Effects of histamine H1-receptor blockade on respiratory and cardiac manifestation of systemic anaphylaxis

Summary In vivo anaphylaxis is associated with respiratory distress and cardiovascular failure. The present investigation was designed to further characterize respiratory and cardiac anaphylactic events. In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin together with Freund's adjuvant. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed application of the antigen induced an initial increase of left ventricular pressure which was followed by a rapid decrease 5 min after antigenic challenge. Enddiastolic left ventricular pressure increased within 3 min, thus indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, heart rate steadily decreased. All animals died within 15 min. Simultaneously with cardiac anaphylactic malfunction, severe arterial hypoxia and carbon dioxide retention occurred, revealing respiratory distress.Histamine is known as a potent bronchoconstrictor via histamine H₁-receptor stimulation. Administration of H₁-recpetor antagonists to improve respiration may therefore provide further information on the contribution of pulmonary malfunction to anaphylactic cardiovascular shock. Therefore, additional experiments were performed with sensitized guinea pigs pretreated with the histamine H₁-receptor blocker mepyramine. In these experiments the antigenic challenge induced a dissociation of cardiac and respiratory manifestation of anphylaxis. Despite inhibition of hypoxia and carbon dioxide retention, left ventricular pump failure and occurrence of myocardial ischemia were delayed but not suppressed.It is concluded that histamine is an important mediator of anaphylactic respiratory distress. However, vasoactive anaphylactic mediators other than histamine are primarily involved in anaphylactic cardiac malfunction occurring during the later phase of systemic anaphylaxis.Supported by grant Fe 250/1-1 from the Deutsche Forschungsgemeinschaft (DFG).     

Histaminwirkungen am Herzen unter besonderer Berücksichtigung kardialer Nebenwirkungen von H2-Rezeptor-Antagonisten

Summary The existence of cardiac h₁- and h₂-receptors is evidenced by pharmacologic studies. Despite of the relatively high content of cardiac histamine it is not clarified whether histamine actually plays a physiologic role — apart from pharmacologic effects — in the regulation of myocardial function and coronary blood flow. Under pathophysiologic conditions (during anaphylaxis, surgical procedures, accidents, stress etc.), however, when a local or systemic histamine release occurs both hemodynamic and arrhythmogenic effects are evident. Numerous studies in animal models conclusively demonstrated a role of cardiac histamine as a major mediator of serious arrhythmias. Consequently, a combination of h₁- and h₂-receptor antagonists (f.e. Dimetinden/Cimetidin) was recommended as a prophylactic treatment against severe anaphylaxis including life-threatening arrhythmias for cardiac patients at risk.There is pharmacologic evidence of both a positive inotropic and chronotropic effect in the human heart via h₂-receptor and stimulation of adenylate cyclase. Histamine-induced coronary effects such as vasoconstriction via h₁-receptor and coronary dilatation via h₂-receptor are not yet sufficiently validated. Studies on the human heart in vitro using coronary strips from explanted hearts and in vivo investigations on the intact coronary system yielded conflicting results.H₂-receptor blocking agents cimetidine, ranitidine and famotidine have qualitatively a different pharmocodynamic spectrum of side effects due to differences in chemical structure. Data on cardiac arrhythmias are mostly associated to cimetidine. Symptomatic bradycardia were reported for both ranitidine and cimetidine. A possible negative inotropic effect of famotidine, although presently not validated, requires further studies.— Causative and adverse side effects of cimetidine on the cardiovascular system, however, are to be expected extremely seldom due to easily reversible competetive h₂-receptor binding. For prophylaxis rapid intravenous injections of h₂-blockers, particularly in elder patients with cardiac diseases, should be avoided. Compared to cimetidine, a tendency of explainable difference seems to become apparent for ranitidine and famotidine due to higher receptor affinity.

