title: Regulation and role of the presynaptic and myocardial Na+/H+ exchanger NHE1: effects on the sympathetic nervous system in heart failure.
abstract: In acute myocardial ischemia and in chronic heart failure, sympathetic activation with excessive norepinephrine (NE) release from and reduced NE reuptake into sympathetic nerve endings is a prominent cause of arrhythmias and cardiac dysfunction. The Na(+)/H(+) exchanger NHE1 is the predominant isoform in the heart. It contributes to cellular acid-base balance, and electrolyte, and volume homeostasis, and is activated in response to intracellular acidosis and/or activation of guanine nucleotide binding (G) protein-coupled receptors. NHE1 mediates its signaling via protein kinases A (PKA) or C (PKC). In cardiomyocytes, NHE1 is restricted to specialized membrane domains, where it regulates the activity of pH-sensitive proteins and modulates the driving force of the Na(+)/Ca(2+) exchanger. During acute ischemia/reperfusion and in heart failure the activity/amount of NHE1 is increased, leading to intracellular Ca(2+) overload and promoting structural (apoptosis, hypertrophy) and functional (arrhythmias, hypercontraction) myocardial damage. In sympathetic nerve endings, increased NHE1 activity results in the accumulation of axoplasmic Na(+) that diminishes the inward and/or favors the outward transport of NE via the neuronal norepinephrine transporter (NET). The increased NE levels within the nerve-muscle junction facilitate the sustained stimulation of myocardial alpha- and beta-adrenoceptors (ARs), which in turn aggravate the increases in myocardial NHE1 activity and the associated deleterious effects. Furthermore, the responsiveness of the beta-AR declines overtime, which results in further release of NE, initiating a vicious cycle. Accordingly, NHE1 is a potential candidate for targeted intervention to suppress this feedback loop.
authors.affiliation: Institute of Pathophysiology, University of Essen School of Medicine, D-45122 Essen, Germany. rainer.schulz@uni-duisburg-essen.de
authors.forename: Kirsten
authors.initials: K
authors.lastname: Leineweber
authors.forename: Gerd
authors.initials: G
authors.lastname: Heusch
authors.forename: Rainer
authors.initials: R
authors.lastname: Schulz
mesh_terms: D000818:Animals; D027682:Cation Transport Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000502:physiology*; D004195:Disease Models, Animal; D006333:Heart Failure / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D006801:Humans; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000209:etiology* / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism*; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D013566:Sympathomimetics / Q000378:metabolism*
chemical_list: D027682:Cation Transport Proteins; C490998:SLC9A1 protein, human; D000074082:Sodium-Hydrogen Exchanger 1; D017923:Sodium-Hydrogen Exchangers; D013566:Sympathomimetics; D009638:Norepinephrine