Comparison of the cardiovascular effects of the novel 5-HT(1B/1D) receptor agonist, SB 209509 (VML251), and sumatriptan in dogs.
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.
Parsons
A A
AA
Department of Neurology Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, England.
Parker
S G
SG
Raval
P
P
Campbell
C A
CA
Lewis
V A
VA
Griffiths
R
R
Hunter
A J
AJ
Hamilton
T C
TC
King
F D
FD
D000818:Animals; D001682:Biological Availability; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000493:pharmacokinetics / Q000494:pharmacology*; D002319:Cardiovascular System / Q000187:drug effects*; D002339:Carotid Arteries / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects; D004285:Dogs; D004386:Duodenum; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D007262:Infusions, Intravenous; D008297:Male; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D012039:Regional Blood Flow / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D018170:Sumatriptan / Q000493:pharmacokinetics / Q000494:pharmacology*; D014363:Tryptamines; D014655:Vascular Resistance / Q000187:drug effects
D002227:Carbazoles; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; D018170:Sumatriptan; C108128:frovatriptan