act-058362 and Hypertension--Pulmonary

Pulmonary arterial hypertension (PAH) is a progressive and fatal disorder that any valuable advance in the management of diseases has crucial importance. The present study aimed to compare the Endothelin1 (ET1) inhibitor bosentan which is regarded as standard therapy with different dose regimens of palosuran which is urotensin-II (UII) inhibitor and explore the discrepancy for mean pulmonary arterial pressure (mPAP), UII, ET1 levels, and pulmonary vascular pathology. Seventy rats were randomly divided into seven groups of ten animals each: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran 30 mg) received subcutaneous MCT and palosuran. Other groups consist of group 4 (MCT + palosuran 100 mg), group 5 (MCT + bosentan 30 mg), group 6 (MCT + bosentan 100 mg), and group 7 (combination therapy). Serum ET1, UII, mPAP levels, and pulmonary arteriolar pathology of different diameter vessels of all groups have been measured and recorded. The ET1 and UII levels of untreated rats (group 2) were significantly higher than the other groups (p < 0.05). Moreover, mPAP levels of group 2 were significantly higher than the other groups (p = 0.001). Finally, 50-125-μm diameter of arteriole wall thickness was found to be significantly thicker in monocrotaline group compared to groups 4 and 6 (p < 0.001). Statistical differences of wall thickness/diameter ratios of arteries and arterioles larger than 125 was found to be significant between group 5, group 6, and the control group (p < 0.001). UII inhibitor is at least as effective as standard therapy bosentan. Findings of this study consolidate that palosuran could be a new future promising therapeutic option in PAH.

Topics: Animals; Arterial Pressure; Bosentan; Disease Models, Animal; Endothelin Receptor Antagonists; Endothelin-1; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Monocrotaline; Pulmonary Artery; Quinolines; Rats; Rats, Wistar; Sulfonamides; Urea; Urotensins

Pulmonary arterial hypertension (PAH) is a progressive and a life-threatening disease with its high morbidity and mortality ratios. On searching for new shining targets in pathogenesis, we noticed, in our previous studies, urotensin-II (UII) in systemic sclerosis with potent angiogenic and pro-fibrotic features. Owing to the mimicking properties of UII with endothelin-1 (ET1), we attempted to investigate the effect of palosuran in a PAH rat model. Thirty rats were randomly divided into three groups, with each group comprising 10 rats: group 1 (control group) received the vehicle subcutaneously, instead of monocrotaline (MCT) and vehicle; group 2 (MCT group) received subcutaneous MCT and vehicle; and group 3 (MCT + palosuran group) received subcutaneous MCT and palosuran. Serum UII, ET1, transforming growth factor-β1 (TGF-β1) levels, pulmonary arteriolar pathology of different diameter vessels, and cardiac indices were evaluated. The ET1, TGF-β1, and UII levels were significantly diminished in the treatment group, similar to the controls (p < 0.001). Right ventricular hypertrophy index and mean pulmonary arterial pressure scores were also significantly reduced in the treatment group (p = 0.001). Finally, in the 50-125-μm diameter arterioles, in contrast to Groups 3 and 1, there was a statistically significant thickness (p < 0.01) in the arteriolar walls of rats in Group 2. The treatment effect on arteries of more than 125-μm diameters was found to be valuable but not significant. Owing to its healing effect on hemodynamic, histological, and biochemical parameters of MCT-induced PAH, palosuran as an antagonist of UII might be an optional treatment alternative for PAH.

Topics: Animals; Arterial Pressure; Arterioles; Endothelin-1; Familial Primary Pulmonary Hypertension; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Pulmonary Artery; Quinolines; Rats; Rats, Wistar; Transforming Growth Factor beta1; Urea; Urotensins

Meconium aspiration syndrome (MAS) disrupts perinatal decreases in pulmonary vascular resistance (PVR) and is the commonest cause of neonatal pulmonary hypertension. The contribution of the potent vasoactive agent urotensin-II (U-II), in the pathophysiology of this condition, is unknown. In a new perinatal model of MAS, we combined measurement of circulating U-II levels with U-II receptor blockade studies. Nineteen anesthetized lambs were instrumented then randomly allocated to the following groups: 1) control (n = 5), 2) control plus specific U-II receptor blockade with palosuran (n = 5), 3) tracheal instillation of meconium (n = 5), 4) meconium instillation plus palosuran (n = 4). Hemodynamics, PVR, and plasma U-II were measured for 6 h after delivery. After birth in controls, U-II increased (p < 0.05), and PVR fell (p = 0.01) and this fall was prevented by U-II receptor blockade. By contrast, meconium lambs displayed a greater rise in U-II levels (p < 0.05 versus control) with an increase in PVR (p < 0.005) that was attenuated by U-II receptor blockade (p < 0.001). These findings suggest that U-II normally acts as a pulmonary vasodilator after birth, but in the presence of MAS, it assumes a vasoconstrictor role. U-II receptor blockade also improves pulmonary hemodynamics in this model.

Topics: Animals; Animals, Newborn; Blood Pressure; Cardiac Output; Disease Models, Animal; Endothelin-1; Female; Humans; Hypertension, Pulmonary; Infant, Newborn; Meconium Aspiration Syndrome; Oxygen; Pulmonary Artery; Quinolines; Receptors, G-Protein-Coupled; Sheep; Time Factors; Up-Regulation; Urea; Urotensins; Vascular Resistance; Vasoconstriction; Vasodilation