Alterations by Norepinephrine of Cardiac Sympathetic Nerve Terminal Function and Myocardial β-Adrenergic Receptor Sensitivity in the Ferret

Abstract

Background —Chronic excessive norepinephrine (NE) causes cardiac sympathetic nerve terminal abnormalities, myocardial β-adrenergic receptor downregulation, and β-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 (β-carotene, ascorbic acid, and α-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 β-adrenergic receptor density with a selective decrease of the β 1 -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 β-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 β-adrenergic receptor downregulation and postreceptor abnormalities. Thus, antioxidant therapy may be beneficial in heart failure, in which cardiac NE release is increased.