Valentin J P, Bonnafous R, John G W
Centre de Recherche Pierre Fabre, Division of Cardiovascular Diseases, Castres, France.
Fundam Clin Pharmacol. 1998;12(2):152-7. doi: 10.1111/j.1472-8206.1998.tb00935.x.
Contractile responses evoked by the 5-HT IB/D receptor agonists, dihydroergotamine, naratriptan and sumatriptan, were compared in canine isolated coronary artery rings before and after endothelial dysfunction as obtained by inhibition of nitric oxide synthase with Nw-nitro-L-arginine methyl ester (L-NAME; 10 microM). The three agonists contracted rings in the potency order of dihydroergotamine (geometric mean pD2 value with 95% confidence limits in parentheses: 6.9 [5.3-7.9] and 7.0 [5.4-7.3] in the absence and presence of nitric oxide synthase (NOS) inhibition [I], respectively) > or = naratriptan (6.8 [5.7-7.3] and 6.4 [5.7-6.6]) > sumatriptan (4.8 [3.6-5.6] and 5.0 [3.6-5.6]) independently of the presence or absence of L-NAME. In absence of L-NAME, efficacy, as assessed by the mean maximal contractile response (Emax), tended to be greater, although not significantly, for sumatriptan and naratriptan compared to dihydroergotamine. L-NAME per se markedly increased developed tension (43.0 +/- 4.6 mN; n = 50) and potentiated maximal responses (0.6 +/- 0.2 and 10.7 +/- 2.4 mN for dihydroergotamine in the absence and presence of L-NAME respectively; 1.7 +/- 0.6 and 18.7 +/- 3.7 mN for naratriptan; 2.5 +/- 0.6 and 21.3 +/- 3.8 mN for sumatriptan; P < 0.01 in each case). Emax values of sumatriptan and naratriptan were greater than those produced by dihydroergotamine in the presence of L-NAME but remained lower than the sub-maximal contractile responses evoked by the thromboxane A2 analogue, U-46619 (ie, 32.4 +/- 5.2 mN in the absence of L-NAME; n = 50), or L-NAME per se. In conclusion, 5-HT IB/D receptor agonist efficacies in contracting coronary arteries are relatively low under basal conditions and are potentiated in the presence of a dysfunctional endothelium, whereas agonist potencies remain unaffected.
使用Nω-硝基-L-精氨酸甲酯（L-NAME；10μM）抑制一氧化氮合酶，从而造成犬离体冠状动脉环内皮功能障碍，在此前后比较了5-HT IB/D受体激动剂二氢麦角胺、那拉曲普坦和舒马曲坦所诱发的收缩反应。这三种激动剂使冠脉环收缩的效价顺序为：二氢麦角胺（括号内为几何平均pD2值及95%置信区间：无一氧化氮合酶（NOS）抑制[I]时为6.9 [5.3 - 7.9]，有NOS抑制时为7.0 [5.4 - 7.3]）≥那拉曲普坦（6.8 [5.7 - 7.3]和6.4 [5.7 - 6.6]）＞舒马曲坦（4.8 [3.6 - 5.6]和5.0 [3.6 - 5.6]），与是否存在L-NAME无关。在不存在L-NAME时，以平均最大收缩反应（Emax）评估，舒马曲坦和那拉曲普坦的效能虽无显著差异，但相较于二氢麦角胺有升高趋势。L-NAME本身显著增加了舒张张力（43.0±4.6 mN；n = 50），并增强了最大反应（二氢麦角胺在无L-NAME时为0.6±0.2 mN，有L-NAME时为10.7±2.4 mN；那拉曲普坦分别为1.7±0.6 mN和18.7±3.7 mN；舒马曲坦分别为2.5±0.6 mN和21.3±3.8 mN；每种情况P＜0.01）。在存在L-NAME时，舒马曲坦和那拉曲普坦的Emax值大于二氢麦角胺所产生的值，但仍低于血栓素A2类似物U-46619诱发的次最大收缩反应（即无L-NAME时为32.4±5.2 mN；n = 50）或L-NAME本身。总之，5-HT IB/D受体激动剂在基础条件下收缩冠状动脉的效能相对较低，在内皮功能障碍时效能增强，而激动剂效价不受影响。
