Therapeutic potential of H(3)-receptor agonists in myocardial infarction.
Sympathetic over-activity accompanied by excessive noradrenaline (NA) release within the heart is a recognised cause of dysfunction in myocardial ischaemia. Myocardial infarction is often accompanied by arrhythmias with high morbidity and mortality. Indeed, NA enhances intracellular Ca(2+) by increasing its influx through voltage-dependent channels, mobilising it from intracellular stores and favouring its inward transport by Na(+)/Ca(2+) exchange. Ca(2+) overload eventually results in dysrhythmia and uncoordinated myocyte contraction. Moreover, NA increases metabolic demand. In concert with other contributing factors, this will aggravate the primary ischaemia and initiate a vicious cycle that can culminate in myocardial damage and heart failure. Therefore, reduction of NA release from cardiac sympathetic nerves is an important protective measure. Adrenergic nerves possess inhibitory receptors, such as alpha(2)-adrenoceptors, adenosine A(1)-receptors and histamine H(3)-receptors (H(3)R). In myocardial infarction, NA is released by both exocytotic (Ca(2+)-dependent) and carrier-mediated (Na(+)/H(+) exchange-dependent) mechanisms, associated with short-term and protracted ischaemia, respectively. Unlike alpha(2)-adrenoceptor agonists that reduce NA exocytosis, but enhance carrier-mediated NA release, H(3)R agonists inhibit both exocytotic and carrier-mediated NA release. Moreover, unlike adenosine A(1)-receptor agonists, H(3)R agonists do not depress sinoatrial and atrioventricular nodes, nor cause bronchoconstriction. Therefore, stimulation of H(3)R on cardiac sympathetic nerve endings is an important new way to protect the heart from the consequences of ischaemia and infarction. Although H(3)R agonists alleviate reperfusion arrhythmias in isolated hearts by reducing NA release, this protective action needs to be demonstrated in classical in vivo models of occlusion/reperfusion. Regardless, H(3)R agonists offer the promise of a novel strategy in the treatment of myocardial ischaemia and infarction.
Mackins
C J
CJ
Department of Pharmacology, Cornell University, Weill Medical College, 1300 York Avenue, New York, NY 10021, USA.
Levi
R
R
D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D006321:Heart / Q000187:drug effects / Q000294:innervation; D017442:Histamine Agonists / Q000627:therapeutic use*; D006801:Humans; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000378:metabolism; D009411:Nerve Endings / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism; D013564:Sympathetic Nervous System / Q000187:drug effects
D017442:Histamine Agonists; D017923:Sodium-Hydrogen Exchangers; D009638:Norepinephrine