Mechanism of the indirect adrenergic effect of histamine in cat cerebral arteries

KCl (50 mM), tyramine (10(-7) M), and histamine (10(-4) M) induced an increase in tritium release from cat cerebral arteries preincubated with [3H]noradrenaline, this increase being due in part to noradrenaline. When calcium was absent from the superfusion medium, only tyramine (10(-7) M) enhanced the tritium outflow. Colchicine (10(-3) M) partially inhibited the increase in radioactivity brought about by 10(-4) M histamine. KCl (50 mM) also evoked release of radioactivity from cerebral arteries preloaded with [3H]histamine; this release was unaffected by reserpine pretreatment or removal of both superior cervical sympathetic ganglia. Neither tyramine (10(-7) M) nor compound 48/80 (300 micrograms ml-1) altered the spontaneous tritium outflow from cerebral blood vessels preincubated with [3H]histamine. These results suggest that histamine is not accumulated by sympathetic nerve endings and elicits its noradrenaline-releasing effect by means of an exocytotic process.     

Indirect adrenergic effect of histamine in human cerebral arteries: influence of post-mortem period

Histamine (10(-4) M) increased the radioactivity released from human cerebral arteries obtained within 6 h of death and preincubated with [3H]noradrenaline. In the presence of 10(-6) M cocaine or if 7 or more hours had elapsed since death, 10(-4) M histamine was unable to change basal levels of tritium outflow. The radioactivity retained by the tissue was higher when cerebral blood vessels were obtained within a post-mortem period of 6 h. These results suggest that histamine may release noradrenaline from the sympathetic innervation of human cerebral arteries and that the function of this innervation lasts only 6 h after death.     

Differential effects of Ca antagonists on the noradrenaline release and contraction evoked by nerve stimulation in the presence of 4-aminopyridine.

We previously reported that verapamil, nicardipine and diltiazem inhibited both neurotransmitter release and contraction evoked by transmural nerve stimulation (TNS) in the canine saphenous vein. To evaluate whether the three Ca antagonists act on the nerve endings by inhibiting Ca2+ influx, the effects of the three antagonists were studied in the presence of 4-aminopyridine (4-AP) 3 X 10(-4) M on the TNS-evoked tritium overflow and contraction of canine saphenous veins preloaded with [3H]-noradrenaline. 4-AP increased both tritium overflow and contraction evoked by TNS, but did not enhance the contraction induced by exogenous noradrenaline (10 nmol). In the veins pretreated with 4-AP, verapamil (3 X 10(-5) M) and nicardipine (10(-5) M and 3 X 10(-5) M) caused no significant effects on the TNS-evoked tritium overflow, but they still inhibited the contraction. Diltiazem (10(-5) M and 3 X 10(-5) M) significantly inhibited both responses to TNS in the veins pretreated with 4-AP, the effects being nearly equipotent to those in the absence of 4-AP. The (-)-cis isomer of diltiazem (10(-5) M and 3 X 10(-5) M), which is about 100 times less potent than diltiazem in inhibiting Ca2+ influx, inhibited both responses to TNS in the presence of 4-AP to almost the same degree as diltiazem. When 4-AP was added after the Ca antagonists, it reversed the TNS-evoked tritium overflow inhibiting actions of verapamil (3 X 10(-5) M) and nicardipine (3 X 10(-5) M) much more effectively than that of diltiazem (3 X 10(-5) M). Tetracaine (4 X 10(-6) M) significantly inhibited the TNS-evoked tritium overflow and contraction, which were unaffected by 4-AP. Sodium salicylate (10(-2) M) failed to modify the inhibition of TNS-evoked tritium overflow following diltiazem (3 X 10(-5) M), but it enhanced that of tetracaine (4 X 10(-6) M). Verapamil but not diltiazem and nicardipine significantly increased the spontaneous tritium overflow from veins pretreated with 4-AP. The present study together with previous results suggests that diltiazem but not verapamil and nicardipine may inhibit the TNS-evoked neurotransmitter release through an action other than inhibition of Ca2+ influx into the adrenergic nerve endings, allowing an inhibition of the resulting contraction.     

