Therapeutic potential of H-3-receptor agonists in myocardial infarction

Sympathetic over-activity accompanied by excessive noradrenaline (NA) relea se within the heart is a recognised cause of dysfunction in myocardial isch aemia; Myocardial infarction is often accompanied by arrhythmias with high morbidity and mortality. Indeed, NA enhances intracellular Ca2+ by increasi ng its influx through voltage-dependent channels, mobilising it from intrac ellular stores and favouring its inward transport by Na+/Ca2+ exchange. Ca2 + overload eventually results in dysrhythmia and uncoordinated myocyte cont raction. Moreover, NA increases metabolic demand. In concert with other con tributing factors, this will aggravate the primary ischaemia and initiate a vicious cycle;hat can culminate in myocardial damage and heart failure. Th erefore, reduction of NA release from cardiac sympathetic nerves is an impo rtant protective measure. Adrenergic nerves possess inhibitory receptors, s uch as alpha (2)-adrenoceptors, adenosine A(1)-receptors and histamine H-3- receptors (H3R). In myocardial infarction, NA is released by both exocytoti c (Ca2+-dependent) and carrier-mediated (Na+/H+ exchange-dependent) mechani sms, associated with short-term and protracted ischaemia, respectively. Unl ike ar-adrenoceptor agonists that reduce NA exocytosis, but enhance carrier -mediated NA release, H3R agonists inhibit both exocytotic and carrier-medi ated NA release. Moreover, unlike adenosine A(1)-receptor agonists, H3R ago nists do not depress sinoatrial and atrioventricular nodes, nor cause bronc hoconstriction. Therefore, stimulation of H3R on cardiac sympathetic nerve endings is an important new way to protect the heart from the consequences of ischaemia and infarction, Although H3R agonists alleviate reperfusion ar rhythmias in isolated hearts by reducing NA release, this protective action needs to be demonstrated in classical in vivo models of occlusion/reperfus ion. Regardless, H3R agonists offer the promise of a novel strategy in the treatment of myocardial ischaemia and infarction.