Receptor systems involved in norepinephrine release in heart failure: focus on dopaminergic systems.
The sympathetic nervous system is under extraordinarily complex modulation, involving numerous presynaptic and postsynpatic 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 alpha 2 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.
Francis
G S
GS
Department of Medicine, University of Minnesota Medical School, Minneapolis 55455, USA.
D003846:Deoxyepinephrine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018491:Dopamine Agonists / Q000627:therapeutic use*; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy / Q000503:physiopathology*; D006801:Humans; D009638:Norepinephrine / Q000378:metabolism*; D011954:Receptors, Dopamine / Q000187:drug effects / Q000502:physiology*
D018491:Dopamine Agonists; D011954:Receptors, Dopamine; C023487:ibopamine; D003846:Deoxyepinephrine; D009638:Norepinephrine