Comparative investigation of pulmonary vasodilating effects of inhaled Nitric Oxide (NO) gas therapy and inhalation of SIN-1, a new drug formulation containing an NO-donor metabolite

Abstract

Abstract Background The management of acute pulmonary hypertension has recently been in the center of attention as Coronavirus Disease 2019 (COVID-19) might lead to acute respiratory distress syndrome associated with hypoxia-induced pulmonary vasoconstriction. Therefore inhalation therapy has been the object of several clinical trials. Purpose In this experimental study we aimed at investigating the hemodynamic effect of inhalative SIN-1a (3-morpholino-syndnonimine, the unstable active metabolite of molsidomine, stabilized by cyclodextrine) administration during physiological and pathological conditions in a large animal model. Methods Landrace pigs were randomized into the following experimental groups: iNO (inhaled nitric-oxide, n=3), SIN-1-5 (5 mg, n=3), SIN-1-10 (10 mg, n=3). Hemodynamic parameters were recorded after parallel insertion of PiCCO system and Swan-Ganz catheter. The effect of iNO and SIN-1 inhalation (30 min) was investigated under physiologic conditions and U46619, a thromboxane-receptor agonist induced pulmonary hypertension. Results The observed alterations after inhalation therapy were quite similar under physiological and pathological condition. Pulmonary arterial pressure (PAP) was decreased by all of these drugs, SIN-1-10 had similar effect as iNO (physiological contidiont: -36.1% iNO, -23.8% SIN-1-5, -35.5% SIN-1-10; U46619-induced pulmonary hypertension: -30.1% iNO, -22.1% SIN-1-5, -31.2% SIN-1-10). While iNO therapy did not influence the mean arterial pressure (MAP) and systemic vascular resistance (SVR) values, SIN-1 administration resulted in decreased MAP and SVR values. Pulmonary vascular resistance (PVR) was decreased by iNO greater than with using SIN-1. As a result of these alterations, the PVR/SVR ratio decreased markedly in the iNO group, while it was stepwisely increased in the SIN-1-5 and SIN-1-10 group. Conclusion The pulmonary vasodilator effect of SIN-1 was dose dependent, and in case of larger dose it was comparable to that of iNO. However, the vasodilatory effects of SIN-1 inhalation was not limited to the pulmonary circulation, a significant and dose-dependent systemic vasodilation could also be documented.