Chronotropic Effect Of Histamine Research Articles

Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-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 H2 receptor only in their cardiac myocytes (labelled H2-TG). Contractile studies were performed in an organ bath on isolated, electrically driven (1Hz) left atrial preparations and spontaneously beating right atrial preparations from H2-TG mice and wild-type (WT) littermate control mice. The basal beating rate in the right atrial preparations from H2-TG mice was lowered by hypothermia (23°C) and elevated by hyperthermia (42°C). Furthermore, the efficacy of histamine (0.01-100µM) at exerting positive inotropic effects was more severely attenuated in the left and right H2-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 (1Hz) 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 H2-TG mice in the presence of 10µM histamine. In contrast, in human atrial preparations, the phosphorylation state of phospholamban at serine 16 in the presence of 100µM 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 H2-TG mice than in those from WT mice. We conclude that the inotropic effects of histamine in H2-TG mice and in human atrial preparations, as well as the chronotropic effects of histamine in H2-TG mice, are temperature dependent. Furthermore, we observed that, even without stimulation of the H2 receptors by exogenous agonists, temperature elevation can increase arrhythmias in isolated right atrial preparations from H2-TG mice. We propose that H2 receptors play a role in hyperthermia-induced supraventricular arrhythmias in human patients.

Hemodynamic significance of histamine synthesis and histamine H1- and H2-receptor gene expression during endotoxemia.

The hypothesis that endotoxemia may modify histamine synthesis or histamine receptor expression and that these changes may contribute to cardiovascular dysfunction was tested in rabbits which were rendered endotoxemic by lipopolysaccharide (LPS; 100 micro g/kg, i.v.). The plasma histamine concentration was elevated shortly after LPS, remaining elevated (a 50-fold increase) over the experimental period of 6 h. The sustained increase in plasma histamine was associated with a time-dependent increase in expression of histidine decarboxylase (HDC) in different tissues including atrium, as determined by Western blot analysis. The H(1)-receptor antagonist diphenhydramine significantly shortened the duration of the initial hypotension and the H(2)-receptor antagonist ranitidine greatly suppressed the lasting tachycardia following LPS injection. Northern blot analysis showed that LPS dramatically induced gene expressions of histamine H(1)- and H(2)-receptors in cardiac tissues. In right atrium isolated from the septic animal, the positive chronotropic effect of histamine was significantly diminished. This was possibly due to a marked reduction in G(s)(alpha) protein expression, indicating the impaired H(2)-receptor cellular signaling. In conclusion, LPS-induced endotoxemia causes prominent increases in production of histamine through induction of HDC and in gene expression of histamine receptors. We suggest that overproduction of histamine may be partly responsible for the hemodynamic alterations of endotoxemia.

Chronotropic and inotropic effects of histamine in developing chick heart: differential mechanisms before and after hatching.

Chronotropic and inotropic effects of histamine were examined in isolated atrial and ventricular preparations from embryonic and hatched chicken hearts. Histamine produced positive chronotropic and inotropic responses both in embryonic and hatched hearts. The responses to histamine in middle embryonic myocardia, which were observed in the micromolar range, were antagonized by H2 antagonists but not by H1, H3 antagonists and propranolol. Isobutyl-methylxantine, an inhibitor of phosphodiesterase, produced a leftward shift of the concentration-response curve for the chronotropic effect of histamine in the embryo. The responses to histamine in myocardia from hatched chicks, which were observed in the milimolar range, appeared concurrently with the responses to tyramine during development and were antagonized by beta adrenoceptor antagonists but not by any of the histamine antagonists. The positive inotropic response to histamine in hatched ventricular preparations were greatly attenuated by reserpine pretreatment or in the presence of desipramine. Thus, we demonstrated that exogenously applied histamine produces positive chronotropic and inotropic responses in developing chicken hearts and that the mechanisms are different between embryonic and hatched chicks: direct action on H2 receptors in the embryonic heart and release of norepinephrine from sympathetic nerve terminals in hatched hearts.

Effects of halothane with and without histamine and/or epinephrine on automaticity, intracardiac conduction times, and development of dysrhythmias in the isolated guinea pig heart.

