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  • 1
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    Online Resource
    Effects of acute ischemia and hypoxia in young and adult calsequestrin (CSQ2) knock-out and wild-type mice
    Springer Science and Business Media LLC ; 2022
    In:  Molecular and Cellular Biochemistry Vol. 477, No. 6 ( 2022-06), p. 1789-1801
    Details
    In: Molecular and Cellular Biochemistry, Springer Science and Business Media LLC, Vol. 477, No. 6 ( 2022-06), p. 1789-1801
    Abstract: Calsequestrin (CSQ2) is the main Ca 2+ -binding protein in the sarcoplasmic reticulum of the mammalian heart. In order to understand the function of calsequestrin better, we compared two age groups (young: 4–5 months of age versus adult: 18 months of age) of CSQ2 knock-out mice (CSQ2(−/−)) and littermate wild-type mice (CSQ2(+/+)). Using echocardiography, in adult mice, the basal left ventricular ejection fraction and the spontaneous beating rate were lower in CSQ2(−/−) compared to CSQ2(+/+). The increase in ejection fraction by β-adrenergic stimulation (intraperitoneal injection of isoproterenol) was lower in adult CSQ2(−/−) versus adult CSQ2(+/+). After hypoxia in vitro (isolated atrial preparations) by gassing the organ bath buffer with 95% N 2 , force of contraction in electrically driven left atria increased to lower values in young CSQ2(−/−) than in young CSQ2(+/+). In addition, after global ischemia and reperfusion (buffer-perfused hearts according to Langendorff; 20-min ischemia and 15-min reperfusion), the rate of tension development was higher in young CSQ2(−/−) compared to young CSQ2(+/+). Finally, we evaluated signs of inflammation (immune cells, autoantibodies, and fibrosis). However, whereas no immunological alterations were found between all investigated groups, pronounced fibrosis was found in the ventricles of adult CSQ2(−/−) compared to all other groups. We suggest that in young mice, CSQ2 is important for cardiac performance especially in isolated cardiac preparations under conditions of impaired oxygen supply, but with differences between atrium and ventricle. Lack of CSQ2 leads age dependently to fibrosis and depressed cardiac performance in echocardiographic studies.
    Type of Medium: Online Resource
    ISSN: 0300-8177 , 1573-4919
    URL: Article
    DOI: 10.1007/s11010-022-04407-2
    RVK:
    WD 5725
    RVK:
    WD 5275
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
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    Evidence for Arrhythmogenic Effects of A2A-Adenosine Receptors
    Frontiers Media SA ; 2019
    In:  Frontiers in Pharmacology Vol. 10 ( 2019-9-18)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 10 ( 2019-9-18)
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    DOI: 10.3389/fphar.2019.01051
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2019
    detail.hit.zdb_id: 2587355-6
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  • 3
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    Image2.PDF
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 12 ( 2021-5-11)
    Details
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-5-11)
    Abstract: Histamine is metabolized by several enzymes in vitro and in vivo . The relevance of this metabolism in the mammalian heart in vivo is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H 2 -histamine receptors. In transgenic mice (H 2 -TG) that overexpress the human H 2 receptor in cardiomyocytes but not in wild-type littermate mice (WT), histamine induced PIE and PCE in isolated left or right atrial preparations. These H 2 -TG were used to investigate the putative relevance of histamine degrading enzymes in the mammalian heart. Histidine, the precursor of histamine, increased force of contraction (FOC) in human atrial preparations. Moreover, histamine increased the phosphorylation state of phospholamban in human atrium. Here, we could detect histidine decarboxylase (HDC) and histamine itself in cardiomyocytes of mouse hearts. Moreover, our data indicate that histamine is subject to degradation in the mammalian heart. Inhibition of the histamine metabolizing enzymes diamine oxidase (DAO) and monoamine oxidase (MAO) shifted the concentration response curves for the PIE in H 2 -TG atria to the left. Moreover, activity of histamine metabolizing enzymes was present in mouse cardiac samples as well as in human atrial samples. Thus, drugs used for other indication (e.g. antidepressants) can alter histamine levels in the heart. Our results deepen our understanding of the physiological role of histamine in the mouse and human heart. Our findings might be clinically relevant because we show enzyme targets for drugs to modify the beating rate and force of the human heart.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    URL: Article
    URL: Article
    URL: Article
    DOI: 10.3389/fphar.2021.582916
    DOI: 10.3389/fphar.2021.582916.s001
    DOI: 10.3389/fphar.2021.582916.s002
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
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  • 4
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    Role of Dopamine in the Heart in Health and Disease
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 5 ( 2023-03-06), p. 5042-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 5 ( 2023-03-06), p. 5042-
