Histamine release with intravenous narcotics: Protective effects of H1 and H2-receptor antagonists

Summary High dose narcotic anesthesia with fentanyl or morphine is not associated with significant direct myocardial depression. Morphine is reported to produce arteriolar dilatation and a decrease in SVR (probably due to histamine release) while fentanyl is not. Studies were undertaken to determine if morphine or fentanyl caused histamine release; if such a release correlated with hemodynamic changes, and if H₁ and H₂ antagonists could provide protection. In a randomized double blind study of 40 patients in 4 groups, patients who received morphine (1 mg/kg) demonstrated significant increases in plasma histamine (880±163 to 7,437±2,684 pg/ml–p<0.01) accompanied by an increase in CI (2.4±0.2 to 3.0±0.2 l/min/m²–p<0.01) and decreases in (88±4 to 61±4 torr–p<0.01) and SVR (15.5±1 to 9.0±1 torr-l-min^–1 p<0.01). The prior administration of H₁ (dyphenhydramine 1 mg/kg) and H₂ (cimetidine 4 mg/kg) antagonists provided significant protection (SVR 17.4±1 to 14.6±1 torr-l-min^–1–p<0.05) although histamine increased comparably (1,059±22 to 7,653±4,242 pg/ml–p<0.05). In a separate study, seven patients receiving fentanyl 50 µg/kg showed no histamine changes (935±51 to 685±51 pg/ml) and no significant hemodynamic response. Eight patients receiving morphine 1 mg/kg again showed significant increases in plasma histamine (880±163 to 7,480±2,230 pg/ml–p<0.05) which collelated with the decrease in SVR (r=0.81). These data demonstrate that morphine releases histamine in amounts which correlate with the hemodynamic changes seen. Prior administration of H₁ and H₂ histamine antagonists provide significant protection — more so than either alone. Fentanyl produced no histamine release which may account for much of the cardiovascular stability reported with this drug.     

Effects of histamine H1- and H2-receptor antagonists on cardiovascular function during systemic anaphylaxis in guinea pigs

The heart is a target organ of anaphylaxis. In isolated perfused hearts, an anaphylactic reaction is characterized by arrhythmias, coronary constriction, and severe impairment of ventricular contractile force. Various mediators such as PAF, thromboxane A₂ and leukotrienes, are responsible for anaphylactic coronary constriction and negative inotropic effects. The cardiac effects of anaphylactic histamine release are related to the stimulation of two antagonistic receptor types. Histamine induces atrioventricular conduction delay and constriction of the epicardial coronary vessels via H₁-receptor stimulation. H₂-receptors, however, mediatecoronary vasodilation and an increase in heart rate and myocardial contractility. It may therefore be concluded that administration of histamine H₂-receptor antagonists is disadvantageous. During anaphylactic states, the cardiodepressive effects of the other mediators of anaphylaxis are unmasked, resulting in a sustained coronary constriction and impairment of myocardial contractility. To verify this speculation, we investigated the effects of H₁- and H₂-receptor antagonists on cardiovascular function of guinea pigs during systemic anaphylaxis.In guinea pigs, sensitization was produced by subcutaneous application of ovalbumin. Fourteen days after sensitization, the effects of an intravenous infusion of ovalbumin were tested in the anesthetized artificially ventilated guinea pigs. The renewed administration of the antigen induced severe cardiac dysfunction. Within a few minutes, cardiac output markedly decreased and left ventricular end-diastolic pressure increased significantly, indicating left ventricular pump failure. In the same time range, ECG recordings uniformly showed signs of acute myocardial ischemia. In addition, arrhythmias occurred in terms of an atrioventricular block. After 4 min, blood pressure rapidly declined. All animals died within 12 min. Pretreatment with the selective H₁-receptor antagonist astemizol (5 mg/kg i.v.) delayed the onset of myocardial ischemia, arrhythmias and cardiac pump failure. After 10 min, however, left ventricular contractility and blood pressure steadily declined, leading to severe hypotension within 30 min. In the case of a pretreatment with astemizol (5 mg/kg i.v.) and the H₂-receptor antagonist famotidine (10 mg/kg i.v.), no relevant changes of cardiovascular function were seen compared to pretreatment with astemizol alone. It is therefore concluded that endogenous histamine, via H₁-receptor stimulation plays an important part during the early phase of systemic anaphylaxis, whereas mediators other than histamine are involved at a later stage of the process. Furthermore, H₂-receptor-mediated effects are of minor importance in cardiovascular manifestation of anaphylaxis. Pretreatment with H₂-receptor antagonists has no detrimental effects on cardiovascular function during anaphylactic reactions in guinea pigs underin vivo conditions.Supported by grant Fe250/1-1 from the Deutsche Forschungsgemeinschaft (DFG).     

