Regional desensitization of beta-adrenergic receptor signaling in swine with chronic hibernating myocardium.
Contractile reserve during submaximal beta-adrenergic stimulation is attenuated in patients and swine with hibernating myocardium. We tested the hypothesis that this arises as a regional adaptive response in beta-adrenergic adenylyl cyclase coupling. Pigs (n=8) were studied 3 months after instrumentation with a left anterior descending artery (LAD) stenosis when flow (LAD, 0.7+/-0.2 versus 1.2+/-0.1 mL/min per gram in normal remote; P<0.05) and wall thickening (LAD, 15.5 [corrected]+/-3.2% versus 40.0+/-5.5% in remote; P<0.05) were reduced in the absence of infarction. Whereas basal cAMP production was normal (LAD, 87+/-18 versus 91+/-19 pmol/mg per minute; P=NS), responses to isoproterenol were blunted (LAD, 83+/-6 versus 146+/-25 pmol/mg per minute in remote; P<0.05). beta-receptor density and subtype were unchanged, but there was a reduction in the number of high-affinity binding sites (LAD, 40+/-4% versus 53+/-7% in normal remote; P<0.05). The Gialpha2/Gsalpha ratio increased (LAD, 1.8+/-0.3 versus 0.99+/-0.3 in remote myocardium; P<0.05), although GppNHp-stimulated cAMP production was equivocally reduced. Forskolin responses were unchanged and similar to shams. These data indicate regional attenuation of beta-receptor adenylyl cyclase signaling in hibernating myocardium. This blunts the local contractile response to beta-adrenergic stimulation and may serve to protect against a myocardial supply/demand imbalance when external determinants of myocardial workload increase during sympathetic activation.
Iyer
Vijay S
VS
Veterans Affairs Western New York Health Care System, Buffalo, NY, USA.
Canty
John M
JM
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000209:etiology; D002908:Chronic Disease; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins / Q000032:analysis; D017202:Myocardial Ischemia / Q000503:physiopathology; D017682:Myocardial Stunning / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000201:enzymology; D009638:Norepinephrine / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis; D011869:Radioligand Assay; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology*; D013552:Swine
D011943:Receptors, Adrenergic, beta; D017346:Protein Serine-Threonine Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine