Protracted myocardial ischemia

Imamura M, Lander HM, Levi R Activation of histamine H3-receptors inhibits carrier-mediated norepinephrine release during protracted myocardial ischemia. Comparison with adenosine Aj-receptors and a2-adrenoceptors. Circ Res 1996 78 475. 

As for the cardiovascular system, the cardioprotective effects of selective H3-receptor agonists, demonstrated in models of protracted myocardial ischemia (Imamura et al., 1994, 1995, 1996a Hatta et al., 1996, 1997), could be predictive of beneficial effects in coronaropatic patients. Hence, the attenuation of carrier-mediated noradrenaline release in hypoxic and/or ischemic myocardium by H3-agonists would limit the sympathetic overactivity and the associated incidence of ventricular arrhythmias and angina, as well as the increase of metabolic demand by the myocardium, thus preventing further damage and cardiac failure. 

In myocardial ischemia, several of the mechanisms presented above come into play. First, neuropeptides such as CGRP are released from cardiac sensory C fibers and subsequently release histamine from mast cells as just mentioned. Histamine then can act at least at two presynaptic H3 heteroreceptors on the C fibers to attenuate further neuropeptide release (Section 3.9), and on postganglionic sympathetic fibers to attenuate exocytotic as well as carrier-mediated noradrenaline release (Section 3.3). Both presynaptic effects are potentially beneficial. The H3 receptors are unique in this pattern of effects. Presynaptic adenosine Ai receptors, when activated, also inhibit both exocytotic and carrier-mediated noradrenaline release, but cardiac Ai receptors in addition mediate negative chronotropic and dro-motropic effects. Presynaptic 0C2-adrenoceptors, when activated, reduce exocytotic noradrenaline release but enhance carrier-mediated noradrenaline release (due to stimulation of the Na+/H+ exchanger, Imamura et al. 1996b), which is the major mode of noradrenaline release and the major arrhythmogenic risk in protracted myocardial ischemia (see Levi and Smith 2000 Koyama et al. 2003). 

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