Histamine H₁and H₂Receptor Gene and Protein Levels Are Differentially Expressed in the Hearts of Rodents and Humans

Abstract

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...

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