardiovascular effects of a novel 5-hydroxtryptamine (5-HT)(1B/1D)-receptor agonist were investigated in the anaesthetised dog. SB 209509 (VML 251) was more potent than sumatriptan in producing increases in carotid vascular resistance after intravenous administration and was similar in potency to sumatriptan after sequential intraduodenal administration at 30-min intervals. In open-chest dogs, sequential intravenous administration of SB 209509 or sumatriptan produced marked increases in carotid vascular resistance without changing coronary vascular resistance. In contrast to sumatriptan, after administration of high doses of SB 209509 (>790 nmol/kg), a reduction in coronary vascular resistance was observed. After a single bolus intraduodenal dose of SB 209509 (260, 520, or 790 nmol/kg), increases in carotid vascular resistance could be detected over a 5-h period. Sumatriptan (i.d.), 2.4 micromol/kg but not 700 nmol/kg, produced a sustained effect similar to the effects of SB 209509 (790 nmol/kg). In all experiments, SB 209509 and sumatriptan had minimal effects on arterial blood pressure or heart rate but produced marked changes in carotid vascular resistance over the same concentration range. SB 209509 was rapidly absorbed after intraduodenal administration in conscious dogs and had good bioavailability. These data indicate that SB 209509 is a potent 5-HT(1B/1D)-receptor agonist that is rapidly absorbed from the duodenum. The effects of SB 209509 are long lasting and selective for the carotid vascular bed.

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1 The dopamine agonist, bromocriptine, produced a hypotensive response following oral administration to conscious normotensive and spontaneously hypertensive (SH-) rats. 2 In SH-rats the dose-related falls in blood pressure to bromocriptine, 3 to 30 mg/kg orally or intraperitoneally, were biphasic, an initial fall at 1 h being followed by some recovery at 2 h and a subsequent fall in blood pressure at 4 and 6 h.3 The dopamine antagonists, metoclopramide, sulpiride, haloperidol and pimozide, had little or no effect on the hypotensive response to bromocriptine, 10 mg/kg orally, in SH-rats. 4 Pretreatment with a-methyl-p-tyrosine augmented the hypotensive response to bromocriptine, 10 mg/kg orally, in SH-rats.5 In adrenal demedullated SH-rats, the hypotensive response to bromocriptine, 3 to 30 mg/kg orally, was abolished.6 In SH-rats the hypotensive response to bromocriptine, 10 mg/kg orally, was prevented by the ,3-adrenoceptor blocking drugs, propranolol and oxprenolol, but was unaffected by (+)-propranolol and by the cardio-selective ,8-adrenoceptor blocking drug, atenolol. 7 In SH-rats pretreated with bromocriptine, 10 mg/kg orally, and then anaesthetized, the pressor responses to low doses of intravenous adrenaline were reversed to depressor, indicating that bromocriptine possesses a-adrenoceptor blocking activity.8 The results suggest that the hypotensive response to bromocriptine in conscious SH-rats is mediated by adrenaline released from the adrenal medullae which, in the presence of a-adrenoceptor blockade, stimulates vascular,f-adrenoceptors producing vasodilatation.

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