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(Circulation. 2000;102:96.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial ß-Adrenergic Receptor Sensitivity in the Ferret
Normalization by Antioxidant Vitamins
Presented in part at the 46th Annual Scientific Sessions of the American College of Cardiology, Anaheim, Calif, March 19, 1997, and the 71st Scientific Sessions of the American Heart Association, Dallas, Tex, November 11, 1998, and published in abstract form (J Am Coll Cardiol. 1997;29[suppl]:500A; Circulation. 1998;98[suppl I]:I-650).
From the Cardiology Unit, Department of Medicine, and Department of Neurobiology and Anatomy, University of Rochester Medical Center, Rochester, NY.
Correspondence to Chang-seng Liang, MD, PhD, Cardiology Unit, Box 679, University of Rochester Medical Center, 601 Elmwood Ave, Box 679, Rochester, NY 14642-8679. E-mail chang-seng_liang{at}urmc.rochester.edu
Background—Chronic excessive norepinephrine (NE) causes cardiac sympathetic nerve terminal abnormalities, myocardial ß-adrenergic receptor downregulation, and ß-adrenergic subsensitivity. The present study was carried out to determine whether these changes could be prevented by antioxidants.
Methods and Results—Ferrets were administered either NE (1.33
mg/d) or vehicle by use of subcutaneous pellets for 4 weeks. Animals
were simultaneously assigned to receive either antioxidant
vitamins (ß-carotene, ascorbic acid, and 
-tocopherol)
or placebo pellets. NE increased plasma NE 4- to 5-fold but had no
effect on heart rate, heart weight, arterial pressure, or
left ventricular systolic function. However,
myocardial NE uptake activity and NE uptake-1 site density were
reduced, as well as cardiac neuronal NE, tyrosine hydroxylase, and
neuropeptide Y. In addition, there was a decrease in myocardial
ß-adrenergic receptor density with a selective decrease of the
ß1-receptor subtype, reduction of the high-affinity site
for isoproterenol, decreased basal adenylyl cyclase activity, and the
adenylyl cyclase responses to isoproterenol, Gpp(NH)p, and forskolin.
All of these changes were prevented by antioxidant vitamins. The
effects of NE on myocardial ß-adrenergic receptor density, NE
uptake-1 carrier site density, and neuronal NE were also prevented by
superoxide dismutase or Trolox C.
Conclusions—The toxic effects of NE on the sympathetic nerve terminals are mediated via the formation of NE-derived oxygen free radicals. Preservation of the neuronal NE reuptake mechanism is functionally important, because the antioxidants also prevented myocardial ß-adrenergic receptor downregulation and postreceptor abnormalities. Thus, antioxidant therapy may be beneficial in heart failure, in which cardiac NE release is increased.
Key Words: norepinephrine • antioxidants • receptors, adrenergic, beta • heart failure
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