Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Giα2) and β-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia

• Published in: The Journal of clinical investigation 1993-12, Vol.92 (6), p.2644-2652
• Main Authors: HAMMOND, H. K, ROTH, D. A, MCKIRNAN, M. D, PEIPEI PING
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Animals; Base Sequence; Biological and medical sciences; Cardiology. Vascular system; Cell Membrane - metabolism; Coronary Circulation; Coronary heart disease; Disease Models, Animal; DNA Primers; DNA, Complementary - metabolism; Down-Regulation; GTP-Binding Proteins - biosynthesis; GTP-Binding Proteins - metabolism; Heart; Heart - physiology; Heart - physiopathology; Immunoblotting; Isoproterenol - pharmacology; Kinetics; Medical sciences; Molecular Sequence Data; Myocardial Infarction - metabolism; Myocardial Infarction - physiopathology; Myocardial Ischemia - metabolism; Myocardial Ischemia - physiopathology; Myocardium - metabolism; Physical Exertion; Polymerase Chain Reaction; Radioligand Assay; Receptors, Adrenergic, beta - biosynthesis; Receptors, Adrenergic, beta - metabolism; Recombinant Fusion Proteins - biosynthesis; Swine; Swine, Miniature
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI116880

Regional myocardial ischemia is associated with increased levels of adenosine and norepinephrine, factors that may alter activation of the beta-adrenergic receptor (beta AR)-G protein-adenylyl cyclase pathway in the heart. We have used the ameroid constrictor model to determine whether alterations in myocardial signal transduction through the beta AR-G protein-adenylyl cyclase pathway occur in the setting of chronic episodes of reversible ischemia. Pigs were instrumented with ameroid occluders placed around the left circumflex coronary artery. 5 wk later, after ameroid closure, flow and function were normal in the ischemic bed, but flow (P = 0.001) and function (P < 0.03) were abnormal when metabolic demands were increased. The ischemic bed showed a reduction in myocardial beta AR number (P < 0.005). Despite regional downregulation of myocardial beta AR number, adenylyl cyclase activity was similar in the ischemic and control beds. Quantitative immunoblotting showed that the cardiac inhibitory GTP-binding protein, Gi alpha 2, was decreased in the ischemic bed (P = 0.02). In contrast, the cardiac stimulatory GTP-binding protein, Gs alpha, was increased in endocardial sections from the ischemic bed (P = < 0.05). Decreased Gi alpha 2 content was associated with decreased inhibition of adenylyl cyclase. Reduced Gi alpha 2 content, in conjunction with increased Gs alpha content in the endocardium, may provide a means by which adrenergic activation is maintained in the setting of chronic episodic myocardial ischemia.