Receptor systems involved in norepinephrine release in heart failure: Focus on dopaminergic systems

Abstract

The sympathetic nervous system is under extraordinarily complex modulation, involving numerous presynaptic and postsynaptic control mechanisms. These highly conserved and very redundant control mechanisms allow for the sympathetic nervous system to adapt quickly and precisely to altered environmental stress or conditions. Heart failure (HF) is characterized by excessive sympathetic activity, with both enhanced “spillover” and reduced clearance of norepinephrine (NE). The normal inhibitor control mechanisms appear faulty, with unleashed sympathetic activity likely contributing to the pathophysiology of the clinical syndrome and being associated with excessive mortality. Attempts to attenuate pharmacologically the release or “spillover” of NE from sympathetic neurons in HF has remained an attractive therapeutic strategy, and various alpha2 adrenergic agonists and dopaminergic agents have been studied in several small clinical trials. Agents designed to activate both presynaptic (DA2) and postsynaptic or vascular (DA1) receptors have demonstrated promise. Ibopamine, a prodrug that is converted metabolically to epinine, a DA1 > DA2 agonist, has potential for selective vasodilation of mesenteric, renal, cerebral, and coronary vascular beds while reducing NE release and aldosterone activity. Preliminary clinical trials with ibopamine are encouraging, but placebo‐controlled multicenter studies will be necessary to establish its role in the treatment of HF.

Expressions of cardiac sympathetic norepinephrine transporter and β1-adrenergic receptor decreased in aged rats

“…Sympathetic nerve system (SNS) regulates the function of innervated effector organs through releasing and terminating neurotransmitter NE (Esler et al, 1990;Francis, 1995). The released transmitters in the cleft bind receptors on the postsynsptic membrane through diffusion, transmitting the signals to the postsynaptic neurons.…”

“…The norepinephrine transporter (NET) at presynaptic nerve terminals mediates the uptake of released norepinephrine (NE), resulting in the rapid termination of synaptic transmission and thereby controlling the fine tuning of neuronal activities (Esler et al, 1990;Povlock and Amara, 1997). Age-related reduction in reuptake of NE and β-AR density in the heart of health senescent human and animals was reported (Esler et al, 1990;1995;Chevalier et al, 1991;Dawson and Meldrum, 1992;Sakai et al, 1992;White et al, 1994;Ferrara et al, * Project supported by the Postdoctoral Fellow Foundation of the Science and Technology Committee of Shanghai and the Natural Science Foundation of Chinese People's Armed Police Force (Nos. WKH2006-5 and WKH2008ZO4), China 1997; Hardouin et al, 1997;Guimaraes et al, 1998;Snyder et al, 1998;Xiao et al, 1998).…”

Effects of Beta-Adrenoceptors Overexpression on Cell Survival Are Mediated by Bax/Bcl-2 Pathway in Rat Cardiac Myocytes

“…In diseases such as congestive heart failure (CHF), chronic activation of cardiac ␤ -ARs by endogenous agonists like adrenaline and noradrenaline results in a diminished number of cardiac myocytes, which is a leading cause of morbidity and mortality [16,17] . Our data demonstrated that as the concentrations of isoprenaline increased the death rates of ventricular myocytes in vitro rose too.…”