High Doses Of Histamine Research Articles

Effects of atropine, acetylsalicylic acid, FPL 55712, and phentolamine on increased histamine responsiveness of cat lung strips under conditions of airway inflammation

Our recent in vitro studies on airway smooth muscles of cats with turpentine oil inflammation showed an increase of isometric tension of the lung strips to histamine application. This communication describes the effect of atropine, acetylsalicylic acid, FPL 55712, and phentolamine on the histamine contractions of the lung strips derived from control and experimental groups of cats. Pretreatment of the lung strips with atropine and acetylsalicylic acid had no significant effect on histamine induced contraction. FPL 55712 significantly decreased the mean values of isometric contractions after the low doses of histamine in experimental groups of strips. The isometric contractions after higher doses of histamine were not affected by FPL 55712 in both groups of strips. The significant increase of histamine contractions of the lung strips induced by experimental inflammation was reduced by phentolamine. The role of alpha adrenergic receptors in the increased responsiveness of the inflamed lung tissues to histamine is discussed.

Role of histamine receptor in mesencephalic nucleus dorsalis raphe in cardiovascular regulation

The effects of microinjection of histamine and its antagonists into mesencephalic nucleus dorsalis raphe, were investigated on mean arterial pressure and heart rate in cats to elucidate the nature and role of histaminergic receptors in cardiovascular regulation. Microinjection of histamine (5 and 10 micrograms) into nucleus dorsalis raphe elicited both inhibitory and excitatory cardiovascular responses respectively. On the other hand, microinjection of H2-receptor blocker, cimetidine (10 micrograms) resulted in hypertension and tachycardia while H1-receptor antagonist, mepyramine (10 micrograms) microinjection evoked hypotension and bradycardia. Furthermore, local pretreatment with cimetidine and mepyramine blocked the inhibitory and excitatory cardiovascular responses of graded doses of histamine microinjection. These H1 and H2 receptors are localized in nucleus dorsalis raphe since microinjection of histamine into adjoining neural structures did not evoke any cardiovascular change. Furthermore, both the inhibitory and excitatory cardiovascular responses to histamine microinjection could not be observed in animals with spinal cord transection and in animals pretreated with p-chlorophenylalanine while they could be observed in bilateral cervical vagotomized animals. Thus, it appears that these cardiovascular responses to microinjection of histamine into nucleus dorsalis raphe, are due to modulation of serotonergic bulbospinal influence on sympathetic preganglionic neurones in the spinal cord. Moreover, the excitatory cardiovascular responses of high dose of histamine (10 micrograms) seem to result from a local release of noradrenaline since they were blocked by prior microinjection of guanethidine and piperoxan into nucleus dorsalis raphe. A release of noradrenaline in turn, modulates the activity of the neurones of the nucleus by acting on alpha adrenoceptors and thereby alters the activity of sympathetic preganglionic neurones.(ABSTRACT TRUNCATED AT 250 WORDS)

Omeprazole in the short-term treatment of reflux oesophagitis.

Studies with short-term administration of omeprazole in patients with erosive or ulcerative reflux oesophagitis have demonstrated that strong inhibition of gastric acid secretion will become the therapy of choice for these patients. However, because reflux oesophagitis relapses rapidly when short-term treatment is discontinued, these patients are candidates for maintenance treatment. In most cases, long-term treatment will also require strong inhibition of gastric acidity. Until more information on the long-term safety of strong inhibition of gastric acid secretion is available, this therapeutic option should preferably be restricted to those patients who do not respond appropriately to other therapeutic regimens. Future studies are needed to determine whether higher doses of histamine H2-receptor antagonist are equally efficacious as omeprazole in ulcerative oesophagitis and whether profound acid inhibition is also needed to alleviate reflux symptoms in patients with an intact oesophageal mucosa.

Characteristics of tachyphylaxis to inhaled histamine in anesthetized dogs.