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Abkürzungsverzeichnis A Atrium - AVN AV-Knoten - HF Herzfrequenz - V Ventrikel     

Effects of SK&F 93479 on experimentally induced ventricular arrhythmias in dogs,rats and mice

The effects of SK&F 93479, a potent histamine H₂-receptor antagonist, on ventricular arrhythmias induced by coronary artery ligation in dogs and rats, and by aconitine infusion in mice were investigated. It was found that SK&F 93479 in large doses, significantly prevented the occurrence of spontaneous ventricular fibrillation and the changes in ventricular fibrillation threshold following coronary artery ligation in dogs. In rats subjected to ligation of the main left coronary artery, it significantly reduced the incidence of ventricular fibrillation, and significantly prolonged the time of onset of ventricular tachycardia and ventricular fibrillation. On the contrary, SK&F 93479 did not significantly alter the incidence or the time of onset of cardiac dysrhythmias caused by aconitine infusion in mice. These findings suggest that SK&F 93479 lacks non-specific antiarrhythmic activity and that its protective effects against coronary artery ligation may be mediated by its histamine H₂-receptor antagonizing action. They also support the hypothesis that histamine may contribute to the genesis of ventricular arrhythmias resulting from acute myocardial ischaemia.     

Effects of ranitidine and cimetidine on experimentally induced ventricular arrhythmias in anaesthetized rats

The effects of two histamine H₂-receptor antagonists, ramitidine and cimetidine, on ventricular arrhythmias induced by acute coronary artery ligation and by aconitine infusion were studied in pentobarbitone-anaesthetized rats. The changes in arterial blood pressure and heart rate were also observed. It was found that both drugs significantly reduced the incidence, and prolonged the time of onset, of ventricular tachycardia and ventricular fibrillation following acute coronary artery ligation; however, they did not significantly alter the incidence or time of onset of ventricular dysrhythmias caused by aconitine infusion. These findings further support the hypothesis that histamine release may contribute to the genesis of early ventricular arrhythmias resulting from acute myocardial ischaemia. Since the decreased blood pressure induced by coronary artery ligation was not significantly prevented by pretreatment with either histamine H₂-receptor blocker, this suggests that histamine may not be responsible for the blood pressure changes during acute myocardial ischaemia.     

In vitro cardiac pharmacology of the new histamine H2-receptor agonist amthamine: Comparisons with histamine and dimaprit

The cardiac activity of the novel histamine H₂-receptor agonist amthamine was investigated in a variety of isolated heart preparations from guinea pigs and humans and in the isolated rabbit aorta. Amthamine caused an increase in the sinus rate of spontaneously beating guinea-pig atria (pD₂=6.72) and in the contractility of the electrically driven guinea-pig papillary muscle (pD₂=6.17) and of the human atrium (pD₂=5.38). In all these systems, amthamine behaved as a full agonist with a potency comparable to or slightly higher than that of histamine and 10 times higher than that of dimaprit. The positive effects of amthamine were competitively antagonized by ranitidine which had pA₂ values (6.46 and 6.25 in the guinea-pig atria and papillary muscle, respectively) comparable with those calculated against histamine and dimaprit. In the isolated rabbit aorta amthamine was devoid of H₁-mediated activities up to 3×10^–4 M. These results indicate that amthamine is a potent and selective histamine H₂-receptor agonist which can be considered a valuable tool for investigating H₂-receptor mediated effects in cardiac tissues.     

Effects of histamine H1-receptor stimulation on coronary hemodynamics in man

Exogenous histamine in man induces significant cardiovascular effects mediated by activation of H₁ and H₂-receptors present on human heart and on coronary arteries. We studied the effects of selective H₁-receptor stimulation on human coronary hemodynamics in 10 patients undergoing cardiac catheterization. All patients were pretreated with cimetidine before the histamine infusion (0.5 g/kg/min i.v. for 5 min). Six of these patients had normal coronary arteries and four had single vessel coronary artery disease (CAD) and vasospastic angina. During the study heart rate was held constant (100 beats/min) by coronary sinus pacing. We measured mean aortic pressure (MAP), coronary sinus blood flow (CSBF), coronary vascular resistance (CVR) and myocardial oxygen consumption (MVO₂) at rest, during histamine infusion, and 10 min after the end of the infusion. During infusion, MAP decreased from 103±5 to 85±6 mmHg (p<0.02) and CVR from 1.00±0.16 to 0.81±0.14 mmHg/ml/min (p<0.05); CSBF and MVO₂ did not significantly change. All parameters returned to baseline at the end of the infusion. The response was similar in patients with normal coronary arteries and in 3 patients with CAD. Only one patient with CAD developed angina with ST segment elevation in D₃, reduction in CSBF and an increase in CVR. These results indicate that H₁-receptor stimulation in man induces significant coronary dilatation and that histamine infusion after cimetidine pretreatment is unlikely to provoke coronary spasm in patients with vasospastic angina.     

