In vivo demonstration of H3-histaminergic inhibition of cardiac sympathetic stimulation by R-alpha-methyl-histamine and its prodrug BP 2.94 in the dog.
(1/251)
1. The aim of this study was to investigate whether histamine H3-receptor agonists could inhibit the effects of cardiac sympathetic nerve stimulation in the dog. 2. Catecholamine release by the heart and the associated variation of haemodynamic parameters were measured after electrical stimulation of the right cardiac sympathetic nerves (1-4 Hz, 10 V, 10 ms) in the anaesthetized dog treated with R-alpha-methyl-histamine (R-HA) and its prodrug BP 2.94 (BP). 3. Cardiac sympathetic stimulation induced a noradrenaline release into the coronary sinus along with a tachycardia and an increase in left ventricular pressure and contractility without changes in mean arterial pressure. Intravenous administration of H3-receptor agonists significantly decreased noradrenaline release by the heart (R-HA at 2 micromol kg(-1) h(-1): +77 +/- 25 vs +405 +/- 82; BP 2.94 at 1 mg kg(-1): +12 +/- 11 vs +330 +/- 100 pg ml(-1) in control conditions, P < or = 0.05), and increases in heart rate (R-HA at 2 micromol kg(-1) h(-1): +26 +/- 8 vs +65 +/- 10 and BP 2.94 at 1 mg kg(-1): +30 +/- 8 vs 75 +/- 6 beats min(-1), in control conditions P < or = 0.05), left ventricular pressure, and contractility. Treatment with SC 359 (1 mg kg(-1)) a selective H3-antagonist, reversed the effects of H3-receptor agonists. Treatment with R-HA at 2 micromol kg(-1) h(-1) and BP 2.94 at 1 mg kg(-1) tended to decrease, while that with SC 359 significantly increased basal heart rate (from 111 +/- 3 to 130 +/- 5 beats min(-1), P < or = 0.001). 4. Functional H3-receptors are present on sympathetic nerve endings in the dog heart. Their stimulation by R-alpha-methyl-histamine or BP 2.94 can inhibit noradrenaline release by the heart and its associated haemodynamic effects. (+info)
Exhaled nitric oxide; relationship to clinicophysiological markers of asthma severity.
(2/251)
Bronchial asthma is an airway disorder associated with bronchial hyperresponsiveness, variable airflow obstruction and elevated levels of nitric oxide (NO) in exhaled air. The variables all reflect, in part, the underlying airway inflammation in this disease. To understand their interrelationships we have investigated the relationship between exhaled NO levels and clinicophysiological markers of asthma severity. Twenty-six steroid naive atopic asthmatics participated in the analysis. All were given diary cards and were asked to record their peak expiratory flow (PEF) rates twice daily together with their asthma symptom scores and beta-agonist use. Diary cards were collected 2 weeks later and measurements of exhaled NO levels, FEV1 and histamine bronchial hyperreactivity (PC20 histamine) were undertaken. Exhaled NO levels were significantly higher in our study population than in normal control subjects and correlated negatively with PC20 histamine (r = -0.51; P = 0.008) and positively with PEF diurnal variability (r = 0.58; P = 0.002), but not with symptom scores, beta-agonist use of FEV1 (%). We conclude that a significant relationship exists between exhaled NO levels and the two characteristic features and markers of asthma severity, namely bronchial hyperreactivity and PEF diurnal variability. The lack of correlation between symptom score and beta-agonist use, of FEV1 (%) predicted and exhaled NO suggests that these measures are reflective of differing aspects of asthma. (+info)
Alcohol-histamine interactions.
(3/251)
Alcohol and histamine metabolic pathways in the body have the common enzymes aldehyde dehydrogenase and aldehyde oxidase. The metabolite of ethanol, acetaldehyde, can effectively compete with the metabolites of histamine, methylimidazole acetaldehyde, and imidazole acetaldehyde. At the periphery, alcohol and acetaldehyde liberate histamine from its store in mast cells and depress histamine elimination by inhibiting diamine oxidase, resulting in elevated histamine levels in tissues. Histamine mediates alcohol-induced gastric and intestinal damage and bronchial asthma as well as flushing in Orientals. On the other hand, alcohol provokes food-induced histaminosis and histamine intolerance, which is an epidemiological problem. There are many controversial reports concerning the effect of H2 receptor antagonists on ethanol metabolism and the activity of alcohol dehydrogenase in the stomach. In addition, alcohol affects histamine levels in the brain by modulating histamine synthesis, release, and turnover. Histamine receptor antagonists can affect ethanol metabolism and change the sensitivity of animals to the hypnotic effects of alcohol. In contrast to other neurotransmitters, the involvement of the brain histamine system in the mechanisms of the central actions of alcohol and in the pathogenesis of alcoholism is poorly studied and understood. (+info)
Effects of different subtypes of histamine receptors on proliferation and differentiation of murine colony forming unit granulocyte-macrophage and colony forming unit megakaryocyte.
(4/251)
OBJECTIVE: To investigate the function and characteristics of histamine receptors on the hemopoietic progenitor cells. METHODS: BDF1 mice (both male and female), inbred at our university, aged 8-12 weeks, weighing 20-24 g, were used in this study. Bone marrow cells were incubated for 1 hour at 37 degrees C with 2-AT (H1 receptor agonist) or impromidine (H2 receptor agonist) alone, or in combination with the antagonists pyrilamine or cimetidine respectively. Control experiment was performed in Dulbecco's modified Eagle's Medium (DMEM) alone. Cells treated with different drugs were performed by colony forming unit-granulocyte-macrophage (CFU-GM) and colony forming unit-megakaryocyte (CFU-Meg) assay. RESULTS: When bone marrow cells were treated with 10(-8) mol/L to 10(-5) mol/L of 2-thiazolylethylamine (2-AT) which had no influence on CFU-GM and CFU-Meg proliferation, 10(-8) mol/L to 10(-5) mol/L of impromidine could increase the number of CFU-GM and CFU-Meg colonies. The effects of H2 receptor agonists on CFU-GM, CFU-Meg could be antagonized by H1 receptor agonist. CONCLUSIONS: Our findings suggest the existence of histamine H1 and H2 receptors on the hemopoietic progenitor cells and the antagonism between two different histamine receptor subtypes on the proliferation of CFU-GM and CFU-Meg. (+info)
Nitric oxide synthase inhibition by dimaprit and dimaprit analogues.
(5/251)
1. The similarity in molecular structure between the histamine H2-agonist dimaprit (3-dimethylamino-propyl-isothiourea) and the endogenous nitric oxide synthase (NOS) substrate L-arginine prompted us to study the effect of dimaprit and some dimaprit analogues on NOS activity. Dimaprit and some of its analogues were tested in an in vitro assay which measures the conversion of [3H]-L-arginine to [3H]-L-citrulline. Dimaprit inhibits rat brain NOS (nNOS) concentration dependently with an IC50 of 49+/-14 microM. 2. Removal of one or both of the methyl groups from the non-isothiourea nitrogen of dimaprit improved nNOS inhibitory properties. Aminopropylisothiourea is the most potent compound (IC50 = 4.1+/-0.9 microM) of the series followed by methylaminopropylisothiourea (IC50 = 7.6 +/- microM). 3. The observed effect of aminopropylisothiourea and methylaminopropyl-isothiourea are probably not due to the compounds themselves but to the corresponding mercaptoalkylguanidines, rearrangement products formed in aqueous solutions. This hypothesis is strengthened by the finding that aminobutylisothiourea is not active since a rearrangement to mercaptobutylguanidine does not occur. 4. Remarkably, nitrosylation of the isothiourea group of dimaprit decreases nNOS inhibitory activity, while nitrosylation of the guanidine analogue of dimaprit increases the inhibition of nNOS activity. 5. The pharmacological profile of dimaprit includes inhibition of nNOS. The nNOS inhibitory activity occurs in the same concentration range as the H2-agonist and H3-agonist activity of this compound. (+info)
Differential effect of histamine 3 receptor-active agents on brain, but not peritoneal, mast cell activation.
