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Initial characterization of histamine H2‐receptor overexpressing mice

Histamine is known to have positive inotropic and positive chronotropic effects in the human heart. The involvement of histamine receptors in human heart failure is controversial. However, some lines of evidence suggest that the histamine H2‐ receptor is downregulated in end‐stage heart failure and its blockade is beneficial for the patient. Therefore, we set out to generate transgenic mice which overexpress the human H2‐ receptor, labeled with a C‐terminal His tag, specifically in the heart by means of the α‐myosin heavy‐chain promoter. We obtained one line of animals where histamine was able to increase contractility in isolated left atrial preparations or isolated perfused hearts or in vivo using left ventricular echocardiography. Of importance, this effect could be blocked by cimetidine, a H2‐receptor antagonist. In contrast, histamine was inactive in preparations from littermate wild type animals. The EC50 for the inotropic and chronotropic effects in atrial preparations amounted to about 10−6M (n=6–8). The effect was accompanied by an increase in the phosphorylation state of serine 16 on phospholamban and this effect could be completely blocked by cimetidine. Immunohistochemisty revealed that the transgene using an anti His antibody was located mainly to the sarcolemma. In summary, we have generated a novel model system to study the functional role of the human histamine H2‐ receptor in a mammalian model.