scholarly journals Amitriptyline functionally antagonizes cardiac H2 histamine receptors in transgenic mice and human atria

2021 ◽  
Author(s):  
Joachim Neumann ◽  
Maximilian Benedikt Binter ◽  
Charlotte Fehse ◽  
Margaréta Marušáková ◽  
Maren Luise Büxel ◽  
...  
Keyword(s):  
Antidepressant Drug ◽  
Histamine Receptor ◽  
Right Atrial ◽  
Inotropic Effects ◽  
Positive Inotropic Effects ◽  
Contractile Parameters ◽  
Left And Right ◽  
Chronotropic Effects ◽  
Perfused Hearts ◽  
Right Atria

AbstractWe have previously shown that histamine (2-(1H-imidazol-4-yl)ethanamine) exerted concentration-dependent positive inotropic effects (PIE) or positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic (H2R-TG) mice that overexpress the human H2 histamine receptor (H2R) in the heart; however, the effects were not seen in their wild-type (WT) littermates. Amitriptyline, which is still a highly prescribed antidepressant drug, was reported to act as antagonist on H2Rs. Here, we wanted to determine whether the histamine effects in H2R-TG were antagonized by amitriptyline. Contractile studies were performed on isolated left and right atrial preparations, isolated perfused hearts from H2R-TG and WT mice and human atrial preparations. Amitriptyline shifted the concentration-dependent PIE of histamine (1 nM–10 μM) to higher concentrations (rightward shift) in left atrial preparations from H2R-TG. Similarly, in isolated perfused hearts from H2R-TG and WT mice, histamine increased the contractile parameters and the phosphorylation state of phospholamban (PLB) at serine 16 in the H2R-TG mice, but not in the WT mice. However, the increases in contractility and PLB phosphorylation were attenuated by the addition of amitriptyline in perfused hearts from H2R-TG. In isolated electrically stimulated human atria, the PIE of histamine that was applied in increasing concentrations from 1 nM to 10 μM was reduced by 10-μM amitriptyline. In summary, we present functional evidence that amitriptyline also acts as an antagonist of contractility at H2Rs in H2R-TG mouse hearts and in the human heart which might in part explain the side effects of amitriptyline.

Leukotriene C4 action and metabolism in the isolated perfused bullfrog heart

1988 ◽  
Vol 66 (7) ◽  
pp. 980-984 ◽  
Author(s):  
R. Peter Herman ◽  
R. Scott Heller ◽  
Christopher M. Canavan ◽  
Ceil A. Herman
Keyword(s):  
Heart Tissue ◽  
Major Product ◽  
Leukotriene C4 ◽  
Inotropic Effects ◽  
First Derivative ◽  
Ventricular Tissue ◽  
Positive Inotropic Effects ◽  
Order Of Magnitude ◽  
Chronotropic Effects ◽  
Perfused Hearts

The effects of leukotrienes (LTs) have been widely studied in the isolated perfused mammalian heart; however, little is known about the effect or metabolism of LTs in the isolated bullfrog heart. Isolated perfused bullfrog hearts were administered randomized doses of LTC4, LTD4, or LTE4. The cardiac parameters of heart rate, developed tension, and its first derivative (dT/dt) were recorded. LTC4 was the most potent of the leukotrienes tested in eliciting positive inotropic effects. LTD4 and LTE4 were equally effective but about one order of magnitude less potent than LTC4. None of the LTs showed any chronotropic effects in this preparation. A series of [3H]LTC4 metabolism experiments were carried out using whole perfused hearts and minced bullfrog heart tissue. Isolated perfused bullfrog hearts administered [3H]LTC4 converted significant amounts to [3H]LTD4, and to a lesser degree, [3H]LTE4, during the 6-min course of collection. Both minced atrial and ventricular tissue converted [3H]LTC4 to radioactive metabolites that co-migrated with authentic LTD4 and LTE4 standards. In both tissues, the major product was [3H]LTD4, with smaller amounts of [3H]LTE4 produced. The atrium converted significantly more [3H]LTC4 to its metabolites than did the ventricle. The metabolism of [3H]LTC4 to [3H]LTD4 by both tissues was virtually abolished in the presence of serine borate. Cysteine had no effect on [3H]LTE4 production. The data in this study demonstrate that leukotrienes have the opposite inotropic effect on the heart when compared with mammals. Also in contrast to mammals, frogs metabolize LTC4 to a less potent compound and may use the LTC4 to LTD4 conversion as a mechanism of LTC4 inactivation.

scholarly journals Phosphodiesterases 2, 3 and 4 can decrease cardiac effects of H2-histamine-receptor activation in isolated atria of transgenic mice

