Effects Of Exogenous Histamine Research Articles

Regulation of Norepinephrine Release from Isolated Bovine Irides by Histamine

In the present study, we investigated the effect of histamine on sympathetic neurotransmission from isolated, superfused bovine irides. We also studied the pharmacology of prejunctional histamine receptors that regulate the release of norepinephrine (NE) from this tissue. The effect of exogenous histamine and various histamine receptor agonists was examined on the release of [(3)H]-norepinephrine ([(3)H]NE) triggered by electrical field stimulation using the Superfusion Method. Histamine receptor agonists caused a concentration-dependent inhibition of field-stimulated [(3)H]NE overflow with the following rank order of potency: imetit > histamine > R-alpha-methylhistamine. In all cases, the inhibitory action of histamine receptor agonists was attenuated at high concentrations of these compounds. The histamine receptor antagonists, clobenpropit (H(3)-antagonist/H(4)-agonist) and thioperamide (H(3)-antagonist) blocked the inhibitory response elicited by R-alpha-methylhistamine and imetit, respectively. Inhibitory effects of R-alpha-methylhistamine and clonidine were not additive suggesting that prejunctional H(3)- and alpha(2)-adrenoceptors coexist at neurotransmitter release sites. We conclude that histamine produces an inhibitory action on sympathetic neurotransmission in the bovine iris, an effect mimicked by selective H(3)-receptor agonists and blocked by H(3)-antagonists.

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Efeito da histamina na regeneração hepática: estudo experimental em ratos

Muitas substâncias têm sido utilizadas após hepatectomias parciais a fim de conhecer como elas atuam sobre o processo de regeneração hepática. Adequado fluxo sangüíneo parece ter muita importância neste processo. Autores descreveram, após hepatectomias em ratos, elevação dos níveis plasmáticos de histamina. Substâncias inibidoras da histidina-decarboxilase e da histaminase leva a elevação da histamina endógena com vasodilatação sinusoidal e aceleração da regeneração hepática. No presente estudo busca-se conhecer a influência da histamina exógena administrada à ratos parcialmente hepatectomizados. Utilizaram-se 32 ratos Wistar que sofreram hepatectomia de aproximadamente 67% da víscera. Os animais do grupo experimento receberam por via subcutânea 0,5 mg/Kg/dia de histamina e os do grupo controle igual volume de solução salina isotônica. As aferições foram realizadas com 36 horas e 7 dias. A avaliação do peso da víscera não mostrou diferença entre os grupos. O número de figuras de mitose em 10 campos foi maior no grupo experimento com 36 horas (p=0,010). No sétimo dia o número delas era semelhante nos dois grupos. Concluiu-se que a administração de histamina exógena, talvez pela sua vida média curta, aumenta o número de figuras de mitose no início do processo, não interferindo na regeneração ao final de 7 dias.

The role of histamine in platelet aggregation by physiological and immunological stimuli.

Platelets participate in allergic and inflammatory processes beside their role in haemostasis and thrombosis. This paper reports the level, the uptake, the metabolism and the release of histamine in human platelets. The effects of exogenous histamine, as well as the receptor and signal transduction of these effects, are also described. Purified suspensions of platelets, prepared from healthy volunteers and from atopic patients, were exposed in vitro to physiological and immunological stimuli. Platelet aggregation was measured by the increase in light transmission; histamine content and release, as well as cytosolic free Ca2+ concentration, were measured fluorimetrically. Platelet histamine forming capacity, and the uptake of exogenous histamine, were measured with a radioisotopic method. Human platelets contain 72.5 +/- 9.6pmoles of histamine x 10(9) platelets, and their capacity to form histamine is 18.7 +/- 3.5pmoles h(-1)g(-1) protein, which is reduced by alpha-fluoromethylhistidine (10(-5) M) a selective inhibitor of the specific histidine decarboxylase. Human platelets take up the preformed amine by a calcium and energy-dependent process, and the uptake of histamine is reduced by mepyramine, an H1-receptor antagonist, and N,N-diethyl-2-[4-(phenylmethyl) phenoxyl] ethanamine (10(-6) M), a blocker of intracellular histamine receptors. Histamine is also metabolized by human platelets. The exposure of platelets to thrombin (10-60 mUml(-1)) produced a progressive aggregation, associated with histamine release. The same is observed in platelets isolated from atopic patients exposed to anti-IgE antibodies. Exogenous histamine dose-dependently potentiates the aggregation induced by physiological and immunological stimuli. In resting platelets cytosolic calcium level (207 +/- 4.2 nM/10(8) platelets) is increased by thrombin as well as by anti-IgE; this effect is potentiated by 10(-5) M histamine. The synergistic effect between histamine and other monoamines on platelet aggregation may explain some aspects of allergic vasculitis in which platelet aggregation is present.