Purinergic and cyclic AMP modulation of noradrenaline release in cat femoral arteries

1. Adenosine, AMP, ATP (5 x 10(-4) M), 5'-N-ethylcarboxamide adenosine (NECA) and N6-L-phenylisopropyl adenosine (L-PIA) (10(-4) M) decreased tritium release elicited by electrical stimulation (ES) or 50 mM K+ in cat femoral arteries preincubated with [3H]noradrenaline (NA). 2. This effect was antagonized by 1-methyl-3-isobutylxanthine (MIX, 5 x 10(-5) M). 3. The release induced by ionophore X-537A (10(-5) M) was unaffected by adenosine and AMP. 4. The increase of intracellular cAMP levels caused by dibutyryl cAMP (5 x 10(-4) M), Ro-20 1724 (10(-4) M), forskolin (5 x 10(-6) M), NaF (2 x 10(-3) M) reduced, but MIX (5 x 10(-5) M) increased tritium release elicited by ES and K+. 5. Dipyridamole (5 x 10(-5) M) and erythro-9-2-hydroxy-3 nonyl adenosine (EHNA) (10(-4) M) also reduced tritium release. 6. Dipyridamole decreased both the uptake of [3H]NA and [3H]adenosine. 7. These data indicate: (a) the existence of A1 and A2 subtypes of purinoceptors situated presynaptically, which modulates NA release, (b) the intracellular increase of cAMP negatively modulates this secretion, and (c) these arteries possess an active system for incorporating and degrading adenosine.     

Nalpha-methyl histamine and histamine stimulate gastrin release from rabbit G-cells via histamine H2-receptors

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.     

Anthracycline-induced histamine release from rat mast cells

Comparisons were made of the ability of doxorubicin, daunorubicin, rubidazone and aclacinomycin A to release histamine from rat peritoneal mast cells. Preliminary in vitro experiments indicated that doxorubicin (10(-6) to 2.5 X 10(-4) M), in contrast to compound 48/80 and the calcium ionophore A23187, did not produce significant release under any condition tested when purified or unpurified rat mast cells were used. In in vitro experiments, released histamine was measured in the cell-free supernatant of peritoneal fluid of rats after intraperitoneal injection of the agents. The time course of doxorubicin-induced histamine release from the peritoneum was rapid, with maximal release occurring within 4 to 6 min. Dose-response curves of the 4 agents over the range 10(-5) to 3.3 X 10(-3) M revealed that all caused histamine release, with 10(-3) M concentrations of each causing maximal release of comparable magnitude to that produced by 9.5 X 10(-6) M A23187. Treated mast cells recovered from the peritoneal cavity showed degranulation and vacuolization when examined by electron microscopy. Increased vascular permeability by the Evans-blue test was also noted with all 4 agents, and zones were of comparable size after injection of the highest concentration of each agent. The results indicate that in vivo, doxorubicin, daunorubicin, rubidazone and aclacinomycin A cause a rapid release of histamine from rat mast cells and an increase in vascular permeability in rat sin. There also appeared to be a reasonable correlation between the blueing reaction and histamine release in the peritoneal cavity in that the doses that did not cause skin blueing also failed to cause histamine release. The lack of histamine release by doxorubicin from mast cell preparations in vitro suggests that alterations to the doxorubicin molecule or the presence of other critical substances may be necessary for this activity to commence.     

The effect of amitriptyline on presynaptic mechanisms in noradrenergic nerves.

1 Electrically evoked and resting overflow of tritium was measured from mouse vas deferens previously incubated with [3H]-(--)-noradrenaline. 2 At low concentrations (1.6 X 10(-7) to 4 X 10(-6)M) amitriptyline increased only the evoked tritium overfow while higher concentrations increased both evoked and resting overflow. 3 In the presence of atropine (1 X 10(-6 M) amitriptyline still produced an increase in evoked tritium overflow. 4 In the presence of a concentration of cocaine (1.1 X 10(-5) M) which produced a maximal blockade of the uptake of exogenous noradrenaline the application of amitriptyline still produced an increase in evoked tritium overflow. 5 In the presence of a concentration of phentolamine (1 X 10(-5) M) that produced complete blockade of the presynaptic alpha-adrenoceptors, amitriptyline still produced an increase in evoked tritium overflow. 6 In the presence of cocaine and phentolamine together the effect of amitriptyline on evoked overflow was abolished. 7 It is concluded that amitriptyline may raise synaptic levels of noradrenaline by blocking presynaptic alpha-adrenoceptors controlling noradrenaline release and by blocking its uptake into sympathetic neurones.     