    Abstract: Dopamine has effects on the mammalian heart. These effects can include an increase in the force of contraction, and an elevation of the beating rate and the constriction of coronary arteries. Depending on the species studied, positive inotropic effects were strong, very modest, or absent, or even negative inotropic effects occurred. We can discern five dopamine receptors. In addition, the signal transduction by dopamine receptors and the regulation of the expression of cardiac dopamine receptors will be of interest to us, because this might be a tempting area of drug development. Dopamine acts in a species-dependent fashion on these cardiac dopamine receptors, but also on cardiac adrenergic receptors. We will discuss the utility of drugs that are currently available as tools to understand cardiac dopamine receptors. The molecule dopamine itself is present in the mammalian heart. Therefore, cardiac dopamine might act as an autocrine or paracrine compound in the mammalian heart. Dopamine itself might cause cardiac diseases. Moreover, the cardiac function of dopamine and the expression of dopamine receptors in the heart can be altered in diseases such as sepsis. Various drugs for cardiac and non-cardiac diseases are currently in the clinic that are, at least in part, agonists or antagonists at dopamine receptors. We define the research needs in order to understand dopamine receptors in the heart better. All in all, an update on the role of dopamine receptors in the human heart appears to be clinically relevant, and is thus presented here.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms24055042
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
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  • 5
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    Glucagon and Its Receptors in the Mammalian Heart
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 16 ( 2023-08-15), p. 12829-
    Details
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 16 ( 2023-08-15), p. 12829-
    Abstract: Glucagon exerts effects on the mammalian heart. These effects include alterations in the force of contraction, beating rate, and changes in the cardiac conduction system axis. The cardiac effects of glucagon vary according to species, region, age, and concomitant disease. Depending on the species and region studied, the contractile effects of glucagon can be robust, modest, or even absent. Glucagon is detected in the mammalian heart and might act with an autocrine or paracrine effect on the cardiac glucagon receptors. The glucagon levels in the blood and glucagon receptor levels in the heart can change with disease or simultaneous drug application. Glucagon might signal via the glucagon receptors but, albeit less potently, glucagon might also signal via glucagon-like-peptide-1-receptors (GLP1-receptors). Glucagon receptors signal in a species- and region-dependent fashion. Small molecules or antibodies act as antagonists to glucagon receptors, which may become an additional treatment option for diabetes mellitus. Hence, a novel review of the role of glucagon and the glucagon receptors in the mammalian heart, with an eye on the mouse and human heart, appears relevant. Mouse hearts are addressed here because they can be easily genetically modified to generate mice that may serve as models for better studying the human glucagon receptor.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    URL: Article
    DOI: 10.3390/ijms241612829
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
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  • 6
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    Correction to: Functional interaction of H2‑receptors and 5-HT4‑receptors in atrial tissues isolated from double transgenic mice and from human patients
    Springer Science and Business Media LLC ; 2021
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology Vol. 394, No. 12 ( 2021-12), p. 2475-2476
    Details
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC, Vol. 394, No. 12 ( 2021-12), p. 2475-2476
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    URL: Article
    DOI: 10.1007/s00210-021-02167-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1462940-9
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  • 7
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    Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-receptor overexpressing mice
    Springer Science and Business Media LLC ; 2023
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology Vol. 396, No. 9 ( 2023-09), p. 2137-2150
    Details
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC, Vol. 396, No. 9 ( 2023-09), p. 2137-2150
    Abstract: We investigated whether hypothermia and hyperthermia can alter the efficacy and potency of histamine at increasing the force of cardiac contractions in mice that overexpress the human H 2 receptor only in their cardiac myocytes (labelled H 2 -TG). Contractile studies were performed in an organ bath on isolated, electrically driven (1 Hz) left atrial preparations and spontaneously beating right atrial preparations from H 2 -TG mice and wild-type (WT) littermate control mice. The basal beating rate in the right atrial preparations from H 2 -TG mice was lowered by hypothermia (23 °C) and elevated by hyperthermia (42 °C). Furthermore, the efficacy of histamine (0.01–100 µM) at exerting positive inotropic effects was more severely attenuated in the left and right H 2 -TG mouse atria under hypothermia and hyperthermia than under normothermia (37 °C). Similarly, the inotropic response to histamine was attenuated under hypothermia and hyperthermia in isolated electrically stimulated (1 Hz) right atrial preparations obtained from humans undergoing cardiac surgery. The phosphorylation state of phospholamban at serine 16 at 23 °C was inferior to that at 37 °C in left atrial preparations from H 2 -TG mice in the presence of 10 µM histamine. In contrast, in human atrial preparations, the phosphorylation state of phospholamban at serine 16 in the presence of 100 µM histamine was lower at 42 °C than at 37 °C. Finally, under hyperthermia, we recorded more and longer lasting arrhythmias in right atrial preparations from H 2 -TG mice than in those from WT mice. We conclude that the inotropic effects of histamine in H 2 -TG mice and in human atrial preparations, as well as the chronotropic effects of histamine in H 2 -TG mice, are temperature dependent. Furthermore, we observed that, even without stimulation of the H 2 receptors by exogenous agonists, temperature elevation can increase arrhythmias in isolated right atrial preparations from H 2 -TG mice. We propose that H 2 receptors play a role in hyperthermia-induced supraventricular arrhythmias in human patients.
