COMPARISON OF THE CARDIOVASCULAR EFFECTS OF THE NOVEL 5-HT1B 1D RECEPTOR AGONIST, SB-209509 (VML251), AND SUMATRIPTAN IN DOGS/

The systemic cardiovascular effects of a novel 5-hydroxtryptamine (5-H T)(1B/1D)-receptor agonist were investigated in the anaesthetised dog, SE 209509) (VML 251) was more potent than sumatriptan in producing in creases in carotid vascular resistance after intravenous administratio n and was similar in potency to sumatriptan after sequential intraduod enal administration at 30-min intervals. In open-chest dogs, sequentia l intravenous administration of SE 209509 or sumatriptan produced mark ed increases in carotid vascular resistance without changing coronary vascular resistance. In contrast to sumatriptan, after administration of high doses of SE 209509 (>790 nmol/kg), a reduction in coronary vas cular resistance was observed. After a single bolus intraduodenal dose of SE 209509 (260, 520, or 790 nmol/kg), increases in carotid vascula r resistance could be detected over a 5-h period. Sumatriptan (i.d.), 2.4 mu mol/kg but not 700 nmol/kg, produced a sustained effect similar to the effects of SE 209509 (790 nmol/kg). In all experiments. SE 209 509 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. SE 209509 was rapidly absorbed afte r intraduodenal administration in conscious dogs and had good bioavail ability. These data indicate that SE 209509 is a potent 5-HT1B/1D-rece ptor agonist that is rapidly absorbed from the duodenum. The effects o f SE 209509 are long lasting and selective for the carotid vascular be d.