Histaminase Inhibitor Research Articles

Is the airway epithelium responsible for histamine metabolism in the trachea of guinea pigs?

The aim of the study was to investigate whether or not the epithelium plays an active role in histamine metabolism, via the histaminase and/or methyltransferase pathways. Isolated tracheas from guinea pigs sensitized to egg albumin (EA) were used. The epithelium was either left intact or removed from the preparations. The tracheal tubes were mounted in a chamber, allowing estimation of smooth muscle tension, and perfused with buffer. In some experiments the perfusate was collected for determination of histamine and methylhistamine. Mepyramine was used to evaluate the contribution of histamine to the EA-induced contraction. Mepyramine reduced the contraction by 90% when the epithelium was removed; with intact epithelium the reduction was 47%. Aminoguanidine, a histaminase inhibitor, significantly potentiated the response to EA when the epithelium was left intact. Traces of methylhistamine were detected in tissue extracts and perfusates. We conclude that histaminase is present in the preparation and that it can contribute to the inhibitory effect of the epithelium by means of histamine degradation.

Anaphylactic death: the effect of aminoguanidine and heparin on histamine and stress hormones in guinea pigs.

The modifying effect of aminoguanidine (a histaminase inhibitor) and heparin (a histaminase liberator) on anaphylactic shock in guinea pigs was studied using ovalbumin as an antigen and trigger. The animals died of the shock, the time to death remaining unaltered by the drugs. Serum histamine and cortisol values were high after shock, but were reduced by heparin. Both noradrenaline and adrenaline in plasma were also elevated after shock, the final concentration of the latter being lowered by heparin. The lungs were dilated, indicating bronchoconstriction. The results confirm the role of histamine in anaphylactic shock and its potential value for the diagnosis in this kind of rapid death, in which morphological signs are scarce or lacking. Its diagnostic value still requires confirmation, however, which only autopsy studies can supply. It also appears that pretreatment of the animals with heparin affected the blood cortisol and catecholamines, which are involved in the shock mechanism as countermeasures, although aminoguanidine did not have any effect.

Mechanisms of histamine stimulated secretion in rabbit ileal mucosa.

Histamine is present in high concentrations in the intestine and we investigated the possibility that it might have a role here in intestinal transport. When added to the basal side of rabbit ileal mucosa in vitro histamine (10(-4)M) induced a short-lived increase in electrical potential difference and short circuit current. It inhibited net chloride absorption but did not influence sodium transport. Alkali secretion, measured by a pH stat technique, was inhibited, suggesting that bicarbonate secretion was reduced. Both the electrical and ion flux responses to histamine were blocked by the H1 receptor blocker diphenhydramine, but not by the H2 receptor blocker cimetidine. The presence of specific H1 histamine receptors was further supported by shifts in the dose-response curve to histamine by four different concentrations of diphenhydramine. Calculation of a pA2 value from these "Schild' plots provided a figure of 7.85, which is similar to that for H1 receptors in other tissues. Aminoguanidine, a histaminase blocker, had no electrical effects alone but shifted the histamine dose response curve to the left. These studies indicate that histamine inhibits chloride absorption and alkali secretion, possibly by influencing a chloride/bicarbonate exchange process, through specific mucosal H1 receptors. Enhancement of histamine effects by a histaminase inhibitor suggests that histaminases are present in the intestinal mucosa and supports the possibility of a role for endogenous histamine in influencing ion transport. The observations indicate a mechanism by which absorption might be impaired in diseases in which histamine is liberated locally in the intestine.

Histamine intoxication in a tuberculous patient after ingestion of cheese

A case is reported of a tuberculous patient who developed a reaction compatible with histamine intoxication after ingestion of cheese. It is suggested that the reaction was mediated through isoniazid, which is a histaminase inhibitor.

Influence of pregnancy on the development of various gastric lesions in rats.

The influence of pregnancy, and to some extent lactation, on various gastric lesions in rats were studied. Shay ulceration and gastric lesions induced by cold-restraint stress and ulcerogenic agents, such as acetylsalicylic acid (ASA), reserpine, or epinephrine, in rats were significantly aggravated by pregnancy (day 20 of pregnancy). Gastric hypersecretion, which was observed during pregnancy in pylorus ligation preparation, appears to contribute to the mechanism of aggravation of gastric lesions. ASA induced a marked back-diffusion of acid in pregnant rats which might resulted in the aggravation of ASA-induced gastric lesions. In contrast, histamine-induced gastric lesions were markedly inhibited according according to the progress of pregnancy but after 10 days' lactation returned to the level seen in nonpregnant rats. The histaminase inhibitor aminoguanidine strongly aggravated the histamine-induced gastric lesions in pregnant rats as compared with the non-pregnant ones.

Histaminase activity: A biochemical marker for medullary carcinoma of the thyroid

Histaminase activity in tumor and tissues from seven patients with medullary carcinoma of the thyroid was compared with that from control patients with other diseases. In control patients, tissue histaminase activity was high only in kidney and ileum. In one patient who died of widely disseminated medullary carcinoma, high histaminase activity was found in both solid tumor and tissues which did not have gross tumor. Histologic studies showed that the tissues with high enzyme activity contained microscopic foci of the tumor. In a second patient with widely disseminated medullary thyroid carcinoma, who had received the histaminase inhibitor aminoguanidine five hours before death, low enzyme activity was found in serum, tumor, kidney, ileum and other tissues. This patient had high serum histaminase activity before administration of aminoguanidine. It appeared that the drug had inhibited the enzyme activity in both serum and tissues. Tumors removed from four patients with localized medullary carcinoma of the thyroid had high enzyme activity. Pheochromocytomas from six patients had low histaminase activity and could thus be differentiated from medullary thyroid carcinoma. A pheochromocytoma from one patient, who died of disseminated medullary carcinoma, had high histaminase activity and microscopic foci of medullary carcinoma. Another patient with a tumor of the mediastinum and a pheochromocytoma had high histaminase activity in serum and the mediastinal tumor. This finding raised the possibility that the mediastinal tumor was an unusual primary tumor of the mediastinal parafollicular cells and may be related to medullary thyroid carcinoma. No other tumor examined had high histaminase activity. It was concluded that histaminase activity in surgical and autopsy specimens can serve as a specific biochemical marker for the presence of medullary thyroid carcinoma.

Alleviation of the Leg Abnormality in Zinc-deficient Chicks by Histamine and by Various Anti-arthritic Agents

Two experiments were conducted with zinc-deficient chicks fed a diet based on soybean protein (13 ppm Zn) to assess the effects, on the “arthritis-like” or “perosis-like” leg defect, of feeding a number of commonly used anti-arthritic agents. Prevention of the leg deformity in chicks was compared with that elicited by dietary histamine dihydrochloride (0.2%) and by dietary zinc (88 ppm Zn). Either histamine or zinc essentially prevented the occurrence of leg abnormalities. Of the five antiarthritic agents tested, four were highly effective in preventing the leg disorder. The effective agents and approximate dietary level (in percent) required for protection were: aspirin, 0.5 to 1.0; phenylbutazone, 0.2; cortisone acetate, 0.1; and indomethacin, 0.025. Dietary gold sodium thiosulfate (0.2%), the fifth anti-arthritic agent, had little effect, but it was not tested by intramuscular injection, the way it is usually administered to human patients. Histamine, as well as the anti-arthritic agents, had little or no effect on the symptoms of zinc deficiency other than the leg defect. Three other drugs related to histamine (pyrilamine maleate, an anti-histaminic, 0.2%; β-histine, a vasodilator, 0.3%; and aminoguanidine, a histaminase inhibitor, 0.1%) had no significant effect on the zinc-deficient chick. The possible use of the zinc-deficient chick in the study of arthritis and anti-arthritic agents is discussed.

BIOGENIC AMINES AND FECUNDITY OF TRIBOLIUM CONFUSUM DUVAL (COLEOPTERA).

Aminoguanidine, a histaminase inhibitor, was found to increase fecundity of Tribolium confusum (Coleoptera) when added as a supplement to the basal diet in concentrations of 0.01 and 0.5%. On the other hand alpha-methyl dopa, a decarboxylase inhibitor, had no effect on larval development except at a concentration of 1% where it was shown to be highly toxic. No catechol amines were found in adults of this species, but histamine was always detected and reached higher levels in insects fed higher concentrations of aminoguanidine. These results suggest a possible role for histamine in insect reproduction.

EFFECT OF THYROID HORMONES ON HISTAMINE FORMATION IN THE RAT

Treatment with thyroxine or liothyronine increased the urinary excretion of free histamine in male and female rats under the influence of aminoguanidine, a histaminase inhibitor. There was no evidence for an altered catabolism of histamine in rats treated with liothyronine, since the same percentage of subcutaneously injected [(14)C]-histamine appeared unchanged in the urine. After subcutaneous injection of [(14)C]-L-histidine, rats treated with liothyronine excreted more [(14)C]-histamine than control rats. An increased formation of [(14)C]-histamine from [(14)C]-histidine could also be demonstrated in vitro, in the glandular portion of the stomach, while no increase was found in the skin.

Effect of a histaminase inhibitor (aminoguanidine sulfate) on pregnant and nonpregnant rats

Effect of a histaminase inhibitor (aminoguanidine sulfate) on pregnant and nonpregnant rats

Effect of certain histaminase inhibitors on gastric secretion.

Dogs with Heidenhain pouches were used to study the effect of aminoguanidine (AG) and iproniazid (IPN) (1-isonicotinyl-2-isopropylhydrazine) (‘Marsilid’) on gastric secretion. AG and IPN given subcutaneously or orally were found to stimulate the basal secretion and to augment the gastric secretory response to a meal. In vitro studies have shown that AG is a diamino oxidase (DO) inhibitor and IPN is both a di- and monoamino oxidase (MO) inhibitor. IPN augments gastric secretion by its DO and not its MO inhibitor activity. Doses of IPN which cause evidences of mild toxicity depress gastric secretion. Evidence of the accumulative action of IPN on gastric secretion was obtained. Dogs vary considerably in their sensitivity to iproniazid. Since inflammation increases sensitivity to the gastric augmentory effects of both AG and IPN, and since man is 10 times more sensitive to histamine than the dog, it is suggested that the use of iproniazid in the treatment of active tuberculosis should augment gastric secretion, unless evidences of toxicity occur, and that the drug should be used cautiously in peptic ulcer patients. B1-pyrimidine, a DO inhibitor, given subcutaneously slightly augments the secretory response to a meal in a sensitive dog.

Potentiation by histaminase inhibitors of the effects of histamine on the rectal temperature in the unanaesthetized guinea pig.

Summary. The effects of subcutaneous injections of histamine on the rectal temperature of guinea‐pigs were potentiated by amino‐guanidine and 2‐methyl‐4‐amino‐5‐methylaminopyrimidine, two histaminase inhibitors. The histaminase inhibitors did not increase the response of the rectal temperature to two “histamine analogues”, which have pharmacological effects resembling those of histamine. The “histamine analogues” used are resistant to histaminase in vitro. I am grateful to dr. H. O. Schild for advice on the statistical treatment of the data. The technical assistance given by Miss M.‐B. Johansson was highly appreciated.This investigation was aided by a grant from the Medical Faculty, University of Lund.

Potentiation of histamine effects by histaminase inhibitors in the unanaesthetized guinea-pig.

SUMMARY Histamine was given subcutaneously to unanaesthetized guinea pigs and its effects on the respiration were studied by counting the respiratory frequency and observing the external respiratory movements. The respiratory symptoms caused by histamine were potentiated by some histaminase in hibitors in doses, which did not increase the responses to β‐2‐pyridylethylamine, acetylcholine or carbaminoylcholine. The specificity of the potentiation and the parallelism found between potentiating effects and histaminase inhibiting properties of the different histaminase inhibitors suggest that the increase in histamine sensitivity was due to diminished histaminase activity. The maximum increase in sensitivity obtained by these inhibitors was about two‐fold. The skilful technical assistance given by miss M.‐B. Johansson was highly appreciated.

Effects of Histaminase Inhibitors on the Blood Pressure Responses in Dogs to Histamine Injected into the Renal Artery.

Summary.1. The effects on the dog's blood pressure of histamine injected by vein or into the femoral or renal artery have been studied.2. The effects of two histamine analogues, which were not oxidized by histaminase in vitro were also studied under the same conditions.3. As judged from the relative effectiveness of histamine injected by these routes the kidney had a considerable capacity to remove injected histamine from the circulating blood.4. Histaminase‐resistant histamine analogues were not removed as effectively as histamine by the kidney.5. Histaminase inhibitors, such as aminoguanidine, B1‐pyrimidine and isonicotinylhydrazine potentiated the depressor responses to histamine given into the renal artery but not those to histamine given into the femoral artery or by vein.6. The depressor responses to the histaminase‐resistant histamine analogues were not potentiated by the inhibitors.

Observations on the action of histamine and related substances on the bronchial resistance in the guinea-pig.

Summary. The action of 2‐β‐aminoethyl pyridine, 3‐β‐amiuoethyl‐1, 2, 4–triazole and 1‐methyl–4‐β‐aminoethyl imidazole on the bronchial resistance was studied in anaesthetized guinea‐pigs. The substances examined acted like histamine and their actions were antagonized by mepyramine in the same degree as was that of histamin. Two histaminase inhibitors, aminoguanidine and IV pyrimidine, did not potentiate the actions of histamine.

Potentiation by histaminase inhibitors of the blood pressure responses to histamine in cats.

Summary.1. The effects on the cat's arterial blood pressure of histamine, β‐(2‐pyridyl)‐ethylamine and acetylcholine injected into the femoral vein, femoral artery and renal artery have been studied.2. As judged by the relative effectiveness of these injections the cat's kidney has a considerable capacity to remove injected histamine from the circulating blood.3. After the administration of histaminase inhibitors the depressor response to histamine injected into the renal artery was potentiated.4. Evidence is presented that this potentiation is due to the inhibition of the histaminase in the kidney.5. The maximum potentiation obtained in these experiments would correspond to an approximate reduction by 60 per cent of the kidney's capacity to remove injected histamine from the blood.6. No potentiation of the effect of histamine injected into the femoral artery or vein was observed.Valuable technical assistance was given by miss 81.‐B. Johansson. The investigation was supported by grants from the Medical Faculty, Lund.

Effect of histaminase inhibitors on gastric secretion.

1-Isonicotinyl-2-isopropylhydrazine, ‘Marsilid,’ and isonicotinylhydrazine, ‘Rimifon,’ stimulate gastric secretion in a Heidenhain and Ivy transplanted pouch dog when given intravenously during the fasting basal state. The secretory threshold for these compounds, especially ‘Rimifon,’ is close to a toxic dose. Aminoguanidine given intravenously stimulates gastric secretion in the anesthetized dog and cat in doses which do not reduce blood pressure and do not give rise to evidences of toxicity. In the Heidenhain and Ivy transplanted pouch dog an intravenous threshold dose of aminoguanidine, an inhibitor of histaminase or histamine metabolizing enzyme I, decidedly augments the gastric secretory response to a small test-meal, even when the test-meal contains little or no histamine. Assuming on the basis of evidence published by Schayer and his colleagues (13–16) that aminoguanidine does not act directly on the parietal cell, it is concluded that histamine (or a substance inactivated by diamine oxidase) acts directly and physiologically to stimulate gastric secretion either by being released into the blood stream or by being released in the region of the parietal cell by a nonhistamine gastrin.

Potentiation of pharmacological effects of histamine by histaminase inhibitors.

The Journal of PhysiologyVolume 123, Issue 1 p. 32-54 ArticleFree Access Potentiation of pharmacological effects of histamine by histaminase inhibitors O. Arunlakshana, O. ArunlakshanaSearch for more papers by this authorJ. L. Mongar, J. L. MongarSearch for more papers by this authorH. O. Schild, H. O. SchildSearch for more papers by this author O. Arunlakshana, O. ArunlakshanaSearch for more papers by this authorJ. L. Mongar, J. L. MongarSearch for more papers by this authorH. O. Schild, H. O. SchildSearch for more papers by this author First published: 28 January 1954 https://doi.org/10.1113/jphysiol.1954.sp005032Citations: 64AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume123, Issue1January 28, 1954Pages 32-54 RelatedInformation