Clin Res Cardiol (2022). https://doi.org/10.1007/s00392-022-02002-5

The pan-Gq inhibitor FR is a strong pulmonary vasorelaxant in health and disease

A. Seidinger1, R. Roberts2, G. M. König3, E. Kostenis4, B. K. Fleischmann3, D. Wenzel1

1Abteilung für Systemphysiologie, Ruhr-Universität Bochum, Bochum; 2Queen's Medical Centre, University of Nottingham, Nottingham, UK; 3Physiologie I Life & Brain Center, Universitätsklinikum Bonn, Bonn; 4Institut für Pharmazeutische Biologie, Universität Bonn, Bonn;

Pulmonary arterial hypertension (PAH) is a progressive disease based on excessive pulmonary vasoconstriction, vascular remodeling and right heart hypertrophy that can result in heart failure and premature death. Although therapeutic approaches have improved over the last years, there are still patients that do not adequately respond to currently approved drugs. Gq proteins are signaling hubs mediating pulmonary vasoconstriction and therefore they are promising targets for pharmacological therapy. Thus, we applied the specific pharmacological pan-Gq protein inhibitor FR900359 (FR) in various in vitro, ex vivo and in vivo approaches using mouse, pig and human cells/tissues in order to compare its efficacy with currently approved drugs and to analyze its potential to affect the development of PAH. To investigate the effect of FR on pulmonary vascular tone ex vivo isometric force measurements of mouse and pig pulmonary arteries (PAs) were performed and FR was analyzed in precision-cut lung slices and the isolated perfused lung (IPL) model of mouse. The vasodilatory effect as well as the impact of FR on human pulmonary artery smooth muscle cell (hPASMC) growth was compared with that of drugs approved for PAH (bosentan, iloprost, sildenafil). To test FR in vivo, FR or sildenafil was acutely applied followed by serotonin during monitoring of pulmonary hemodynamics by a Millar pressure catheter. Finally, the potential of FR to prevent and reverse hypoxia-induced pulmonary hypertension (PH) was assessed in a disease model. FR induced a pronounced relaxation of mouse PAs pre-constricted with 5-HT (79.2 ± 2.5 %), ET-1 (71.8 ± 1.2 %) or the thromboxane analog U-466419 (52.2 ± 3.0 %). Furthermore, FR attenuated dose-dependent constriction of 5-HT and U-46619 in mouse and ET-1 in mouse and pigs. Additionally, we found a much stronger dose-dependent relaxation of FR after ET-1-dependent pre-constriction (74.6 ± 2.8 %, n=7) compared to that of equal concentrations of bosentan (8.8 ± 2.9 %, n=5), iloprost (27.5 ± 3.9 %, n=7) and sildenafil (34.6 ± 3.5 %, n=6). Apart from its effect on large PAs in mouse FR induced a prominent relaxation in pathophysiologically relevant small intrapulmonary arteries (93.0 ± 1.2 %, n=7) and in the whole lung IPL model (98.9 ± 6.4 %, n=6). FR reduced PDGF and thrombin-dependent cell growth of hPASMCs to a similar extent as bosentan and iloprost, while sildenafil was ineffective. Acute i.t. application of FR in vivo prevented serotonin-induced pressure increase by 65 % in healthy animals and 75 % in animals with hypoxia-induced PH compared to vehicle. In both experimental paradigms, sildenafil showed no effect. In addition, the repetitive application of FR prevented all signs of hypoxia-induced PH. Most importantly, FR also reversed right ventricular systolic pressure increase (DMSO: 29.1 ± 3.9 mmHg vs. FR 24.5 ± 0.5 mmHg), pulmonary vascular wall thickening (DMSO: 23.3 ± 0.5 % vs. FR: 18.0 ± 0.5 %) and right ventricular cardiomyocyte area increase/hypertrophy (DMSO: 302.4 ± 4.2 µm2 vs. FR: 270.5 ± 4.7 µm2) in animals with pre-existing PH (all p<0.001). In conclusion, the pan-Gq inhibitor FR is a powerful relaxant of PAs in mouse and pig ex and/or in vivo and prevents hPASMC growth in vitro. Interestingly, the FR effect appears superior to clinically applied drugs for PH, as it can reduce both vascular tone and hPASMC growth. Thus, inhibition of Gq proteins could be a promising future treatment strategy in PAH.

https://dgk.org/kongress_programme/jt2022/aV1300.html