H1 histamine receptors in the heart

• Applicant: Privatdozent Dr. Ulrich Gergs
• Subject Area: Pharmacology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 528629916

Our aim is to better understand the importance of the H1 histamine receptor for contractility in the human heart. Both negative inotropic and positive inotropic effects of the H1 histamine receptor have been published. Various hypotheses regarding signal transduction of the receptor have been described. The aim of the present project is to find out how signal transduction and force are coupled via the human H1 histamine receptor in the heart. The interaction with the H2 histamine receptor should also be taken into account, since both receptors are expressed in the human heart. For this we use two transgenic mouse models that we have established. In these mice, the cDNA of the human H1 histamine receptor or of the human H2 histamine receptor is expressed cardiomyocyte-specific by use of the alpha-myosin heavy chain promoter. The H1-TG mouse has the advantage of not expressing a functional H2 histamine receptor in the heart, which means that the effect of H1 histamine receptors can be measured and biochemically examined very well in this model. Isolated ventricular cardiomyocytes can be produced from the H1-TG hearts. After that, the contractility can be examined in more detail in comparison with the biochemistry of these cells. This will clarify whether the H1 histamine receptor in the cardiomyocytes is responsible for the contractility changes. The following hypotheses are to be examined for the course of signal transduction: 1) The H1 histamine receptor stimulation couples to a phospholipase C in the sarcolemma of the cardiomyocytes. This ultimately increases the release of Ca2+ from stores in the SR via an IP3 increase in the cell and thus leads to an increase in the free cytosolic concentration of Ca2+. A positive inotropic effect could thus come about via a Ca2+ effect on the myofilaments. 2) The negative inotropic effect of the H1 histamine receptor stimulation should to be based on an increase in cGMP. 3) The H1 histamine receptor increases the levels of cGMP, this cGMP inhibits phosphodiesterase III, which then no longer degrades cAMP. The biphasic effect observed so far could be explained with this hypothesis. The cGMP increases, on the other hand, could also originate from endothelial cells or smooth muscle cells and would then be meaningless for the contractility because it would not be present in the cardiomyocyte. This should be clarified by our model, as we only overexpressed the human H1 histamine receptor in cardiomyocytes and not in endothelial cells or smooth muscle cells. In addition, we want to investigate the importance of the H1 histamine receptor in cardiac stress. For example, the negative inotropic and negative chronotropic effect of H1 histamine receptor stimulation could contribute to reduced oxygen demand. These findings could contribute to improved diagnostics and therapy for important cardiac diseases such as heart failure and arrhythmias.

• DFG Programme: Research Grants
• Co-Investigator: Professor Dr. Joachim Neumann