The effects of exogenous histamine in isolated rat hearts.

The role of histamine in cardiac physiology and pathophysiology is not clarified, but is dependent on species. The effects of exogenous histamine in Langendorff-perfused rat hearts were investigated. 1 mM, 100, 10, 1 and 0.1 microM of histamine (n = 7 each) as 15 min infusions were employed in a dose-response study, and compared to control perfused hearts (n = 7). In another experimental series, 100 microM histamine (n = 15) was added during reperfusion after 25 min global ischemia, and compared to control ischemia-reperfusion (n = 15). The maximal response to histamine in the dose-response study (100 microM) was an increase of left ventricular developed pressure to 126 +/- 8% of initial value (mean +/- SEM, p < 0.04), and increase of coronary flow to 152+6% (p < 0.02) after 5 min infusion. 100 microM histamine did not significantly influence heart rate or rhythm. The lowest concentration (0.1 microM) did not have effects cardiac performance. Reperfusion with histamine for 2 min after ischemia reduced left ventricular developed pressure to 68 +/- 10% of initial value versus 116+17% in ischemic controls (p < 0.05), and increased left ventricular end-diastolic pressure to 24 +/- 8 mmHg compared to 6 +/- 2 mmHg in controls (p < 0.04). Left ventricular pressures were similar in hearts reperfused with histamine and in ischemic controls for the rest of the observation. Coronary flow increased during reperfusion in hearts given histamine. Histamine had a dose-dependent positive inotropic and vasodilatory effect in isolated rat hearts. Exogenous histamine had only minor effects on post-ischemic cardiac function.

Histamine N-Methyltransferase Modulates Histamine- and Antigen-induced Bronchoconstriction in Guinea PigsIn Vivo

To examine whether histamine N-methyltransferase (HMT; EC 2.1.1.8) modulates the effects of allergic reaction in vivo, we studied the effects of aerosolized SKF 91488, a specific HMT inhibitor, on the responses to aerosolized histamine in unsensitized guinea pigs and to ovalbumin (OA) antigen inhalation in guinea pigs sensitized to OA. Airway responsiveness was assessed by determining provocation concentrations of histamine and OA aerosols that increased pulmonary resistance to twice the baseline values. SKF 94188 shifted, in a dose-dependent fashion, the dose-response curves to histamine and OA antigen to lower concentrations, and it significantly decreased provocation concentrations of both histamine and OA antigen (p < 0.01). In contrast of SKF 91488, aerosolized aminoguanidine, a specific inhibitor of diamine oxidase (10(-2) M, 90 breaths), did not alter the provocation concentration of histamine (p > 0.20). SKF 91488 (10(-2) M, 90 breaths) caused no significant changes in response to acetylcholine (p > 0.30). HMT activities were observed in the entire airways of the trachea, main bronchi, segmental bronchi and bronchioles, and parenchymal tissues. These findings suggest that HMT modulates the effects of exogenous histamine and endogenously released histamine by antigen challenge on bronchoconstrictor responses in guinea pigs in vivo.

Histamine alters prostaglandin output from diestrous rat uteri. Involvement of H 2-receptors and 9-keto-reductase

The effects of exogenous histamine (H) on prostaglandin (PG) generation and release in uteri isolated from diestrous rats and the influences of H 2-receptors blockers (cimetidine and mitiamide) on the output of uterine PGs, were explored. Moreover, the action of H on the uterine 9-keto-reductase, was also studied. Histamine (10 −4M) failed to alter the basal output of PGE 1 but reduced significantly the generation and release of PGE 2 and augmented the output of PGF 2α. On the other hand, cimetidine (10 −5M) enhanced the basal release of PGE 2 but had no action on the outputs of PGs E 1 or F 2α. The enhancing effect of H on the production and release of PGF 2α was abolished in the presence of cimetidine. Also, the antagonist reversed the influence of H on the output of PGE 2. Metiamide, another H 2-receptor antagonist, did not alter the basal control generation and release of uterine PGs, but antagonized the augmenting influence of H on PGF 2α uterine output, as much as cimetidine did, and prevented the depressive action of H on the release of PGE 2 from uteri. Histamine (10 −4M) significantly stimulated uterine formation of cyclic-adenosine monophosphate, an action which was antagonized by the presence of cimetidine (10 −5M), a blocker of H 2 receptors. Also, histamine (10 −5M) and dibutyril-cyclic-adenosine monophosphate (DB-cAMP) at 10 −3M, enhanced significantly the formation 3H-PGF 2α from 3H-PGE 2. Results presented herein demonstrate that H is able to diminish the generation of PGE 2 in uteri from rats at diestrus augmenting the synthesis of PGF 2α, apparently via the activation of H 2-receptors, enhancing adenylate-cyclase. These effects appear to increase uterine 9-keto-reductase activity which transforms PGE 2 into PGF 2α. Relationships between the foregoing results and those evoked by estradiol, are also discussed.

