Circulation, Vol 86, 1584-1595, Copyright © 1992 by American Heart Association
AL Warner, KL Bellah, TE Raya, WR Roeske and S Goldman
BACKGROUND. beta-Adrenergic receptor blockade has been reported to improve
hemodynamics and beta-adrenergic receptor-adenylate cyclase function in
idiopathic dilated cardiomyopathy. The purpose of this study was to
determine the effects of beta-adrenergic receptor blockade on the
beta-adrenergic receptor system and myocardial function in a model of
compensated ischemic heart failure. METHODS AND RESULTS. We examined the
effects of propranolol treatment on the beta-adrenergic receptor-adenylate
cyclase system and isolated papillary muscle isometric function in
noninfarcted left ventricular myocardium in rats after coronary artery
ligation. In untreated rats with large myocardial infarction (MI),
developed tension (DT) (3.0 +/- 0.7 versus 5.1 +/- 1.1 g/mm2), peak rate of
tension rise (+dT/dt) (40.3 +/- 9.5 versus 71.2 +/- 12.0 g/mm2/sec), and
peak rate of tension fall (-dT/dt) (24.4 +/- 5.0 versus 38.2 +/- 6.0
g/mm2/sec) were decreased (p < 0.05). In addition, DT, +dT/dt, and
-dT/dt of untreated MI rats demonstrated an impaired response to
isoproterenol stimulation compared with controls. beta- Adrenergic receptor
density (Bmax) measured by [125I]iodocyanopindolol (ICYP) binding was
decreased 23% after infarction (9.3 +/- 0.6 versus 12.0 +/- 1.8 fmol/mg
protein [prot]) (p < 0.05); however, the dissociation constant (Kd) for
ICYP was not changed (24.1 +/- 5.7 versus 33.2 +/- 12.1 pM). Adenylate
cyclase activity in the presence of 10(-2) M MgCl2 was reduced (p <
0.05) in MI rats (30.3 +/- 10.8 versus 45.9 +/- 12.5 pmol cAMP/min/mg
prot). Maximal isoproterenol (52.5 +/- 7.3 versus 79.9 +/- 10.0 pmol
cAMP/min/mg prot), guanyl-5'- imidodiphosphate (GppNHp) (95 +/- 8 versus
141 +/- 25 pmol cAMP/min/mg prot) and forskolin (503 +/- 76 versus 753 +/-
157 pmol cAMP/min/mg prot) stimulation of adenylate cyclase was also
decreased (p < 0.05). In addition, manganese-stimulated adenylate
cyclase activity was depressed (p < 0.05) in MI rats compared with
controls (23.5 +/- 2.8 versus 52.1 +/- 9.0 pmol cAMP/min/mg prot). Chronic
propranolol treatment in MI rats improved DT (4.1 +/- 0.9 versus 3.0 +/-
0.7 g/mm2) and +dT/dt (54.4 +/- 11.3 versus 40.5 +/- 9.5 g/mm2/sec) (p <
0.05); however, isoproterenol-stimulated isometric function remained
impaired. Propranolol treatment normalized Bmax (11.9 +/- 1.7 versus 9.3
+/- 0.6 fmol/mg prot) (p < 0.05), whereas adenylate cyclase activity
remained depressed. CONCLUSIONS. After large MI in rats, there is impaired
papillary muscle function with decreased beta-adrenergic receptors and
adenylate cyclase activity in the noninfarcted myocardium. Propranolol
treatment improved basal isometric muscle function and beta-adrenergic
receptor density in rats after myocardial infarction but did not improve
adenylate cyclase activity or isoproterenol-stimulated muscle function.
These data suggest that there is a primary defect in adenylate cyclase
function that persists despite upregulation of receptors with propranolol
treatment.
ARTICLES
Effects of beta-adrenergic blockade on papillary muscle function and the beta-adrenergic receptor system in noninfarcted myocardium in compensated ischemic left ventricular dysfunction
Department of Internal Medicine, Tucson Veterans Administration Medical Center, AZ 85723.
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