SHORT-TERM PULMONARY VASODILATION WITH L-ARGININE IN PULMONARY-HYPERTENSION

Background Endothelial dysfunction may contribute to the pathogenesis of pulmonary hypertension through impaired production of the endotheli um-derived vasodilator nitric oxide (NO). L-Arginine, the substrate fo r NO synthase (NOS), has a vasodilatory effect in systemic vascular be ds and can correct abnormal endothelium-dependent vasodilation. It has been suggested that these two effects of L-arginine are mediated thro ugh NOS metabolism and enhanced NO production. Therefore, we assessed the short-term pulmonary hemodynamic effects of exogenous L-arginine i n patients with pulmonary hypertension of various origins. Methods and Results During continuous hemodynamic monitoring, 10 subjects with pu lmonary hypertension (mean pulmonary artery pressure [PAP], 54+/-5 mmH g [mean+/-SEM]) received a 30-minute control infusion of hypertonic sa line followed by a 30-minute infusion of 500 mg/kg of L-arginine. The hemodynamic effects of L-arginine were compared with those of prostacy clin titrated to maximally tolerated doses. The hemodynamic response t o L-arginine was also studied in 5 subjects with heart failure but wit hout pulmonary hypertension (mean PAP, 20+/-2 mm Hg) and 5 healthy con trol subjects. In subjects with pulmonary hypertension; infusion of L- arginine reduced mean PAP by 15.8+/-3.6% (P<.005) and pulmonary vascul ar 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 pro stacyclin. L-Arginine infusion also increased the mean plasma level of L-arginine from 59+/-6 mu mol/L to 10 726+/-868 mu mol/L (P<.005), wh ich was associated with a significant increase in the plasma level of L-citrulline, the immediate product of NOS metabolism of L-arginine. M oreover, the peak plasma level of L-citrulline correlated significantl y with the reductions in mean PAP (r=.71, P<.05) and PVR (r=.70, P<.05 ), consistent with vasodilation mediated by NOS metabolism of exogenou s L-arginine and increased NO production. L-Arginine also had a modest hypotensive effect in healthy control subjects and reduced systemic v ascular resistance in subjects with heart failure in the absence of pu lmonary hypertension. However, only small reductions in absolute pulmo nary vascular resistance were observed in this latter group in respons e to L-arginine that did not reach significance. Conclusions An exagge rated short-term pulmonary vasodilatory response to L-arginine in pati ents with pulmonary hyper tension suggests a relative impairment in pu lmonary vascular endothelial NO production that may contribute to incr eased pulmonary vascular tone and thus be important in the pathophysio logy of pulmonary hypertension.