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 concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 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 sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, 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 significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.
Parsons
A A
AA
Neurosciences Research, SmithKline Beecham Pharmaceuticals, Harlow, Essex, England.
Valocik
R
R
Koster
P
P
Raval
P
P
Gagnon
R
R
Tilford
N
N
Feuerstein
G
G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000494:pharmacology*; D002302:Cardiac Output / Q000187:drug effects; D003326:Coronary Circulation / Q000187:drug effects*; D004285:Dogs; D005260:Female; D006321:Heart / Q000187:drug effects*; D006339:Heart Rate / Q000187:drug effects; D066298:In Vitro Techniques; D008297:Male; D008881:Migraine Disorders / Q000188:drug therapy; D009203:Myocardial Infarction / Q000503:physiopathology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D014363:Tryptamines
D002227:Carbazoles; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C108128:frovatriptan