Objectives Due to its high morbidity and mortality rates, pulmonary arterial hypertension is a life threatening and a progressive disease. Endothelin-1 (ET1) is a vasoactive peptide that plays important role in the pathogenesis of PAH, and ET1 inhibitors have been widely used in the treatment. ET1 and Urotension-II (UII) have similar effect profiles and features. In our previous studies, UII acts similarly as ET1 and increased in patients with SSc, especially with vascular pathologies. Also we have demonstrated the positive effect of UII inhibitor Palosuran in an animal model on pulmonary arterial pressure (PAP), ET1, UII, Cardiac Muscle Mass and pathology. In this study we aimed to compare the ET1 inhibitor bosentan which is regarded as standard therapy with different dose regimens of palosuran.
Methods Seventy male mice were randomly divided into seven groups, with each group comprising 10 rats. The first level of the study has been terminated at twenty-first day, after determining the optimum dose regimens and drug combinations the study was prolonged to investigate the efficiency of palosuran and bosentan combinations and monotherapy. The extended study group was also sacrificed at the twenty-first day of the experiment. Single dose moncrataline (MCT) were injected subcutaneously to create the PAH model. Palosuran and bosentan were given twice a day by gavages. Group 1 (control group) received the serum physiologic (SP); Group 2 (untreated MCT control group) received subcutaneous MCT and SP; Group 3 (Palosuran 30 mg therapy group) received subcutaneous MCT and 30 mg/kg/day palosuran; Group 4 (Palosuran 100 mg therapy group) received subcutaneous MCT and 100 mg/kg/day palosuran; Group 5 (Bosentan 30 mg therapy group) received subcutaneous MCT and 30 mg/kg/day bosentan; Group 6 (Bosentan 100 mg therapy group) received subcutaneous MCT and 100 mg/kg/day bosentan; Group 7 (Combination therapy group) received subcutaneous MCT and 300 mg/kg/day bosentan and palosuran. Among the cardiac indexes, right ventricular hypertrophy (RVH) (right and left ventricule + septum) and right ventricular mass indexes (right ventricule and total body weight) have been used.
Results ET1, UII and PAP findings of all groups have been presented in Table-1. The ET1 and UII levels of untreated rats (group 2) were significantly higher than the other groups (p<0.05). Moreover, PAP levels of group 2 were significantly higher than the other groups (p=0.001).
Conclusions When we have compared the different dose regimens of palosuran with bosentan, UII inhibitor is at least as effective as standard therapy bosentan. Findings of this study consolidates that palosuruan could be a new future promising therapeutic option in PAH. Further human studies may require the findings of our study.
Disclosure of Interest None Declared