Three consecutive dose-response curves to aerosolized histamine were obtained in 11 anesthetized dogs. All dogs showed desensitization (i.e., tachyphylaxis) to high doses of histamine. Tachyphylaxis was highly reproducible. No tachyphylaxis occurred with inhaled acetylcholine or methacholine. Beta-Adrenergic blockade with propranolol or muscarinic blockade with atropine given intravenously had no effect on the histamine tachyphylaxis. Duration of thiamylal anesthesia did not alter the histamine responsiveness. Histamine tachyphylaxis was also seen with chloralose-urethan anesthesia. Since tachyphylaxis is not observed with acetylcholine, it cannot be attributed to a general decline in muscle contractility. We conclude that histamine tachyphylaxis in vivo is not explained by effects of cholinergic reflexes, catecholamine release, duration of anesthesia, or, probably, type of anesthetic agent.

Oxygen free radical scavengers (OFRS) prevent vasodepression induced by anaphylaxis, dextran or u.v.-irradiation in mice and rats

If legs of animals with inflammation (dextran, antigen or adjuvant-induced) are isolated and perfused, the efficacy ofco-perfused or i.a. injected vasoconstrictors (norepinephrine (NE), vasopressin, angiotensin II, PGF2a, ATP-Na2, or substance P) is found to be reduced, i.e., vasodepression develops [1]. Injection into animals (i.v., s.c. etc.) of high doses of histamine, PAFacether and PGI2 can also induce vasodepression. Inflammation-induced vasodepression can partly be prevented or restored by prophylactic administration or co-perfusion of antihistaminics, salicylic acid, acetylsalicylic acid, PAF-antagonists or glucocorticoids whereas other nonsteroidal antiinflammatory drugs (indomethacin, diclofenac, phenylbutazone) are rather inactive in this respect. Here, we report on the protection by OFRS administration against antigen-, dextranor ultra violet light (u.v.)-induced vasodepression.

The combined effects of histamine and methacholine on the maximal degree of airway narrowing in normal humans in vivo

In normal subjects in vivo the dose-response curve to inhaled nonsensitizing stimuli reaches a plateau at mild degrees of airway narrowing. We investigated whether the limitation of the response is due to non-optimal smooth muscle activation, by administering high doses of histamine and methacholine together. In fifteen normal subjects a complete dose-response curve to methacholine was recorded by a tidal breathing method on three randomized days. On a separate day a complete histamine inhalation test was carried out. Each methacholine test was directly followed by double blind inhalation of the highest dose of either histamine or methacholine, or a dose of saline. The response was measured by flows from partial flow-volume curves (V 40p), and was expressed in % fall from baseline. Twelve subjects reached a maximal response plateau to methacholine which was reproducible. The addition of saline or extra methacholine did not change the response from its methacholine plateau value. Histamine caused a small increase in the response on top of the methacholine plateau (+ 9.0% fall; p less than 0.001). However, the response to the combined histamine and methacholine was not significantly larger than the maximal response to histamine alone. We conclude that there is no interaction between histamine and methacholine on the maximal degree of airway narrowing. This suggests that the plateau of the dose-response curve in normal subjects in vivo is due to other factors than limited smooth muscle activation.

The role of histamine in doxorubicin and teniposide-induced cardiotoxicity in dog and mouse.

In previous studies we reported that teniposide (VM26) induced acute cardiac effects in dogs seem to be related to a release of histamine and that a prior treatment with chlorpheniramine, an H1 histamine blocker, prevents the onset of this phenomenon. Since histamine and other vasoactive substances also seem to be involved in doxorubicin (DXR)-induced acute cardiac effects, experiments were undertaken in the aim to prevent, as in the case of VM26, the onset of this phenomenon by administering chlorpheniramine. Since DXR-induced chronic cardiomyopathy also seems to be related to the same mechanisms involved in the onset of acute cardiac effects induced by this drug, additional studies were carried out to investigate whether a long-term treatment with VM26 could induce in mouse alterations of cardiac morphology similar to those of DXR. In addition, because the mouse is known to be extremely insensitive to histamine, further studies were performed to investigate whether DXR or VM26 administration could induce in this animal model a massive histamine release and whether a long-term treatment with high doses of histamine could elicit, similarly to DXR, alterations in cardiac morphology. The results of our experiments demonstrated that DXR (1.5 mg/kg i.v.) caused in the dog a massive histamine release and a marked impairment of cardiac inotropism. As previously described for VM26, prior treatments with chlorpheniramine completely prevented this phenomenon. Furthermore, DXR administration, at a dose level able to induce cardiac damage in the mouse (2.5 mg/kg i.v.), or that of VM26 (2 mg/kg i.v.) failed to induce a massive histamine release. In addition, long-term treatment with VM26 (2 mg/kg i.v.) or high doses of histamine (100 mg/kg i.v.), unlike DXR, did not elicit in this animal alterations of cardiac morphology. Finally, chlorpheniramine (0.15 or 0.45 mg/kg i.v.) did not prevent the onset of chronic cardiomyopathy induced by DXR in mouse. In conclusion, our results show that the role of histamine in the onset of DXR-induced chronic cardiomyopathy, at least in mouse, remains questionable and suggest that this animal, because of its high natural resistance to histamine, is not a suitable experimental model to investigate the cardiovascular pharmacology of drug-induced histamine release.

Action of histamine on PHA chemiluminescence response of blood mononuclear cells in autoimmune patients.

Peripheral blood mononuclear cells (PBMs) of patients suffering from autoimmune diseases showed significantly lower chemiluminescence response to PHA than the controls. High doses of histamine (10(-5) M) inhibited the chemiluminescence while low doses caused a mild enhancement in all groups of patients. The preformed histamine content of the PBMs was not significantly higher in the patients than in the controls. Individually, a reverse correlation was found between the activity of the disease and the sensitivity of the cells to histamine. In very active cases, virtually no inhibition by histamine was found.

Effect of somatostatin on histamine-stimulated gastric acid and pepsin secretion in dogs.

The purpose of the present study was to evaluate the effect of somatostatin on gastric acid secretion and pepsin secretion in conscious dogs with gastric fistula. Infusion of histamine stimulated dose-dependently the acid secretion, whereas pepsin secretion was decreased by the high doses of histamine. Somatostatin inhibited dose-dependently the stimulated acid secretion but only with a maximum of 40%. The pepsin secretion was inhibited by somatostatin dose-dependently and with a higher potency. The acid inhibition was of a competitive type and prostaglandin-independent.

Exogenous serotonin and histamine-stimulated gastric acid and pepsin secretion in dogs.

The effects of serotonin on histamine-stimulated gastric acid and pepsin secretion were evaluated in conscious dogs with a gastric fistula. Histamine stimulated the acid secretion dose-dependently, whereas pepsin secretion was decreased by the high doses of histamine. The acid secretion was inhibited slightly by serotonin, with a maximum of 42% with a dose of 10 micrograms/kg/min. The pepsin secretion was only decreased non-significantly by serotonin, 10-15 micrograms/kg/min. The acid inhibition was counteracted by beta-adrenergic antagonists (propranolol, atenolol) and methysergide (serotonergic antagonist). The dose-response analysis showed inhibition of a competitive type. In conclusion, serotonin inhibits histamine-stimulated gastric acid secretion via serotonergic receptors and beta-adrenoceptors, whereas pepsin secretion is unaffected.

Effect of acid inhibition on gastric endocrine cells.

There is increasing evidence that the numbers of antral G cells and of fundic argyrophil (ECL) cells are influenced by agents that inhibit gastric acid secretion. Antral G cells increase in states of achlorhydria in man and animals provided atrophic antral gastritis is absent. In rats, treatment with substituted benzimidazoles like omeprazole and BY 308 increase G-cell densities dose-dependently. Even high doses of histamine H-2 antagonists and antacids increase antral G-cell densities. In contrast to G cells, antral D cells decrease in these instances. Fundic ECL cells increase in all experimental conditions of complete achlorhydria provided intact antral mucosa is present, i.e. there is elevated serum gastrin. Antacid treatment is not followed by an increase of fundic ECL cells, which could be explained by the less sustained increase of serum gastrin.

