Effect of urogastrone on gastric secretion and plasma gastrin levels in normal subjects.
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Purified human urogastrone was given by intravenous infusion to 12 normal volunteer subjects and measurements made of gastric acid, pepsin and intrinsic factor secretion, and of plasma gastrin concentration. Clinical, haematological, and biochemical screening tests were made throughout the period of study. Urogastrone inhibited acid and intrinsic factor secretion whether stimulated by pentagastrin, histamine, or insulin, but had a much less marked effect on gastric pepsin output. Plasma gastrin levels did not alter significantly. Limited dose-response studies showed that 0-25 mug urogastrone kg--1 hr--1 resulted in inhibition of acid output of 80% and was not associated with clinical side-effects. No significant alteration in any of the haematological or biochemical measurements was observed in any of the subjects. (+info)
Dehydration-induced vasopressin secretion in humans: involvement of the histaminergic system.
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In rats, the hypothalamic neurotransmitter histamine participates in regulation of vasopressin secretion and seems to be of physiological importance, because blockade of the histaminergic system reduces dehydration-induced vasopressin secretion. We investigated whether histamine is also involved in regulation of vasopressin secretion during dehydration in humans. We found that 40 h of dehydration gradually increased plasma osmolality by 10 mosmol/kg and induced a fourfold increase in vasopressin levels. Pretreatment with the H(2)-receptor antagonists cimetidine or ranitidine significantly reduced the dehydration-induced increase in vasopressin levels approximately 40% after 34 and 37 h of dehydration, whereas this was not the case with the H(1)-receptor antagonist mepyramine. Dehydration reduced aldosterone secretion by approximately 50%. This effect of dehydration was reduced by both H(1)- and H(2)-receptor blockade after 16 and/or 34 h of dehydration. We conclude that vasopressin secretion in response to dehydration in humans is under the regulatory influence of histamine and that the effect seems to be mediated via H(2)-receptors. In addition, the regulation of aldosterone secretion during dehydration also seems to involve the histaminergic system via H(1) and H(2) receptors. (+info)
Mediator involvement in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitized Brown Norway rats.
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1. To determine which mediators are involved in antigen-induced bronchospasm and microvascular leakage in the airways of ovalbumin sensitised Brown Norway rats we investigated the effect of a histamine H(1) receptor antagonist, mepyramine, a 5-HT receptor antagonist, methysergide, and a cys-leukotriene-1 receptor antagonist, montelukast. 2. Ovalbumin at 1 mg kg(-1) i.v. caused a significant increase in microvascular leakage in the airways and at 3 mg kg(-1) i.v. caused a significant increase in airways resistance. 3. Histamine (1 mg kg(-1) i.v.), 5-HT (0.1 mg kg(-1) i.v.) and leukotriene D(4) (LTD(4), 50 microg kg(-1) i.v.) caused a significant increase in microvascular leakage in the airways. 4. Mepyramine (1 mg kg(-1) i.v.), methysergide (0.1 mg kg(-1) i.v.), or montelukast (30 mg kg(-1) i.v.) inhibited histamine, 5-HT or LTD(4) -induced microvascular leakage respectively. 5. Methysergide (0.1 mg kg(-1) i.v.) reduced ovalbumin-induced microvascular leakage in the trachea and at 0.3 mg kg(-1) i.v. inhibited bronchospasm (38 and 58%, respectively). Montelukast (30 mg kg(-1) p.o.) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (78%) and inhibited ovalbumin-induced bronchospasm (50%). Mepyramine (3 mg kg(-1) i.v.) had no effect on ovalbumin-induced leakage or bronchospasm. 6. A combination of all three compounds (mepyramine, methysergide and montelukast) reduced ovalbumin-induced microvascular leakage in airway tissue to basal levels (70 - 78%) and almost completely inhibited bronchospasm (92%). 7. Antigen-induced bronchospasm appears to equally involve the activation of 5-HT and cys-leukotriene-1 receptors whereas ovalbumin-induced microvascular leakage appears to be predominantly mediated by cys-leukotriene-1 receptors. (+info)
Role of mast cells in zymosan-induced peritoneal inflammation in Balb/c and mast cell-deficient WBB6F1 mice.
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Zymosan-induced peritonitis was investigated in mast cell-deficient WBB6F1 mice and in Balb/c mice pretreated with mast cell stabilizer (cromolyn) or antagonists of histamine receptors (mepyramine, triprolidine, cimetidine, or ranitidine). The inherited mast cell deficiency in W/Wv knockouts of WBB6F1 mice impaired significantly the level of histamine and plasma exudation (measured 30 min after stimulation) as well as the influx of exudatory leukocytes, accumulation of plasma and exudate chemoattractants, and the release of proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6) measured at 6 h of inflammation. All of those factors were fully restored after selective intraperitoneal reconstitution of W/Wv mice with bone marrow-derived mast cells from their control +/+ counterparts. Cromolyn pretreatment of Balb/c mice reduced exclusively the early plasma exudation and histamine influx. Blocking of histamine receptors inhibited not only the early plasma exudation but also temporarily diminished primary leukocyte influx and levels of MCP-1 and IL-1beta. In conclusion, mast cells play an important role in the initiation of zymosan-induced peritonitis and modulate its further course. (+info)
Cyclo-oxygenase and lipoxygenase pathways in mast cell dependent-neurogenic inflammation induced by electrical stimulation of the rat saphenous nerve.