Noradrenaline release induced by ouabain and vanadate in cat cerebral and peripheral arteries

The effects of 10(-4) M ouabain and 10(-3) M vanadate (Na3VO4) on [3H]noradrenaline release from cat cerebral and femoral arteries was studied. Ouabain induced tritium secretion in cerebral arteries, but not in femoral ones, which was reduced by Ca suppression and potentiated by extracellular Na reduction to 11.9 mM. However, vanadate evoked tritium release from both kinds of vessels was unaffected under these experimental conditions. These data suggest: ouabain elicited secretion from adrenergic nerve endings is likely due to inhibition of the Na, K-ATPase and subsequent Ca influx through Na-Ca exchange, and vanadate action is mediated by another mechanism different to the Na pump blockade.     

Neurochemical investigations in vitro with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in preparations of rat brain

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in concentrations ranging from 10(-8) M to 10(-6) M induced a decrease, and at 10(-5) M an increase of both basal and electrically evoked tritium outflow from [3H]dopamine-prelabeled rat striatal slices. These effects of MPTP were almost abolished in the presence of nomifensine. Chromatographic separation of the released tritium compounds revealed that the decrease of tritium outflow was mostly due to a decrease in the outflow of the dopamine metabolite [3H]3,4-dihydroxyphenylacetic acid (DOPAC) and the increase of tritium outflow due to a massive release of [3H]dopamine. MPTP inhibited oxidative deamination of [3H]dopamine non-competitively in a crude mitochondrial preparation of rat brain, with an apparent Ki value of 4.5 microM. No relevant effect of MPTP on adenylate cyclase activity in homogenates and on basal and electrically evoked tritium outflow from [3H]choline-prelabeled slices of rat striatum could be detected. In contrast, MPTP facilitated both basal and electrically evoked tritium outflow from [3H]noradrenaline-prelabeled rat cerebral occipital cortex slices. Furthermore, MPTP counteracted the inhibitory effect of clonidine on evoked tritium outflow from rat cerebral occipital cortex slices. Moreover, in the presence of cocaine, the effect on basal, but not that on electrically evoked tritium outflow was attenuated. These results are compatible with the view that MPTP has no affinity to dopamine receptors but is preferentially taken up into dopaminergic nerve terminals by the nomifensine-sensitive uptake system where it reaches a concentration sufficient to inhibit intraneuronal monoamine oxidase (MAO). In contrast, the facilitatory effect of MPTP on evoked tritium outflow from [3H]noradrenaline prelabeled rat cerebral occipital cortex slices appears to result from antagonistic effects at presynaptic alpha 2-adrenoceptors. The observation that MPTP at lower concentrations (10(-8) to 10(-7) M) inhibits basal tritium outflow from rat cerebral occipital cortex slices suggests that this compound inhibits also intraneuronal deamination of noradrenaline by MAO in noradrenergic nerve terminals.     

Modulatory effect of imetit, a histamine H3 receptor agonist, on C-fibers, cholinergic fibers and mast cells in rabbit lungs in vitro.

