Effects of the novel antimigraine agent, frovatriptan, on coronary and cardiac function in dogs

The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low conc entrations of frovatriptan produced contraction with -logEC(50) 7.55 +/- 0. 08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 mu M) response. At high concentratio ns of frovatriptan (>6 mu M), reversal of sumatriptan (10 mu M)-induced con tractions was noted. In arteries precontracted with the thromboxane mimetic , U46619, frovatriptan produced a bell-shaped concentration-response relati on with a maximal response at 600 nM. Concentrations of frovatriptan >2 mu M produced marked reversal of tone, with full relaxation of precontracted t issues at 200 mu M. In anesthetized, open-chest mongrel dogs, intravenous ( n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.00 01-1 mg/kg) had no consistent effect on left ventricular end-diastolic pres sure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular res istance, mean arterial blood pressure, or heart rate when compared with veh icle (n = 3). Intravenous sumatriptan produced minor effects on blood press ure and heart rate. Intracoronary artery administration of sumatriptan (0.0 003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of suma triptan also produced a significant increase in coronary blood flow and dec rease in coronary vascular resistance. Intravenous administration of sumatr iptan produced a dose-related reduction in left ventricular diastolic press ure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values ob served at 0.3 and 1 mg/kg, respectively; however, administration of sumatri ptan by an intracoronary route had no effect. In a model of myocardial infa rction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg /kg), in terms of their effect on carotid vascular resistance, had no signi ficant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduct ion in coronary blood flow for less than or equal to 3 h. These studies sho w that frovatriptan has the capability of relaxing coronary arteries in vit ro, has no overall effect on cardiac function at rest with no effect on cor onary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.