L-arginine improves vascular function by overcoming the deleterious effects of ADMA, a novel cardiovascular risk factor

Alternative Medicine Review, March, 2005 by Rainer H. Boger, Eyal S. Ron

Sickle Cell Disease and Pulmonary Hypertension

Pulmonary hypertension is a life-threatening complication of sickle cell disease reported to occur in up to 30 percent of adults with this disease. The etiology of sickle cell disease-related pulmonary hypertension is unclear. Treatment options are limited, and the prognosis is poor. Patients who develop this complication have a shortened lifespan. Its presence is an independent predictor of death, with an average time to death after diagnosis as short as 12 months.

Several studies in non-sickle cell disease patients demonstrate therapeutic benefits of L-arginine therapy for pulmonary hypertension. (58,59) Low plasma L-arginine concentrations have been discovered in infants with persistent pulmonary hypertension of the newborn, (60) correlating with low nitric oxide metabolite levels. (61) L-arginine infusion has decreased pulmonary vascular resistance and improved blood oxygenation in infants with this disease process. (62) L-arginine supplementation also improves pulmonary artery pressures and hemodynamics in patients with primary and secondary pulmonary hypertension, (59) with one recent study demonstrating these effects after only one week of therapy. (58)

Recent studies found that oral L-arginine normalizes red blood cell density and induces Gardos channel inhibition in sickle cell transgenic mice. (63) There is otherwise limited information available on the impact of L-arginine supplementation in sickle cell disease. (64)

There is growing evidence that pulmonary hypertension is a disease process that involves altered L-arginine metabolism or decreased bioavailability. Arginase, the enzyme that converts L-arginine to ornithine and urea, may limit NO bioavailability in sickle cell disease through increased use of its substrate. (65) In one recent study, L-arginine at a dose of 0.1 g/kg three times daily produced a 15.2-percent mean reduction in estimated pulmonary artery systolic pressure (63.9 [ or -] 13 to 54.2 [ or -] 12 mm Hg, p = 0.002) after five days of therapy in 10 patients. Arginase activity was elevated almost two-fold (p = 0.07) in patients with pulmonary hypertension and may limit L-arginine bioavailability. (65) Because L-arginine supplementation improves pulmonary artery pressures in non-sickle cell patients with pulmonary hypertension, L-arginine may also be therapeutic for sickle cell disease patients with pulmonary hypertension by providing increased substrate for NO production.

Beneficial Effects of Supplemental Sustained-release L-Arginine

From the above-mentioned studies of L-arginine, it appears an effective method of improving endothelial function would be to supplement with L-arginine. Oral L-arginine, however, is absorbed and metabolized quickly; the half-life of L-arginine in human circulating plasma is less than one hour. (66) A controlled-release formulation of L-arginine would increase the length of time in which L-arginine achieves an effective concentration.

Boger et al found 1.5 g of a sustained-release L-arginine taken twice daily improved endothelium-dependent vasodilation in patients with high plasma ADMA levels. (45) In previous studies, the same group of researchers showed at least 6 g L-arginine in a nonsustained release formulation was needed to achieve a similar effect. (67)