title: Novel dual endothelin receptor antagonist macitentan reverses severe pulmonary arterial hypertension in rats.
abstract: The efficacy of endothelin (ET) receptor antagonist bosentan in patients with severe pulmonary arterial hypertension (PAH) remains limited, partly because its higher doses for potential blockade of ET receptors have never been tested due to liver dysfunction. We hypothesized that rigorous blockade of ET receptors using the novel dual ET receptor antagonist macitentan would be effective in treating severe PAH without major side effects in a preclinical model appropriately representing the human disorder. In normal rats, 30 mg·kg·d of macitentan completely abolished big ET-1-induced increases in right ventricle (RV) systolic pressure. Adult male rats were injected with SU5416, a vascular endothelial growth factor blocker, and exposed to hypoxia for 3 weeks and then to normoxia for an additional 5 weeks (total 8 weeks). In intrapulmonary arterial rings isolated from rats with severe PAH, macitentan concentration dependently inhibited ET-1-induced contraction. Long-term treatment with macitentan (30 mg·kg·d, from week 3 to 8) reversed the high RV systolic pressure with preserved cardiac output. Development of RV hypertrophy, luminal occlusive lesions and medial wall thickening were also significantly improved without increasing serum levels of liver enzymes by macitentan. In conclusion, efficacious blockade of ET receptors with macitentan would reverse severe PAH without major adverse effects.
authors.affiliation: Departments of *Cardiovascular Medicine; †Advanced Cardiovascular Regulation and Therapeutics; and ‡Division of Molecular Cardiology, Research Institute of Angiocardiology, Kyushu University Graduate School of Medicine, Fukuoka, Japan; and §Department of Internal Medicine, University of South Alabama, Mobile, AL.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Kunita-Takanezawa
authors.forename: Kohtaro
authors.initials: K
authors.lastname: Abe
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Hirooka
authors.forename: Yukimitsu
authors.initials: Y
authors.lastname: Kuwabara
authors.forename: Katsuya
authors.initials: K
authors.lastname: Hirano
authors.forename: Masahiko
authors.initials: M
authors.lastname: Oka
authors.forename: Kenji
authors.initials: K
authors.lastname: Sunagawa
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D065131:Endothelin B Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy; D007211:Indoles / Q000494:pharmacology; D008297:Male; D011743:Pyrimidines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D013997:Time Factors; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors
chemical_list: D065130:Endothelin A Receptor Antagonists; D065131:Endothelin B Receptor Antagonists; D007211:Indoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D042461:Vascular Endothelial Growth Factor A; C116890:Semaxinib; C533860:macitentan