title: The Effect of Sorafenib, Tadalafil and Macitentan Treatments on Thyroxin-Induced Hemodynamic Changes and Cardiac Abnormalities.
abstract: Multikinase inhibitors (e.g. Sorafenib), phosphodiesterase-5 inhibitors (e.g. Tadalafil), and endothelin-1 receptor blockers (e.g. Macitentan) exert influential protection in a variety of animal models of cardiomyopathy; however, their effects on thyroxin-induced cardiomyopathy have never been investigated. The goal of the present study was to assess the functional impact of these drugs on thyroxin-induced hemodynamic changes, cardiac hypertrophy and associated altered responses of the contractile myocardium both in-vivo at the whole heart level and ex-vivo at the cardiac tissue level. Control and thyroxin (500 μg/kg/day)-treated mice with or without 2-week treatments of sorafenib (10 mg/kg/day; I.P), tadalafil (1 mg/kg/day; I.P or 4 mg/kg/day; oral), macitentan (30 and 100 mg/kg/day; oral), and their vehicles were studied. Blood pressure, echocardiography and electrocardiogram were non-invasively evaluated, followed by ex-vivo assessments of isolated multicellular cardiac preparations. Thyroxin increased blood pressure, resulted in cardiac hypertrophy and left ventricular dysfunction in-vivo. Also, it caused contractile abnormalities in right ventricular papillary muscles ex-vivo. None of the drug treatments were able to significantly attenuate theses hemodynamic changes or cardiac abnormalities in thyroxin-treated mice. We show here for the first time that multikinase (raf1/b, VEGFR, PDGFR), phosphodiesterase-5, and endothelin-1 pathways have no major role in thyroxin-induced hemodynamic changes and cardiac abnormalities. In particular, our data show that the involvement of endothelin-1 pathway in thyroxine-induced cardiac hypertrophy/dysfunction seems to be model-dependent and should be carefully interpreted.
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
authors.forename: Nancy S
authors.initials: NS
authors.lastname: Saad
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Kyle
authors.initials: K
authors.lastname: Floyd
authors.affiliation: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
authors.forename: Amany A E
authors.initials: AA
authors.lastname: Ahmed
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.
authors.forename: Paul M L
authors.initials: PM
authors.lastname: Janssen
authors.affiliation: Department of Physiology and Cell Biology, College of Medicine, The Ohio State University, Columbus, Ohio, United States of America.|Dorothy M. Davis Heart & Lung Research Institute, The Ohio State University, Columbus, Ohio, United States of America.|Department of Pharmacology and Toxicology, Faculty of Pharmacy, Helwan University, Cairo, Egypt.
authors.forename: Mohammad T
authors.initials: MT
authors.lastname: Elnakish
mesh_terms: D000818:Animals; D001794:Blood Pressure; D009202:Cardiomyopathies / Q000188:drug therapy; D004195:Disease Models, Animal; D004452:Echocardiography; D004562:Electrocardiography; D006330:Heart Defects, Congenital / Q000139:chemically induced / Q000188:drug therapy*; D006339:Heart Rate; D006439:Hemodynamics; D008297:Male; D051379:Mice; D009200:Myocardial Contraction; D009536:Niacinamide / Q000008:administration & dosage / Q000031:analogs & derivatives*; D009929:Organ Size; D010671:Phenylurea Compounds / Q000008:administration & dosage*; D011743:Pyrimidines / Q000008:administration & dosage*; D000077157:Sorafenib; D013449:Sulfonamides / Q000008:administration & dosage*; D000068581:Tadalafil / Q000008:administration & dosage*; D013974:Thyroxine / Q000008:administration & dosage / Q000009:adverse effects*
chemical_list: D010671:Phenylurea Compounds; D011743:Pyrimidines; D013449:Sulfonamides; D009536:Niacinamide; D000068581:Tadalafil; D000077157:Sorafenib; D013974:Thyroxine; C533860:macitentan