2021 ◽  
Author(s):  
Joachim Neumann ◽  
Rafaela Voss ◽  
Ulrich Laufs ◽  
Christian Werner ◽  
Ulrich Gergs
Keyword(s):  
Transgenic Mice ◽  
Histamine Receptor ◽  
Receptor Activation ◽  
Heart Beat ◽  
Right Atrial ◽  
Pde4 Inhibitor ◽  
Inotropic Effects ◽  
Pde Inhibitors ◽  
Isolated Atria ◽  
Left And Right

AbstractHistamine exerts cAMP-dependent positive inotropic effects (PIE) and positive chronotropic effects (PCE) on isolated left and right atria, respectively, of transgenic mice which overexpress the human H2-receptor in the heart (=H2-TG). To determine whether these effects are antagonized by phosphodiesterases (PDEs), contractile studies were done in isolated left and right atrial preparations of H2-TG. The contractile effects of histamine were tested in the additional presence of the PDE-inhibitorserythro-9-(2-hydroxy-3-nonyl)adenine hydrochloride (EHNA, 1 μM, PDE2-inhibitor) or cilostamide (1 μM, PDE3-inhibitor), rolipram (10 μM, a PDE4-inhibitor), and their combinations. Cilostamide (1 μM) and EHNA (1 μM), rolipram (1 μM), and EHNA (1 μM) and the combination of rolipram (0.1 μM) and cilostamide (1 μM) each increased the potency of histamine to elevate the force of contraction (FOC) in H2-TG. Cilostamide (1 μM) and rolipram (10 μM) alone increased and EHNA (1 μM) decreased alone, and their combination increased the potency of histamine to increase the FOC in H2-TG indicating that PDE3 and PDE4 regulate the inotropic effects of histamine in H2-TG. The PDE inhibitors (EHNA, cilostamide, rolipram) alone did not alter the potency of histamine to increase the heart beat in H2-TG whereas a combination of rolipram, cilostamide, and EHNA, or of rolipram and EHNA increased the potency of histamine to act on the beating rate. In summary, the data suggest that the PCE of histamine in H2-TG atrium involves PDE 2 and 4 activities, whereas the PIE of histamine are diminished by activity of PDE 3 and 4.

Effects of Hypothermia on Contractility of the Intact Dog Heart

1958 ◽  
Vol 194 (1) ◽  
pp. 92-98 ◽  
Author(s):  
Leon I. Goldberg
Keyword(s):  
Ventricular Arrhythmias ◽  
Contractile Force ◽  
Right Atrial ◽  
Ventricular Contractility ◽  
Body Temperatures ◽  
Epinephrine Administration ◽  
Epidural Injections ◽  
Left And Right ◽  
Chronotropic Effects ◽  
Contraction And Relaxation

The effects of hypothermia on ventricular contractility were studied in intact dogs, directly, by attachment of a strain gauge arch to the myocardium and indirectly, by observation of left and right atrial, pulmonary and femoral arterial pressures. Marked increments in heart contractile force and reduction in the rates of contraction and relaxation occurred in all experiments during cooling. Myocardial depression occurred in several experiments, but only at temperatures near 20°C, and in the presence of extreme bradycardia. Total sympathetic block produced by epidural injections of 0.45% procaine solution and large doses of hexamethonium did not prevent development of the increments in heart contractile force, but did further decrease the rates of contraction and relaxation at low body temperatures. Epinephrine administration resulted in pronounced increments in heart contractile force and increases in rates of contraction and relaxation, often in the absence of chronotropic effects. No relationship was found between occurrence of ventricular arrhythmias and magnitude of heart contractile force. Spontaneous occurrence of fused contractions, with apparent summation and incomplete tetanus was observed in several experiments at low body temperatures.

Characterization of the histamine receptors in rabbit left atria

1981 ◽  
Vol 59 (1) ◽  
pp. 19-24 ◽  
Author(s):  
Alicia Polanin ◽  
John H. McNeill
Keyword(s):  
Left Atrial ◽  
Histamine Receptor ◽  
Histamine Receptors ◽  
Receptor Blockade ◽  
Inotropic Response ◽  
Receptor Stimulation ◽  
Inotropic Effects ◽  
Receptor Antagonism ◽  
Positive Inotropic Effects

The effects of selective histamine receptor analogs were studied in electrically paced rabbit left atria. Atrial tension was increased by histamine (an H1 and H2 agonist), 4-methylhistamine and impromidine (H2 agonists), and 2-pyridylethylamine (PEA) (an H1 agonist). The responses to histamine and impromidine were not altered by propranolol (1 × 10−7 M) or reserpine pretreatment. However, the responses to 4-methylhistamine and PEA were significantly decreased upon pretreatment with propranolol or reserpine. Promethazine pretreatment (H1 receptor blockade) antagonized the inotropic effects of histamine and PEA but had no effect on the responses to 4-methylhistamine or impromidine. Cimetidine pretreatment (H2 receptor antagonism) competitively blocked the positive inotropic effects of histamine, 4-methylhistamine, and impromidine. These results suggest that the left atrial inotropic response is mediated through H1 and H2 receptor stimulation.

