Alterations in cardiac adrenergic terminal function and beta-adrenoceptor density in pacing-induced heart failure

Congestive heart failure is associated with cardiac adrenergic nerve termin al changes and P-adrenoceptor density downregulation. To study the temporal sequence of these changes, we pet-formed 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 acti vity, NE uptake-1 density, and adenylyl cyclase responses to isoproterenol, 5'-guanylyl imidodiphosphate [Gpp(NH)p], and forskolin reduced. However, i mmunostained tyrosine hydroxylase profile, beta-adrenoceptor density, and N E histofluorescence did not reduce until 4-8 wk of pacing. After cessation of cardiac pacing, LV function normalized quickly, followed by return of ty rosine hydroxylase and NE profiles in I wk and adenylyl cyclase responses t o agonists and NE uptake activity in 2 wk. Myocardial beta-adrenoceptor den sity returned to normal by 4 wk after cessation of pacing. Our results sugg est that there is no permanent structural neuronal damage in the myocardium within the first 8 wk of rapid cardiac pacing. Abnormal myocardial NE reup take mechanism may play an important pathophysiological role in heart failu re.