EFFECTS OF THE NOVEL HIGH-AFFINITY 5-HT1B 1D-RECEPTOR LIGAND FROVATRIPTAN IN HUMAN ISOLATED BASILAR AND CORONARY-ARTERIES/

The contractile actions of the novel high-affinity 5-hydroxytryptamine (5-HT1B/1D) ligand, frovatriptan (formerly VML 251/SB-209509) were in vestigated in human isolated basilar and coronary arteries in which th e endothelium had been removed. Basilar arteries were obtained post mo rtem, and coronary arteries were obtained from patients undergoing hea rt transplant (recipient) or from donor hearts that were not suitable for transplant. Frovatriptan was a potent contractile agent in isolate d 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 activi ty 1.11 +/- 0.08 relative to 5-HT (n = 4). In coronary arteries, frova triptan produced contraction with -log EC50 values of 7.38 +/- 0.12 an d 7.81 +/- 0.2 in recipient (n = 7) and donor (n = 3) arteries, respec tively. The relative degree of contraction of frovatriptan was lower t han chat of 5-HT. with relative intrinsic activities of 0.42 +/- 0.06 and 0.40 +/- 0.09, respectively. Sumatriptan produced contraction of h uman recipient and donor arteries with -log EC50 values (intrinsic act ivity) 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 c oncentrations >6 mu M in some tissues. In contrast, no bell-shaped con centration-response curves were apparent for sumatriptan or 5-HT. Thre shold concentrations for frovatriptan-induced contractions were also d ifferent between basilar (>2 nM) and coronary arteries (>20 nM). No se paration of threshold activity was observed with sumatriptan or 5-HT. These data show that frovatriptan produces constriction of human isola ted basilar and coronary arteries. However, frovatriptan produces a co mplex pharmacologic response in the coronary artery, with threshold co ntractile activity requiring similar to 10-fold greater concentrations of agonist than in the basilar artery. Frovatriptan also shows a diff erential pharmacologic profile compared with sumatriptan in coronary a rteries, with reversal of tone predominating at high concentration.