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  • Histamine which was used as the agonist

    2022-01-21

    Histamine, which was used as the agonist, had low potencies in our functional experiments when compared to its affinity from binding studies (e.g. Lim et al., 2005). This phenomenon is related to the fact that the coupling of the presynaptic receptor to the transduction machinery and the final functional response is impaired due to the experimental conditions including the stimulation protocol. This can be shown if one e.g. compares the potency of histamine for the H3 receptor-mediated inhibition of noradrenaline release in guinea-pig peripheral tissues (pEC50 of 5.6 in the atp 4 and of 5.9 in the kidney; present study) and cerebral cortex slices (pEC50 of 6.5; Timm et al., 1998). In the latter study, a lower stimulation frequency (0.3 vs. 3 Hz) and a lower Ca2+ concentration (1.3 vs. 3.25 mM) could be used, both of which are associated with an improved effect mediated via presynaptic receptors (Starke, 1977). Acetylcholine release from hippocampal slices was not affected by R-α-methylhistamine and this finding is in harmony with previous studies on hippocampal slices from the rat (Alves-Rodrigues et al., 1998). On slices of another brain region of the rat, the entorhinal cortex, an inhibitory effect was obtained (Clapham and Kilpatrick, 1992), which, however, did not occur on synaptosomes, i.e. isolated nerve endings (Arrang et al., 1995). The latter data suggest that the H3 receptor cannot be located on the cholinergic nerve endings themselves but must be located on an interneurone. This phenomenon may also explain why H3 receptor activation in various brain regions of the rat in vivo can even increase acetylcholine release (e.g. Passani et al., 2001, Cangioli et al., 2002) although an inhibition was observed as well (e.g. Ligneau et al., 2007, Munari et al., 2013). In conclusion, using superfused atrial tissue pieces we could not detect the histamine H4 receptor suggested by Chan et al. (2012) on the basis of experiments on synaptosomes from the same tissue. This receptor could also not been found in another four superfusion models of the present study (aorta, renal cortex, vas deferens, hippocampus) and in the superfused cerebral cortex of humans, guinea-pigs and mice in our previous paper (Feliszek et al., 2015). H3 receptors although not detected in the hippocampus could be shown in the atrium, vas deferens, aorta and renal cortex and for the latter two tissues the involvement of this receptor could be proven by an interaction study with thioperamide.
    Acknowledgements This work was supported by the “BONFOR” programme of the Medical Faculty of the University of Bonn. We would like to thank Boehringer-Ingelheim and Schering-Plough Research for gifts of AF-DX 384 and thioperamide, respectively. R-α-Methylhistamine has been kindly donated by Professor Walter Schunack (deceased on April 6, 2011), who has supported the work of this group on numerous occasions.