Tissue differences in vascular permeability changes induced by histamine

A new method is described for assessing changes in vascular permeation by albumin in multiple tissues of the same animal in response to intravascular injection of vasoactive agents. Following intravenous injection of 51Cr-RBC , 125I-BSA , and 57Co-EDTA , a test substance (i.e., histamine) is injected intravascularly or subcutaneously. Eight minutes later approximately 2.0 ml of blood is withdrawn and the heart is severed from the great vessels. Samples of tissue are then taken for determination of water content and for the ratio of counts in 125I and 51Cr in each tissue. That ratio is then divided by the corresponding ratio of the same isotopes in the blood. If the resulting quotient is greater than 1, it indicates that the volume of distribution of 125I in the tissues is greater than the ratio of plasma to red cells in large blood vessels and is indicative of permeation of the vasculature by albumin into the extravascular space. With this technique we have demonstrated that following intravenous injection of histamine, albumin permeation of vessels in the cecum is increased much more than for vessels in any other tissue in the body including skin and muscle. Following intravenous injection of 1.5 mg/kg histamine, albumin permeation in the cecum is increased 4-fold while that in skin is unchanged, except at sites where histamine also has been injected subcutaneously where it is increased 1.7-fold by 3 μg and 10-fold by 15 μg of histamine. The magnitude of increases in albumin permeation of the vasculature after intravenous injection of 7.5 mg/kg of histamine was: cecum—5.1 × > pancreas—2.8 × > small intestine—2.7 × > cremaster and stomach—2.0 × > eye and aorta—1.9 × > fat—1.7 × > skin—1.6 × > diaphragm and forelimb—1.5 ×. Even at this high dose of histamine, tissue to blood isotope ratio (tbir)- I Cr values were not increased for heart, brain, kidney, lung, or testis. These findings attest to marked tissue differences in sensitivity to histamine-induced changes in vascular permeation by albumin. The additional finding that histamine-induced tbir- I Cr increases in most tissues far exceed tbir- Co Cr increases indicates that the increase in albumin permeation of vessels is mediated in large part by an increased rate of diffusion (rather than filtration) via an increase in the number and/or size of vascular pores large enough to accommodate albumin.

A possible physiological role of histamine H2-receptors in rat mesenteric circulation

Dose-response curves of histamine were studied on the mesenteric circulation of the anaesthetized rat. The vasodilation produced by small doses of histamine was prevailingly H2-receptor-dependent, as shown by its inhibition by cimetidine but not bypyramine, and by its reproducibiilty by some H2-receptor agonists, but not by specific H1-receptor agonists. The vasodilation produced by high doses of histamine was mainly due to stimulation of H1-receptors, as shown by its 70% inhibition by mepyramine. Mepyramine and cimetidine given simultaneously nearly completely inhibited the vasodilating action of high doses of histamine. Certain H2-receptor agonists, administered at high doses, induced a paradoxical vasocontriction. It is suggested that a small number of H2-receptors is present in rat mesenteric arterioles, and that these receptors may play a physiological role in the control of mesenteric circulation.

'Non-active' pepsin secretion compared with stimulated secretion by bethanechol, histamine, pentagastrin, and 2-deoxy-D-glucose. The role of vagal innervation.

