Histamine is highly concentrated in the heart of animals and humans. Excessive release in pathophysiological conditions, such as immediate hypersensitivity and septic shock, causes cardiac dysfunction and arrhythmias. Previous pharmacological studies revealed that H 1 and H 2 receptors mediate these effects. Yet, an accurate estimate of the distribution and molecular characteristics of cardiac histamine receptors is missing. Recently, the genes encoding H 1 and H 2 receptors have been cloned, and the amino acid sequence and protein structure have been elucidated. Accordingly, we analyzed gene and protein expression levels of H 1 and H 2 receptors in atria and ventricles of guinea pig, rabbit, rat, and human hearts. With immunocytochemical techniques, we examined the regional expression of H 1 and H 2 receptor proteins in the sinoatrial and atrioventricular nodes and surrounding myocardium of the guinea pig heart. Northern and Western blot studies revealed that cardiac histamine H 1 and H 2 receptors are variably distributed among different mammalian species and different regions of the heart, whereas H 2 receptors are abundantly expressed in human atrial and ventricular myocardium. These findings agree with those of previous pharmacological studies, clearly demonstrating that the responses of the heart to histamine depend on the expression level of H 1 and H 2 receptors. The highly abundant expression of H 2 receptors in the human heart substantiates histamine arrhythmogenicity in various disease states. The new knowledge of a differential distribution of histamine receptor subtypes in the human heart will foster a better understanding of histamine roles in cardiovascular pathophysiology and may contribute to new therapeutic approaches to histamine-induced cardiac dysfunctions.The actions of histamine as a cardiac stimulant have been appreciated for more than 90 years since the seminal work of Dale and Laidlaw (1910). The primary and direct actions of histamine in the heart are characterized by an increase in sinus rate and ventricular automaticity, a decrease in AV conduction velocity, and an increase in force of contraction (Levi et al., 1991;Hattori, 1999). Because histamine is present in high concentrations in cardiac tissues in most animal species, including humans (Bristow et al., 1982;Wolff and Levi, 1986), its release from cardiac stores and its subsequent actions on the heart may be of importance in pathological conditions associated with histamine release (Levi, 1988). In this context, we recently reported that superinduction of histamine receptor gene products and histamine overproduction contribute to the hemodynamic derangement characteristic of septic shock (Matsuda et al., 2002).The negative dromotropic and positive chronotropic effects of histamine invariably result from the activation of H 1 and H 2 receptors, respectively (Levi et al., 1991;Hattori, 1999). In contrast, there is a marked species difference in the subtype of histamine receptors mediating the positive inotropic effect. Mor...

Exogenous bradykinin (BK), acting at B2-receptors, enhances norepinephrine (NE) release and exacerbates arrhythmias (VF) in myocardial ischemia/reperfusion. Inhibition of BK formation (with serine proteinase inhibitors) alleviates NE release and VF, whereas prevention of BK degradation (with kininase inhibitors) potentiates them. Yet serine proteinase and kininase inhibitors also prevent the formation of angiotensin (AII), a potent NE-release enhancer. Thus we assessed the respective contribution of AII and BK to NE release and VF by using selective B2- and AT1-receptor antagonists. Isolated guinea pig hearts were subjected to 10- and 20-min global ischemia and 45-min reperfusion. NE overflow (pmol/g) was approximately 8 (exocytotic) and approximately 750 (carrier mediated). VF, associated with carrier-mediated NE release, lasted approximately 2 min. The B2-receptor antagonist Hoe 140 (30 nM) affected neither NE overflow nor VF. In contrast, the AT1-receptor antagonist EXP3174 (100 nM) markedly reduced exocytotic and carrier-mediated NE release and shortened VF. When EXP3174 was combined with Hoe 140, NE overflow and VF were decreased even further. Thus in myocardial ischemia, local AII production contributes to NE release and VF via AT1-receptors. Although BK production increases in myocardial ischemia, the effects of BK on adrenergic nerve terminals are uncovered only when BK half-life is prolonged and/or when AII effects are suppressed.

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Yohimbine, an ␣ 2 -adrenoceptor antagonist, has been reported to protect hypoxic myocardium and inhibit carrier-mediated norepinephrine (NE) release and reperfusion arrhythmias (ventricular fibrillation; VF) in normothermic ischemia. In heart surgery, mild hypothermic (tepid) cardioplegia has been reported to reduce metabolic demand and permit immediate recovery of cardiac function. Therefore, we determined the effect of yohimbine on NE release and reperfusion arrhythmias in isolated perfused guinea pig hearts of tepid temperature (32°C) ischemia model. Stepwise increase of global ischemia period (20, 40, and 60 min) induced a progressive increase of NE release and duration of VF. Neuronal uptake 1 inhibitor desipramine (100 nM) and Na ϩ -H ϩ exchanger inhibitor 5-N-ethyl-N-isopropyl-amiloride (10 M) decreased NE and VF in 60-min hypothermic ischemia. This indicated that NE release induced by protracted tepid ischemia was due to carrier-mediated release. Yohimbine (1 M) markedly reduced NE release and VF (p Ͻ 0.01 versus control) and 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine [UK 14,304 (UK); 10 M], an ␣ 2 -adrenoceptor agonist, increased NE release and VF (p Ͻ 0.01 versus control). Yohimbine (1 M) prevented the potentiated effect of UK (10 M) in hypothermia (p Ͻ 0.01 versus UK). Our findings indicate that presynaptic reduction of carrier-mediated NE release seems to be one of the most important factors controlling reperfusion arrhythmias, and ␣ 2 -adrenoceptor blockade by yohimbine (1 M) in tepid ischemia may contribute to effective myocardial protection in terms of NE release and reperfusion arrhythmia.Protracted myocardial ischemia induces much greater release of norepinephrine (NE) from sympathetic nerve endings than normal conditions. In this case, excessive NE release is carrier-mediated release rather than exocytosis (Schöming, 1990;Dart and Du, 1993). It is caused by reversal of the uptake 1 carrier that is responsible for reuptake of extracellular NE under normoxic condition (Schöming, 1990;Dart and Du, 1993;Kurz et al., 1995). Exaggerated NE release induced by ischemia increases oxygen demand by stimulating heart rate and contractility and decreases oxygen supply by constricting coronary vessels. This vicious cycle accelerates the progression of cell damage in ischemic myocardium and potentiates the arrhythmogenicity of NE (Braunwald and Sobel, 1988; Schöming et al., 1991;Kü bler and Strasser, 1994). Therefore, the modulation of excessive NE release would be expected to protect myocardium or improve functional recovery, or limit reperfusion arrhythmias.Antagonists of ␣ 2 -adrenoceptors, yohimbine (1 M), idazoxan (10 M), and rauwolscine (1 M), were reported to attenuate not only carrier-mediated NE release from sympathetic nerve terminals but also reperfusion arrhythmias in perfused guinea pig heart model in normothermic conditions (Imamura et al., 1996).In cardiac surgery, a surgeon cannot perform an operation without some form of cardioprotection. Hypothermia has been widely ac...

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