(6/251)
The activation of presynaptic histamine 3 (H(3)) receptors inhibits the release of histamine and other neurotransmitters from central nervous system neurons. Rat brain mast cells (MCs) release histamine and 5-hydroxytryptamine (5-HT) in response to neuropeptides and neurotransmitters secreted from adjacent neurons. Dura MCs also degranulate in response to antidromic trigeminal nerve stimulation and with acute psychological stress. Such findings have implicated brain MCs in certain neuroinflammatory disorders, such as migraines. We investigated the ultrastructural appearance of control and stimulated thalamic/hypothalamic (brain) MCs before and after treatment with the H(3) receptor agonist N(alpha)-methylhistamine (N(alpha)-mH) and the H(3) receptor antagonist thioperamide (Th). Ultrastructural investigation of brain MCs stimulated with compound 48/80 revealed extensive intragranular changes that paralleled 5-HT secretion but without degranulation by exocytosis typical of connective tissue MCs. N(alpha)-mH significantly reduced these morphological changes, as well as 5-HT release from brain MCs and neurons stimulated with KCl; conversely, Th augmented both histamine and 5-HT release from brain neurons and MCs. Neither N(alpha)-mH nor Th had any effect on peritoneal MCs. Simultaneous addition of both drugs largely antagonized each other's effects on brain MC activation and 5-HT secretion. Ultrastructural observations and lack of lactic dehydrogenase release in the perfusate excluded any cytotoxic effect. The ability of H(3) agonists to inhibit brain MC activation, as well as secretion of 5-HT from both brain MCs and neurons, may be useful in the management of migraines. (+info)
The fate of released histamine: reception, response and termination.
(7/251)
Histamine released from ECL cells elicits responses from a variety of cellular targets in the vicinity. Three sets of receptors are involved (H1, H2 and H3). Receptor occupation is promptly transduced into cellular responses. The responses, in turn, are terminated by diverse mechanisms: enzymatic inactivation, cellular uptake and desensitization at the receptor level. Under specific pathological conditions, histamine effects could be exaggerated by the presence of derivatives that may be of marginal relevance under physiological conditions. (+info)
Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors.
(8/251)
BACKGROUND: Gastrin release by Helicobacter pylori may be an important step in the pathway leading to duodenal ulceration. A histamine H3-receptor agonist was found to release gastrin from antral mucosal fragments; this was interpreted as being due to suppression of somatostatin release. H. pylori is reported to produce Nalpha-methyl histamine (NalphaMH), which is an agonist of H3 as well as other histamine receptors. H. pylori infection also recruits mast cells, which release histamine. AIM: To determine the direct effects of histamine receptor agonists on isolated gastrin cells. METHODS: Rabbit G-cells were prepared by countercurrent elutriation and cultured on 24-well plates. RESULTS: NalphaMH (10-6-10-4 M) caused a dose-dependent increase in gastrin release from a basal level of 2.3 +/- 0.2% total cell content (TCC; mean +/- S.E.M.) to a maximum of 5.1 +/- 0.7%, an increase of 117% (P < 0. 005) above basal. This was abolished by the H2-antagonist ranitidine (10-5 M), but not by immunoblockade with anti-somatostatin antibody, the H1-antagonist chlorpheniramine (10-5 M) or the H3-antagonist thioperamide (10-4 M). The histamine H2-receptor agonist dimaprit (10-6-10-4 M) increased gastrin release from 2.4 +/- 0.2% to 3.6 +/- 0.2% TCC (P < 0.001). Gastrin release was also stimulated by histamine (10-7-10-4 M) from a basal value of 3.0 +/- 0.3% to 5.4 +/- 0.5% TCC (P < 0.001). This also was inhibited by ranitidine (10-5 M) (P < 0.01). CONCLUSION: NalphaMH and histamine release gastrin from G-cells via H2-receptors; this might contribute to H. pylori-associated hypergastrinaemia. (+info)