The pharmacological mechanisms involved in the interactions between C-fibers, cholinergic fibers and mast cells were investigated in tracheally perfused rabbit lungs by measuring the simultaneous release of substance P and histamine in lung effluents. The amounts of substance P and histamine released in lung superfusates were measured by radioimmunoassay (RIA) after administration of capsaicin and carbachol. Capsaicin (10(-4) M) induced a simultaneous increase in substance P (273 +/- 56% of baseline) and histamine (460 +/- 138%) release. Similarly, carbachol (10(-4) M) caused an increase in the release of both substance P (367 +/- 111%) and histamine (1379 +/- 351%). The effect of capsaicin was prevented by pretreating the lungs with the tachykinin NK1 receptor antagonist SR 140333 (10(-7) M), and atropine (10(-6) M). SR 140333 prevented the carbachol-induced release of substance P but not of histamine. Exogenous substance P induced an increase in histamine release (136 +/- 7%) which was significantly greater in lungs perfused with the neutral endopeptidase inhibitor, thiorphan (10(-5) M) (272 +/- 35%). This effect was prevented by atropine (10(-6) M). Pretreatment of lungs with imetit (5 x 10(-8) M), a selective H3 receptor agonist, prevented the capsaicin-induced release of both mediators. Imetit also blocked the carbachol-induced release of substance P but not of histamine. Exogenous substance P-evoked histamine release was inhibited by imetit. Therefore, it can be concluded that substance P released through the action of capsaicin can activate cholinergic fibers, leading to cholinoceptor stimulation with subsequent activation of C-fibers and mast cells. While the presence of presynaptic H3 receptors modulating substance P-induced acetylcholine release was only surmised, the existence of modulating histamine H3 receptors on C-fibers was confirmed.     

Stimulation of histamine release by the peptide kinetensin

The peptide kinetensin isolated from pepsin-treated human plasma induced a dose-dependent release of histamine when exposed to rat peritoneal mast cells. The threshold concentration was around 10(-6) M, the ED50 was 10(-5) M, and the optimal concentration of between 10(-4) to 10(-3) M released 80% of the total histamine. Kinetensin was 10 to 100 times less potent than neurotensin and equipotent with the opioid peptide dynorphin. The histamine release was clearly temperature-dependent, with no release occurring at 0 degrees or 45 degrees C and with an optimum around 37 degrees C. The histamine release was significantly reduced in the absence of extracellular calcium. Kinetensin also induced a dose-dependent increase in vascular permeability when injected intradermally into rats. The findings indicate that kinetensin is a potent histamine releaser in the rat and may serve as an inflammatory mediator.     

Study of the mechanism of inhibitory action of tranilast on chemical mediator release

We investigated the mechanism of inhibitory action of tranilast on chemical mediator release by antigen-antibody reactions. Tranilast (10(-5)-10(-3) M) inhibited antigen (DNP-Ascaris)-induced histamine release from sensitized purified rat mast cells (PMC), but did not show an obvious influence on intracellular cyclic AMP. 45Ca uptake into PMC induced by antigen (300 micrograms/ml) was obviously suppressed by tranilast (10(-6)-10(-3) M). Tranilast (10(-4) M) inhibited antigen-induced histamine release from and 45Ca uptake into PMC independently of the presence or absence of glucose in the medium. On the other hand, 2-deoxyglucose (10(-2) M) markedly inhibited both responses in the absence but not in the presence of glucose. Tranilast slightly inhibited Ca-induced contraction of guinea pig taenia coli, but had no influence on aggregation of rabbit platelets. Verapamil (10(-6)-10(-4) M) had no effect on antigen-induced histamine release, but it markedly suppressed Ca-induced contraction and platelet aggregation. From these results, we suggest that the mechanism of inhibitory action of tranilast on the release of antigen-induced chemical mediator from mast cells involves the suppression of Ca uptake, but that its mode of action is apparently different from those of 2-deoxyglucose and verapamil.     

Blockade by methylation inhibitors of the anaphylactic response of guinea-pig lung strips.

1. The combination of two methylation inhibitors 3-deazaadenosine (10(-4) or 4 x 10(-4) M) plus L-homocysteine (2 x 10(-4) M) caused a time-dependent inhibition of antigen-induced contraction, formation of thromboxane B2 (TxB2) and release of histamine from lung parenchyma strips taken from guinea-pigs actively sensitized with ovalbumin (OA). 2. The methylation inhibitors also prevented the lung strip contractions induced by the mediators platelet-activating factor (Paf-acether, 10(-6) M), leukotriene D4 (LTD4, 10(-8) and 3 x 10(-8) M), and in part to arachidonic acid (10(-6) and 10(-5) M), under conditions where the contractions to histamine (10(-6)-10(-4) M) were virtually unaffected. 3. TxB2 formation induced by these mediators or by OA was more affected by the methylation inhibitors than the lung strip contractions, indicating that prostaglandin formation is more sensitive to these inhibitors than the myotropic activity. In contrast, the suppressive effect of the methylation inhibitors on histamine secretion by parenchyma lung strips induced by OA followed the inhibition of the contraction. 4. These results show that inhibitors of methyltransferases interfere with the myotropic responses and with the release of mediators by actively sensitized guinea-pig lung strips stimulated with antigen, and suggest a major role for a methylation process in mediating the contraction of and mediator release by the lung parenchyma.     

