Effects of the novel high-affinity 5-HT(1B/1D)-receptor ligand frovatriptan in human isolated basilar and coronary arteries.
The contractile actions of the novel high-affinity 5-hydroxytryptamine (5-HT(1B/1D)) ligand, frovatriptan (formerly VML 251/SB-209509) were investigated in human isolated basilar and coronary arteries in which the endothelium had been removed. Basilar arteries were obtained post mortem, and coronary arteries were obtained from patients undergoing heart transplant (recipient) or from donor hearts that were not suitable for transplant. Frovatriptan was a potent contractile agent in isolated basilar artery with a -log mean effective concentration (EC50) value of 7.86 +/- 0.07 and intrinsic activity of 1.25 +/- 0.10 relative to 5-HT (n = 4). Frovatriptan was 8.5-fold more potent than sumatriptan, which produced a -log EC50 value of 6.93 +/- 0.09 and intrinsic activity 11.1 +/- 0.08 relative to 5-HT (n = 4). In coronary arteries, frovatriptan produced contraction with -log EC50 values of 7.38 +/- 0.12 and 7.81 +/- 0.2 in recipient (n = 7) and donor (n = 3) arteries, respectively. The relative degree of contraction of frovatriptan was lower than that of 5-HT, with relative intrinsic activities of 0.42 +/- 0.06 and 0.40 +/- 0.09, respectively. Sumatriptan produced contraction of human recipient and donor arteries with -log EC50 values (intrinsic activity) of 6.57 +/- 0.13 (0.79 +/- 0.27; n = 6) and 7.35 (1.41; n = 2), respectively. Furthermore, marked bell-shaped responses were apparent for frovatriptan in coronary arteries, with relaxation occurring at concentrations >6 microM in some tissues. In contrast, no bell-shaped concentration-response curves were apparent for sumatriptan or 5-HT. Threshold concentrations for frovatriptan-induced contractions were also different between basilar (>2 nM) and coronary arteries (>20 nM). No separation of threshold activity was observed with sumatriptan or 5-HT. These data show that frovatriptan produces constriction of human isolated basilar and coronary arteries. However, frovatriptan produces a complex pharmacologic response in the coronary artery, with threshold contractile activity requiring approximately 10-fold greater concentrations of agonist than in the basilar artery. Frovatriptan also shows a differential pharmacologic profile compared with sumatriptan in coronary arteries, with reversal of tone predominating at high concentration.
Department of Neuroscience Research, SmithKline Beecham Pharmaceuticals, New Frontiers Science Park (North), Harlow, Essex, UK.
A A
AA
Parsons
P
P
Raval
S
S
Smith
N
N
Tilford
F D
FD
King
A J
AJ
Kaumann
J
J
Hunter
D001488:Basilar Artery / Q000187:drug effects / Q000502:physiology; D002227:Carbazoles / Q000494:pharmacology*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects*; D018170:Sumatriptan / Q000494:pharmacology; D014363:Tryptamines; D014662:Vasoconstrictor Agents / Q000494:pharmacology*
D002227:Carbazoles; C470302:HTR1B protein, human; D008024:Ligands; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D014363:Tryptamines; D014662:Vasoconstrictor Agents; D018170:Sumatriptan; C108128:frovatriptan