Münzel T, Mülsch A, Holtz J, Just H, Harrison D G, Bassenge E
Department of Medicine, Freiburg University, FRG.
Circulation. 1992 Sep;86(3):995-1003. doi: 10.1161/01.cir.86.3.995.
L-Methionine potentiates systemic hemodynamic effects of intravenous glyceryl trinitrate (GTN) in tolerant and nontolerant patients to a similar extent as N-acetylcysteine (NAC). This potentiation of GTN action by L-methionine has been attributed to enhanced intracellular formation of nitrosothiols, known to be potent stimulators of soluble guanylyl cyclase. This study was performed to analyze directly the effects of L-methionine on GTN-induced dilation of large epicardial arteries and the venous capacitance system of the dog in the tolerant and nontolerant states. Cultured rat aortic vascular smooth muscle cells and purified guanylyl cyclase were used to study potential intracellular and extracellular mechanisms responsible for this interaction.
In awake nontolerant dogs, L-methionine (100 mg/kg) potentiated the tachycardic response to GTN (5.0 and 15 micrograms/kg/min) and enhanced the hypotensive action of GTN (1.5 and 5.0 micrograms/kg/min) in anesthetized, nonreflexic dogs. In nontolerant and tolerant dogs, however, L-methionine did not alter the dose-response of large epicardial artery dilation to intravenous GTN challenges and did not modify nitrate tolerance of the low pressure system of the dog. The infusion of L-methionine (100 mg/kg) significantly increased plasma methionine levels (from 52 +/- 12 to 1,141 +/- 239 microM), cystine levels (from 12 +/- 4 to 26 +/- 7 microM), but not homocystine levels. In vitro, the L-methionine conversion product L-cysteine (0.1-1.0 mM) but not homocysteine significantly enhanced the augmentation of purified guanylyl cyclase activity by GTN (100 microM). Incubation of cultured rat aortic smooth muscle cells with L-methionine (10 microM or 1 mM) did not result in a significant increase of free intracellular sulfhydryl group content.
The L-methionine conversion product L-cysteine mediates tolerance independent the potentiation of GTN action. This may result from an L-cysteine-induced formation of a vasoactive metabolite of GTN (nitric oxide) or nitrosothiol. This effect occurs primarily in the resistance vessel circulation, not in large epicardial arteries and veins. The lack of effect of L-methionine on sulfhydryl group content in large conductance vessels indicates that hepatic L-methionine metabolism constitutes the significant source of L-cysteine. These findings strongly suggest that administration of sulfhydryl-group precursor L-methionine does not represent a therapeutic alternative to a nitrate-free interval to restore nitrate sensitivity in tolerant large epicardial arteries and veins.
L-蛋氨酸增强静脉注射硝酸甘油（GTN）对耐受和非耐受患者的全身血流动力学效应，其程度与N-乙酰半胱氨酸（NAC）相似。L-蛋氨酸对GTN作用的这种增强归因于亚硝基硫醇细胞内生成增加，已知亚硝基硫醇是可溶性鸟苷酸环化酶的有效刺激剂。本研究旨在直接分析L-蛋氨酸对GTN诱导的犬在耐受和非耐受状态下大的心外膜动脉和静脉容量系统扩张的影响。使用培养的大鼠主动脉血管平滑肌细胞和纯化的鸟苷酸环化酶来研究负责这种相互作用的潜在细胞内和细胞外机制。
在清醒的非耐受犬中，L-蛋氨酸（100mg/kg）增强了对GTN（5.0和15μg/kg/min）的心动过速反应，并增强了GTN（1.5和5.0μg/kg/min）对麻醉、无反射犬的降压作用。然而，在非耐受和耐受犬中，L-蛋氨酸并未改变大的心外膜动脉对静脉注射GTN刺激的剂量反应，也未改变犬低压系统的硝酸盐耐受性。输注L-蛋氨酸（100mg/kg）显著提高了血浆蛋氨酸水平（从52±12μM升至1141±239μM）、胱氨酸水平（从12±4μM升至26±7μM），但未提高同型半胱氨酸水平。在体外，L-蛋氨酸的转化产物L-半胱氨酸（0.1 - 1.0mM）而非同型半胱氨酸显著增强了GTN（100μM）对纯化鸟苷酸环化酶活性的增强作用。用L-蛋氨酸（10μM或1mM）孵育培养的大鼠主动脉平滑肌细胞并未导致细胞内游离巯基含量显著增加。
L-蛋氨酸的转化产物L-半胱氨酸介导耐受性，与GTN作用的增强无关。这可能是由于L-半胱氨酸诱导形成了GTN的血管活性代谢产物（一氧化氮）或亚硝基硫醇。这种效应主要发生在阻力血管循环中，而非大的心外膜动脉和静脉中。L-蛋氨酸对大传导血管中巯基含量缺乏影响表明肝脏L-蛋氨酸代谢是L-半胱氨酸的重要来源。这些发现强烈表明，给予巯基前体L-蛋氨酸并不能替代无硝酸盐间期来恢复耐受的大的心外膜动脉和静脉的硝酸盐敏感性。