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1. We investigated the role of arachidonic acid metabolism and assessed the participation of mast cells and leukocytes in neurogenic inflammation in rat paw skin. We compared the effect of lipoxygenase (LOX) and cyclo-oxygenase (COX) inhibitors on oedema induced by saphenous nerve stimulation, substance P (SP), and compound 48/80. 2. Intravenous (i.v.) pre-treatment with a dual COX/LOX inhibitor (RWJ 63556), a dual LOX inhibitor/cysteinyl-leukotriene (CysLt) receptor antagonist (Rev 5901), a LOX inhibitor (AA 861), a five-lipoxygenase activating factor (FLAP) inhibitor (MK 886), or a glutathione S-transferase inhibitor (ethacrynic acid) significantly inhibited (40 to 60%) the development of neurogenic oedema, but did not affect cutaneous blood flow. Intradermal (i.d.) injection of LOX inhibitors reduced SP-induced oedema (up to 50% for RWJ 63556 and MK 886), whereas ethacrynic acid had a potentiating effect. 3. Indomethacin and rofecoxib, a highly selective COX-2 inhibitor, did not affect neurogenic and SP-induced oedema. Surprisingly, the structurally related COX-2 inhibitors, NS 398 and nimesulide, significantly reduced both neurogenic and SP-induced oedema (70% and 42% for neurogenic oedema, respectively; 49% and 46% for SP-induced oedema, respectively). 4. COX-2 mRNA was undetectable in saphenous nerves and paw skin biopsy samples, before and after saphenous nerve stimulation. 5. A mast cell stabilizer, cromolyn, and a H(1) receptor antagonist, mepyramine, significantly inhibited neurogenic (51% and 43%, respectively) and SP-induced oedema (67% and 63%, respectively). 6. The co-injection of LOX inhibitors and compound 48/80 did not alter the effects of compound 48/80. Conversely, ethacrynic acid had a significant potentiating effect. The pharmacological profile of the effect of COX inhibitors on compound 48/80-induced oedema was similar to that of neurogenic and SP-induced oedema. 7. The polysaccharide, fucoidan (an inhibitor of leukocyte rolling) did not affect neurogenic or SP-induced oedema. 8. Thus, (i) SP-induced leukotriene synthesis is involved in the development of neurogenic oedema in rat paw skin; (ii) this leukotriene-mediated plasma extravasation might be independent of mast cell activation and/or of the adhesion of leukocytes to the endothelium; (iii) COX did not appear to play a significant role in this process. (+info)
Sensitivity of neonatal rabbit ileum to histamine.
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Segments of ileum from newborn rabbits contracted in response to histamine but sensitivity declined from age 11 days. Intestine from adult animals barely contracted to histamine, even in a concentration of 3 times 10- minus 3 M. Such variation with age was not observed with acetylcholine. The response to histamine was effected by mepyramine-sensitive receptors which appeared to decrease in number as the animals aged. (+info)
Comparison of cedar pollen-induced allergic rhinitis in passively and actively sensitized guinea pigs.
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We have developed an allergic rhinitis model in guinea pigs using Japanese cedar pollen as antigen. In the present study, we examined whether provocation by pollen induces similar magnitudes of rhinitis symptoms in passively and actively sensitized guinea pigs. One group of animals was actively sensitized by intranasal application of pollen extract, and another was passively sensitized by intraperitoneal injection with anti-pollen serum. Actively and passively sensitized groups were then challenged by repeated and a single pollen inhalation, respectively. In both groups, sneeze was induced immediately after the challenge. The actively sensitized animals developed not only early but also late nasal blockage, whereas the passively sensitized animals showed only early nasal blockage. In both groups, an H1 antagonist, mepyramine, inhibited the occurrence of sneezing but did not inhibit nasal blockage. Nasal hyperresponsiveness to intranasal instillation of leukotriene D4 was obvious only in the actively sensitized animals. We thus conclude that although early nasal blockage is induced by a single antigen-antibody reaction, repetitive anaphylactic reaction is required for occurrence of late nasal blockage and hyperresponsiveness to stimuli. Furthermore, histamine plays a central role in induction of sneezing but not in nasal blockage, irrespective of whether animals are actively or passively sensitized. (+info)
VUF-K-8788, a periphery-selective histamine H1 antagonist with anti-pruritic activities.
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The pharmacological properties of 7-[3-[4-(2-quinolinylmethyl)-1-piperazinyl]-propoxy]-2,3-dihydro-4H-1,4-benzothia zin-3-one (VUF-K-8788) were investigated in vitro and in vivo. VUF-K-8788 inhibited [3H]-mepyramine from binding to the cell membrane of lung parenchyma (Ki value: 5.0 nM) and the histamine-induced contraction of isolated guinea pig ileum (pA2: 9.71) without affecting ileal contractions induced by acetylcholine, serotonin, KCl and BaCl2. The increase of vascular permeabilities induced by histamine and passive cutaneous anaphylaxis (PCA) in guinea pigs were inhibited by VUF-K-8788 in a dose-dependent fashion (ED50: 0.24 and 0.26 mg/kg, p.o., respectively). Moreover, the anti-histaminic effect of VUF-K-8788 was also observed in rats. In experiments on the effects on the central nervous system, VUF-K-8788 at 1 mg/kg, p.o. hardly antagonized the H1 receptor at all in the cerebral cortex of guinea pigs. VUF-K-8788 inhibited the PCA-induced scratching behavior completely without affecting thiopental-induced sleep in mice. These results suggested that VUF-K-8788 would be useful in the treatment of allergic disorders such as atopic dermatitis and eczema. (+info)