Effect of a histamine H2-receptor antagonist on immunologically induced mediator release in vitro

The histamine H₂-receptor has been implicated in the autoregulation of endogenous histamine release from actively sensitized human basophils. Consequently, the activity of metiamide (SK & F 92058), a specific histamine H₂-receptor antagonist, was investigated for its effect on immunologically-induced histamine release in several in vitro models of immediate hypersensitivity. Metiamide enhanced the release of histamine from passively sensitized fragmented Rhesus monkey lung and skin when these tissues were challenged in a reversed type anaphylactic reaction with antihuman IgE. The enhancing effect of metiamide on the release of ‘slow reacting substance of anaphylaxis, from monkey lung was considerably less pronounced. In contrast, metiamide failed to significantly enhance the antigen-induced release of histamine from fragmented rat lung which had been passively sensitized with rat anti-ovalbumin serum. The data supports a species-specific enhancement of immunologic histamine release in vitro, perhaps by H₂-receptor blockade on cells responsible for such release.     

Cardiovascular and respiratory mechanisms in anaphylactic and anaphylactoid shock reactions

Summary Different mediators such as histamine, leukotrienes, prostaglandins and bradykinin are involved in different reaction mechanisms such as cytotropic anaphylaxis (CA), immune complex anaphylaxis (ICA), reactions due to direct histamine liberation or activation of the complement system or hyperosmolarity induced anaphylactoid reactions.In the monkey CA induces systemic vasodilatation, a transient pulmonary hypertension and increase of cardiac output followed by peripheral blood pooling and depression of cardiac output. ICA induces peripheral vasoconstriction, a severe increase in pulmonary vascular resistance and decreased cardiac output, the latter possibly being partially due to decreased cardiac contractility.In hypersensitivity reactions in man cutaneous vasodilatation as well as vasoconstriction may occur alternatively. Peripheral blood pooling and increased vascular permeability are the cause of severe relative and absolute hypovolemia, respectively. Pulmonary vasoconstriction seems to occur in connection with serious bronchospasm. Decreased venous return, myocardial ischemia and hypoxemia can contribute to a reduction of cardiac performance. The most frequent changes in the ECG are sinus tachycardia, sinus bradycardia, extrasystoles, conduction disturbances as A-V block and bundle branch block; lethal or sublethal shock is often associated with malign arrhythmias or cardiac arrest.Almost normal blood gas values are seen in anaphylactic shock without clinical signs of respiratory obstruction. The very few documented cases of anaphylactic shock with respiratory obstruction indicate that increased airway resistance and reduced lung compliance may be present as well as mild to moderate hypoxemia with normal or subnormal CO₂ values.     

The effects of H2-receptor antagonists on anaphylaxis in the guinea-pig

Histamine has been shown to inhibit a variety of immune responses including the antigen-induced, IgE mediated, release of histamine from sensitized human leucocytes and from sensitized monkey and dog mast cells. The inhibitory action of histamine appears to be mediated by action at a histamine H₂-receptor. In in vitro experiments the H₂-receptor antagonist metiamide has been shown to block this histamine effect and it has been suggested that H₂-receptor antagonists could intensify immediate hypersensitivity reactions in vivo.The effects of the H₂-receptor antagonist metiamide and cimetidine have been studied in in vitro and in vivo models of anaphylaxis in the guinea-pig. The amount of extracellular histamine found after antigen challenge is greater when an H₂-receptor antagonist is present during the incubation of mast cells with antigen. Bronchoconstriction induced by antigen in sensitized guinea-pig is exacerbated only by high doses of cimetidine. Possible explanations for the mechanism of action involved are discussed.     

