Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus Medical Center, Rotterdam, The Netherlands.
Am J Physiol Heart Circ Physiol. 2011 Sep;301(3):H1080-9. doi: 10.1152/ajpheart.01307.2010. Epub 2011 Jun 17.
Myocardial infarction (MI) is associated with endothelial dysfunction resulting in an imbalance in endothelium-derived vasodilators and vasoconstrictors. We have previously shown that despite increased endothelin (ET) plasma levels, the coronary vasoconstrictor effect of endogenous ET is abolished after MI. In normal swine, nitric oxide (NO) and prostanoids modulate the vasoconstrictor effect of ET. In light of the interaction among NO, prostanoids, and ET combined with endothelial dysfunction present after MI, we investigated this interaction in control of coronary vasomotor tone in the remote noninfarcted myocardium after MI. Studies were performed in chronically instrumented swine (18 normal swine; 13 swine with MI) at rest and during treadmill exercise. Furthermore, endothelial nitric oxide synthase (eNOS) and cyclooxygenase protein levels were measured in the anterior (noninfarcted) wall of six normal and six swine with MI. eNOS inhibition with N(ω)-nitro-L-arginine (L-NNA) and cyclooxygenase inhibition with indomethacin each resulted in coronary vasoconstriction at rest and during exercise, as evidenced by a decrease in coronary venous oxygen levels. The effect of l-NNA was slightly decreased in swine with MI, although eNOS expression was not altered. Conversely, in accordance with the unaltered expression of cyclooxygenase-1 after MI, the effect of indomethacin was similar in normal and MI swine. L-NNA enhanced the vasodilator effect of the ET(A/B) receptor blocker tezosentan but exclusively during exercise in both normal and MI swine. Interestingly, this effect of L-NNA was blunted in MI compared with normal swine. In contrast, whereas indomethacin increased the vasodilator effect of tezosentan only during exercise in normal swine, indomethacin unmasked a coronary vasodilator effect of tezosentan in MI swine both at rest and during exercise. In conclusion, the present study shows that endothelial control of the coronary vasculature is altered in post-MI remodeled myocardium. Thus the overall vasodilator influences of NO as well as its inhibition of the vasoconstrictor influence of ET on the coronary resistance vessels were reduced after MI. In contrast, while the overall prostanoid vasodilator influence was maintained, its inhibition of ET vasoconstrictor influences was enhanced in post-MI remote myocardium.
心肌梗死（MI）与内皮功能障碍有关，导致内皮衍生的血管舒张剂和血管收缩剂失衡。我们之前已经表明，尽管内皮素（ET）的血浆水平升高，但 MI 后内源性 ET 的冠状动脉收缩作用被消除。在正常猪中，一氧化氮（NO）和前列腺素调节 ET 的血管收缩作用。鉴于 MI 后存在的 NO、前列腺素和 ET 之间的相互作用以及内皮功能障碍，我们研究了这种相互作用在 MI 后远程非梗死心肌的冠状动脉血管舒缩张力控制中的作用。研究在慢性仪器化猪（18 只正常猪；13 只 MI 猪）在休息和跑步机运动时进行。此外，还测量了前壁（非梗死）壁中的内皮型一氧化氮合酶（eNOS）和环氧化酶蛋白水平在六只正常猪和六只 MI 猪中。eNOS 抑制用 N（ω）-硝基-L-精氨酸（L-NNA）和环氧化酶抑制用吲哚美辛在休息和运动时都导致冠状动脉收缩，这表现为冠状静脉氧水平下降。尽管 eNOS 表达没有改变，但 MI 猪中的 L-NNA 作用略有降低。相反，与 MI 后环氧化酶-1 表达不变一致，吲哚美辛在正常和 MI 猪中的作用相似。L-NNA 增强了 ET(A/B)受体阻滞剂替扎森坦的血管扩张作用，但仅在正常和 MI 猪的运动期间。有趣的是，与正常猪相比，MI 中的这种 L-NNA 作用减弱。相比之下，尽管吲哚美辛仅在正常猪的运动时增加了替扎森坦的血管扩张作用，但吲哚美辛在 MI 猪中揭示了替扎森坦在休息和运动时的冠状动脉血管扩张作用。总之，本研究表明，MI 后重塑心肌中冠状动脉血管的内皮控制发生改变。因此，MI 后，NO 的整体血管扩张作用及其对 ET 血管收缩作用的抑制作用降低了冠状动脉阻力血管的整体血管扩张作用。相比之下，虽然整体前列腺素血管扩张作用得到维持，但 MI 后远程心肌中其对 ET 血管收缩作用的抑制作用增强。
