Monocrotaline-induced pulmonary arterial hypertension: Time-course of injury and comparative evaluation of macitentan and Y-27632, a Rho kinase inhibitor.

Abstract

Novel pharmacological approaches are needed to improve outcomes of patients with idiopathic pulmonary hypertension. Rho-associated protein kinase (ROCK) inhibitors have shown beneficial effects in preclinical models of pulmonary arterial hypertension (PAH), because of their role in the regulation of pulmonary artery vasoconstrictor tone and remodeling. We compared a ROCK inhibitor, Y-27632, for the first time with the dual endothelin receptor antagonist, macitentan, in a monocrotaline-induced rat pulmonary hypertension model. Different methods (echocardiography, hemodynamics, histology of right ventricle and pulmonary vessels, and circulating biomarkers) showed consistently that 100 mg/kg daily of Y-27632 and 10 mg/kg daily of macitentan slowed the progression of PAH both at the functional and structural levels. Treatments started on day 14 after monocrotaline injection and lasted 14 days. The findings of all experimental methods show that the selective ROCK inhibitor Y-27632 has more pronounced effects than macitentan, but a major limitation to its use is its marked peripheral vasodilating action.

• Authors: Deborah Novelli, Francesca Fumagalli, Lidia Staszewsky, Giuseppe Ristagno, Davide Olivari, Serge Masson, Daria De Giorgio, Sabina Ceriani, Roberta Affatato, Francesco De Logu, Romina Nassini, Marco Milioli, Fabrizio Facchinetti, Silvia Cantoni, Marcello Trevisani, Teresa Letizia, Ilaria Russo, Monica Salio, Roberto Latini
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 865 Pg. 172777 (Dec 15 2019) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 31697933 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Amides
• Endothelin Receptor Antagonists
• Protein Kinase Inhibitors
• Pyridines
• Pyrimidines
• Sulfonamides
• Y 27632
• Monocrotaline
• rho-Associated Kinases
• macitentan

Topics

• Amides (therapeutic use)
• Animals
• Endothelin Receptor Antagonists (therapeutic use)
• Heart Ventricles (pathology)
• Hemodynamics (drug effects)
• Hypertrophy, Right Ventricular (chemically induced, drug therapy)
• Male
• Monocrotaline
• Protein Kinase Inhibitors (therapeutic use)
• Pulmonary Arterial Hypertension (chemically induced, drug therapy, pathology)
• Pulmonary Artery (drug effects, pathology)
• Pyridines (therapeutic use)
• Pyrimidines (therapeutic use)
• Rats, Wistar
• Sulfonamides (therapeutic use)
• rho-Associated Kinases (antagonists & inhibitors)