Stimulation of histamine H-receptors produces a positive inotropic effect in the human atrium.

There is a controversy whether histamine H-receptor activation raises or lowers or does not affect contractility in the human heart. Therefore, we studied stimulation of H-receptors in isolated electrically stimulated (one beat per second) human atrial preparations (HAP). For comparison, we measured force of contraction in left atrial preparations (LA) from mice with overexpression of the histamine H-receptor in the heart (H-TG).

Clozapine is a functional antagonist at cardiac human H-histamine receptors.

Clozapine is an atypical antipsychotic (neuroleptic) drug. Clozapine binds to H-histamine receptors in vitro. We wanted to test the hypothesis that clozapine might be a functional antagonist at human cardiac H-histamine receptors.

Loss of protein phosphatase 2A regulatory subunit is associated with increased incidence of stress-induced proarrhythmia.

Background: Protein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme that controls Ca homeostasis and contractility of the heart via dephosphorylation of regulatory proteins. In some genetically modified mouse models with increased arrhythmogenicity, a reduced expression of the regulatory subunit B56α of PP2A was found as a concomitant effect. Whether there is a general correlation between the abundance of B56α and the promotion of cardiac arrhythmogenesis remains unclear.

Initial Characterization of a Transgenic Mouse with Overexpression of the Human H-Histamine Receptor on the Heart.

There is a debate on whether H-histamine receptors can alter contractility in the mammalian heart. We studied here a new transgenic mouse model where we increased genetically the cardiac level of the H-histamine receptor. We wanted to know if histamine could augment or decrease contractile parameters in mice with cardiac-specific overexpression of human H-histamine receptors (H-TG) and compared these findings with those in littermate wild-type mice (WT).

Effects of hallucinogenic drugs on the human heart.

Hallucinogenic drugs are used because they have effects on the central nervous system. Their hallucinogenic effects probably occur via stimulation of serotonin receptors, namely, 5-HT-serotonin receptors in the brain. However, a close study reveals that they also act on the heart, possibly increasing the force of contraction and beating rate and may lead to arrhythmias.

Effects of congeners of amphetamine on the human heart.

Central stimulatory and hallucinogenic drugs of abuse like amphetamine and most congeners of amphetamine can have cardiac harmful effects. These cardiac side effects can lead to morbidities and death. In this paper, we review current knowledge on the direct and indirect effects of these amphetamine congeners on the mammalian heart-more specifically, the isolated human heart muscle preparation.

Hypercontractile cardiac phenotype in mice overexpressing the regulatory subunit PR72 of protein phosphatase 2A.

Background: The activity, localization, and substrate specificity of the protein phosphatase 2A (PP2A) heterotrimer are controlled by various regulatory B subunits. PR72 belongs to the B'' gene family and has been shown to be upregulated in human heart failure. However, little is known about the functions of PR72 in the myocardium.

Clonidine stimulates force of contraction via histamine H receptors in the human atrium.

Clonidine has various clinical effects mediated by agonism of α- or α-adrenoceptors and the blocking of hyperpolarization-activated-nucleotide-gated pacemaker channels (HCN). It is unknown whether clonidine can also stimulate human cardiac histamine H receptors (hHRs). We used isolated electrically stimulated left and spontaneously beating right atrial preparations from mice overexpressing the hHR specifically in the heart (H-TG), and spontaneously beating right atrial preparations of guinea pigs for comparison.

Lysergic acid diethylamide stimulates cardiac human H histamine and cardiac human 5-HT-serotonin receptors.

Lysergic acid diethylamide (LSD) is an artificial hallucinogenic drug. Thus, we hypothesized that LSD might act 5-HT serotonin receptors and/or H 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 receptor (5-HT-TG) or of the H-histamine receptor (H-TG).

Ergometrine stimulates histamine H receptors in the isolated human atrium.

Ergometrine (6aR,9R)-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 receptors (h5-HTR) and/or human histamine H receptors (hHR) 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-HTR (5-HT-TG) or of mice with cardiac specific overexpression of the hHR (H-TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery.

Function and Role of Histamine H Receptor in the Mammalian Heart.

Histamine can change the force of cardiac contraction and alter the beating rate in mammals, including humans. However, striking species and regional differences have been observed. Depending on the species and the cardiac region (atrium versus ventricle) studied, the contractile, chronotropic, dromotropic, and bathmotropic effects of histamine vary.

Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H-receptor overexpressing mice.

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 receptor only in their cardiac myocytes (labelled H-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-TG mice and wild-type (WT) littermate control mice. The basal beating rate in the right atrial preparations from H-TG mice was lowered by hypothermia (23 °C) and elevated by hyperthermia (42 °C).

Ergotamine Stimulates Human 5-HT-Serotonin Receptors and Human H-Histamine Receptors in the Heart.

