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(Circulation. 1995;92:1539-1545.)
© 1995 American Heart Association, Inc.
Articles |
Short-term Pulmonary Vasodilation With L-Arginine in Pulmonary Hypertension
From the McGill Vascular Biology Group, Respiratory and Cardiology Divisions, and Meakins-Christie Laboratories, Royal Victoria Hospital, and the Cardiology Division, Sir Mortimer B. Davis Jewish General Hospital, McGill University, Montréal, Québec, Canada.
Correspondence and reprint requests to D.J. Stewart, MD, Cardiology Division, Room 712B, St Michael's Hospital, 30 Bond St, Toronto, Ontario M5B 1W8, Canada.
Background 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.
Methods and Results 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 µmol/L to 10 726±868 µmol/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.
Conclusions 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.
Key Words: hypertension, pulmonary • endothelium • endothelium-derived factors • vasodilation
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