Mehta S, Stewart D J, Langleben D, Levy R D
Respiratory Division, Royal Victoria Hospital, Montréal, Québec, Canada.
Circulation. 1995 Sep 15;92(6):1539-45. doi: 10.1161/01.cir.92.6.1539.
Endothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension through impaired production of the endothelium-derived vasodilator nitric oxide (NO). L-Arginine, the substrate for NO synthase (NOS), has a vasodilatory effect in systemic vascular beds and can correct abnormal endothelium-dependent vasodilation. It has been suggested that these two effects of L-arginine are mediated through NOS metabolism and enhanced NO production. Therefore, we assessed the short-term pulmonary hemodynamic effects of exogenous L-arginine in patients with pulmonary hypertension of various origins.
During continuous hemodynamic monitoring, 10 subjects with pulmonary hypertension (mean pulmonary artery pressure [PAP], 54 +/- 5 mm Hg [mean +/- SEM]) received a 30-minute control infusion of hypertonic saline followed by a 30-minute infusion of 500 mg/kg of L-arginine. The hemodynamic effects of L-arginine were compared with those of prostacyclin titrated to maximally tolerated doses. The hemodynamic response to L-arginine was also studied in 5 subjects with heart failure but without pulmonary hypertension (mean PAP, 20 +/- 2 mm Hg) and 5 healthy control subjects. In subjects with pulmonary hypertension, infusion of L-arginine reduced mean PAP by 15.8 +/- 3.6% (P < .005) and pulmonary vascular resistance (PVR) by 27.6 +/- 5.8% (P < .005) compared with decreases of 13.0 +/- 5.5% (P < .005) and 46.6 +/- 6.2% (P < .005), respectively, with prostacyclin. L-Arginine infusion also increased the mean plasma level of L-arginine from 59 +/- 6 mumol/L to 10,726 +/- 868 mumol/L (P < .005), which was associated with a significant increase in the plasma level of L-citrulline, the immediate product of NOS metabolism of L-arginine. Moreover, the peak plasma level of L-citrulline correlated significantly with the reductions in mean PAP (r = .71, P < .05) and PVR (r = .70, P < .05), consistent with vasodilation mediated by NOS metabolism of exogenous L-arginine and increased NO production. L-Arginine also had a modest hypotensive effect in healthy control subjects and reduced systemic vascular resistance in subjects with heart failure in the absence of pulmonary hypertension. However, only small reductions in absolute pulmonary vascular resistance were observed in this latter group in response to L-arginine that did not reach significance.
An exaggerated short-term pulmonary vasodilatory response to L-arginine in patients with pulmonary hypertension suggests a relative impairment in pulmonary vascular endothelial NO production that may contribute to increased pulmonary vascular tone and thus be important in the pathophysiology of pulmonary hypertension.
内皮功能障碍可能通过内皮源性血管舒张因子一氧化氮（NO）生成受损而促进肺动脉高压的发病机制。L-精氨酸是一氧化氮合酶（NOS）的底物，在体循环血管床具有血管舒张作用，并可纠正异常的内皮依赖性血管舒张。有人提出，L-精氨酸的这两种作用是通过NOS代谢和增强NO生成介导的。因此，我们评估了外源性L-精氨酸对各种原因所致肺动脉高压患者的短期肺血流动力学影响。
在持续血流动力学监测期间，10例肺动脉高压患者（平均肺动脉压[PAP]，54±5 mmHg[平均值±标准误]）先接受30分钟的高渗盐水对照输注，随后接受30分钟的500 mg/kg L-精氨酸输注。将L-精氨酸的血流动力学效应与滴定至最大耐受剂量的前列环素的效应进行比较。还在5例心力衰竭但无肺动脉高压（平均PAP，20±2 mmHg）的患者和5例健康对照者中研究了对L-精氨酸的血流动力学反应。在肺动脉高压患者中，与前列环素分别使平均PAP降低13.0±5.5%（P<0.005）和肺血管阻力（PVR）降低46.6±6.2%（P<0.005）相比，输注L-精氨酸使平均PAP降低15.8±3.6%（P<0.005），PVR降低27.6±5.8%（P<0.005）。输注L-精氨酸还使L-精氨酸的平均血浆水平从59±6 μmol/L升高至10726±868 μmol/L（P<0.005），这与L-精氨酸的NOS代谢直接产物L-瓜氨酸的血浆水平显著升高相关。此外，L-瓜氨酸的血浆峰值水平与平均PAP的降低（r = 0.71，P<0.05）和PVR的降低（r = 0.70，P<0.05）显著相关，这与外源性L-精氨酸的NOS代谢介导血管舒张和NO生成增加一致。L-精氨酸在健康对照者中也有适度的降压作用，并在无肺动脉高压的心力衰竭患者中降低了体循环血管阻力。然而，在后者组中，仅观察到L-精氨酸使绝对肺血管阻力有小幅度降低，未达到显著水平。
肺动脉高压患者对L-精氨酸的短期肺血管舒张反应过度提示肺血管内皮NO生成相对受损，这可能导致肺血管张力增加，因此在肺动脉高压的病理生理学中起重要作用。
