s GC stimulation totally reverses hypoxia‐induced pulmonary vasoconstriction alone and combined with dual endothelin‐receptor blockade in a porcine model

Aim Stimulation of soluble guanylate cyclase (s GC ) with BAY 41‐8543 was hypothesized to attenuate acute hypoxic pulmonary vasoconstriction alone and combined with dual endothelin ( ET )‐receptor antagonist tezosentan. Methods Measurements were taken in 18 anaesthetized pigs with a mean ±  SEM weight of 31.1 ± 0.4 kg, in normoxia ( FiO 2 ~0.21) and hypoxia ( FiO 2 ~0.10) without (control protocol, n  = 6), and with right atrial infusion of BAY 41‐8543 at 1, 3, 6, 9 and 12 μg min −1 per kg (protocol 2, n  = 6) or tezosentan at 5 mg kg −1 followed by BAY 41‐8543 at 1, 3 and 6 μg min −1 per kg (protocol 3, n  = 6). Results Hypoxia ( n  = 18) increased ( P  < 0.001) mean pulmonary artery pressure ( MPAP ) and pulmonary vascular resistance ( PVR ) by 14.2 ± 0.6 mmHg and 2.8 ± 0.3 WU respectively. During sustained hypoxia without treatment, MPAP and PVR remained stable. BAY 41‐8543 ( n  = 6) dose‐dependently decreased ( P  < 0.001) MPAP and PVR by 15.0 ± 1.2 mmHg and 4.7 ± 0.7 WU respectively. Tezosentan ( n  = 6) decreased ( P  < 0.001) MPAP and PVR by 11.8 ± 1.2 mmHg and 2.0 ± 0.2 WU , respectively, whereafter BAY 41‐8543 ( n  = 6) further decreased ( P  < 0.001) MPAP and PVR by 6.6 ± 0.9 mmHg and 1.9 ± 0.4 WU respectively. Both BAY 41‐8543 and tezosentan decreased ( P  < 0.001) systemic arterial pressure and systemic vascular resistance. Blood‐ O 2 consumption remained unaltered ( P  = ns) during all interventions. Conclusion BAY 41‐8543 totally reverses the effects of acute hypoxia‐induced pulmonary vasoconstriction, and enhances the attenuating effects of tezosentan, without affecting oxygenation. Thus, s GC stimulation, alone or combined with dual ET ‐receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.