| Abstrakt: |
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 Ca2+by increasing its influx through voltage-dependent channels, mobilising it from intracellular stores and favouring its inward transport by Na+/Ca2+ exchange. Ca2+ 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 2-adrenoceptors, adenosine A1-receptors and histamine H3-receptors (H3R). In myocardial infarction, NA is released by both exocytotic (Ca2+-dependent) and carrier-mediated (Na+/H+ exchange-dependent) mechanisms, associated with short-term and protracted ischaemia, respectively. Unlike 2-adrenoceptor agonists that reduce NA exocytosis, but enhance carrier-mediated NA release, H3R agonists inhibit both exocytotic and carrier-mediated NA release. Moreover, unlike adenosine A1-receptor agonists, H3R agonists do not depress sinoatrial and atrioventricular nodes, nor cause bronchoconstriction. 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 arrhythmias in isolated hearts by reducing NA release, this protective action needs to be demonstrated in classical in vivo models of occlusion/reperfusion. Regardless, H3R agonists offer the promise of a novel strategy in the treatment of myocardial ischaemia and infarction. |
