Regional myocardial downregulation of the inhibitory guanosine triphosphate-binding protein (Gi alpha 2) and beta-adrenergic receptors in a porcine model of chronic episodic myocardial ischemia.
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.
Hammond
H K
HK
Veteran's Affairs Medical Center, San Diego, California.
Roth
D A
DA
McKirnan
M D
MD
Ping
P
P
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D002462:Cell Membrane / Q000378:metabolism; D003326:Coronary Circulation; D017931:DNA Primers; D018076:DNA, Complementary / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D019204:GTP-Binding Proteins / Q000096:biosynthesis* / Q000378:metabolism; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D015151:Immunoblotting; D007545:Isoproterenol / Q000494:pharmacology; D007700:Kinetics; D008969:Molecular Sequence Data; D009203:Myocardial Infarction / Q000378:metabolism / Q000503:physiopathology; D017202:Myocardial Ischemia / Q000378:metabolism* / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism*; D005082:Physical Exertion; D016133:Polymerase Chain Reaction; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000096:biosynthesis* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis; D013552:Swine; D013556:Swine, Miniature
D017931:DNA Primers; D018076:DNA, Complementary; D011943:Receptors, Adrenergic, beta; D011993:Recombinant Fusion Proteins; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol