Histamine Dose-response Curve Research Articles

A dual action of histamine on isolated human pulmonary arteries.

Isometric tension changes in 22 isolated segmental human pulmonary arteries obtained from 17 patients at thoracic surgery were studied after histamine challenge. Cumulative dose-response contraction curves were constructed. A slight potentiation could be found with the H2 antagonist cimetidine, whereas the H1 blocker mepyramine moved the log dose-response curve for histamine to the right indicating competitive antagonism at specific receptors. When mepyramine was added after maximal contraction with histamine, a relaxation occurred that could be blocked by adding cimetidine prior to mepyramine. The in vitro tests reveal a dual action of histamine with a dominating H1 receptor mediated contraction, but with the possibility of relaxation via specific H2 receptors in human pulmonary arteries.

ICI 125,211: A new gastric antisecretory agent acting on histamine H 2-receptors

In vitro , ICI 125,211 competitively antagonized the action of dimaprit on guinea pig atrium with an apparent dissociation constant of 1.5 × 10 −8M (pA 2 = 7.8). In vivo , the histamine dose-response curve in conscious gastric fistula beagles was shifted rightward in parallel without change in the maximal response by intravenous infusions of ICI 125,211 at doses of 0.01 and 0.03 umol/kg/hr (estimated pA 2 = 7.3). Our data show that this new drug is at least 10x more potent than cimetidine as an inhibitor of gastric secretion in the dog. ICI 125,211, which is an orally effective antisecretory agent in man and devoid of antiandrogenic activity, is the most potent selective H 2-blocker described to date.

Cooperative interactions of histamine and competitive antagonism by cimetidine at neuronal histamine receptors in the marine mollusc, Aplysia californica

Dose-response curves and Hill plots were used to analyze the interaction between histamine (HA), two HA agonists and an HA antagonist, and the HA receptors mediating membrane hyperpolarizations in Aplysia neurons. Dose-response curves for both HA and the HA agonists (2-methylhistamine and 4-methylhistamine) were sigmoidal and the corresponding Hill plots had slopes greater than one (mean = 2). This result is interpreted as evidence for a cooperative type of interaction between HA and HA agonists and the neuronal HA receptors. Cimetidine (10 −6 to 4 × 10 −6 M), an HA antagonist, produced reversible, dose-dependent, parallel shifts in the HA dose-response curves. Modified Schild plots constructed from this data were linear. These results demonstrate that cimetidine is a competitive antagonist at the neuronal HA receptors. The slope of the modified Schild plots, which gives an estimate of the minimum number of antagonist molecules that interact with each receptor, was greater than one (mean = 1.7). This result is interpreted as evidence for a cooperative type of interaction between cimetidine and the neuronal HA receptors.

Does the gastric mucosa contain inhibitory histamine H1-receptors? [proceedings

From the results it is concluded that in contrast to data reported in the literature, in cats histamine, dimaprit and tolazoline produce an identical acid response and differ only in their affinity to the histamine H2-receptor. The effects of mepyramine and phenoxybenzamine do not indicate the presence of H1-receptors, which is confirmed by missing inhibitory effects of PEA. The effects of the former two, however, suggest that reversal of the histamine dose-response curve is caused by histamine-released catecholamines which are prevented from being released by mepyramine and blocked in their peripheral action by phenoxybenzamine.

Bronchial hyperreactivity to histamine and methacholine in asthmatic children after inhalation of SCH 1000 and chlorpheniramine maleate

Nine asthmatic patients with a mean age of 14 yr received bronchial challenges with histamine and methacholine. The challenges were repeated after inhalation of 80 μg of SCH 1000 (ipratropium bromide) and 5 mg of chlorpheniramine maleate. The provocation doses which produced a 20% fall in forced expiratory volume in 1 sec (FEV 1 ) and the slopes of the dose-response curves were analyzed. SCH 1000 prevented methacholine-induced bronchoconstriction and chlorpheniramine prevented methacholine-induced bronchoconstriction. There was no significant change in the dose-response curve of histamine after SCH 1000 or in the dose-response curve of methacholine after chlorpheniramine. The findings indicate that the mechanisms and receptor sites involved in bronchial provocation by histamine and methacholine are distinctly different. The histamine response is unlikely to be vagally mediated because histamine-induced bronchoconstriction was not prevented by SCH 1000. Both SCH 1000 and chlorpheniramine caused significant bronchodilatation, suggesting the presence of both histamine-and vagal-dependent bronchomotor tone.

Histamine Release Due to Bivalent Penicilloyl Haptens Control by the Number of Cross-Linked IgE Antibodies on the Basophil Plasma Membrane

Abstract We describe the characteristics of in vitro histamine release from human basophils passively sensitized with serum from a penicillin-allergic individual. The histamine release is induced by a synthetic bivalent hapten, bis benzylpenicilloyl 1,6 diaminohexane (BPO)2. We present data on the effect of a monovalent hapten, benzylpenicilloyl formyl-l-lysine (BPO)1, on the histamine release. We also examine how histamine release depends on the concentration of serum used for passive sensitization, the source of cells used for passive sensitization, and the time allowed for histamine release. We interpret these experiments in terms of a theory of equilibrium binding of bivalent haptens to cell surface antibody that is presented in the previous paper. The results are consistent with the idea that the amount of histamine release is controlled by the number of cross-linked IgE molecules on the cell surface. In particular, the histamine dose-response curve rises because cross-links rise, has a maximum because the cross-links are a maximum, and falls because the cross-links fall.

The effects of stimulants and inhibitors of histamine receptors on acid secretion from guinea pig gastric fundus

Two selective H 2 receptor stimulants (5-methyl-N-methylhistamine and dimaprit) so far never tested in isolated gastric preparations, were found to be strong stimulants of acid secretion from the guinea pig isolated gastric fundus. Although some differences were observed in the cumulative dose-response curves for these two agonists, the peak responses obtained were not significantly different from the maximum response to histamine. Cimetidine produced parallel displacement of the dose-response curves to the right with the maximum response unchanged, suggesting competitive antagonism on H 2 receptors. The dose-response curve for histamine was not affected by the simultaneous administration of an H 1 receptor agonist, 2(2-aminoethyl)thiazole, or of an H 1 receptor antagonist, pyrilamine. This indicates that the action of histamine on the isolated guinea pig gastric fundus is associated exclusively with H 2 receptor stimulation.

Histamine receptors in mesenteric circulation of the cat and rat.

This study was designed to ascertain the types and functions of histamine receptors in the mesenteric circulation of the cat and rat. Superior mesenteric artery (SMA) flow was measured via an electromagnetic probe in the cat and intestinal submucosal arteriolar diameter by an image-splitting in vivo microscopy technique in the cat and rat. Histamine infusion into the SMA caused dose-dependent decreases in mesenteric vascular resistance. Mepyramine, an H1 receptor antagonist (H1A), inhibited this effect, displacing the histamine dose-response curve to the right. Metiamide, an H2 receptor antagonist (H2A), alone had no effect, but in the presence of H1A caused further displacement of the curve to the right. In both the cat and the rat, histamine superfusion dilated the submucosal arterioles. H1A attenuated this effect. H2A alone had no effect, but in the presence of H1A there was nearly complete inhibition of the histamine effect. In conclusion, both H1 and H2 histamine receptors, both subserving vasodilatation, are present in the mesenteric circulation and the H1 receptor effect predominates.

Histamine receptors in the coronary circulation of the dog. Effects of mepyramine and metiamide on responses to histamine infusions.

The effect of histamine on coronary blood flow (CBF) was studied in anaesthetized grayhounds. CBF and systemic blood pressure were measured using electromagnetic flow transducers and catheters in the aorta during infusions of drugs into the left circumflex coronary artery. Histamine infusions (5, 10, and 20 microng/min) produced dose-related increases in CBF without changing heart rate or blood pressure. Metiamide (100 microng/min) given simultaneously produced a parallel displacement of the histamine dose-response curve to the right (P less than 0.05) with a dose ratio of 2. Mepyramine (100 microng/min) produced a larger parallel displacement of the dose-response curve (dose ratio = 4). Together, metiamide and mepyramine greatly reduced the histamine response (dose ratio = 16), showing that the metiamide blockade is augmented in the presence of mepyramine. Similarly, mepyramine blockade is augmented in the presence of metiamide. The increase in CBF produced by histamine infusion (20 microng/min) was similar to the peak flow response of reactive hyperemia following 8-second occlusions. However, mepyramine and metiamide together had no effect on the peak flow response, duration, or total repayment of flow debt in reactive hyperemia. These results show that histamine-induced coronary vasodilation is mediated by both H1 and H2 receptors. However, the vasodilation of reactive hyperemia after brief coronary artery occlusions does not appear to involve histamine.

Involvement of hypothalamic histamine-receptors in the central cardiovascular actions of histamine

Bilateral stereotaxic injections of histamine (0.01–10 μg) into the posterior hypothalamus of urethane-anaesthetised rats, elicited dose-related rises in blood pressure and heart rate. Pretreatments with mepyramine (25 and 50 μg) into the posterior hypothalamus, effected progressive parallel shifts of the histamine dose-response curve to the right, suggesting competitive histamine H 1-receptor antagonism. Pretreatments with either phentolamine (50 μg) or atropine (50 μg) did not significantly modify either of the histamine-induced responses. Histamine (1.0 μg) injected into the anterior hypothalamus also induced rises in blood pressure and heart rate, but when injected into the ventromedial hypothalamus, lateral hypothalamus or preoptic area failed to evoke any changes in blood pressure or heart rate. Local injections of 2-methyl histamine and 4-methyl histamine (1 and 10 μg) into the posterior hypothalamus elicited rises in blood pressure and heart rate, but these analogues were less potent than histamine. 5-Hydroxytryptamine, noradrenaline, adrenaline, isoprenaline and carbachol. all at a dose of 1.0 μg, elicited mixed cardiovascular responses when injected into the posterior hypothalamus. The results suggest that histamine H 1-receptor stimulation in selective areas of the hypothalamus of rats, elicits short-lasting rises in blood pressure and heart rate.

Somatostatin mode of action on gastric acid secretion in dogs.

The aim of the present study was to investigate the mode of the inhibitory effect of somatostatin on gastric acid secretion. This was done in Heidenhain-pouch dogs studying the effect of somatostatin on cumulative dose response curves of pentagastrin, carbachol and histamine. Somatostatin inhibited gastric secretion after all three stimuli, with decreasing potency against carbachol, pentagastrin and histamine. The pentagastrin-stimulated acid secretion was inhibited in a noncompetitive way; in contrary to this the carbachol and also the histamine-stimulated secretion was inhibited in a competitive way.

Analysis of the actions of cimetidine and metiamide on gastric acid secretion in the isolated guinea pig gastric mucosa.

Cumulative dose-response curves for histamine were determined on acid secretion from the isolated guinea pig gastric mucosa. Two H2-receptor antagonists-metiamide and cimetidine-behaved like competitive antagonists to histamine on gastric acid secretion in vitro. The isolated guinea pig gastric mucosa seems to be a suitable in vitro model for analysing the action of compounds on receptors involved in acid secretion.

A quantitative study of metiamide, a histamine H2-antagonist, on the isolated whole rat stomach.

1. An isolated whole stomach preparation from immature rats is described. The lumen of the stomach was perfused and the hydrogen ion activity of the perfusate recorded continuously. 2. The mean basal acid secretion before stimulation was 4-19 +/- 0-31 X 10 (-8) mol min-1. Metiamide did not significantly reduce this spontaneous secretion. 3. The preparation gave dose-dependent responses to histomine (10(-5)-10(-4)M) which were readily reversed on washing. 4. The effect of metiamide on histamine-stimulated acid secretion was investigated. Metamide, at doses of 3 X 10(-6)M, and 3 X 10(-5)M, caused a parallel displacement of the histamine dose-response curve, indicating competitive antagonism. These dose-response curves were used to calculate dose ratios (DR) for metiamide. 5. A plot of log10 (DR - 1) against log 10 [antagonist] gave a pA2 value for metiamide of 5-91.

