β-Adrenergic Receptor-G Protein-Adenylate Cyclase Complex in Experimental Canine Congestive Heart Failure Produced by Rapid Ventricular Pacing

• Published in: Circulation research Vol. 69; no. 6; pp. 1546 - 1556
• Main Authors: Marzo, Kevin P, Frey, Martin J, Wilson, John R, Liang, Bruce T, Manning, David R, Lanoce, Vita, Molinoff, Perry B
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 01-12-1991; Lippincott
• Subjects: Adenylate Cyclase Toxin; Adenylyl Cyclases - physiology; Animals; Biological and medical sciences; Cardiology. Vascular system; Catecholamines - blood; Dihydropyridines - metabolism; Dobutamine - pharmacology; Dogs; Electric Stimulation; GTP-Binding Proteins - physiology; Heart; Heart Failure - physiopathology; Heart failure, cardiogenic pulmonary edema, cardiac enlargement; Heart Rate; Hemodynamics; Medical sciences; Pertussis Toxin; Receptors, Adrenergic, beta - physiology; Virulence Factors, Bordetella - metabolism; Heart failure; Fissipedia; Animal model; Carnivora; Enzyme; Cardiovascular disease; Left ventricle; β-Adrenergic receptor; Adenylate cyclase; Instrumental stimulation; Vertebrata; Experimental disease; Mammalia; Animal; Dog; G protein
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/01.res.69.6.1546

Changes in the β-adrenergic receptor-G protein-adenylate cyclase complex were investigated in an experimental canine model of low-output heart failure produced by chronic rapid ventricular pacing. The contractile response occurring after exposure to the β-adrenergic agonist dobutamine, measured as peak left ventricular +dP/dt, was decreased after 3 weeks of pacing. To further characterize the diminished functional responsiveness to β-adrenergic receptor stimulation, β-adrenergic receptor-adenylate cyclase coupling was investigated using membranes prepared from both control and paced animals. The density of β-adrenergic receptors was decreased by 40% with a selective downregulation of the β1-subtype. The affinity of the receptor for the antagonist radioligand [1]iodocyanopindolol remained unchanged. A defect in coupling was suggested by a decreased ability of isoproterenol, fluoride, and forskolin to stimulate adenylate cyclase in membranes prepared from failing hearts. Determination of the levels of Giα (the α-subunit of Gi) by immunoblotting and pertussis toxin labeling revealed modest increases of ∼30%. Furthermore, Mn and purified Gs failed to stimulate adenylate cyclase in membranes prepared from failing hearts, indicating an impairment in the catalytic moiety of adenylate cyclase itself or in the ability of adenylate cyclase to couple to Gs. In contrast, complementation assay did not reveal differences in the functional activity of Gsα (the a-subunit of Gs). Taken together, these data demonstrate a selective decrease in the β1-subtype of adrenergic receptors and an increase in a 40-kd Gi-like protein in the failing heart. Similar changes have been described in human idiopathic dilated cardiomyopathy. In addition to these changes, we identified a possible defect at the level of the catalytic subunit of adenylate cyclase.