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Neuroendocrine properties of intrinsic cardiac adrenergic cells in fetal rat heart

¹Department of Internal Medicine, Cardiology Division, University of Texas Medical Branch, Galveston, Texas; ²Department of Medicine, Cardiology Division and Sarver Heart Center, and Departments of ³Pharmacology and Toxicology and ⁴Surgery, University of Arizona College of Medicine, Tucson, Arizona

Submitted 15 June 2004 ; accepted in final form 22 September 2004

Intrinsic cardiac adrenergic (ICA) cells in developing rat heart constitute a novel adrenergic signaling system involved in cardiac regulation. Regulatory mechanisms of ICA cells remain to be defined. Immunohistochemical study of fetal rat hearts demonstrated ICA cells with catecholamine biosynthetic enzyme tyrosine hydroxylase (TH) and phenylethanolamine N-methyltransferase (PNMT). The mRNA of TH and PNMP was also detected in fetal rat hearts before sympathetic innervation. Immunoreactivity of norepinephrine transporter (NET) was localized to ICA cells in rat heart tissue and primary cell culture. For the functional study, the activity of intracellular Ca²⁺ concentration ([Ca²⁺]_i) transients was quantified by a ratio fluorescent spectrometer in cultured ICA cells and myocytes. ICA cells generated spontaneous [Ca²⁺]_i transients that were eliminated by tetrodotoxin or Ca²⁺-free solutions and showed greatly reduced amplitude with the addition of L-type Ca²⁺ channel blocker nifedipine. [³H]norepinephrine studies demonstrate release and uptake of norepinephrine. Functional interaction between catecholamines produced by the ICA cells and cocultured myocytes was evident by the effect of the -adrenergic blocker atenolol eliciting a dose-dependent reduction in the amplitude and frequency of [Ca²⁺]_i transients of beating myocytes. Hypoxia inhibited [Ca²⁺]_i transient activity of ICA cells, which subsequently produced a reoxygenation-mediated rebound augmentation of [Ca²⁺]_i transients. We conclude that ICA cells are capable of catecholamine synthesis, release, and uptake. They generate spontaneous [Ca²⁺]_i transient activity that can be regulated by oxygen tension. ICA cells may provide an alternative adrenergic supply to maintain cardiac contractile and pacemaker function at rest and during stress in the absence of sympathetic innervation.

calcium; hypoxia/reoxygenation; intrinsic cardiac adrenergic cells; myocytes; norepinephrine

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