Inhibition of adrenergic neuroeffector transmission in rabbit pulmonary artery and aorta by adenosine and adenine nucleotides

The effect of adenosine and adenine nucleotides on sympathetic neuroeffector transmission in the rabbit isolated pulmonary artery and aorta was studied. Adenosine (10(-5)-3 x 10(-4)M) decreased the contractile response of pulmonary artery and aorta evoked by electrical-field stimulation. The decrease was reversible. No tachyphylaxis developed. Inhibition of either adenosine deaminase by deoxycoformycin (3.6 x 10(-6)M) or of adenosine transport by dilazep (3 x 10(-6)M) did not alter the inhibitory effect of adenosine on the neurogenic contractions in the pulmonary artery. However, deoxycoformycin plus dilazep markedly enhanced the inhibitory effect of adenosine. The calcium antagonists nifedipine (1.5 x 10(-8)M) and nimodipine (1.3 x 10(-8)M) had no effect on the adenosine-induced inhibition. This was also the case with theophylline (5 x 10(-5)M), atropine (10(-7)M), and the prostaglandin synthetase inhibitors indomethacin (5 x 10(-5)M and suprofen (3 x 10(-5)M). The contractile response of the pulmonary artery elicited by exogenous (-)-noradrenaline (NA; 10(-9)-3 x 10(-4)M) was essentially not altered by adenosine (10(-5)-3 x 10(-4)M). Adenosine (10(-4)M) did not alter the spontaneous 3H-outflow from rabbit aorta preloaded with 3H-(-)-noradrenaline (3H-NA). Adenosine (10(-5)-3 x 10(-4)M), ADP (10(-4)M), ATP (10(-5)M), and inosine (10(-4)M) diminished the overflow of tritium from pulmonary artery and aorta preloaded with 3H-NA. The spontaneous outflow of tritium from aorta preloaded with 3H-NA consisted of 3H-NA (17%), 3H-dihydroxyphenylglycol (3H-DOPEG; 30%), 3H-dihydroxymandelic acid (3H-DOMA, 4%), 3H-O-methylated and deaminated metabolites (3H-OMDA; 42%), and 3H-normethanephrine (3H-NMN; 2%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-DOPEG and 2H-NMN, decreased 3H-NA, and did not alter 3H-DOMA and 3H-OMDA. The stimulation-evoked overflow of tritium for aorta preloaded with 3H-NA consisted of 3H-NA (31%), 3H-DOPEG (18%), 3H-DOMA (2%), 3H-ONDA (46%), and 3H-NMN (3%). Adenosine (10(-5) and 10(-4)M) enhanced 3H-NA and 3H-DOPEG, decreased 3H-OMDA and did not alter 3H-DOMA and 3H-NMN. Adeosine (10(-6)-10(-4)M) did not alter the accumulation of 3H-NA (10(-8)M) by aorta. It is concluded that adenosine inhibits vascular sympathetic neuroeffector transmission by diminishing the release of transmitter from the nerve terminals.     

