Related Experiment Videos
Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused guinea pig heart
1Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Insights
Sumatriptan did not affect coronary flow or left ventricular function in guinea pig hearts. However, it caused diastolic contracture when endothelial dysfunction was present, suggesting absent or low 5-HT1B/D receptor activity.
Area of Science:
- Pharmacology
- Cardiovascular Physiology
Background:
- Sumatriptan is a 5-HT1B/D receptor agonist.
- Coronary endothelial dysfunction can alter cardiac function.
Purpose of the Study:
- To investigate the effects of sumatriptan on coronary flow and left ventricular function in guinea pig hearts.
- To determine if these effects are altered by nitric oxide synthase inhibition-induced endothelial dysfunction.
Main Methods:
- Isolated perfused guinea pig hearts were used.
- Coronary endothelial dysfunction was induced using Nomega-nitro-L-arginine methyl ester (L-NAME).
- Sumatriptan's effects on coronary flow, left ventricular developed pressure, and left ventricular end-diastolic pressure were measured.
Main Results:
- Sumatriptan did not significantly affect coronary flow or left ventricular function in normal hearts.
- L-NAME induced significant coronary vasoconstriction and reduced left ventricular developed pressure.
- In L-NAME treated hearts, sumatriptan caused a concentration-dependent increase in left ventricular end-diastolic pressure, indicative of diastolic contracture, which was not blocked by a 5-HT1B/D antagonist.
Conclusions:
- Sumatriptan does not significantly impact coronary flow or left ventricular function in guinea pig hearts, even with endothelial dysfunction.
- Sumatriptan induces diastolic contracture in the presence of coronary endothelial dysfunction via a non-5-HT1B/D receptor mediated mechanism.
- The guinea pig heart appears to have minimal or no functional 5-HT1B/D receptor expression or signaling.
Abstract:
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.