Ergotamine (2'-methyl-5'α-benzyl-12'-hydroxy-3',6',18-trioxoergotaman) is a tryptamine-related alkaloid from the fungus . Ergotamine is used to treat migraine. Ergotamine can bind to and activate several types of 5-HT-serotonin receptors.

Myocardial overexpression of protein phosphatase 2A-B56α improves resistance against ischemia-reperfusion injury.

Protein phosphatase 2A (PP2A) plays a central role in myocardial ischemia-reperfusion (I/R) injury. Several studies showed a detrimental function of PP2A by using either overexpression models of the catalytic subunit (PP2Ac) or exogenous inhibitors of PP2Ac. However, all of these approaches underestimate the contribution of regulatory B subunits in modulating the PP2A holoenzyme.

Whole Exome Sequencing Identifies a Heterozygous Variant in the Cav1.3 Gene Associated with Familial Sinus Node Dysfunction and Focal Idiopathic Epilepsy.

Cav1.3 voltage-gated L-type calcium channels (LTCCs) are involved in cardiac pacemaking, hearing and hormone secretion, but are also expressed postsynaptically in neurons. So far, homozygous loss of function mutations in encoding the Cav1.

Impaired myocellular Ca cycling in protein phosphatase PP2A-B56α KO mice is normalized by β-adrenergic stimulation.

The activity of protein phosphatase 2A (PP2A) is determined by the expression and localization of the regulatory B-subunits. PP2A-B56α is the dominant isoform of the B'-family in the heart. Its role in regulating the cardiac response to β-adrenergic stimulation is not yet fully understood.

Activation of PKC results in improved contractile effects and Ca cycling by inhibition of PP2A-B56α.

Protein phosphatase 2A (PP2A) represents a heterotrimer that is responsible for the dephosphorylation of important regulatory myocardial proteins. This study was aimed to test whether the phosphorylation of PP2A-B56α at Ser by PKC is involved in the regulation of myocyte Ca cycling and contraction. For this purpose, heart preparations of wild-type (WT) and transgenic mice overexpressing the nonphosphorylatable S41A mutant form (TG) were stimulated by administration of the direct PKC activator phorbol 12-myristate 13-acetate (PMA), and functional effects were studied.

The Roles of Cardiovascular H-Histamine Receptors Under Normal and Pathophysiological Conditions.

This review addresses pharmacological, structural and functional relationships among H-histamine receptors and H-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-histamine-receptors in cardiac diseases will be examined.

Functional interaction of H-receptors and 5HT-receptors in atrial tissues isolated from double transgenic mice and from human patients.

In the past, we generated transgenic mice that overexpress the human histamine 2 (H)-receptor (H-TG) or that overexpress the human serotonin 4 (5-HT)-receptor (5-HT-TG) in the heart. Here, we crossbred these lines of mice to generate double transgenic mice that overexpress both receptors (DT). This was done to study a conceivable interaction between these receptors in the mouse heart as a model for the human heart.

Cardiac Effects of Novel Histamine H Receptor Agonists.

In an integrative approach, we studied cardiac effects of recently published novel H receptor agonists in the heart of mice that overexpress the human H receptor (H-TG mice) and littermate wild type (WT) control mice and in isolated electrically driven muscle preparations from patients undergoing cardiac surgery. Under our experimental conditions, the H receptor agonists UR-Po563, UR-MB-158, and UR-MB-159 increased force of contraction in left atrium from H-TG mice with pEC values of 8.27, 9.

Conserved cholesterol-related activities of Dispatched 1 drive Sonic hedgehog shedding from the cell membrane.

The Sonic hedgehog (Shh) pathway controls embryonic development and tissue homeostasis after birth. Long-standing questions about this pathway include how the dual-lipidated, firmly plasma membrane-associated Shh ligand is released from producing cells to signal to distant target cells and how the resistance-nodulation-division transporter Dispatched 1 (Disp, also known as Disp1) regulates this process. Here, we show that inactivation of Disp in Shh-expressing human cells impairs proteolytic Shh release from its lipidated terminal peptides, a process called ectodomain shedding.

Human histamine H receptors can initiate cardiac arrhythmias in a transgenic mouse.

Histamine is known to lead to arrhythmias in the human heart. A mouse model to mimic these effects has hitherto not been available but might be useful to study the mechanism(s) of H-histamine receptor-induced arrhythmias and may support the search for new antiarrhythmic drugs. In order to establish such a model in mice, we studied here the incidence of cardiac arrhythmias under basal and under stimulated conditions in atrial and ventricular preparations from mice that overexpressed the human H-histamine receptors in a cardiac-specific way (H-TG) in comparison with their wild-type (WT) littermate controls.

Histamine can be Formed and Degraded in the Human and Mouse Heart.

Histamine is metabolized by several enzymes and . The relevance of this metabolism in the mammalian heart is unclear. However, histamine can exert positive inotropic effects (PIE) and positive chronotropic effects (PCE) in humans via H-histamine receptors.