Comparison of different vasodilators, endothelin antagonist, PDE5 inhibitior and sGC stimulators, in an animal model of secondary pulmonary hypertension: effects on “desaturation”

Abstract

Methods Single-lung ventilation (right sided) was induced in 7-wk old minipigs (4-5 kg BW). In each animal 5 repetitive cycles of 10 min. left lobe blockade were followed by 30 min. bilateral ventilation. Hemodynamics (e.g. mean pulmonary artery pressure (mPAP), blood pressure (BP)) and arterial hemoglobin saturation (SaO2) were monitored continuously. We compared 5 different groups (n=6 each): vehicle control group, the endothelin antagonist bosentan (0.3, 1, 3, 10 mg/kg i.v.), the PDE5 inhibitor sildenafil (3, 10, 30, 100 μg/kg i.v.), and the sGC stimulators BAY 41-8543 (1, 3, 10, 30 μg/kg i.v.) and riociguat (1, 3, 10, 30 μg/kg i.v.). The vasodilator doses were chosen to achieve equal BP reduction. Cumulative doses of vasoactive compounds were applied before successive unilateral ventilation and effects on desaturation (area under the SaO2 curve, AUCSaO2) and maximal hypoxic mPAP were compared to vehicle conditions in each animal. Results Single-lung ventilation resulted in transient increases in mPAP and desaturation (=increase in AUCSaO2). The vasodilators were compared in respect to their ability to decrease maximal hypoxic mPAP (positive treatment effect) and AUCSaO2 (unwanted desaturation effect). In contrast to vehicle treated control animals all vasodilators lead to a dose-dependent decrease in hypoxic mPAP (Figure 1) and an increase in AUCSaO2 during successive unilateral ventilation. Maximal changes in