Chronic dosing with metformin plus bosentan decreases in vitro pulmonary artery contraction from isolated arteries in adults with pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) specific drug therapy using bosentan has significantly improved quality of life and survival, although PAH is still an incurable disease. Recent studies suggest metformin may have additional treatment benefits in PAH. We therefore investigated in vitro pulmonary artery reactivity after combination therapy of bosentan and metformin in PAH patients as compared with bosentan monotherapy in a prospective, randomized study. Methods: Adult patients with PAH associated with congenital heart defects (PAH-CHD) were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily). Vessel reactivity of isolated pulmonary arteries was examined using a wire myograph. Results: Phenylephrine (PE)-induced contractions of arteries in patients received combination therapy were significantly attenuated at concentrations of 3 × 10(-7) M, 10(-6) M and 3 × 10(-6) M, compared to those received bosentan monotherapy. After denudation, PE-induced contractions at concentrations of 3 × 10(-6) M and 10(-5) M were significantly decreased in the combination therapy group. AMP-activated protein kinase (AMPK) inhibitor compound C abrogated the inhibitory effects of metformin on PE-induced contractility. AMPK and eNOS phosphorylation in the pulmonary arteries of patients treated with combination therapy was increased compared to monotherapy (P < 0.05). Conclusion: Adding metformin to bosentan therapy in patients with PAH-CHD decreased in vitro pulmonary artery contraction induced by PE, which is possibly related to increased AMPK phosphorylation.