Histamine is released during allergic reactions, and is known to produce cardiac dysrhythmias. The authors compared the cardiac effects of histamine and epinephrine during exposure to halothane in the isolated perfused guinea pig heart. Responses studied were spontaneous sinus rate, intra-atrial conduction time, atrial-septal conduction time (ASCT), intraventricular conduction time (IVCT), and left ventricular pressure (LVP). The incidence and type of dysrhythmias with histamine and halothane and with epinephrine and halothane were analyzed from electrograms. The authors found that halothane alone (0.7 to 2.1 vol%) causes dose-dependent depressions of sinus rate and LVP, prolongs ASCT and IVCT, and produces atrioventricular (AV) block with junctional bradycardia. Histamine alone (.01-10 microM) increases sinus rate and LVP but, like halothane, prolongs ASCT. Halothane antagonizes the inotropic and chronotropic effects of histamine, but enhances ASCT compared with histamine alone. Histamine with halothane greatly increases the incidence of junctional tachycardia with AV dissociation from 0% with histamine alone up to 48%. Epinephrine alone (0.1-5 microM), like histamine, increases sinus rate and LVP, but does not cause a relative increase in ASCT. Halothane antagonizes the inotropic and chronotropic effects of epinephrine, but increases the incidence of ventricular tachycardia from 6% to 28%, and the incidence of premature ventricular excitations from 0% to 40%, compared with epinephrine alone. The authors' in vitro findings show that histamine and halothane, like epinephrine and halothane, can cause dysrhythmias, but that the genesis and type of dysrhythmias induced by these agents are dissimilar. Consequently, the release of histamine with an anaphylactoid reaction during halothane anesthesia, and the treatment of the reaction with epinephrine, could result in dangerous ventricular tachydysrhythmias.

Chronotropic cardiac effects of histamine in the conscious dog with chronic atrioventricular block: interactions with the autonomic nervous system.

Chronotropic effects of histamine and dimaprit were studied in the conscious dog with chronic atrioventricular block. Histamine at 0.2-5 micrograms/kg and dimaprit at equimolar doses (i.e. 0.25-6.25 micrograms/kg) increased atrial rate dose-relatedly. Blockade of muscarinic receptors reduced these effects and simultaneous blockade of muscarinic and beta-adrenergic receptors abolished them. Histamine and dimaprit moderately increased ventricular rate. Blockade of muscarinic receptors did not modify these effects, but blockade of beta-adrenoceptors with or without simultaneous blockade of muscarinic receptors suppressed them. After blockade of beta-adrenoceptors, histamine and more rarely dimaprit sometimes decreased atrial and ventricular rates. These effects were prevented by additional muscarinic blockade. Histamine and dimaprit lowered mean blood pressure to the same degree before and after each antagonist. The positive chronotropic effects of histamine and dimaprit, at these doses, are probably reflex responses to their hypotensive effects. The negative chronotropic effects of histamine after pindolol are due to muscarinic receptor activation. No evidence was found to implicate histamine-specific receptors in any of the chronotropic effects of histamine and dimaprit.

Inhibition by the tetramine disulphide, benextramine, of cardiac chronotropic histamine H2-receptor-mediated effects.

1 Benextramine (N,N1-bis[o-methoxybenzylamino)-n-hexyl]cystamine), which irreversibly blocks alpha-adrenoceptors and does not inhibit the H1-receptor-mediated contractile effect of histamine on guinea-pig isolated ileum, also did not inhibit the H1-receptor-mediated inotropic effect of histamine on guinea-pig isolated atrium. 2 Benextramine irreversibly inhibited the H2-receptor-mediated chronotropic effect of histamine on guinea-pig isolated atrium. 3 Since its combination with the competitive H2-receptor blocking drug cimetidine had a additive blocking effect, benextramine appears to act directly on the chronotropic H2-receptor.

Chronotropic effect of histamine on cultured neonatal rat heart cells

The positive chronotropic effect (PCE) of histamine in cultured neonatal rat heart cells was monitored using a microscopic method as well as an electro-optically recording device. The action potential frequency was also measured (by means of microelectrodes). An increase in PCE was noted when histamine (from 1 × 10 −6 M to 1 × 10 −5 M) was added to the cells. However, higher concentrations (from 1 × 10 −5 M to 1 × 10 −4 M) were less effective. The PCE of histamine was reduced by pretreating the cells with antihistaminic drugs. H 1-blocking agents (promethazine and mepyramine) were more potent than H 2-blocking drugs (metiamide and cimetidine). In addition, the PCE of histamine was abolished when the cells were in presence of high K + medium (26 mEq) but contraction and action potential amplitudes were increased. Our results demonstrate that these cultures respond to histamine and that this response is abolished by antihistaminic drugs thus suggesting that H 1 and/or H 2 receptors may be present in the neonatal rat heart cell cultures.

Effects of the H1-antagonist promethazine and the H2-antagonist burimamide on chronotropic, inotropic and coronary vascular responses to histamine in isolated perfused guinea-pig hearts.