Effects of Ca antagonists on the norepinephrine release and contractile responses of isolated canine saphenous veins to high KCl

Effects of verapamil, diltiazem and nicardipine on tritium overflow and contraction evoked by 40 mM KCl were evaluated using canine saphenous vein strips preloaded with [3H]norepinephrine. Phentolamine, 10(-6) M, almost completely inhibited the contraction induced by KCl, while it significantly enhanced the evoked tritium overflow. These responses to KCl were dependent on external Ca2+. All Ca antagonists tested significantly increased the spontaneous tritium overflow in a concentration-dependent manner without any changes in basal tension. Verapamil at 10(-6) M significantly inhibited the contraction with no significant effect on the evoked overflow; and at concentrations above 10(-5) M, it inhibited the contraction much more strongly than the evoked tritium overflow. Diltiazem and nicardipine at concentrations above 3 X 10(-6) M significantly inhibited both tritium overflow and contraction evoked by KCl. A significant correlation between inhibitions of both responses to KCl by the three Ca antagonists was observed, although the y-intercept and slope of the regression line for verapamil obtained by plotting the inhibition of the KCl-evoked contraction as a function of the inhibition of the evoked tritium overflow were greater than those for the other two antagonists. The inhibitory effects of verapamil and diltiazem on the tritium overflow and contraction evoked by KCl were not related to their local anesthetic activities. Neither the increase in the spontaneous tritium overflow nor inhibitions of the evoked tritium overflow and contraction by nicardipine were related to its phosphodiesterase inhibiting activity. These results suggest that diltiazem and nicardipine may inhibit the KCl-evoked contraction mainly by inhibiting Ca2+-dependent transmitter release from the nerve endings, while verapamil may inhibit it by acting on the postsynaptic sites and at the relatively higher concentrations used, by further inhibition of transmitter release.     

Effects of methyl p-hydroxybenzoate (methyl paraben) on Ca2+ concentration and histamine release in rat peritoneal mast cells

1 Mechanisms of methyl p-hydroxybenzoate (methyl paraben) action in allergic reactions were investigated by measuring the intracellular Ca(2+) concentration ([Ca(2+)](i)) and histamine release in rat peritoneal mast cells (RPMCs). 2 In the presence or absence of extracellular Ca(2+), methyl paraben (0.1-10 mM) increased [Ca(2+)](i), in a concentration-dependent manner. Under both the conditions, methyl paraben alone did not evoke histamine release. 3 In RPMCs pretreated with a protein kinase C (PKC) activator (phorbol 12-myristate 13-acetate (PMA) 3 and 10 nM), methyl paraben (0.3-3 mM) induced histamine release. However, a high concentration (10 mM) of the agent did not increase the histamine release. 4 U73122 (0.1 and 0.5 micro M), an inhibitor of phospholipase C (PLC), significantly inhibited the methyl paraben-induced histamine release in PMA-pretreated RPMCs. U73343 (0.5 micro M), an inactive analogue of U73122, did not inhibit the histamine release caused by methyl paraben. 5 In Ca(2+)-free solution, PLC inhibitors (U73122 0.1 and 0.5 micro M, D609 1-10 micro M) inhibited the methyl paraben-induced increase in [Ca(2+)](i), whereas U73343 (0.5 micro M) did not. 6 Xestospongin C (2-20 micro M) and 2 aminoethoxydiphenyl borate (30 and 100 micro M), blockers of the inositol 1,4,5-trisphosphate (IP(3)) receptor, inhibited the methyl paraben-induced increase in [Ca(2+)](i) in Ca(2+)-free solution. 7 In conclusion, methyl paraben causes an increase in [Ca(2+)](i), which may be due to release of Ca(2+) from storage sites by IP(3) via activation of PLC in RPMCs. In addition, methyl paraben possibly has some inhibitory effects on histamine release via unknown mechanisms.     

Release of [3H]noradrenaline induced by 5-hydroxytryptamine from cat pial arteries.

Pial arteries of cats were used to analyse the effects of 5-hydroxytryptamine (5-HT) on the release of [3H]noradrenaline. To achieve this the vessels were preincubated with [3H]noradrenaline and the effect of different concentrations of 5-HT (10(-6), 10(-5), 10(-4) M) on the release of tritium was studied. 5-HT elicited release of radioactivity in a dose-dependent manner. Removal of both superior cervical sympathetic ganglia 15 days before the experiment of pretreatment of the animals with reserpine (3 mg kg-1, total dose) produced a significant decrease in the outflow of tritium induced by 5-HT. In these arteries, the amount of radioactivity retained at the end of the experiment was much diminished. Cocaine (10(-6) M) caused a significant decrease in the tritium efflux induced by 5-HT (1"0(-5) M). These results show that 5-HT has an indirect adrenergic effect in the pial arteries of the cat only at high doses of 5-HT, and confirm that sympathetic innervation of these vessels mainly comes from the superior cervical ganglia.     

