sGC 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 (sGC) 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 +/- 0.4kg, in normoxia (FiO20.21) and hypoxia (FiO20.10) without (control protocol, n=6), and with right atrial infusion of BAY 41-8543 at 1, 3, 6, 9 and 12 mu gmin-1per kg (protocol 2, n=6) or tezosentan at 5mg kg-1 followed by BAY 41-8543 at 1, 3 and 6 mu gmin-1per 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 +/- 0.6mmHg 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 +/- 1.2mmHg and 4.7 +/- 0.7 WU respectively. Tezosentan (n=6) decreased (P<0.001) MPAP and PVR by 11.8 +/- 1.2mmHg and 2.0 +/- 0.2 WU, respectively, whereafter BAY 41-8543 (n=6) further decreased (P<0.001) MPAP and PVR by 6.6 +/- 0.9mmHg 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-O2 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, sGC stimulation, alone or combined with dual ET-receptor blockade, could offer a means to treat pulmonary hypertension related to hypoxia and potentially other causes.