内皮型一氧化氮合酶在血管紧张素转换酶抑制剂和氨氯地平对心肌氧消耗的治疗性控制中的潜在作用。

Loke K E, Messina E J, Shesely E G, Kaley G, Hintze T H

Department of Physiology, New York Medical College, Valhalla, NY 10595, USA.

Cardiovasc Res. 2001 Jan;49(1):86-93. doi: 10.1016/s0008-6363(00)00196-6.

OBJECTIVES

Our aim was to investigate the potential therapeutic role of endothelial nitric oxide synthase (eNOS) in the modulation of cardiac O(2) consumption induced by the angiotensin converting enzyme (ACE) inhibitor ramiprilat and amlodipine.

METHODS

Three different groups of mice were used; wild type, wild type in the presence of N-nitro-L-arginine methyl ester (L-NAME, 10(-4) mol/l) or genetically altered mice lacking the eNOS gene (eNOS -/-). Myocardial O(2) consumption was measured using a Clark-type O(2) electrode in an air-tight stirred bath. Concentration-response curves to ramiprilat (RAM), amlodipine (AMLO), diltiazem (DIL), carbachol (CCL), substance P (SP) and S-nitroso-N-acetyl-penicillamine (SNAP) were performed. The rate of decrease in O(2) concentration was expressed as a percentage of the baseline.

RESULTS

Baseline O(2) consumption was not different between the three groups of mice. In tissues from wild type mice, RAM (10(-5) mol/l), AMLO (10(-5) mol/l), DIL (10(-4) mol/l), CCL (10(-4) mol/l), SP (10(-7) mol/l) and SNAP (10(-4) mol/l) reduced myocardial O(2) consumption by -32+/-4, -27+/-10, -20+/-6, -25+/-2, -22+/-4 and -42+/-4%, respectively. The responses to RAM, AMLO, CCL and SP were absent in tissues taken from eNOS -/- mice (-7.1+/-4.3, -5.0+/-6.0, -5.2+/-5.1 and -0.4+/-0.2%, respectively). In addition, L-NAME significantly (P<0.05) inhibited the reduction in O(2) consumption induced by RAM (-9.8+/-4.4%), AMLO (-1.0+/-6.0%), CCL (-8.8+/-3.7%) and SP (-6.6+/-4.9%) in cardiac tissues from wild type mice. In contrast, NO-independent responses to the calcium channel antagonist, DIL, and responses to the NO donor, SNAP, were not affected in cardiac tissues taken from eNOS -/- (DIL: -20+/-4%; SNAP: -46+/-6%) or L-NAME-treated (DIL: -17+/-2%; SNAP: -33+/-5%) mice.

CONCLUSIONS

These results suggest that endogenous endothelial NO synthase derived NO serves an important role in the regulation of myocardial O(2) consumption. This action may contribute to the therapeutic action of ACE inhibitors and amlodipine.

目的

我们的目的是研究内皮型一氧化氮合酶（eNOS）在调节血管紧张素转换酶（ACE）抑制剂雷米普利拉和氨氯地平诱导的心脏氧消耗中的潜在治疗作用。

方法

使用三组不同的小鼠；野生型、存在N-硝基-L-精氨酸甲酯（L-NAME，10⁻⁴mol/L）的野生型或缺乏eNOS基因的基因改造小鼠（eNOS -/-）。使用克拉克型氧电极在气密搅拌浴中测量心肌氧消耗。进行了对雷米普利拉（RAM）、氨氯地平（AMLO）、地尔硫卓（DIL）、卡巴胆碱（CCL）、P物质（SP）和S-亚硝基-N-乙酰青霉胺（SNAP）的浓度-反应曲线。氧浓度的降低速率以基线的百分比表示。

结果

三组小鼠的基线氧消耗没有差异。在野生型小鼠的组织中，RAM（10⁻⁵mol/L）、AMLO（10⁻⁵mol/L）、DIL（10⁻⁴mol/L）、CCL（10⁻⁴mol/L）、SP（10⁻⁷mol/L）和SNAP（10⁻⁴mol/L）分别使心肌氧消耗降低-32±4%、-27±10%、-20±6%、-25±2%、-22±4%和-42±4%。eNOS -/-小鼠的组织中对RAM、AMLO、CCL和SP的反应缺失（分别为-7.1±4.3%、-5.0±6.0%、-5.2±5.1%和-0.4±0.2%）。此外，L-NAME显著（P<0.05）抑制了野生型小鼠心脏组织中由RAM（-9.8±4.4%）、AMLO（-1.0±6.0%）、CCL（-8.8±3.7%）和SP（-6.6±4.9%）诱导的氧消耗降低。相比之下，在eNOS -/-（DIL：-20±4%；SNAP：-46±6%）或L-NAME处理（DIL：-17±2%；SNAP：-33±5%）的小鼠的心脏组织中，对钙通道拮抗剂DIL的非NO依赖性反应以及对NO供体SNAP的反应未受影响。