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  • 1
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2023
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology Vol. 396, No. 3 ( 2023-03), p. 499-511
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC, Vol. 396, No. 3 ( 2023-03), p. 499-511
    Abstract: Heart failure is a syndrome that can result from impaired heart muscle contractions like in dilative cardiomyopathy but also from hypertrophic obstructive cardiomyopathy (HOCOM). A pharmacological therapy might lie in Ca 2+ -sensitizing or Ca 2+ -desensitizing drugs, respectively. Such drugs are thought to be omecamtiv mecarbil (OME) and mavacamten (MYK-461), respectively. Their function in contracting human muscle is not fully understood and was the focus of the present study. OME from 1 nM to 10 µM cumulatively applied failed to raise force of contraction in human right atrial preparations strips (HAP) or mouse left atrial preparations (LA). However, OME prolonged time to peak tension and time of relaxation in HAP and LA but did not alter the beating rate in right atrial preparations from mice (RA). In contrast, MYK-461 (10 nM to 10 µM) reduced concentration- and time-dependently force of contraction in HAP and LA. MYK-461 (10 µM) did not affect the beating rate in RA. In summary, the present data failed to detect an increase in force of contraction for OME, in human and mouse atrium. In contrast, a Ca 2+ desensitizer studied for comparison was able to reduce force of contraction in HAP and LA. We conclude that putative beneficial effects of OME in dilated cardiomyopathy cannot be explained by positive inotropic effects in the HAP, whereas beneficial functional effects of MYK-461 in HOCOM can be explained by negative inotropic effects in HAP.
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 2
    Online Resource
    Online Resource
    Wiley ; 2015
    In:  The FASEB Journal Vol. 29, No. S1 ( 2015-04)
    In: The FASEB Journal, Wiley, Vol. 29, No. S1 ( 2015-04)
    Type of Medium: Online Resource
    ISSN: 0892-6638 , 1530-6860
    URL: Issue
    Language: English
    Publisher: Wiley
    Publication Date: 2015
    detail.hit.zdb_id: 1468876-1
    SSG: 12
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  • 3
    Online Resource
    Online Resource
    American Physiological Society ; 2017
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 313, No. 6 ( 2017-12-01), p. H1087-H1097
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 313, No. 6 ( 2017-12-01), p. H1087-H1097
    Abstract: Using transgenic (TG) mice that overexpress the human serotonin (5-HT) 4a receptor specifically in cardiomyocytes, we wanted to know whether 5-HT can be formed and degraded in the mammalian heart and whether this can likewise lead to inotropic and chronotropic effects in this TG model. We noted that the 5-HT precursor 5-hydroxy-tryptophan (5-HTP) can exert inotropic and chronotropic effects in cardiac preparations from TG mice but not from wild-type (WT) mice; similar results were found in human atrial preparations as well as in intact TG animals using echocardiography. Moreover, by immunohistochemistry we could detect 5-HT metabolizing enzymes and 5-HT transporters in mouse hearts as well as in human atria. Hence, in the presence of an inhibitor of aromatic l-amino acid decarboxylase, the positive inotropic effects of 5-HTP were absent in TG and isolated human atrial preparations, and, moreover, inhibitors of enzymes involved in 5-HT degradation enhanced the efficacy of 5-HT in TG atria. A releaser of neurotransmitters increased inotropy in the isolated TG atrium, and this effect could be blocked by a 5-HT 4a receptor antagonist. Fluoxetine, an inhibitor of 5-HT uptake, elevated the potency of 5-HT to increase contractility in the TG atrium. In addition, inhibitors of organic cation and monoamine transporters apparently reduced the positive inotropic potency of 5-HT in the TG atrium. Hence, we tentatively conclude that a local production and degradation of 5-HT in the mammalian heart and more specifically in mammalian myocytes probably occurs. Conceivably, this formation of 5-HT and possibly impaired degradation may be clinically relevant in cases of unexplained tachycardia and other arrhythmias. NEW & NOTEWORTHY The present work suggests that inotropically active serotonin (5-HT) can be formed in the mouse and human heart and probably by cardiomyocytes themselves. Moreover, active degradation of 5-HT seems to occur in the mammalian heart. These findings may again increase the interest of researchers for cardiac effects of 5-HT.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    RVK:
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2017
    detail.hit.zdb_id: 1477308-9
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  • 4
    Online Resource
    Online Resource
    Elsevier BV ; 2022