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 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.

     

IgE-mediated cardiac hypersensitivity reactions. An experimental model.

To investigate the involvement of the heart in acute allergic reactions in a system immunologically analogous to that of humans, a model of cardiac anaphylaxis mediated by IgE antibodies was developed in the guinea pig. Hearts obtained from guinea pigs, passively sensitized with homologous antidinitrophenyl IgE antibodies, were perfused and challenged in vitro with antigen. Challenge resulted in sinus and ventricular tachycardia, atrioventricular conduction block and substantial histamine release. The results demonstrate that IgE antibodies can sensitize the heart and that the severity of cardiac dysfunction, which follows challenge with specific antigen, directly correlates with the magnitude of histamine released. Since myocardial ischemia and similar arrhythmias occur during immediate hypersensitivity reactions in humans, this experimental model will be helpful in the investigation of cardiac involvement in acute allergic reactions.     

Histamine H2-receptors in guinea pig lung and their role in anaphylaxis

Conclusions Thus the protective action of metiamide against anaphylaxis in anaesthetized, artificially-respired guinea pigs does not derive from an action on the smooth muscle of the airways, which appear to lack histamine H₂-receptors, or from an effect upon pulmonary vascular muscle.     

Species differences in histamine receptors in the vas deferens

Histamine, specific H₁-and H₂-receptor agonists in conjunction with specific H₁-and H₂-receptor antagonists and other types of classical antagonists were used to characterize histamine receptors in the vasa deferentia of mice, rats and guinea pigs. The H₁-receptor mediates contraction while the H₂-receptor produces inhibition. There were marked qualitative and quantitative differences in the distribution of the two types of histamine receptors in the vas deferens of different species. Results indicate that mouse and rat vas deferens contain an inhibitory H₂-receptor, but virtually no excitatory H₁-receptor. In contrast, guinea pig vas deferens contained an excitatory H₁-receptor but was essentially devoid of an inhibitory H₂-receptor. The rank order of relative potencies of various agonists as well as the calculated pA ₂ values of cimetidine in the mouse and rat vas deferens suggest that the two species probably have the same H₂-receptor. High concentrations of histamine and 2-methyl histamine have a stimulant action in the mouse and rat vas deferens which was secondary to release of endogenous noradrenaline rather than to the stimulation of an excitatory H₁-receptor.     

Histamine receptors in the lower esophageal sphincter (LES)

The motor response of histamine on the lower esophageal sphincter and the receptors involved were investigated on isolated preparations from rats, guinea pigs and humans. Histamine exerted a spasmogenic effect through excitation of H₁-receptors. H₁-receptor selective agonists in the rat but not in the guinea pig seem to act through release of prostaglandin-like substances. Apparently H₂-receptors, whose stimulation causes relaxation of the sphincter, do not occur in the LES of rat and human whereas they are present in the guinea pig.H₂-receptor antagonists exerted different and some-times opposite effects and this suggests that their actions depend on the specific molecules and not on the H₂-receptor blockade. The significance and the importance of the above findings are discussed.     

Nitric oxide modulates cardiac and mast cell anaphylaxis

Anaphylaxis in the isolated guinea-pig heart was associated with a sudden release of histamine with a long-lasting release of nitrite (NO ⁻₂ ), an oxidation product of NO.N ^G-monomethyl-l-arginine (MeArg, 300 μM) increased the severity of cardiac anaphylaxis, as shown by the decrease in the coronary flow and by a prolonged duration of antigen-induced arrhythmias. Concomitantly, MeArg increased the release of histamine while decreasing the release of nitrite. Sodium nitroprusside (NaNP, 10⁻⁵–10⁻⁴ M) reduced the severity of cardiac anaphylaxis by increasing coronary flow and shortening the duration of antigen-induced arrhythmias. Concomitantly, NaNP decreased the release of histamine while increasing the release of nitrite. In mast cells isolated from actively sensitized guinea-pigs, the release of histamine elicited by specific antigen was increased by MeArg and decreased by NaNP.

