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CARDIOVASCULAR

Histamine H₁ and H₂ Receptor Gene and Protein Levels Are Differentially Expressed in the Hearts of Rodents and Humans

Departments of Pharmacology (Y.H.), Anesthesiology and Critical Care Medicine (N.M., Y.T., S.G.), Cardiovascular Medicine (S.J., I.S.) and Cardiovascular Surgery (E.H.), Hokkaido University School of Medicine, Sapporo, Japan; Division of Cancer Biology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan (M.K.); Department of Pharmacology, Faculty of Pharmaceutical Sciences, University of Tokushima, Tokushima, Japan (K.M., N.K., H.F.); and Department of Pharmacology, Weill Medical College of Cornell University, New York, New York (R.L.)

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 H₁ and H₂ receptors mediate these effects. Yet, an accurate estimate of the distribution and molecular characteristics of cardiac histamine receptors is missing. Recently, the genes encoding H₁ and H₂ receptors have been cloned, and the amino acid sequence and protein structure have been elucidated. Accordingly, we analyzed gene and protein expression levels of H₁ and H₂ receptors in atria and ventricles of guinea pig, rabbit, rat, and human hearts. With immunocytochemical techniques, we examined the regional expression of H₁ and H₂ 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 H₁ and H₂ receptors are variably distributed among different mammalian species and different regions of the heart, whereas H₂ 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 H₁ and H₂ receptors. The highly abundant expression of H₂ 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.

Address correspondence to: Dr. Yuichi Hattori, Department of Pharmacology, Hokkaido University, School of Medicine, Sapporo 060-8638, Japan. E-mail: yhattori{at}med.hokudai.ac.jp

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