Mizumura T, Nithipatikom K, Gross G J
Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee 63226, USA.
Cardiovasc Res. 1996 Aug;32(2):274-85. doi: 10.1016/0008-6363(96)00061-2.
We wished to determine whether the cardioprotective effect of nicorandil to reduce infarct size is blocked by glibenclamide, a selective KATP channel antagonist, or methylene blue, a nitric oxide (NO)/guanylate cyclase inhibitor, in dogs. The second aim was to determine if glyceryl trinitrate produces a cardioprotective effect in the same model and to test if this effect is blocked by methylene blue and not by glibenclamide. We also determined whether adenosine release from the ischemic-reperfused area is an accurate index of ischemic severity in the presence of these drugs.
Barbiturate-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. In the first three groups, either nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), glyceryl trinitrate (10 micrograms/kg bolus + 1 microgram/kg/min) or an equivalent volume of saline was given intravenously 15 min before LAD occlusion and continued to the time of reperfusion. In the next three groups, glibenclamide (0.3 mg/kg) was administered 15 min before drug infusion. In the final three groups, methylene blue (80 microM) was given intracoronarily 5 min before nicorandil or glyceryl trinitrate and continued until 15 min following reperfusion. Coronary venous blood samples were collected at various times during ischemia and following reperfusion and the concentration of adenosine measured.
Nicorandil produced a marked reduction in infarct size expressed as a percent of the area at risk (NC group, 12.2 +/- 3.2% vs. Control group, 25.7 +/- 4.1%, P < 0.05) and this effect was completely abolished by pretreatment with glibenclamide. However, intracoronary administration of methylene blue did not block the cardioprotective effect of nicorandil. On the other hand, glyceryl trinitrate also produced a significant reduction in infarct size (GTN group, 13.0 +/- 3.1%) and this effect was reversed by methylene blue but not by glibenclamide. Adenosine concentrations in coronary venous blood were significantly reduced after reperfusion in the groups with small infarctions as compared with the Control group.
These results suggest that at equieffective cardioprotective doses the infarct size-reducing effect of nicorandil in dogs is mediated via opening of myocardial KATP channels and that the cardioprotective effect of glyceryl trinitrate is most likely to be mediated via activation of guanylate cyclase at a site yet to be determined.
我们希望确定在犬类中，格列本脲（一种选择性KATP通道拮抗剂）或亚甲蓝（一种一氧化氮（NO）/鸟苷酸环化酶抑制剂）是否会阻断尼可地尔减少梗死面积的心脏保护作用。第二个目的是确定硝酸甘油在同一模型中是否产生心脏保护作用，并测试这种作用是否被亚甲蓝而非格列本脲阻断。我们还确定了在这些药物存在的情况下，缺血再灌注区域释放的腺苷是否是缺血严重程度的准确指标。
用巴比妥类药物麻醉的犬，左冠状动脉前降支（LAD）闭塞60分钟，随后再灌注3小时。在前三组中，在LAD闭塞前15分钟静脉给予尼可地尔（100微克/千克推注+10微克/千克/分钟）、硝酸甘油（10微克/千克推注+1微克/千克/分钟）或等量的生理盐水，并持续至再灌注时。在接下来的三组中，在药物输注前15分钟给予格列本脲（0.3毫克/千克）。在最后三组中，在给予尼可地尔或硝酸甘油前5分钟冠状动脉内给予亚甲蓝（80微摩尔），并持续至再灌注后15分钟。在缺血期间和再灌注后的不同时间采集冠状静脉血样本，并测量腺苷浓度。
尼可地尔使梗死面积占危险区域面积的百分比显著降低（NC组，12.2±3.2%对对照组，25.7±4.1%，P<0.05），且格列本脲预处理可完全消除这种作用。然而，冠状动脉内给予亚甲蓝并未阻断尼可地尔的心脏保护作用。另一方面，硝酸甘油也使梗死面积显著降低（GTN组，13.0±3.1%），且这种作用被亚甲蓝逆转，但未被格列本脲逆转。与对照组相比，梗死面积较小的组再灌注后冠状静脉血中的腺苷浓度显著降低。
这些结果表明，在等效的心脏保护剂量下，尼可地尔在犬类中减少梗死面积的作用是通过心肌KATP通道的开放介导的，而硝酸甘油的心脏保护作用很可能是通过尚未确定的位点激活鸟苷酸环化酶介导的。
