Myocardial beta-adrenergic receptor function during the development of pacing-induced heart failure.
The development of pacing-induced heart failure was studied in chronically instrumented, conscious dogs paced at a rate of 240 beats/min for 1 d (n = 6), 1 wk (n = 6), and 3-4 wk (n = 7). Left ventricular (LV) dP/dt was decreased (P < 0.0125) at 1 d, LV end-diastolic pressure and heart rate were increased (P < 0.0125) at 1 wk, but clinical signs of heart failure were only observed after 3-4 wk of pacing. Plasma norepinephrine rose (P < 0.0125) after 1 d of pacing, whereas LV norepinephrine was reduced (P < 0.0125) only after 3-4 wk of pacing. Both the fraction of beta-adrenergic receptors binding agonist with high affinity and adenylyl cyclase activity decreased (P < 0.0125) after 1 d of pacing. Total beta-adrenergic receptor density was not changed at any time point, but beta 1-adrenergic receptor density was decreased (P < 0.0125) after 1 wk. The functional activity of the guanine nucleotide binding protein, Gs, was not reduced, but the Gi alpha 2 isoform of the alpha subunit of the GTP-inhibitory protein rose after 3-4 wk of pacing. Thus, myocardial beta-adrenergic signal transduction undergoes change shortly (1d) after the initiation of pacing, before heart failure develops. The mechanism of beta-adrenergic receptor dysfunction in pacing-induced heart failure is characterized initially by elevated plasma levels of catecholamines, uncoupling of beta-adrenergic receptors, and a defect in the adenylyl cyclase catalytic unit. Selective down-regulation of beta 1-adrenergic receptors, increases in Gi alpha 2, and decreases in myocardial catecholamine levels occur as later events.
Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115.
K
K
Kiuchi
R P
RP
Shannon
K
K
Komamura
D J
DJ
Cohen
C
C
Bianchi
C J
CJ
Homcy
S F
SF
Vatner
D E
DE
Vatner
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D001794:Blood Pressure; D002303:Cardiac Output, Low / Q000097:blood / Q000503:physiopathology*; D003971:Diastole; D004285:Dogs; D005260:Female; D019204:GTP-Binding Proteins / Q000378:metabolism; D006321:Heart / Q000502:physiology / Q000503:physiopathology*; D006339:Heart Rate; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000378:metabolism*; D009638:Norepinephrine / Q000097:blood / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013599:Systole; D016277:Ventricular Function, Left
D011943:Receptors, Adrenergic, beta; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D009638:Norepinephrine