Histamine release in anaesthesia and surgery. Premedication with H1- and H2-receptor antagonists: Indications,benefits and possible problems

Summary Our clinical and experimental studies have so far demonstrated, that the drugs used in anaesthesia; such as hypnotics, sedatives, narcotics or muscle relaxants, release histamine.The intravenous short acting anaesthetic etomidat has not shown either in experimental studies or in clinical use for 10 years any anaphylactoid reaction. The benzodiazepines are another group of drugs which appear not to release high amounts of histamine.Accurate studies on volunteers as well as on patients on the application of H₁- and H₂-receptor antagonists have demonstrated an effective inhibition of the anaphylactoid reaction. We suggest that in case of a history of allergy H₁- and H₂-receptor antagonists should be administered as a prophylactic premedication.Supported by Grant of Deutsche Forschungsgemeinschaft (Lo 199) 13-6     

Histamine H1- and H2-receptor antagonists reduce histamine-induced increases in vascular permeability and oedema formation in cat skeletal muscle

Intra-arterial infusions of histamine cause vasodilatation of resistance vessels, extravasation of albumin and oedema in cat skeletal muscle. Treatment with either mepyramine or metiamide significantly reduced the extravasation of albumin and rate of oedema formation. The doses of mepyramine and metiamide used did not modify the vascular responses to bradykinin.     

Histamine receptors on guinea-pig alveolar macrophages: Chemical specificity and the effects of H1- and H2-receptor agonists and antagonists

Various guinea-pig leucocytes were tested for their capacity to bind histamine coupled as a rabbit serum albumin conjugate (H-RSA) to formalised ox red cells. The percentage of rosette-forming target cells was directly related to the concentration of erythrocyte-bound H-RSA. Under optimal experimental conditions the numbers of rosettes varied from 60 to 81% for alveolar macrophages, 14 to 73% for peritoneal macrophages, 14 to 30% for blood monocytes, 27 to 48% for lymph node cells, 7 to 24% for blood lymphocytes and 0 to 29% for peritoneal and blood neutrophils. Virtually no histamine rosettes were formed with eosinophils or basophils.

Free histamine partially inhibited rosette formation by alveolar macrophages in a dose-dependent fashion from 10⁻³ to 10⁻⁵ mol/l, and complete inhibition was achieved by the H-RSA conjugate. In contrast, amines closely related to histamine such as L-histidine and the major histamine catabolites, imidazoleacetic acid, 1,4-methylhistamine, l-methyl-4-imidazoleacetic acid and N-acetylhistamine, had no inhibitory effect.

The histamine H1–receptor antagonists, mepyramine and chlorpheniramine, and the H1-receptor agonist, 2– (2–aminoethyl) thiazole, all inhibited rosette formation by alveolar macrophages in a dose-dependent fashion. However, the H2-receptor antagonists, burimamide and metiamide, and the H2-receptor agonists, Dimaprit and 4–methyl–histamine, were inactive.

These experiments suggest that (1) compared to other leucocytes, histamine receptors are particularly well expressed on the alveolar macrophage, (2) these receptors have a high degree of specificity for histamine in that other amines, closely related chemically, did not inhibit rosette formation, and (3) the binding of histamine to the alveolar macrophage membrane is H1- and not H2- receptor dependent.

     

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.     

Histamine response to various stimuli during CABG-surgery: A study in patients with and without prophylactically administered H1- and H2-receptor antagonists

Inflammation Research -     

Histamine H1- and H2-receptors in coronary arteries of pigs

Histamine exerts its action in smooth muscle via two types of receptors. In coronary arteries of pigs both types of receptors are also involved in responses to histamine. Histamine initiates by an interaction with H₁-receptors a contraction and with H₂-receptors a relaxation. The histamine-induced contraction is reduced by the competitively antagonistic action of mepyramine. Metiamide potentiates dose-dependently the histamine-caused contraction in the absence and presence of mepyramine.The proportion of H₂-receptors in relation to H₁-receptors is calculated.     