Effects of hyperthyroidism on delayed rectifier K+ currents in left and right murine atria

2005 ◽  
Vol 289 (4) ◽  
pp. H1448-H1455 ◽  
Author(s):  
Ying Hu ◽  
S. V. Penelope Jones ◽  
Wolfgang H. Dillmann
Keyword(s):  
Protein Expression ◽  
Left Atrium ◽  
Right Atrial ◽  
Delayed Rectifier ◽  
Rnase Protection ◽  
Expression Levels ◽  
Mrna And Protein Expression ◽  
Left And Right ◽  
The Right ◽  
Right Atria

Hyperthyroidism has been associated with atrial fibrillation (AF); however, hyperthyroidism-induced ion channel changes that may predispose to AF have not been fully elucidated. To understand the electrophysiological changes that occur in left and right atria with hyperthyroidism, the patch-clamp technique was used to compare action potential duration (APD) and whole cell currents in myocytes from left and right atria from both control and hyperthyroid mice. Additionally, RNase protection assays and immunoblotting were performed to evaluate the mRNA and protein expression levels of K+ channel α-subunits in left and right atria. The results showed that 1) in control mice, the APD was shorter and the ultra-rapid delayed rectifier K+ conductance ( IKur) and the sustained delayed rectifier K+ conductance ( Iss) were larger in the left than in the right atrium; also, mRNA and protein expression levels of Kv1.5 and Kv2.1 were higher in the left atrium; 2) in hyperthyroid mice, the APD was shortened and IKur and Iss were increased in both left and right atrial myocytes, and the protein expression levels of Kv1.5 and Kv2.1 were increased significantly in both atria; and 3) the influence of hyperthyroidism on APD and delayed rectifier K+ currents was more prominent in right than in left atrium, which minimized the interatrial APD difference. In conclusion, hyperthyroidism resulted in more significant APD shortening and greater delayed rectifier K+ current increases in the right vs. the left atrium, which can contribute to the propensity for atrial arrhythmia in hyperthyroid heart.

Comparison of time- and voltage-dependent K+ currents in myocytes from left and right atria of adult mice

2003 ◽  
Vol 285 (5) ◽  
pp. H1837-H1848 ◽  
Author(s):  
Alan E. Lomax ◽  
Colleen S. Kondo ◽  
Wayne R. Giles
Keyword(s):  
Current Density ◽  
Right Atrium ◽  
Left Atrial ◽  
Right Atrial ◽  
Atrial Myocytes ◽  
Adult Mice ◽  
Voltage Dependent ◽  
Left And Right ◽  
The Right ◽  
Right Atria

Consistent differences in K+ currents in left and right atria of adult mouse hearts have been identified by the application of current- and voltage-clamp protocols to isolated single myocytes. Left atrial myocytes had a significantly ( P < 0.05) larger peak outward K+ current density than myocytes from the right atrium. Detailed analysis revealed that this difference was due to the rapidly activating sustained K+ current, which is inhibited by 100 μM 4-aminopyridine (4-AP); this current was almost three times larger in the left atrium than in the right atrium. Accordingly, 100 μM 4-AP caused a significantly ( P < 0.05) larger increase in action potential duration in left than in right atrial myocytes. Inward rectifier K+ current density was also significantly ( P < 0.05) larger in left atrial myocytes. There was no difference in the voltage-dependent L-type Ca2+ current between left and right atria. As expected from this voltage-clamp data, the duration of action potentials recorded from single myocytes was significantly ( P < 0.05) shorter in myocytes from left atria, and left atrial tissue was found to have a significantly ( P < 0.05) shorter effective refractory period than right atrial tissue. These results reveal similarities between mice and other mammalian species where the left atrium repolarizes more quickly than the right, and provide new insight into cellular electrophysiological mechanisms responsible for this difference. These findings, and previous results, suggest that the atria of adult mice may be a suitable model for detailed studies of atrial electrophysiology and pharmacology under control conditions and in the context of induced atrial rhythm disturbances.

