a-61603 and Heart-Failure

Right ventricular (RV) failure (RVF) is a serious disease with no effective treatment available. We recently reported a disease prevention study showing that chronic stimulation of α

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Antioxidants; Glutathione Peroxidase; Heart Failure; Imidazoles; Male; Mice; Mice, Inbred C57BL; Mitogen-Activated Protein Kinase 3; Myocardial Contraction; Myocytes, Cardiac; Oxidative Stress; Protein Carbonylation; Proto-Oncogene Proteins c-bcl-2; Tetrahydronaphthalenes; Troponin I; Ventricular Dysfunction, Right

Recent studies report that a single subtype of α1-adrenergic receptor (α1-AR), the α1A-subtype, mediates robust cardioprotective effects in multiple experimental models of heart failure, suggesting that the α1A-subtype is a potential therapeutic target for an agonist to treat heart failure. Moreover, we recently found that the α1A-subtype is present in human heart. The goal of this study was to assess the inotropic response mediated by the α1A-subtype in human myocardium, and to determine whether the response is downregulated in myocardium from failing human heart. We measured in vitro contractile responses of cardiac muscle preparations (trabeculae) isolated from the right ventricle from nonfailing and failing human hearts. Addition of the α1A-subtype agonist A61603 (100 nM) resulted in a large positive inotropic response (force increased ≈ 2-fold). This response represented ≈70% of the response mediated by the β-adrenergic receptor agonist isoproterenol (1 μM). Moreover, in myocardium from failing hearts, α1A-subtype responses remained robust, and only slightly reduced relative to nonfailing hearts. We conclude that α1A-subtype-mediated inotropy could represent a significant source of inotropic support in the human heart. Furthermore, the α1A-subtype remains functional in myocardium from failing human hearts and thus, might be a therapeutic target to support cardioprotective effects in patients with heart failure.

Topics: Adrenergic alpha-1 Receptor Agonists; Adrenergic beta-Agonists; Adult; Aged; Cardiotonic Agents; Case-Control Studies; Female; Heart Failure; Humans; Imidazoles; In Vitro Techniques; Isoproterenol; Male; Middle Aged; Myocardial Contraction; Myocardium; Receptors, Adrenergic, alpha-1; Signal Transduction; Tetrahydronaphthalenes; Ventricular Function, Right

Failure of the right ventricle (RV) is a serious disease with a poor prognosis and limited treatment options. Signaling by α

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Antioxidants; Bleomycin; Cardiotonic Agents; Disease Models, Animal; Fibrosis; Heart Failure; Heart Ventricles; Imidazoles; Male; Matrix Metalloproteinase 2; Mice, Inbred C57BL; Myocardial Contraction; NADPH Oxidase 4; Necrosis; Oxidative Stress; Pulmonary Fibrosis; Receptors, Adrenergic, alpha-1; Recovery of Function; Superoxide Dismutase-1; Tetrahydronaphthalenes; Ventricular Dysfunction, Right; Ventricular Function, Right; Ventricular Remodeling

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.

Topics: Adrenergic alpha-1 Receptor Agonists; Animals; Cardiomyopathies; Doxorubicin; Electrocardiography; Female; Heart Failure; Imidazoles; Male; MAP Kinase Signaling System; Mice; Mice, Knockout; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic, alpha-1; Tetrahydronaphthalenes