The present studies were performed on a double-pouch dog with one vagally innervated Amdrup pouch (AP) and one denervated Heidenhain pouch (HP), allowing comparison of pepsin secretion from innervated and denervated mucosa at the same time in the same animal. 'Non-active' secretion of pepsin was determined by instillation in the pouches of 0.1 M and 0.005 M HCl, 0.15 M NaCl, and 0.03 M phosphate buffer, and well-known stimulators of gastric secretion such as histamine, pentagastrin, bethanechol, and 2-deoxy-D-glucose (2-DG) were tested as pepsigogues. Cholinergic stimulation by 2-DG and bethanechol (Urecholine) was clearly the most potent stimulus of pepsin secretion. 2-DG elicited secretion only from innervated mucosa, whereas the responses to bethanechol were similar in the two pouches. Histamine and pentagastrin were weak stimulators, but both provoked active and sustained secretion of pepsin when given in small doses. Higher doses of histamine strongly inhibited pepsin output. The effects of histamine were independent of vagal innervation. By contrast, the active stimulation by pentagastrin only took place in innervated mucosa. The highest outputs were seen in the lowest doses, but also very high doses of pentagastrin elicited active pepsin secretion in the AP. Medium doses of pentagastrin brought the secretion down the the 'non-active' level. The chief cells in the denervated mucosa were quite insensible to pentagastrin, and the pepsin output in the HP equalled the non-active' response at all dose levels.

Effects of intravenously infused histamine on canine forelimb transvascular protein efflux following adrenergic receptor blockade.

The intravenous infusion of high doses of histamine (400 micrograms base/min) produced only small increases in weight (approximately equal to +30 g) and lymph total protein concentration (+ 0.9 g/100 ml) in canine forelimbs perfused at constant inflow. The weight gain was associated with profound decreases in aortic pressure (112 to 30 mm Hg) and in forelimb perfusion pressure (105 to 75 mm Hg) and marked increases in forelimb skin small-vein pressure (from 12 to 25 mm Hg). After treatment with phentolamine, the intravenous infusion of these doses of histamine under the same conditions produced marked decreases in forelimb perfusion pressure (120 to 60 mm Hg) and failed to increase forelimb skin small-vein pressure, yet still produced only minimal increases in weight (+ 12 g) and lymph total protein concentration (+ 0.8 g/100 ml). Following treatment with both phentolamine and propranolol, the intravenous infusion of histamine caused very marked increases in forelimb weight (approximately equal to +75 g) and lymph total protein concentration (+ 2.9 g/100 ml). These marked increases in forelimb weight and lymph formation were associated with profound decreases in perfusion pressure (112 to 60 mm Hg) but no change in skin small-vein pressure relative to control. These same increases in weight and lymph total protein concentration were observed after treatment with propranolol alone. Thus, treatment with propranolol markedly increased net fluid filtration and protein efflux during intravenous infusions of massive doses of histamine, idicating that this edemogenic agent causes an endogenous release of catecholamines which tend to antagonize the direct actions of histamine on the microvascular membrane via stimulation of beta-adrenergic receptors.

Histamine Receptors in Normal Human Bronchi

1. Nine normal subjects inhaled increasing concentrations of histamine aerosol from an aerosol generator attached to a breath-actuated dosimeter. The responses were monitored by measuring specific airways-conductance in a body plethysmograph, and the results were expressed as cumulative log dose-response curves. On separate days, histamine challenges were repeated after intravenous injections of sodium chloride solution (placebo), or an H1-receptor antagonist chlorpheniramine, or an H2-receptor antagonist cimetidine, or H1- and H2-receptor antagonists together. The anticholinergic activity of chlorpheniramine was estimated by comparing the effect of chlorpheniramine and atropine on methacholine challenge. 2. In all subjects the response to histamine was reproducible. Analysis of the variance showed that placebo did not alter the histamine dose-response curve significantly. In contrast, chlorpheniramine produced a large shift in the histamine dose-response curve to the right and cimetidine produced a significant shift of this curve to the right only at the highest dose of histamine. A combination of cimetidine and chlorpheniramine produced a shift not significantly different from that seen with chlorpheniramine alone. Chlorpheniramine showed no significant anticholinergic activity in this study. 3. In the normal subjects histamine-induced bronchoconstriction appeared to be mediated predominantly by the H1-receptors. The H2-receptor contributed very little to this bronchoconstriction.