Atrial myocardium is the predominant inotropic target of adrenomedullin in the human heart

2007 ◽  
Vol 293 (5) ◽  
pp. H3001-H3007 ◽  
Author(s):  
Egbert Bisping ◽  
Gero Tenderich ◽  
Paul Barckhausen ◽  
Burkhard Stumme ◽  
Sebastian Bruns ◽  
...  
Keyword(s):  
Light Emission ◽  
Ventricular Myocardium ◽  
Right Atrial ◽  
Dependent Manner ◽  
Atrial Myocardium ◽  
Concentration Dependent Manner ◽  
Maximal Increase ◽  
Inotropic Effects ◽  
Positive Inotropic Effects ◽  
Camp Levels

Adrenomedullin (ADM) is an endogenous peptide with favorable hemodynamic effects in vivo. In this study, we characterized the direct functional effects of ADM in isolated preparations from human atria and ventricles. In electrically stimulated human nonfailing right atrial trabeculae, ADM (0.0001–1 μmol/l) increased force of contraction in a concentration-dependent manner, with a maximal increase by 35 ± 8% (at 1 μmol/l; P < 0.05). The positive inotropic effect was accompanied by a disproportionate increase in calcium transients assessed by aequorin light emission [by 76 ± 20%; force/light ratio (ΔF/ΔL) 0.58 ± 0.15]. In contrast, elevation of extracellular calcium (from 2.5 to 3.2 mmol/l) proportionally increased force and aequorin light emission (ΔF/ΔL 1.0 ± 0.1; P < 0.05 vs. ADM). Consistent with a cAMP-dependent mechanism, ADM (1 μmol/l) increased atrial cAMP levels by 90 ± 12%, and its inotropic effects could be blocked by the protein kinase A (PKA) inhibitor H-89. ADM also exerted positive inotropic effects in failing atrial myocardium and in nonfailing and failing ventricular myocardium. The inotropic response was significantly weaker in ventricular vs. atrial myocardium and in failing vs. nonfailing myocardium. In conclusion, ADM exerts Ca2+-dependent positive inotropic effects in human atrial and less-pronounced effects in ventricular myocardium. The inotropic effects are related to increased cAMP levels and stimulation of PKA. In heart failure, the responsiveness to ADM is reduced in atria and ventricles.

Histamine and the heart

1984 ◽  
Vol 62 (6) ◽  
pp. 720-726 ◽  
Author(s):  
John H. McNeill
Keyword(s):  
Histamine Receptor ◽  
Histamine Receptors ◽  
Ion Concentration ◽  
Free Calcium ◽  
Guinea Pig Heart ◽  
Release Of Noradrenaline ◽  
Chronotropic Effects ◽  
Calcium Ion Concentration ◽  
Right Atria ◽  
Stimulation Of

Histamine has been known as a cardiac stimulant for over 70 years. Work in our laboratory over the past decade has established that histamine receptors exist in the hearts of various species. The type of histamine receptor varies not only between species but also in the various regions of the heart. In the guinea pig heart H1 receptors are found in left atria and ventricles while H2 receptors are found in right atria and are the predominant histamine receptor in the ventricles. Rabbit atria contain both H1 and H2 receptors while the ventricles appear to possess only H1. Rat and cat heart do not seem to have histamine receptors and the positive inotropic and chronotropic effects elicited by histamine in cardiac preparations of these species are due to the release of noradrenaline. Dog heart contains H1 receptors while human heart has H2 receptors. In all cases H2 receptors are associated with adenylate cyclase and stimulation of such receptors results in an increase in cyclic AMP levels. H1 receptors are not associated with cyclic nucleotides in the heart. There are certain similarities between β-adrenergic and H2-histaminergic receptors as well as between α-adrenergic and H1-histaminergic receptors. Stimulation of either histamine receptor must result in an increase in the free calcium ion concentration in the cardiac cell but the mechanisms involved are obviously different.

Monoamines and the isolated auricle of sepia officinalis: are there β-like receptors in the heart of a cephalopod?

