Coupling of histamine H3 receptors to neuronal Na+/H+ exchange: a novel protective mechanism in myocardial ischemia.

In myocardial ischemia, adrenergic nerves release excessive amounts of norepinephrine (NE), causing dysfunction and arrhythmias. With anoxia and the concomitant ATP depletion, vesicular storage of NE is impaired, resulting in accumulation of free NE in the axoplasm of sympathetic nerves. Intraneuronal acidosis activates the Na(+)/H(+) exchanger (NHE), leading to increased Na(+) entry in the nerve terminals. These conditions favor availability of the NE transporter to the axoplasmic side of the membrane, causing massive carrier-mediated efflux of free NE. Neuronal NHE activation is pivotal in this process; NHE inhibitors attenuate carrier-mediated NE release. We previously reported that activation of histamine H(3) receptors (H(3)R) on cardiac sympathetic nerves also reduces carrier-mediated NE release and alleviates arrhythmias. Thus, H(3)R activation may be negatively coupled to NHE. We tested this hypothesis in individual human SKNMC neuroblastoma cells stably transfected with H(3)R cDNA, loaded with the intracellular pH (pH(i)) indicator BCECF. These cells possess amiloride-sensitive NHE. NHE activity was measured as the rate of Na(+)-dependent pH(i) recovery in response to an acute acid pulse (NH(4)Cl). We found that the selective H(3)R-agonist imetit markedly diminished NHE activity, and so did the amiloride derivative EIPA. The selective H(3)R antagonist thioperamide abolished the imetit-induced NHE attenuation. Thus, our results provide a link between H(3)R and NHE, which may limit the excessive release of NE during protracted myocardial ischemia. Our previous and present findings uncover a novel mechanism of cardioprotection: NHE inhibition in cardiac adrenergic neurons as a means to prevent ischemic arrhythmias associated with carrier-mediated NE release.

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.