Combined oral administration of L-arginine and tetrahydrobiopterin in a rat model of pulmonary arterial hypertension

Alterations in the nitric oxide (NO) pathway play a major role in pulmonary arterial hypertension (PAH). L-arginine (LA) and tetrahydrobiopterin (BH(4)) are main substrates in the production of NO, which mediates pulmonary vasodilation. Administration of either LA or BH(4) decrease pulmonary artery pressure (PAP). A combined administration of both may have synergistic effects in the therapy of PAH. In a telemetrically monitored model of unilateral pneumonectomy and monocrotaline-induced PAH, male Sprague-Dawley rats received either LA (300 mg/kg; n = 15), BH(4) (20 mg/kg; n = 15), the combination of LA and BH(4) (300 mg/kg, 20 mg/kg; n = 15), or vehicle (control group; n = 10) from day 28 after monocrotaline induction. Therapy was orally administered once daily over consecutive 14 days. LA, BH(4), or both equally lowered PAP, increased pulmonary vascular elasticity, restored spontaneous locomotoric activity, prevented body weight loss and palliated small vessel disease of severely pulmonary hypertensive rats. BH(4) substitution lowered asymmetric dimethylarginine levels sustainably at 60 min after administration and downregulated endothelial NO synthase mRNA expression. No significant survival, macro- and histomorphologic or hemodynamic differences were found between therapy groups at the end of the study period. Administration of LA and BH(4) both mediated a decrease of mean PAP, attenuated right ventricular hypertrophy and small vessel disease in monocrotaline-induced pulmonary hypertensive rats, though a combined administration of both substances did not reveal any synergistic therapy effects in our animal model.