Effects of histamine on chicken airways

This study showed that chicken bronchus is relatively insensitive to histamine. H1 histamine receptors appear to mediate bronchoconstriction to histamine. In the presence of mepyramine, high doses of histamine (10−3 to 5×10−3M) produce weak bronchorelaxation which is susceptible to cimetidine.

The influence of vasoactive substances on blood flow and contractile responses of cat gastrocnemius.

1 The effects of several vasoactive substances have been studied on blood flow and acetylochline-induced contraction of the vascularly isolated gastrocnemius of the cat. All substances, including acetylcholine, were administered intra-arterially to the muscle. Blood flow and contractile tension were monitored simultaneously.2 All substances which increased blood flow, enhanced the contractile responses to acetylcholine; angiotensin, which decreased blood flow, attenuated them.3 Histamine was typical of the vasodilators in doses up to 1 mug (9 nmol), but in a dose tenfold higher it produced only a small and transient increase in blood flow and little or no enhancement of the acetylcholine-induced contractions. These paradoxical effects were brought about by that portion of the high dose of histamine which re-entered the cat's systemic circulation.4 The order of potency of the vasodilators was the same for their potentiating effect on the acetylcholine-induced contractile responses as for their enhancing effect on muscle blood flow: bradykinin >histamine>>papaverine>>NaH(2)PO(4) >KCl. Median effective doses (ED(50)S) determined only for bradykinin, histamine and papaverine were, respectively, 20.5, 49.8, and 3,352 pmol as potentiators, and 13.4, 199.8 and 85,000 pmol as vasodilators.5 In general, the effect of a given vasoactive substance on the contractile response to acetylcholine was dose-dependent and correlated well with its effect on muscle blood flow at the moment the acetylcholine was injected. Two important exceptions were, firstly, that the highest dose of papaverine was only moderately effective as a potentiator even though highly effective as an increaser of muscle blood flow; and, secondly, that histamine produced its greatest potentiating effect 10 s after it was injected, at which time its effect on muscle blood flow was quite small.6 It is suggested that these exceptions and, indeed, the much greater potentiating effectiveness of histamine and bradykinin versus papaverine may be due to the ability of histamine and bradykinin to increase the permeability of the muscle's capillaries as well as increasing blood flow through them, thus facilitating much better than mere vasodilators the access of bloodborne acetylcholine to its receptors on the muscle fibres.

Evidence for a histamine H2 receptor that inhibits pepsin secretion in the dog.

H+ and pepsin output were studied in four gastric fistula dogs with histamine and in five dogs with 4-methylhistamine (4(Me)H), an H2 histamine receptor agonist with little H1 effect. Each amine was given in 45-min incremental step doses to constitute full dose-response curves. Pepsin output was biphasic with both drugs. Peak pepsin output occurred at low doses (less than or equal to 5 microgram/kg-h) and progressive inhibition of output was seen at higher doses, but H+ output was stimulated at all doses. The H2 receptor antagonist, cimetidine, competitively inhibited H+ stimulation. The pepsin response to histamine or 4(Me)H was converted to a positive logsigmoid response when cimetidine was given at the same time. In the presence of cimetidine (1 mg/kg-h), the outputs of H+ and pepsin were positively correlated in the full histamine dose range. These data show that histamine effects on pepsin secretin are a mixture of stimulation and inhibition and that the receptor responsible for pepsin stimulation is of a high affinity, low Km, H2 type, whereas inhibition at high doses of histamine is probably mediated by a low affinity, high Km receptor, also H2 type.

The role of histamine in wound healing I. The effect of high doses of histamine on collagen and glycosoaminoglycan content in wounds.

The effect of high doses of histamine (Hi) on collagen and glycosoaminoglycan (GAG) content in skin wounds of rats was studied on days 1, 3, 5, 10 and 14 after wounding. Injection of high doses of Hi into the wounded area inhibited colagen production, collagen polymerization and GAG synthesis; levels of chondroitin sulphates (chondroitin-4,6-sulphate and dermatan sulphate) and hyaluronic acid were decreased.