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.     

Histamine H2-receptor modulation in two mouse models of seizure susceptibility

Inflammation Research -     

Histamine H2-receptor agonists and antagonists on pancreatic exocrine secretion of the dog

The use of H₂-receptor agonists and antagonists allowed us to establish that histamine H₂-receptors are present in pancreatic exocrine tissue and their stimulation caused a dose-dependent increase in pancreatic juice. The fact that H₂-antagonists from one side and aminoguanidine from the other were unable to modify basal levels of pancreatic secretion, seems to minimize a role for H₂-receptors in the regulation of pancreatic secretion. On the other hand H₂-antagonists modified ceruletide-induced secretion in different ways according to the different molecules. Ranitidine strongly potentiated whereas cimetidine, oxmetidine and mifentidine slightly inhibited the effect of ceruletide. The stimulatory effect of eserine and the inhibitory effect of atropine indicate a cholinergic interference in the action of ceruletide. Therefore the potentiating effect of ranitidine may be related to its cholinomimetic action and the inhibitory effect of the other H₂-antagonists may be connected with an anticholinergic effect. However, the potentiating effect of aminoguanidine on ceruletideinduced secretion may indicate a possible role for histamine in the response to ceruletide.     

Histamine H2-receptor antagonists and gastric acid secretion — A progress report

Summary Histamine H₂-receptor antagonists, including burimamide, metiamide and cimetidine, are effective antagonists of histamine-stimulated acid secretion from mammalian, avian or reptilian gastric mucosa. Acid secretion stimulated by gastrin or pentagastrin is also inhibited by these drugs, but there is disagreement about the effects of these drugs on acid secretion resulting from activation of acetylcholine receptors. Based on the pharmacological evidence possibilities of treatment by these drugs were discussed in cases with excessive stimulation of acid secretion due to high blood levels of histamine or gastrin. The positive results in several trials on Zollinger-Ellison syndrome and peptic ulcer were very impressive. Some practical problems have still to be solved, for example the appropriate phase for applying the drugs. The demonstrated clinical effectiveness, however, against peptic ulceration offers a clear alternative to surgery for many patients.Presented at the meeting on Gastric and duodenal ulcer disease: Basic principles and clinics of treatment by drugs and operations, Marburg, November 22, 1975     

Histamine H1- and H2-receptors in pulmonary and systemic vasculature of the dog.

This study was conducted to identify and clarify the actions of pulmonary and systemic H1- and H2-receptors by utilizing specific histamine receptor antagonists. Histamine was infused in anesthetized dogs during control conditions, after H2-receptor blockade with metiamide, after H1-receptor blockade with chlorpheniramine, and after combined H1- and H2-receptor blockade. Histamine infusion, alone, induced marked systemic vasodilatation, pulmonary vasoconstriction, and transient increases in cardiac output and heart rate. H2-receptor blockade prevented the systemic vasocilatation and potentiated the pulmonary vasoconstriction induced by histamine. H1-receptor blockade augmented the systemic vasodilatation, prevented the pulmonary vasoconstriction, and increased the cardiac output and heart rate responses induced by histamine. Thus, H2-receptors appear to mediate the vasocilatation, tachycardia, and increased cardiac output induced by histamine, whereas H1-receptors appear to mediate the vasoconstrictor and the minimal cardiac depressent actions of histamine. Histamine stimulates only H1- and H2-receptors, since combined H1- and H2-receptor antagonism prevented almost all of the cardiovascular actions of histamine.     

Effect of H1- and H2-receptor antagonists on the hemodynamic changes induced by the intravenous administration of ketamine in sevoflurane-anesthetized cats