Effect of histamine on lung cyclic AMP levels in normal and pertussis-vaccinated mice

The effect of histamine on lung cAMP metabolism in normal and Bordetella pertussis-vaccinated mice was investigated. Histamine was shown to elevate lung cAMP in both types of animals in a dose-dependent manner. Pertussis-vaccinated mice, however, showed a marked shift to the left in the histamine dose-response curve. The ED 50 for normal and pertussis-vaccinated mice was 8·0 and 0·25 mg/kg respectively. The histamine-induced rise in cAMP was maximum 1 min after injection and diminished thereafter. The effect of histamine on pulmonary cAMP may be mediated indirectly, as it occurred in vivo but not in vitro.

Antigen-induced eosinophil chemotactic factor (ECF) release by human leukocytes

A complement-independent eosinophil chemotactic factor (ECF) is described which is released from peripheral leukocytes of allergic and normal human volunteers after antigen stimulation and after exposure to anti-IgE. Dose response and time-release curves for ECF and histamine run closely parallel in this system. Histamine by itself is shown to have no effect on chemotaxis at the concentrations present in antigen-induced release, but is inhibitory at very high concentrations. Evidence suggests that the ECF released from human leukocytes is derived from basophils and is similar, or identical, to the ECF released from mast cells.

Histamine receptors in peripheral vascular beds in the cat.

1. The vasodilator activity of histamine has been studied in anaesthetized cats. 2. Histamine causes dose-dependent vasodilatation in the vasculature of the hind-limb and mesentery, perfused with blood at constant flow. 3. Experiments using the selective antagonists mepyramine and metiamide indicate the involvement of both H1- and H2-receptors in the vasodilator responses to histamine. Mepyramine (2.5 X 10(-6) mol/kg), causes displacement of the histamine dose-response curve. This displacement is maximum with a dose-ratio of about 10. Further dose-dependent displacement of the dose-response curve occurred after metiamide (4 X 10(-7) mol kg-1 min-1 and 2 X 10(-6) mol kg-1 min-1), although these doses of metiamide had no effect on histamine responses in the absence of mepyramine. 4. Vasodilator responses could also be elicited by the selective H1-receptor agonists, 2-methylhistamine, 2-(2-aminoethyl)pyridine and 2-(2-aminoethyl)thiazole and the selective H2-receptor agonist, 4-methylhistamine. 5. The selectivity of mepyramine and metiamide as histamine receptor antagonists was confirmed by their failure to reduce the vasodilator responses to acetylcholine, isoprenaline and bradykinin.

An analysis of the depressor responses to histamine in the cat and dog: involvement of both H1- and H2-receptors.

1 The depressor responses to histamine, in anaesthetized cats and dogs, have been shown to involve both histamine H1- and H2-receptors. 2 In both species, histamine caused dose-dependent falls in blood pressure. The dose-response curve could be displaced to the right by administration of mepyramine 2.5 times 10(-6) mol/kg i.v. The displacement was maximal with a dose-ratio of less than ten. 3 Metiamide alone, up to 2 times 10(-6) mol kg-1 min-1, had no significant effect on the histamine dose-response curve. 4 When administered in the presence of mepyramine, metiamide, 4 times 10(-7) and 2 times 10(-6) mol kg-1 min-1, caused dose-dependent displacements to the right, of the histamine dose-response curve greater than could be achieved with mepyramine alone. 5 The results indicate the presence of both histamine H1- and H2-receptors in the cardiovascular system of the cat and dog. Both receptors produce a common response, i.e. a fall in blood pressure.

Dose-response curves for acid output to histamine and pentagastrin determined by two techniques.

Dose-response (DR) curves for acid output to histamine and pentagastrin were determined by two techniques in conscious cats with gastric fistulas With the continuous DR technique, the dose of the stimulant was doubled each hour; with the single DR technique, only one dose of the stimulant was infused on each test day. The DR curves for histamine did not differ with the two techniques; for pentagastrin, the acid responses were higher with the single DR than with the continuous DR technique. For both histamine and pentagastrin, the dose for half the maximal response did not differ with the two techniques. The DR curves were also analysed by application of the Michaelis-Menten equation.