On guinea-pig atria part of the inotropic response to histamine is attributable to a concomitant increase of the frequency [7]. Since the chronotropic effect of histamine is mediated by a stimulation of H2-receptors a direct interaction of histamine with H1-receptors a direct interaction of histamine with H1-receptors mediating the inotropic response on heart may be overlooked. For this reason the ability of the H1-antagonist promethazine and the H2-antagonist burimamide to inhibit the positive chronotropic, inotropic and coronary vascular responses to histamine was determined in spontaneously beating and electrically driven perfused guinea-pig hearts. (1) Burimamide produced a competitive blockade of the positive chrono- and inotropic responses to histamine. (2) On the other hand, promethazine in concentrations that had no effect on cardiac function by itself, proved to be ineffective against the positive chrono- and inotropic responses produced by histamine on spontaneously beating and electrically driven heart preparations. (3) The predominant coronary vasodilation observed after infusion with histamine was competitively antagonized by promethazine and burimamide. This blockade was not attributable to an interaction with myocardial H2-receptors mediating increases in heart rate and contractility and was, therefore, direct in nature. (4) Based upon the present study and former investigations [7] the following distribution of different histamine receptors in the guinea-pig heart does exist: H1-receptors are present in the atrial muscle and the coronary vascular bed. H2-receptors are located in the sinus node, the ventricular myocardium and the coronary vessels.

A study of the actions of histamine on the isolated rat heart.

1. The effects of histamine on cardiac force, heart rate and coronary perfusion pressure were studied in the isolated rat heart, using the Langendorff perfused heart preparation. 2. Single injections of histamine induced dose-dependent decreases in contractile amplitude, heart rate and coronary perfusion pressure. 3. Perfusions of metiamide (above 1 x 10(-4) m) had a depressant effect on contractile force and heart rate, whereas diphenhydramine (4 x 10(-6) m) reduced only the heart rate. Both agents caused a fall in coronary perfusion pressure. 4. The negative inotropic and chronotropic effects of histamine on the isolated rat heart were not significantly influenced by either metiamide of diphenhydramine, or a combination of these drugs. However, the fall in coronary perfusion pressure induced by injections of histamine was significantly antagonized by metiamide or diphenhydramine. 5. These results suggest that the effects of histamine on the isolated rat heart may not be due entirely to stimulation of H1- or H2-receptors on the cardiac muscle cells. Evidence is presented for the existence of histamine H1- and H2-receptors in the coronary vessels.

Blockade of cardiac histamine receptors by promethazine.

The inotropic and chronotropic effects of histamine on the isolated perfused guinea pig heart were antagonized by promethazine over a concentration range 4 × 10−6 – 16 × 10−6 M. Promethazine (4 × 10−6 M) decreased the ability of histamine (1 μg) to elevate cardiac cyclic AMP. A higher dose of histamine could not overcome the promethazine blockade. Promethazine (4 × 10− 6 M) did not block the inotropic effect of noradrenaline. Higher concentrations of promethazine, particularly 16 × 10−6 M did decrease the noradrenaline response. The data indicate that promethazine can interact with cardiac histamine receptors but the interaction is either noncompetitive or competitive non-equilibrium in nature.

On specificity of histamine receptors in the heart.

