Dissociation between regional dysfunction and beta-adrenergic receptor signaling in heart failure.
We have previously shown that left ventricular (LV) pacing-induced heart failure is associated with preserved wall thickening in the interventricular septum (IVS) compared with the posterolateral wall (PLW). The current study focuses on the relationship between regional myocardial function and altered beta-adrenergic receptor (beta-AR) signaling. We studied 15 pigs: 6 controls and 9 paced from the left ventricle (225 beats/min, 26 +/- 3 days). Heart failure was documented by decreased LV fractional shortening (P < 0.0001) and increased left atrial pressure (P < 0.0001). In heart failure, despite marked differences in basal regional function (percent wall thickening: IVS, 33 +/- 10% vs. PLW, 13 +/- 7%; P = 0.0003), there were no differences between the two regions in beta-AR responsiveness, measured by regional wall thickening in response to dobutamine infusion and any measurement of adrenergic signaling. Adenylyl cyclase activity, beta-AR number, and beta-AR/Gs coupling were markedly reduced in failing LV without regional differences. In animals with heart failure, LV G protein receptor kinase (GRK) isoform 2 content was unchanged and GRK5, the other major GRK isoform, was increased more than threefold (IVS, 0.51 +/- 0.20 vs. 0. 12 +/- 0.12 arbitrary densitometric units, P = 0.01; PLW, 0.47 +/- 0. 15 vs. 0.13 +/- 0.09 arbitrary densitometric units, P = 0.03), but again, there were no regional differences. These data indicate that systemic rather than regional factors govern LV adrenergic signaling and that regional adrenergic signaling abnormalities poorly predict wall thickening in the same regions.
Anzai
T
T
Veterans Affairs Medical Center-San Diego and Department of Medicine, University of California San Diego, La Jolla, California 92161, USA.
Lai
N C
NC
Gao
M
M
Hammond
H K
HK
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D016279:Atrial Function, Left / Q000187:drug effects / Q000502:physiology*; D001794:Blood Pressure; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004280:Dobutamine / Q000494:pharmacology; D004452:Echocardiography / Q000187:drug effects; D005260:Female; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins / Q000378:metabolism; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006321:Heart / Q000187:drug effects / Q000502:physiology* / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects / Q000502:physiology*; D007545:Isoproterenol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013552:Swine; D051552:beta-Adrenergic Receptor Kinases
D011943:Receptors, Adrenergic, beta; D006165:Guanylyl Imidodiphosphate; D004280:Dobutamine; D020794:Receptor Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D054774:G-Protein-Coupled Receptor Kinase 5; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D007545:Isoproterenol; D009638:Norepinephrine