Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused guinea pig heart.
The effects of the 5-HT1B/D receptor agonist, sumatriptan, on coronary flow (CF) and left ventricular function in the isolated perfused guinea pig heart were investigated in the presence and absence of coronary endothelial dysfunction induced by nitric oxide (NO) synthase inhibition with Nomega-nitro-L-arginine methyl ester (L-NAME; 10 microM). Hearts were perfused under constant pressure (80 cm H2O) with oxygenated (95% O2/5% CO2) Krebs bicarbonate buffer (pH 7.4) and were driven at 4 Hz. In the absence of L-NAME (n=37), sumatriptan (0.1-32 microM) failed statistically significantly to affect left ventricular developed pressure (LVDP; maximal change, -8.1+/-1.8%; NS vs. vehicle), left ventricular end-diastolic pressure (LVEDP; +10.4+/-9.8%, NS), or CF (-12.2+/-1.4%; NS compared with vehicle). L-NAME per se significantly reduced coronary flow (CF; -26.3+/-2.9%; p < 0.001), thereby increasing coronary vascular tone, and decreased LVDP (-17.1+/-1.8%; p < 0.01). In hearts perfused with L-NAME (10 microM; n=61), sumatriptan (0.1-32 microM) still failed significantly to affect CF (maximal change, 0.2+/-5.7%, NS) but concentration-dependently increased LVEDP [maximal increase, 89.0+/-30.3%; p < 0.05; geometric mean EC50 3.6 (2.9-5.7) microM], which was not prevented by the 5-HT1B/D receptor antagonist, GR 127935 (0.1 microM; maximal increase, 51.8+/-11.1%; n=48, NS compared with sumatriptan alone). In conclusion, sumatriptan failed significantly to affect CF even in the presence of endothelial dysfunction. LV function similarly remained unaffected in normal hearts, but sumatriptan produced diastolic contracture in the presence of coronary endothelial dysfunction by a mechanism apparently not involving 5-HT1B/D receptors. Collectively the data indicate that 5-HT1B/D receptor expression or effector coupling or both are absent or low in the guinea pig heart, because no detectable functional responses were observed.
Le Grand
B
B
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Vié
B
B
John
G W
GW
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D003971:Diastole / Q000187:drug effects; D004087:Dihydroergotamine / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000502:physiology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D023303:Oxazolidinones; D010477:Perfusion; D010879:Piperazines / Q000494:pharmacology; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D018170:Sumatriptan / Q000494:pharmacology*; D014363:Tryptamines; D016277:Ventricular Function, Left / Q000187:drug effects*
D010069:Oxadiazoles; D010080:Oxazoles; D023303:Oxazolidinones; D010879:Piperazines; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D011985:Receptors, Serotonin; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan; C090701:GR 127935; D004087:Dihydroergotamine; D018170:Sumatriptan; D019331:NG-Nitroarginine Methyl Ester