ARTICLESOn specificity of histamine receptors in the heartMJ Hughes, and IA CoretMJ Hughes, and IA CoretPublished Online:01 Nov 1972https://doi.org/10.1152/ajplegacy.1972.223.5.1257MoreSectionsPDF (1 MB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat Previous Back to Top Download PDF FiguresReferencesRelatedInformation Cited ByH1 antihistamine drug promethazine directly blocks hERG K+ channelPharmacological Research, Vol. 60, No. 5Classification and biological distribution of histamine receptor sub-typesAgents and Actions, Vol. 43, No. 3-4Blockade of Na+ current by promethazine in guinea-pig ventricular myocytes19 July 2012 | British Journal of Pharmacology, Vol. 106, No. 4Differential effects of histamine mediated by histamine H1- and H2-receptors on contractility, spontaneous rate and cyclic nucleotides in the rabbit heartEuropean Journal of Pharmacology, Vol. 153, No. 2-3Functional state of the histamine-histaminase system in the course of experimental acute pancreatitisBulletin of Experimental Biology and Medicine, Vol. 105, No. 3Antagonistic activity of tiotidine and ranitidine on guinea-pig and rabbit atriaEuropean Journal of Pharmacology, Vol. 131, No. 1Effect ofin vivo antiestrogen pretreatment on rabbit atrial chronotropic response to histamineAgents and Actions, Vol. 18, No. 5-6The effects of cimetidine on histamine atrial chronotropic receptor activityAgents and Actions, Vol. 12, No. 4A Question of the Specificity of Rabbit Atrial Chronotropic Histamine Receptors and Agents Which Affect Their Activity8 March 2013 | The Journal of Clinical Pharmacology, Vol. 20, No. 1Effects of histamine on electrical and mechanical activity in voltage-clamped frog atrial fibresJournal of Molecular and Cellular Cardiology, Vol. 12, No. 1Gastric and cardiovascular effects of histamine in the dogAgents and Actions, Vol. 9, No. 5-6Chronotropic effect of histamine on cultured neonatal rat heart cellsEuropean Journal of Pharmacology, Vol. 58, No. 2Liberation of histamine by compound 48/80, tolazoline, betahistine and burimamide from isolated spontaneously beating guinea pig and rabbit atrial pairsAgents and Actions, Vol. 9, No. 2Chronotropic and Dromotropic Effects of Histamine on the Canine HeartChest, Vol. 75, No. 5Effects of promethazine on the isolated perfused rat heartGeneral Pharmacology: The Vascular System, Vol. 10, No. 5Cyclobenzaprine: Some pharmacological cardiac actionsLife Sciences, Vol. 23, No. 27-28Ethanol Increases Rate of Isolated AtriaAlcoholism: Clinical and Experimental Research, Vol. 2, No. 3Pharmacological ActionsBioassay of Antihistaminic ActionAntianaphylactic and Antiallergic EffectsEffects of histamine on contractility and conduction in isolated chicken heartsComparative Biochemistry and Physiology Part C: Comparative Pharmacology, Vol. 61, No. 1Actions of Mescaline on Isolated Rat AtriaJournal of Pharmaceutical Sciences, Vol. 66, No. 7Liberation of endogenous compounds by tolazolineAgents and Actions, Vol. 7, No. 2Evidence for a histamine-component of the heart rate response to stellate ganglion stimulationPharmacological Research Communications, Vol. 9, No. 6H1- and H2-receptor mediated responses to histamine on contractility and cyclic AMP of atrial and papillary muscles from guinea-pig heartsAgents and Actions, Vol. 7, No. 1A NONHISTAMINIC RESPONSE OF RABBIT ATRIA TO BETAHISTINE8 March 2013 | The Journal of Clinical Pharmacology, Vol. 17, No. 1Effects of the H1-antagonist promethazine and the H2-antagonist burimamide on chronotropic, inotropic and coronary vascular responses to histamine in isolated perfused guinea-pig heartsAgents and Actions, Vol. 6, No. 6A study of the actions of histamine on the isolated rat heartClinical and Experimental Pharmacology and Physiology, Vol. 3, No. 4Antiarrhythmic actions of antihistaminesPharmacology & Therapeutics. Part B: General and Systematic Pharmacology, Vol. 2, No. 4Separate receptors mediating the positive inotropic and chronotropic effect of histamine in guinea-pig atriaEuropean Journal of Pharmacology, Vol. 34, No. 1Classification and biological distribution of histamine receptor sub-typesAgents and Actions, Vol. 5, No. 4Antagonism of tolazoline by histamine H2-receptor blockersNature, Vol. 253, No. 5492On a certain class of dose-response relations: A theorem and its corollaryMathematical Biosciences, Vol. 24, No. 1-2Differentiation of H10and H2-receptors mediating positive chronoand inotropic responses to histamine on atrial preparations of the guinea-pigAgents and Actions, Vol. 4, No. 4 More from this issue > Volume 223Issue 5November 1972Pages 1257-1262 Copyright & PermissionsCopyright © 1972 by American Physiological Societyhttps://doi.org/10.1152/ajplegacy.1972.223.5.1257PubMed4654356History Published online 1 November 1972 Published in print 1 November 1972 Metrics

THE NATURE OF THE ANTAGONISM BY METHOXAMINE OF THE CHRONOTROPIC AND INOTROPIC EFFECTS OF CATECHOLAMINES.

Chronotropic and inotropic concentration-effect curves were determined concurrently with a preparation consisting of the right atrium of a guinea-pig, beating spontaneously, and a strip of the left atrium driven at a constant frequency. In concentrations below 10−4, M, methoxamine usually had no effect upon the strength or frequency of contraction; at higher concentrations it depressed both. Methoxamine produces an approximately parallel shift in the log concentration-effect curves for l-isoproterenol, l-norepinephrine, and l-epinephrine, the chronotropic and inotropic curves being shifted about equally. A substantial shift is produced by concentrations of methoxamine that have no inotropic or chronotropic actions themselves. The positive chronotropic effect of histamine is not influenced by methoxamine. The evidence obtained is consistent with the hypothesis that the methoxamine-isoproterenol antagonism is a simple competitive one with a pA2 of 5.2. The methoxamine-epinephrine antagonism is more complicated, possibly partly as a result of a depressant effect of epinephrine itself in high concentrations.