In conclusion, endogenous and exogenous NO antagonizes the effect of vasoconstrictor mediators released after antigen challenge and plays a protective role in anaphylactic reactions “in vitro”,

     

Histamine modification of spontaneous rate and rhythm in infarcted canine ventricle

1. Histamine (10^?3 M) increased the spontaneous rate similarly in isolated preparations of normal left ventricular tissue from control, i.e. normal and sham-operated, dogs (control preparations) and in preparations consisting of normaland contiguous infarcted left ventricular tissue from dogs with subacute, i.e. 24 hours after left coronary artery ligation, myocardial infarction (infarcted preparations).
2. Histamine (10^?3 M) markedly enhanced the irregular rhythm of infarcted preparations.
3. The H₁-receptor antagonist, chlorpheniramine (10^?4 M), and the H₂-receptor antagonist, cimetidine (10^?3 M), antagonized the effects of histamine (10^?3 M) on the spontaneous rate of both control and infarcted preparations.
4. The H₁-receptor agonist, 2-pyridyl ethylamine (PEA, 10^?4 M), increased the spontaneous rate of control and infarcted preparations; these effects were antagonized by chlorpheniramine (10^?4 M). The H₂-receptor agonist, dimaprit, had no effect.
5. Similar to histamine (10^?3 M), PEA (10^?4 M) enhanced the irregular rhythm of infarcted preparations; dimaprit had no effect.
6. High local concentrations of histamine may occur in poorly perfused ischemic tissue. The enhancement of irregular rhythm produced by histamine, and the specific H₁-receptor agonist, PEA, leads us to suggest its involvement in arrhythmias associated with subacute myocardial infarction.

     

Dysrhythmias caused by histamine release in guinea pig and human hearts

Summary Histamine is released into the systemic circulation during anaphylaxis, by drugs and by surgical procedures. Studies in animal models have conclusively demonstrated that released cardiac histamine is a major mediator of arrhythmias that occur during anaphylaxis and following the administration of histamine-releasing drugs. Several lines of evidence suggest a similar arrhythmogenic role for cardiac histamine in humans: (1) The human heart is rich in histamine; (2) cardiac histamine can be readily released from human heartin vitro by therapeutic concentrations of drugs; (3) histamine has potent arrhythmogenic effects on the human heartin vitro.Arrhythmogenic effects of histamine include enhancement of normal automaticity, induction of abnormal automaticity, induction of triggered tachyarrhythmias, depression of atrioventricular conduction, and increase in the vulnerability of the ventricles to fibrillation. A combination of H₁ and H₂ antihistamines is needed to block the arrhythmogenic effects of histamine. Certain arrhythmogenic effects of histamine (e.g. induction of slow responses and delayed afterdepolarizations) can also be blocked by drugs which inhibit the influx of cations through slow channels. In contrast, the commonly-used drug digitalis potentiates the arrhythmogenic effects of histamine.We propose that histamine release produced by drugs and surgical procedures may be an overlooked factor in fatal cardiac arrhythmias. Experimental studies suggest that selective pharmacological methods can be developed to block the arrhythmogenic effects of histamine.Post-Doctoral Research Fellow supported by 1F32 HL 05536     

Histamine release and its effects in ischaemia-reperfusion injury of the isolated rat heart