1999 ◽  
Vol 202 (9) ◽  
pp. 1067-1079
Author(s):  
B. Versen ◽  
S. Gokorsch ◽  
A. Fiedler ◽  
R. Schipp
Keyword(s):  
Sepia Officinalis ◽  
Receptor System ◽  
Ventricular Performance ◽  
Inotropic Effects ◽  
Noradrenergic Innervation ◽  
Positive Inotropic Effects ◽  
Chronotropic Effects ◽  
Hplc Analyses

Pharmacological examinations of isolated auricles from Sepia officinalis were carried out to analyze the putative role of the monoaminergic transmitter/receptor system in the control of auricle function. In conjunction with histofluorescence studies and HPLC analyses, evidence of a double excitatory serotonergic and noradrenergic innervation of the auricles was obtained. Serotonin-induced positive chronotropic and inotropic effects were blocked by mianserin (5-HT1 and 5-HT2) but not by cyproheptadine (5-HT2). It is assumed that the auricular serotonin (5-HT) receptor represents a 5-HT1-like subtype and is not identical to the ventricular 5-HT receptor. Noradrenaline, adrenaline and dopamine evoked mainly positive chronotropic reactions and less prominent positive inotropic reactions. The potency range (pD2 frequency: noradrenaline 6.65 &gt;&gt; adrenaline 5.69 &gt; dopamine 5.34; pD2 amplitude: noradrenaline 6.09 (greater than or equal to) adrenaline 5.91 &gt; dopamine 5.33) indicates out that noradrenaline might be the effective neurotransmitter in vivo. The α -mimetics clonidine (α 2) and phenylephrine (α 1) induced positive chronotropic and inotropic effects, while the β-mimetics albuterol (β2&gt;β1) and dobutamine (β1) revealed only positive inotropic reactions. The β-agonist isoprenaline mimicked the positive chronotropic effects of noradrenaline and induced the strongest positive inotropic effects of all the agonists tested. Urapidil (α 1) or phentolamine (α 1 and α 2) blocked only the positive chronotropic effects of noradrenaline and isoprenaline. The positive inotropic effects of isoprenaline could be blocked by the adenylate cyclase inhibitors MDL-12,330A or SQ-22, 536, which had no effect on the chronotropic effects of isoprenaline. These results suggest that two catecholaminergic receptors are present in the auricles of Sepia officinalis: an α -like adrenoreceptor mediating mainly chronotropic effects, and a β-like receptor which appears to mediate inotropic effects by activating the cyclic AMP pathway. These results suggest that the auricles exert a regulatory effect on ventricular performance.

scholarly journals Role of Phospholipases A2 in Vascular Relaxation and Sympatholytic Effects of Five Australian Brown Snake, Pseudonaja spp., Venoms in Rat Isolated Tissues

2021 ◽  
Vol 12 ◽  
Author(s):  
Nhi Thuc Vuong ◽  
Timothy N. W. Jackson ◽  
Christine E. Wright
Keyword(s):  
Sympathetic Nerve ◽  
Mesenteric Arteries ◽  
Right Atrial ◽  
Phospholipases A2 ◽  
Life Threatening ◽  
Left And Right ◽  
Isolated Tissues ◽  
Right Atria ◽  
Phospholipases A

Human envenoming by Australian brown snakes (Pseudonaja spp.) may result in potentially life-threatening hypotension and subsequent cardiovascular collapse. There have been relatively few studies of the cardiovascular and sympathetic effects of Pseudonaja spp. venoms. In this study, we have examined the effects of venom from five brown snake species—P. affinis, aspidorhyncha, inframacula, nuchalis, and textilis—on cardiac inotropic and chronotropic responses, vascular tone, and sympathetic nerve-induced vascular contractions in rat isolated tissues. The role of phospholipases A2 (PLA2s) in venom-induced effects was assessed with the sPLA2 inhibitor varespladib. In rat isolated left and right atria, there were no physiologically relevant effects of Pseudonaja venoms (0.1–30 µg/ml) on left atrial force of contraction (inotropy) or right atrial rate (chronotropy). In contrast, in isolated small mesenteric arteries precontracted with a thromboxane mimetic, each of the five brown snake venoms (at 30 µg/ml) caused marked vasorelaxation (−60 to –90% of contractile tone). Pretreatment with varespladib (1 µM) significantly inhibited the vasorelaxation caused by P. aspidorhyncha, P. nuchalis, and P. textilis venoms. Electrically induced sympathetic nerve-mediated contractions of mesenteric arteries were significantly attenuated by only P. textilis, and P. affinis venoms (30 µg/ml) and these sympatholytic effects were inhibited by varespladib (1 µM). Based on their inhibition with the sPLA2 inhibitor varespladib, we conclude that PLA2 toxins in P. aspidorhyncha, P. nuchalis, and P. textilis venoms are involved in brown snake venom-induced vasorelaxation and the sympatholytic effects of P. affinis, and P. textilis venoms. Our study supports the promising potential role of varespladib as an initial (pre-referral) and/or adjunct (in combination with antivenom) therapeutic agent for brown snake envenoming.

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