title: An Alpha-1A Adrenergic Receptor Agonist Prevents Acute Doxorubicin Cardiomyopathy in Male Mice.
abstract: Alpha-1 adrenergic receptors mediate adaptive effects in the heart and cardiac myocytes, and a myocyte survival pathway involving the alpha-1A receptor subtype and ERK activation exists in vitro. However, data in vivo are limited. Here we tested A61603 (N-[5-(4,5-dihydro-1H-imidazol-2-yl)-2-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yl]methanesulfonamide), a selective imidazoline agonist for the alpha-1A. A61603 was the most potent alpha-1-agonist in activating ERK in neonatal rat ventricular myocytes. A61603 activated ERK in adult mouse ventricular myocytes and protected the cells from death caused by the anthracycline doxorubicin. A low dose of A61603 (10 ng/kg/d) activated ERK in the mouse heart in vivo, but did not change blood pressure. In male mice, concurrent subcutaneous A61603 infusion at 10 ng/kg/d for 7 days after a single intraperitoneal dose of doxorubicin (25 mg/kg) increased survival, improved cardiac function, heart rate, and cardiac output by echocardiography, and reduced cardiac cell necrosis and apoptosis and myocardial fibrosis. All protective effects were lost in alpha-1A-knockout mice. In female mice, doxorubicin at doses higher than in males (35-40 mg/kg) caused less cardiac toxicity than in males. We conclude that the alpha-1A-selective agonist A61603, via the alpha-1A adrenergic receptor, prevents doxorubicin cardiomyopathy in male mice, supporting the theory that alpha-1A adrenergic receptor agonists have potential as novel heart failure therapies.
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Megan D
authors.initials: MD
authors.lastname: Montgomery
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Trevor
authors.initials: T
authors.lastname: Chan
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Swigart
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Bat-Erdene
authors.initials: BE
authors.lastname: Myagmar
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Dash
authors.affiliation: Department of Medicine, Cardiology Division, VA Medical Center, San Francisco, CA, United States of America.|Department of Medicine and Cardiovascular Research Institute, University of California, San Francisco, San Francisco, CA, United States of America.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Simpson
mesh_terms: D058646:Adrenergic alpha-1 Receptor Agonists / Q000494:pharmacology*; D000818:Animals; D009202:Cardiomyopathies / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D004317:Doxorubicin / Q000009:adverse effects* / Q000494:pharmacology; D004562:Electrocardiography; D005260:Female; D006333:Heart Failure / Q000139:chemically induced / Q000188:drug therapy / Q000235:genetics / Q000503:physiopathology; D007093:Imidazoles / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: C094643:A 61603; D058646:Adrenergic alpha-1 Receptor Agonists; D007093:Imidazoles; D018340:Receptors, Adrenergic, alpha-1; D013764:Tetrahydronaphthalenes; D004317:Doxorubicin