舒马曲坦对离体灌注豚鼠心脏冠脉血流及左心室功能的影响。

Effects of sumatriptan on coronary flow and left ventricular function in the isolated perfused guinea pig heart.

作者信息

Le Grand B, Vié B, John G W

机构信息

Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.

出版信息

J Cardiovasc Pharmacol. 1998 Sep;32(3):435-42. doi: 10.1097/00005344-199809000-00014.

DOI:10.1097/00005344-199809000-00014

PMID:9733357

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.

摘要

在存在和不存在由Nω-硝基-L-精氨酸甲酯（L-NAME；10微摩尔）抑制一氧化氮（NO）合酶诱导的冠状动脉内皮功能障碍的情况下，研究了5-羟色胺1B/D受体激动剂舒马曲坦对离体灌注豚鼠心脏冠状动脉血流（CF）和左心室功能的影响。心脏在恒定压力（80厘米水柱）下用含氧（95% O₂/5% CO₂）的 Krebs 碳酸氢盐缓冲液（pH 7.4）灌注，并以4赫兹驱动。在不存在L-NAME的情况下（n = 37），舒马曲坦（0.1 - 32微摩尔）在统计学上未能显著影响左心室舒张末压力（LVDP；最大变化，-8.1±1.8%；与溶剂相比无显著差异）、左心室舒张末压力（LVEDP；+10.4±9.8%，无显著差异）或CF（-12.2±1.4%；与溶剂相比无显著差异）。L-NAME本身显著降低冠状动脉血流（CF；-26.3±2.9%；p < 0.001），从而增加冠状动脉血管张力，并降低LVDP（-17.1±1.8%；p < 0.01）。在用L-NAME（10微摩尔；n = 61）灌注的心脏中，舒马曲坦（0.1 - 32微摩尔）仍然未能显著影响CF（最大变化，0.2±5.7%，无显著差异），但浓度依赖性地增加LVEDP [最大增加，89.0±30.3%；p < 0.05；几何平均EC50 3.6（2.9 - 5.7）微摩尔]，5-羟色胺1B/D受体拮抗剂GR 127935（0.1微摩尔）不能阻止这种增加（最大增加，51.8±11.1%；n = 48，与单独使用舒马曲坦相比无显著差异）。总之，即使存在内皮功能障碍，舒马曲坦也未能显著影响CF。在正常心脏中左心室功能同样未受影响，但在存在冠状动脉内皮功能障碍的情况下，舒马曲坦通过一种显然不涉及5-羟色胺1B/D受体的机制产生舒张期挛缩。总体数据表明，豚鼠心脏中5-羟色胺1B/D受体表达或效应器偶联或两者均不存在或水平较低，因为未观察到可检测到的功能反应。