Reversal of pulmonary vascular remodeling induced by hypoxia in mice by the soluble guanylate cyclase activator Bay 58–2667

Severe pulmonary hypertension is a disabling disease with high mortality. We investigated the effects of the soluble guanylate cyclase activator Bay 58–2667 on hemodynamics and vascular remodeling in hypoxia-induced pulmonary hypertension in mice. Twenty-one and 35 days after chronic hypoxia (10 % O₂), right ventricular systolic pressure (RVSP) increased from 22,4±2,0 to 38,9±3,8 and 44,3±5,2mm Hg, respectively. Marked right heart hypertrophy was demonstrated by the strongly elevated ratio of right ventricle/left ventricle plus septum weight and thickening of the precapillary artery smooth muscle layer. When chronically applied from day 21–35 (after full establishment of severe pulmonary hypertension) by gavage at a dose of 30mg/kg day, Bay 58–2667 significantly attenuated all hypoxia-induced hemodynamic abnormalities (RVSP: 32,4±3,3mm Hg) as well as right heart hypertrophy. Pulmonary vascular remodeling changes were significantly reversed. We conclude that activation of soluble guanylate cyclase by Bay 58–2667 reverses hypoxia-induced pulmonary hypertension in mice. This regimen may therefore offer a possible anti-remodeling therapy in severe pulmonary hypertension.