Effects of Different Pulmonary Vasodilators on Arterial Saturation in a Model of Pulmonary Hypertension

Abstract

BackgroundApproved therapies for pulmonary arterial hypertension can induce oxygen desaturation when administered to patients with secondary forms of pulmonary hypertension (PH), probably due to an increase in ventilation/perfusion mismatch. Thus, so far these treatments have largely failed in secondary forms of PH.MethodsWe established an animal model of heterogeneous lung ventilation to evaluate the desaturation potential of mechanistically distinct vasoactive drugs launched or currently in clinical development for the treatment of PH. Single-lung ventilation was induced in five groups (N = 6) of anesthetized minipigs (7 weeks, 4 to 5 kg BW), and their hemodynamic parameters were monitored before and after intravenous injection of control (vehicle only), endothelin antagonist (bosentan; 0.3, 1, 3, 10 mg/kg), phosphodiesterase type 5 inhibitor (sildenafil; 3, 10, 30, 100 µg/kg), and soluble guanylate cyclase stimulators (BAY 41–8543 and riociguat; 1, 3, 10, 30 µg/kg). Cumulative doses were administered before successive unilateral ventilation cycles. The doses were chosen to achieve equal effect on blood pressure by the different pharmacologic principles.ResultsSingle-lung ventilation resulted in transient increases in mean pulmonary artery pressure (mPAP) and desaturation. In contrast to control, all drugs dose-dependently decreased hypoxic mPAP (a positive treatment effect) and increased area under the arterial hemoglobin saturation curve (unwanted desaturation effect). Riociguat and bosentan reduced hypoxic mPAP to the greatest extent, while the soluble guanylate cyclase stimulators riociguat and BAY 41–8543 lowered arterial oxygen saturation of hemoglobin the least.ConclusionsFuture investigations will be required to confirm these findings in clinical settings.

JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study

“…Therapeutic administration of JSI-124 from day 7 to day 28 of the experimental procedure improved rat pulmonary artery remodelling, right ventricle hypertrophy, PH, ventilation, lung blood perfusion and V/Q mismatching induced by bleomycin. In contrast, bosentan predominantly increased perfusion and in a lesser extent ventilation, showing a mild impairment of V/Q as previously outlined 49. Although results provided in this work relates JAK2 with IPF and PH, it should be noted that human samples used are from no more than 10 patients, a small sample that can limit the interpretation of this work.…”

Continuous intravenous sildenafil as an early treatment in neonates with congenital diaphragmatic hernia

“…Pulmonary vasodilators have been associated with hypoxemia due to attenuation of hypoxic pulmonary vasoconstriction (Euler‐Liljestrand mechanism) and an increase in intrapulmonary shunts . This effect has been confirmed in animal models of heterogeneous lung ventilation and should be considered in infants with a ventilation‐perfusion mismatch .…”

Riociguat, sildenafil and inhaled nitric oxide reduces pulmonary vascular resistance and improves right ventricular function in a porcine model of acute pulmonary embolism

“…For riociguat, our results contrast with previous studies where systemic vasodilation with decreased SVR and MAP at similar doses were observed. 14,22,23,28 Sildenafil has previously been shown to induce systemic vasodilation and hypotension. 29 Sildenafil did not cause a significant reduction in systemic blood pressure in this study, but this should be taken with caution due to the small sample size.…”

“…This indicates that NO-sGC-cGMP stimulation did not worsen the ventilation/ perfusion mismatch as a result of increased intrapulmonary shunting -an adverse effect reported in experimental studies and clinical cases. 4,28,35,36 The potential for improvement in respiratory parameters was limited by the only mild respiratory impairment of this model. Since hypoxia was avoided, the pulmonary vasodilatory effects found in the present study can be attributed directly to NO-sGC-cGMP vascular stimulation and not to attenuation of hypoxia or hypercapnia.…”