Larosa G, Forster C
Department of Pharmacology, University of Toronto, Ontario, Canada.
Eur J Pharmacol. 1996 Dec 30;318(2-3):387-94. doi: 10.1016/s0014-2999(96)00809-6.
To characterize vasodilator capacity of small coronary arteries (200-350 microm diameter) in the setting of congestive heart failure, we examined relaxation responses to acetylcholine (10(-9)-10(-4) M) and nitroglycerin (10(-9)-10(-4) M), in the absence and presence of the nitric oxide precursor, L-arginine (10(-4) M). Congestive heart failure was reliably induced in dogs by rapid ventricular pacing (250 beats.min(-1) for 4 weeks). Maximum relaxations (means +/- S.E.) to each vasodilator are expressed as a percentage of the relaxation response to papaverine (10(-4) M). Relaxation responses to the endothelium-dependent relaxing agent, acetylcholine, were not altered at heart failure, or in the presence of L-arginine. Contrary to acetylcholine, relaxations to nitroglycerin were significantly enhanced in heart failure compared to control (83 +/- 25% vs. 25 +/- 6%, respectively, P < 0.05). Although L-arginine, alone, did not cause any vasodilator response in coronary microvessels, it was able to potentiate nitroglycerin relaxations at control (no L-arginine: 25 +/- 6% vs. L-arginine: 135 +/- 66%). In contrast, at heart failure, L-arginine diminished nitroglycerin relaxations (no L-arginine: 83 +/- 25%, vs. L-arginine: 48 +/- 15%). These data indicate a unique vasodilator profile in small coronary arteries at heart failure: endothelium-dependent relaxations are unaltered, whereas responses to nitroglycerin are augmented. Addition of the nitric oxide precursor, L-arginine, did not affect acetylcholine relaxation, yet surprisingly had a differential effect in response to nitroglycerin. Moreover, inhibition of nitric oxide synthase with N(omega)-nitro-L-arginine elicited concentration-dependent constriction in heart failure but not control coronary microvessels. In summary, our study suggests an important role for nitric oxide in vasodilator control of coronary microvessels, which may modify nitrovasodilator therapy in congestive heart failure.
为了描述充血性心力衰竭时小冠状动脉（直径200 - 350微米）的血管舒张能力，我们在有无一氧化氮前体L - 精氨酸（10⁻⁴ M）的情况下，检测了对乙酰胆碱（10⁻⁹ - 10⁻⁴ M）和硝酸甘油（10⁻⁹ - 10⁻⁴ M）的舒张反应。通过快速心室起搏（250次/分钟，持续4周）在犬中可靠地诱导出充血性心力衰竭。每种血管舒张剂的最大舒张（均值±标准误）表示为对罂粟碱（10⁻⁴ M）舒张反应的百分比。对内皮依赖性舒张剂乙酰胆碱的舒张反应在心力衰竭时或存在L - 精氨酸时未改变。与乙酰胆碱相反，与对照组相比，心力衰竭时对硝酸甘油的舒张反应显著增强（分别为83±25%和25±6%，P < 0.05）。虽然单独的L - 精氨酸在冠状动脉微血管中未引起任何血管舒张反应，但它能够增强对照组中硝酸甘油的舒张作用（无L - 精氨酸：25±6% vs. L - 精氨酸：135±66%）。相反，在心力衰竭时，L - 精氨酸减弱了硝酸甘油的舒张作用（无L - 精氨酸：83±25%，vs. L - 精氨酸：48±15%）。这些数据表明心力衰竭时小冠状动脉具有独特的血管舒张特征：内皮依赖性舒张未改变，而对硝酸甘油的反应增强。添加一氧化氮前体L - 精氨酸不影响乙酰胆碱的舒张作用，但令人惊讶的是，对硝酸甘油的反应有不同影响。此外，用N（ω）-硝基 - L - 精氨酸抑制一氧化氮合酶在心力衰竭的冠状动脉微血管中引起浓度依赖性收缩，但在对照组中未出现。总之，我们的研究表明一氧化氮在冠状动脉微血管的血管舒张控制中起重要作用，这可能会改变充血性心力衰竭中的硝基血管舒张剂治疗。
