Deka D K, Raviprakash V, Mishra S K
Division of Pharmacology and Toxicology, Indian Veterinary Research Institute, Izatnagar, UP.
Eur J Pharmacol. 1998 May 1;348(1):11-23. doi: 10.1016/s0014-2999(98)00066-1.
In the current investigation, the role of basal nitric oxide (NO) in modulating the vasorelaxant responses to pinacidil and levcromakalim was examined in goat isolated coronary artery. Pinacidil (10(-8) 10(-4) M) elicited concentration-dependent relaxations of the coronary artery ring segments (with intact endothelium) constricted with 30 mM K+ saline solution. The EC50 of the vasodilator was 2.57 x 10(-6) M (95% CL, 1.9-3.46 x 10(-6) M). The removal of endothelium by mechanical rubbing caused a rightward shift in the concentration-response curve of pinacidil with a corresponding increase in EC50 value (1.90 x 10(-5) M; 95% CL, 1.12-3.23 x 10(-5) M). Similar to endothelium removal, treatment of endothelium-intact rings either with the NO synthesis inhibitor L-NAME (NG-nitro-L-arginine methyl ester; 3 x 10(-5) M) or the guanylate cyclase inhibitor, methylene blue (3 x 10(-6) M) resulted in a marked inhibition in the relaxant responses to pinacidil. Hence, the EC50 values of the potassium channel opener were significantly higher in tissues treated either with L-NAME (7.41 x 10(-6) M; 95% CL, 6.02-9.12 x 10(-6) M) or methylene blue (2.29 x 10(-5) M; 95% CL, 1.58-3.31 x 109-5) M) as compared to untreated controls. The ATP-sensitive potassium (KATP) channel blocker glibenclamide, which caused a significant rightward shift in the concentration-relaxation curve of pinacidil in control tissues, was found to be less potent in antagonising the relaxant responses of the KATP channel opener in endothelium-denuded rings and in rings with intact endothelium but treated with either L-NAME or methylene blue. In contrast to the observations made with pinacidil, the vasodilator responses to another KATP channel opener, levcromakalim, were potentiated in the absence of basal NO. Thus, the EC50 of levcromakalim was 1.33 x 10(-8) M (95% CL, 0.8-2.21 x 10(-8) M) in control tissues with intact endothelium, which was significantly higher than those obtained in endothelium-deprived rings (4.81 x 10(-9) M; 95% CL, 4.04-5.73 x 10(-9) M) or endothelium intact rings treated either with L-NAME (2.63 x 10(-9) M; 95% CL, 1.58-4.36 x 10(-9) M) or methylene blue (2.82 x 10(-9) M; 95% CL, 1.7-4.68 x 10(-9) M). The selective modulation by basal NO of the arterial relaxations elicited with the KATP channel openers was evident from the findings that papaverine-induced relaxations were not affected in the absence of basal NO. Taken together, the results of the present study suggest that basal NO differentially modulates the interaction of pinacidil and levcromakalim with the KATP channels in goat coronary artery through a cGMP-dependent pathway.
在当前的研究中，我们在山羊离体冠状动脉中研究了基础一氧化氮（NO）在调节对吡那地尔和左卡尼汀的血管舒张反应中的作用。吡那地尔（10⁻⁸至10⁻⁴M）可引起用30mM K⁺盐溶液收缩的冠状动脉环段（内皮完整）出现浓度依赖性舒张。该血管舒张剂的EC50为2.57×10⁻⁶M（95%置信区间，1.9 - 3.46×10⁻⁶M）。通过机械摩擦去除内皮会导致吡那地尔浓度 - 反应曲线向右移动，EC50值相应增加（1.90×10⁻⁵M；95%置信区间，1.12 - 3.23×10⁻⁵M）。与去除内皮相似，用NO合成抑制剂L - NAME（NG - 硝基 - L - 精氨酸甲酯；3×10⁻⁵M）或鸟苷酸环化酶抑制剂亚甲蓝（3×10⁻⁶M）处理内皮完整的环，会导致对吡那地尔的舒张反应受到显著抑制。因此，与未处理的对照组相比，在用L - NAME（7.41×10⁻⁶M；95%置信区间，6.02 - 9.12×10⁻⁶M）或亚甲蓝（2.29×10⁻⁵M；95%置信区间，1.58 - 3.31×10⁻⁵M）处理的组织中，钾通道开放剂的EC50值显著更高。ATP敏感性钾（KATP）通道阻滞剂格列本脲在对照组织中可使吡那地尔的浓度 - 舒张曲线显著右移，但在去内皮环以及内皮完整但用L - NAME或亚甲蓝处理的环中，其拮抗KATP通道开放剂舒张反应的效力较低。与吡那地尔的观察结果相反，在没有基础NO的情况下，对另一种KATP通道开放剂左卡尼汀的血管舒张反应增强。因此，在具有完整内皮的对照组织中，左卡尼汀的EC50为1.33×10⁻⁸M（95%置信区间，0.8 - 一、21×10⁻⁸M），这显著高于在去内皮环（4.81×10⁻⁹M；95%置信区间，4.四、5.73×10⁻⁹M）或用L - NAME（2.63×10⁻⁹M；95%置信区间，1.58 - 4.36×10⁻⁹M）或亚甲蓝（2.82×10⁻⁹M；95%置信区间，1.7 - 4.68×10⁻⁹M）处理的内皮完整环中的值。从罂粟碱诱导的舒张在没有基础NO时不受影响的发现可以明显看出基础NO对KATP通道开放剂引起的动脉舒张的选择性调节。综上所述，本研究结果表明基础NO通过cGMP依赖性途径差异性地调节吡那地尔和左卡尼汀与山羊冠状动脉中KATP通道的相互作用。