Objective: The anesthetic ketamine has been reported to cause both an increase of the plasma histamine concentration, notably in cats, and a cardiovascular depression. The latter has been described in humans and in other species. However the relevance of the histamine fluctuation for the ketamine-induced hemodynamic changes has not been determined.Subjects and treatment: We studied the contribution of histamine to the hemodynamic effects induced by IV ketamine (7 mg/kg) in 12 sevoflurane anesthetized cats, of which half had been pre-treated with combined H₁- and H₂ -receptor antagonists.Methods: The mean arterial pressure (MAP) and the heart rate (HR) from both untreated (group C) and pre-treated (group AH) cats were recorded before and after the ketamine administration. The plasma histamine concentration was also measured.Results: Plasma histamine fluctuations in the control and the antihistamine-treated group followed a similar pattern (no statistical differences); an initial rise that peaked 2 min after ketamine injection (from 0.63 ± 0.11 ng/ml to 2.22 ± 0.69 ng/ml in the C group, and from 0.71 ± 0.10 ng/ml to 1.09 ± 0.28 ng/ml in the AH group) followed by an immediate decrease in plasma concentrations. As for the hemodynamic variables under analysis, in the control group ketamine administration was followed by an early 30.3 ± 8.1% reduction (p < 0.005) in the MAP with no associated changes in the HR. In the antihistamine pre-treated group, ketamine caused a further decrease of the MAP (41.7 ± 2.3%), and a significant (p < 0.01) 11.6 ± 2.9% reduction of the HR.Conclusion: Ketamine in anesthetized cats triggers histamine release and induces cardiovascular depression. The depression is more pronounced under the blockade of histamine activity through histamine receptor antagonists.Received 22 October 2004; returned for revision 5 January 2005; accepted by A. Falus 14 February 2005     

Electrophysiological actions of histamien and H1-,H 2-receptor antagonists in cardiac tissue

Electrophysiological investigations of histamine in different cardiac tissues have led to the following results:

1. Histamine and the H₂-agonists dimaprit and impromidine show similar actions on electrophysiological parameters of ventricular myocardium (especially a decrease in action potential duration), which are completely blocked by cimetidine and enhanced by the phosphodiesterase inhibitor 1-methyl,3-isobutylxanthine (IBMX). These effects may be explained by an increase in cellular cAMP leading to an increase in slow inward current and outward currents as shown by voltage clamp experiments.
2. Histamine in contrast to IBMX increases action potential duration at 90% repolarization (APD₉₀) in atria. Histamine effects in atrial myocardium are completely reversed by the H₁-antagonist dimetindene. Stimulation of atrial H₁-receptors is suggested to directly cause an increase in Ca-channel conductance independent of intracellular cAMP content.
3. Histamine reduces AH-interval, increases \(\dot V_{max} \) of NH — cells and may induce AV — node arrhythmias (at concentrations ≥ 3 μmol/l). These effects remain unchanged by dimetindene, but are reversed by cimetidine. The results indicate that histamine increases AV — nodal conduction via H₂-receptors.
4. Unspecific membrane actions of cimetidine are not observed up to 100 μmol/l. Dimetindene increases action potential duration (APD) in left atria and decreases \(\dot V_{max} \) at concentrations ≥ 10 μmol/l. However, H₁-antagonistic actions of dimetindene are already observed at concentrations 1,000 to 10,000 times lower (pA₂—values 8.39–9.12) so that unspecific membrane actions are suggested not to occur on a therapeutic dose level.

     

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).     

Hyperlipemic responses induced by centrally administered histamine H1- and H2-receptor agonists in rats

The H₁-receptor agonist 2-pyridylethylamine (PEA), and the H₂-receptor agonists dimaprit and impromidine administered intracerebroventricularly (i.c.v.) to conscious rats considerably increased the concentration of free fatty acids (FFA) in the blood serum.The hyperlipemic effect of PEA was abolished by mepyramine, a H₁-receptor antagonist. Responses to dimaprit and impromidine were not antagonized by cimetidine.These results suggest that central H₁-receptor stimulation elicits the hyperlipemic responses in rats. The role of central H₂-receptors in this reaction is not clear.     

Histamine involvement in the local and systemic microvascular effects produced by intradermal substance P

The cutaneous microvascular changes produced by intradermal substance P were quantitatively evaluated in both substance P-injected and contralateral, saline-injected guinea pig ears. Substance P evoked a dose-dependent increase in cutaneous microvascular permeability in both treated and untreated ears which was reduced, but not abolished, by a mepyramine-cimetidine combination. This indicates that the local effect of substance P on microvascular permeability and the effect on the contralateral ear (presumably the result of systemic substance P absorption) are both partially mediated by histamine. A cutaneous vasodilator response was also observed in substance P treated and contralateral ears, but a bell-shaped dose-response relationship was apparent. Unlike microvascular permeability, pretreatment with mepyramine and cimetidine failed to consistently attenuate the vasodilator response to substance P. Thus, a direct cutaneous vasodilator effect appars to predominate in both substance P-injected and saline-injected ears.