Histamine is released from the heart during ischaemia-reperfusion injury. As histamine has cardiac effects, we investigated the role of histamine in ischaemia-reperfusion injury of isolated rat hearts. A Langendorff-model with 30 min global (37 ^oC) ischaemia followed by 60 min reperfusion was employed. The effects of ischaemia alone (n= 10, group 1.1+n = 10, group 2.1, 2 different series), and ischaemia with H₁- and H₂-receptor blockade with cimetidine (10 μM, n= 10), chlorpheniramine (10 μm, n= 8), terfenadine (10 μM, n= 8), and promethazin (10 μM, n= 9), or both cimetidine and chlorpheniramine (n = 8), were studied. Histamine was measured in the coronary effluent and cardiac tissue of group 1.1. Release of histamine increased from 6.5 ± 1 pmol min^-1 before ischaemia to 19 ± 3 pmol min^-1 at the start of reperfusion. Ischaemia decreased left ventricular developed pressure to 18 ± 11 % (1.1) and 50 ± 11 % (2.1) of initial value (mean ± SEM) at the start of reperfusion. Left ventricular end-diastolic pressure increased from 0 to 79 ± 8 mmHg (1.1) and 39 ± 9 (2.1) mmHg, while left ventricular systolic pressure was unchanged (101 ± 12% in 1.1 and 101 ± 10% in 2.1). Severe arrhythmias were induced in 90 (1.1) and 30 (2.1)% of the hearts, while coronary flow decreased during reperfusion. H₂-blockade did not modify the changes in left ventricular pressures, coronary flow, or heart rate induced by ischaemia. Three different Hj-blockers increased left ventricular systolic pressure, inhibited the decrease of developed pressure, attenuated the increase of end-diastolic pressure, and totally inhibited reperfusion arrhythmias. The effect of both blockers together was similar to that of H₁-blockers alone. Coronary flow was increased during reperfusion in two of the groups with Hj-blocker compared with ischaemic controls. Increased release of histamine from ischaemic-reperfused rat hearts concurred with depression of left ventricular function and arrhythmias during early reperfusion. Cardiac dysfunction during reperfusion was attenuated by three different Hj-receptor blockers.     

The effects of metiamide and H1 receptor blocking agents on anaphylactic response in guinea-pigs

The effects of metiamide and of four H₁ receptor blocking agents (mepyramine, promethazine, clemastine and ketotifene) on anaphylactic reaction were studied in the guinea-pig. The H₁ blockers conferred partial protection which shows that with the experimental protocol utilized (challenge injection with high doses of antigen), histamine plays a lesser role than other mediators released or synthesized. Metiamide (30.0 mg/kg i.v.) noticeably enhanced the increase in pulmonary resistance observed during anaphylactic reaction and reduced the protective effect of the H₁ antagonists on this parameter and on histamine release. These effects might be explained by an inhibition — at least partial — of the negative feed-back mechanism through which histamine controls its own release, or by a specific action of metiamide in high doses. The transient tachycardia initially observed in anaphylactic shock is partly related to stimulation of cardiac H₂ receptors by the histamine released, since it is suppressed by metiamide.     

Relationship between alterations in atrial and ventricular histamine content and cardiac function during cardiac anaphylaxis of isolated guinea pig hearts.

Antigen-induced histamine release from sensitized cardiac tissue has been shown to contribute significantly to the increases in atrial rate, atrioventricular nodal conduction, and ventricular contractile force that occur during cardiac anaphylaxis. These findings suggest that there might be a strong negative correlation between changes in these variables and the residual histamine content in the tissue after the anaphylactic reaction. In the present study using isolated hearts of passively sensitized guinea pigs, antigen challenge evoked transient increases in atrial automaticity, P-R intervals, vascular resistance, and left ventricular pressure. The histamine content of atrial and ventricular tissue from antigen-challenge hearts (1,475 +/- 296 and 4,543 +/- 360 ng/g, respectively) was significantly less than that of nonchallenged hearts (2,652 +/- 335 and 6,298 +/- 251 ng/g, respectively). Significant correlations found were between the residual histamine content of the ventricular tissue or the total histamine released and the magnitude of the antigen-induced increase in left ventricular systolic pressure. These findings suggest that antigen-induced increases in left ventricular systolic pressure can be used as an index of the local ventricular histamine release. The lack of significant correlations between local residual histamine levels and changes in atrial rate, P-R intervals, or coronary vascular resistance suggests that complicated interactions between histamine and other mediators or factors may be involved in the antigen-induced chronotropic, dromotropic, and vasoconstrictive alterations in these preparations.