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    URL: Article
    DOI: 10.1007/s00210-023-02457-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 8
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    Ergometrine stimulates histamine H2 receptors in the isolated human atrium
    Springer Science and Business Media LLC ; 2023
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology
    Details
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC
    Abstract: Ergometrine (6a R ,9 R )- N -(( S )-1-hydroxypropan-2-yl)-7-methyl-4,6,6a,7,8,9-hexa-hydro-indolo-[4,3- fg ]chinolin-9-carboxamide or lysergide acid β-ethanolamide or ergonovine) activates several types of serotonin and histamine receptors in the animal heart. We thus examined whether ergometrine can activate human serotonin 5-HT 4 receptors (h5-HT 4 R) and/or human histamine H 2 receptors (hH 2 R) in the heart of transgenic mice and/or in the human isolated atrium. Force of contraction or beating rates were studied in electrically stimulated left atrial or spontaneously beating right atrial preparations or spontaneously beating isolated retrogradely perfused hearts (Langendorff setup) of mice with cardiac specific overexpression of the h5-HT 4 R (5-HT 4 -TG) or of mice with cardiac specific overexpression of the hH 2 R (H 2 -TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery. Western blots to assess phospholamban (PLB) phosphorylation on serine 16 were performed. Ergometrine exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in atrial preparations starting at 0.3 µM and reaching a plateau at 10 µM in H 2 -TGs ( n  = 7). This was accompanied by an increase in PLB phosphorylation at serine 16. Ergometrine up 10 µM failed to increase force of contraction in left atrial preparations from 5-HT 4 -TGs ( n  = 5). Ten micrometer ergometrine increased the force of contraction in isolated retrogradely perfused spontaneously beating heart preparations (Langendorff setup) from H 2 -TG but not 5-HT 4 -TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergometrine at 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, and these effects were eliminated by 10 µM of the H 2 R antagonist cimetidine but not by 10 µM of the 5-HT 4 R antagonist tropisetron. Furthermore, ergometrine showed binding to human histamine H 2 receptors (at 100 µM and 1 mM) using HEK cells in a recombinant expression system (p K i   〈  4.5, n  = 3). In conclusion, we suggest that ergometrine is an agonist at cardiac human H 2 Rs.
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    URL: Article
    DOI: 10.1007/s00210-023-02573-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 9
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    Lysergic acid diethylamide stimulates cardiac human H2 histamine and cardiac human 5-HT4-serotonin receptors
    Springer Science and Business Media LLC ; 2023
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology
    Details
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC
    Abstract: Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT 4 serotonin receptors and/or H 2 histamine receptors. We studied isolated electrically stimulated left atrial preparations, spontaneously beating right atrial preparations, and spontaneously beating Langendorff-perfused hearts from transgenic mice with cardiomyocyte-specific overexpression of the human 5-HT 4 receptor (5-HT 4 -TG) or of the H 2 -histamine receptor (H 2 -TG). For comparison, we used wild type littermate mice (WT). Finally, we measured isometric force of contraction in isolated electrically stimulated muscle strips from the human right atrium obtained from patients during bypass surgery. LSD (up to 10 µM) concentration dependently increased force of contraction and beating rate in left or right atrial preparations from 5-HT 4 -TG ( n  = 6, p   〈  0.05) in 5-HT 4 -TG atrial preparations. The inotropic and chronotropic effects of LSD were antagonized by 10 µM tropisetron in 5-HT 4 -TG. In contrast, LSD (10 µM) increased force of contraction and beating rate in left or right atrial preparations, from H 2 -TG. After pre-stimulation with cilostamide (1 µM), LSD (10 µM) increased force of contraction in human atrial preparations ( n  = 6, p   〈  0.05). The contractile effects of LSD in human atrial preparations could be antagonized by 10 µM cimetidine and 1 µM GR 125487. LSD leads to H 2 -histamine receptor and 5-HT 4 -receptor mediated cardiac effects in humans.
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    URL: Article
    DOI: 10.1007/s00210-023-02591-6
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 10
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    Cardiovascular effects of metoclopramide and domperidone on human 5-HT4-serotonin-receptors in transgenic mice and in human atrial preparations
    Elsevier BV ; 2021
    In:  European Journal of Pharmacology Vol. 901 ( 2021-06), p. 174074-
    Details
    In: European Journal of Pharmacology, Elsevier BV, Vol. 901 ( 2021-06), p. 174074-
    Type of Medium: Online Resource
    ISSN: 0014-2999
    URL: Article
    DOI: 10.1016/j.ejphar.2021.174074
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1483526-5
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