    In:  Journal of Molecular and Cellular Cardiology Vol. 173 ( 2022-12), p. S135-
    In: Journal of Molecular and Cellular Cardiology, Elsevier BV, Vol. 173 ( 2022-12), p. S135-
    Type of Medium: Online Resource
    ISSN: 0022-2828
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2022
    detail.hit.zdb_id: 1469767-1
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  • 5
    In: Naunyn-Schmiedeberg's Archives of Pharmacology, Springer Science and Business Media LLC
    Abstract: Clonidine has various clinical effects mediated by agonism of α 1 - or α 2 -adrenoceptors and the blocking of hyperpolarization-activated-nucleotide-gated pacemaker channels (HCN). It is unknown whether clonidine can also stimulate human cardiac histamine H 2 receptors (hH 2 Rs). We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the hH 2 R specifically in the heart (H 2 -TG), and spontaneously beating right atrial preparations of guinea pigs for comparison. Moreover, we studied isolated electrically stimulated muscle strips from the human right atrium. Clonidine (1, 3, and 10 µM) increased force of contraction in isolated left atrial preparations from H 2 -TG mice. In contrast, clonidine reduced the spontaneous beating rate in right atrial preparations from H 2 -TG. Clonidine raised the beating rate in guinea pig right atrial preparations. Clonidine failed to increase the force of contraction but reduced beating rate in wild-type litter mate mice (WT). In WT, histamine failed to increase the force of contraction in left atrial preparations and beating rate in right atrial preparations. Clonidine (10 µM) increased the force of contraction in isolated human right atrial preparations. The positive inotropic effect in the human atrium was attenuated by cimetidine (10 µM). Clonidine increased the beating rate of the isolated spontaneously beating guinea pig right atrium and acted as a H 2 R partial agonist. Furthermore, clonidine showed binding to the guinea pig H 2 R (100 µM) using HEK cells in a recombinant expression system (p K i   〈  4.5) but hardly to the human H 2 R. These data suggest that clonidine can functionally activate cardiac human H 2 R.
    Type of Medium: Online Resource
    ISSN: 0028-1298 , 1432-1912
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 6
    Online Resource
    Online Resource
    Frontiers Media SA ; 2021
    In:  Frontiers in Pharmacology Vol. 12 ( 2021-12-20)
    In: Frontiers in Pharmacology, Frontiers Media SA, Vol. 12 ( 2021-12-20)
    Abstract: This review addresses pharmacological, structural and functional relationships among H 2 -histamine receptors and H 1 -histamine receptors in the mammalian heart. The role of both receptors in the regulation of force and rhythm, including their electrophysiological effects on the mammalian heart, will then be discussed in context. The potential clinical role of cardiac H 2 -histamine-receptors in cardiac diseases will be examined. The use of H 2 -histamine receptor agonists to acutely increase the force of contraction will be discussed. Special attention will be paid to the potential role of cardiac H 2 -histamine receptors in the genesis of cardiac arrhythmias. Moreover, novel findings on the putative role of H 2 -histamine receptor antagonists in treating chronic heart failure in animal models and patients will be reviewed. Some limitations in our biochemical understanding of the cardiac role of H 2 -histamine receptors will be discussed. Recommendations for further basic and translational research on cardiac H 2 -histamine receptors will be offered. We will speculate whether new knowledge might lead to novel roles of H 2 -histamine receptors in cardiac disease and whether cardiomyocyte specific H 2 -histamine receptor agonists and antagonists should be developed.
    Type of Medium: Online Resource
    ISSN: 1663-9812
    Language: Unknown
    Publisher: Frontiers Media SA
    Publication Date: 2021
    detail.hit.zdb_id: 2587355-6
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  • 7
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
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  • 8
    In: European Journal of Pharmacology, Elsevier BV, Vol. 901 ( 2021-06), p. 174074-
    Type of Medium: Online Resource
    ISSN: 0014-2999
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 1483526-5
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  • 9
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 1462940-9
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  • 10
    Online Resource
    Online Resource
    Springer Science and Business Media LLC ; 2023
    In:  Naunyn-Schmiedeberg's Archives of Pharmacology Vol. 396, No. 9 ( 2023-09), p. 2137-2150
    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
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
    detail.hit.zdb_id: 1462940-9
    SSG: 15,3
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