Histamine H(3) receptors mediate inhibition of noradrenaline release from intestinal sympathetic nerves

1. The present study investigates whether presynaptic histamine receptors regulate noradrenaline release from intestinal sympathetic nerves. The experiments were performed on longitudinal muscle-myenteric plexus preparations of guinea-pig ileum, preincubated with [(3)H]-noradrenaline. 2. In the presence of rauwolscine, electrically-induced [(3)H]-noradrenaline release was inhibited by histamine or R-alpha-methylhistamine, whereas it was unaffected by pyridylethylamine, impromidine, pyrilamine, cimetidine, thioperamide or clobenpropit. The inhibitory effects of histamine or R-alpha-methylhistamine were antagonized by thioperamide or clobenpropit, but not by pyrilamine or cimetidine. In the absence of rauwolscine, none of these drugs modified the release of [(3)H]-noradrenaline. 3. The modulatory action of histamine was attenuated by pertussis toxin and abolished by N-ethylmaleimide. Tetraethylammonium or 4-aminopyridine enhanced the evoked tritium outflow and counteracted the inhibitory effect of histamine. However, the blocking effects of tetraethylammonium and 4-aminopyridine were no longer evident when their enhancing actions were compensated by reduction of Ca(2+) concentration in the superfusion medium. 4. Histamine-induced inhibition of tritium output was enhanced by omega-conotoxin or low Ca(2+) concentration, whereas it was not modified by nifedipine, forskolin, rolipram, phorbol myristate acetate, H7 or lavendustin A. 5. The present results indicate that presynaptic H(3) receptors, located on sympathetic nerve endings, mediate an inhibitory control on intestinal noradrenergic neurotransmission. It is suggested that these receptors are coupled to G(i)/G(o) proteins which modulate the activity of N-type Ca(2+) channels through a direct link, thus reducing the availability of extracellular Ca(2+) at the level of noradrenergic nerve terminals.     

The influence of H1-, H2- and H3-receptors on the spontaneous and ConA induced histamine release from human adenoidal mast cells.

The effects of the H3-agonist R-alpha-methylhistamine (R-alpha-MeHA) and the H3-antagonist thioperamide on the spontaneous and concanavalin A (ConA) induced histamine release from human mast cells were tested and compared with the effect of some H1- and H2-receptor active substances. R-alpha-MeHA (10(-9)-10(-7) M) exerted no effect on histamine release whereas thioperamide increased the spontaneous release at 10(-6)-10(-4) M but inhibited the ConA induced release in a narrow concentration range (10(-6)-10(-5) M). This enhancement might be taken as an indication of the existence of H3-receptor dependent autoregulation although presently other mechanism cannot be excluded.     

Recognition of the 'calcium paradox' and the effects of verapamil and gallopamil in human adenoidal mast cells

Human mast cells from adenoids show when resuspended in medium containing 10(-3) M CaCl2 after their temporary exposure to Ca2+-free saline for about 20 min an irreversible reduction of responsiveness to a variety of stimuli: The histamine release induced by concanavalin A or ionophore A 23187 is only 30-50% of the one obtained in cells which were kept in 10(-3) M Ca2+ throughout the experiment. This phenomenon called 'calcium paradox' can be almost entirely avoided if the cells are temporarily exposed to 10(-4) M Ca2+ instead of Ca2+-free saline. Number yields, average histamine contents of mast cells and the rate of the spontaneous histamine release are not affected by the transitory lack of Ca2+, nor is the histamine release enhancing effect of adenosine. At 10(-3) M Ca2+ concentration the calcium antagonists verapamil or gallopamil cause a significant inhibition of the Con A-induced histamine release only at concentrations much higher (10(-4) M than those effective in smooth muscle preparations. The actions of both calcium antagonists were not affected by the presence of added extracellular adenosine.