Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in pacing-induced heart failure.
Congestive heart failure is associated with cardiac adrenergic nerve terminal changes and beta-adrenoceptor density downregulation. To study the temporal sequence of these changes, we performed studies in rabbits at 2, 4, and 8 wk of cardiac pacing (360 beats/min) and at 1, 2, and 4 wk after cessation of pacing. Rapid pacing produced left ventricular (LV) dysfunction and an increase in plasma norepinephrine (NE) in 1-2 wk. At week 2, NE uptake activity, NE uptake-1 density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, immunostained tyrosine hydroxylase profile, beta-adrenoceptor density, and NE histofluorescence did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV function normalized quickly, followed by return of tyrosine hydroxylase and NE profiles in 1 wk and adenylyl cyclase responses to agonists and NE uptake activity in 2 wk. Myocardial beta-adrenoceptor density returned to normal by 4 wk after cessation of pacing. Our results suggest that there is no permanent structural neuronal damage in the myocardium within the first 8 wk of rapid cardiac pacing. Abnormal myocardial NE reuptake mechanism may play an important pathophysiological role in heart failure.
Kawai
H
H
Cardiology Unit, Department of Medicine, University of Rochester Medical Center, Rochester, New York 14642, USA.
Mohan
A
A
Hagen
J
J
Dong
E
E
Armstrong
J
J
Stevens
S Y
SY
Liang
C S
CS
D000262:Adenylyl Cyclases / Q000187:drug effects / Q000378:metabolism*; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002304:Cardiac Pacing, Artificial; D005576:Colforsin / Q000494:pharmacology; D004195:Disease Models, Animal; D015536:Down-Regulation; D006165:Guanylyl Imidodiphosphate / Q000494:pharmacology; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D009411:Nerve Endings / Q000201:enzymology*; D009638:Norepinephrine / Q000378:metabolism*; D011817:Rabbits; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000201:enzymology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism; D016277:Ventricular Function, Left
D000318:Adrenergic beta-Agonists; D011943:Receptors, Adrenergic, beta; D005576:Colforsin; D006165:Guanylyl Imidodiphosphate; D014446:Tyrosine 3-Monooxygenase; D000262:Adenylyl Cyclases; D009638:Norepinephrine