Autoinhibition of histamine synthesis mediated by presynaptic H 3-receptors

The regulation of histamine synthesis was studied on rat brain slices or synaptosomes labeled with l-[ 3H]histidine. Depolarization by increased extracellular K + concentration enhanced by about twofold the [ 3H]histamine formation in slices of cerebral cortex. This stimulation was also observed, although to a lesser extent, in synaptosomes from cerebral cortex and slices from the posterior hypothalamus where most histaminergic cell-bodies are located, suggesting that it may occur in nerve endings as well as in perikarya. In the presence of exogenous histamine in increasing concentrations the K +-induced stimulation was progressively reduced by up to 60–70%. The effect of exogenous histamine appears to be receptor-mediated as shown by its saturable character, high pharmacological specificity and competitive reversai by histamine antagonists. The ec 50 value of histamine for synthesis reduction (0.34 ± 0.03 μM) was similar to its ec 50 value for release inhibition known to be mediated by H 3-receptors. In addition, whereas mepyramine and tiotidine, two potent antagonists at H 1- and H 2-receptors, respectively, were poorly effective, the H 3-receptor antagonists burimamide and impromidine reversed the histamine effect in an apparently competitive manner. These effects were observed in slices of cerebral cortex or posterior hypothalamus as well as in cortical synaptosomes. Furthermore, even in the absence of added histamine, H 3-receptor antagonists enhanced the depolarization-induced stimulation of [ 3H]histamine synthesis, indicating a participation of released endogenous histamine in the synthesis control process. The potencies of H 3-receptor antagonists were similar to those of these agents at presynaptic autoreceptors controlling [ 3H]histamine release. It is concluded that H 3-receptors control not only release but also synthesis of histamine at the Ievel of nerve endings and also, presumably, of perikarya. A relationship between the two regulatory processes, possibly via intracellular calcium, seems likely but remains to be investigated at the molecular Ievel.

Attempts to antagonize the effect of histamine on the cold-stimulated thyrotropin secretion in male rats.

Histamine given directly into the 3rd ventricle inhibits the enhancement of thyrotropin secretion induced by cold-exposure (4 degrees, 30 min.) in male rats. This effect was antagonized neither by mepyramine, a H1-receptor antagonist, nor by cimetidine, a H2-receptor antagonist. Histamine would not have an indirect mechanism of action through adrenergic alpha 1- or alpha 2-receptors in rat hypothalamus, since pretreatment with neither phenoxybenzamine nor yohimbine had any effect on histamine suppressed TSH cold-response. Further, it was also tested if histamine could decrease the TSH secretion through cholinergic-, GABA-, serotonergic- or dopaminergic receptors but no results supporting such a mechanism of action were obtained. The effect of histamine was not modified by pretreatment with naloxone or desipramine either. Imidazole acetic acid, IAA, a metabolite of histamine, had no effect on cold-induced TSH secretion. It is concluded that the effect of exogenous histamine on cold-stimulated TSH secretion is not mediated through H1- or H2-receptors. Histamine may decrease brain noradrenergic activity which is important in the generation of TSH cold-response. In addition, the effect of exogenous histamine might be due to decreased endogenous histaminergic activity in rat brain.

Histamine antagonists in the treatment of shock hyperglycemia in the rat

The present study was undertaken to determine the effect of exogenous histamine and histamine blockers on blood glucose and hepatic glycogen in the rat. Forty-one nonfasted male Sprague-Dawley rats that had been anesthetized with intraperitoneal injections of urethane were injected intravenously (femoral) with histamine (10 mg/kg) five minutes after pretreatment with Ringer's solution (control), diphenhydramine (1 mg/kg) (H-1 blocker); metiamide (1 mg/kg) (H-2 blocker); or a combination of these blockers. Mean arterial pressure (carotid), blood glucose, and hepatic glycogen were measured. Within 30 minutes, histamine evoked a significant increase in blood glucose, and a decrease in hepatic glycogen, and a reduction in blood pressure. However, rats treated with the H-2 blocker metiamide or with a combination of H-1 and H-2 blockers did not show as significant a hypotensive response as rats treated with the H-1 blocker diphenhydramine alone. The hyperglycemic-glycogenolytic response to histamine was modified by diphenhydramine as well as by a combination of blockers, but not by metiamide alone. These results suggest that a) the hypotension did not initiate the hyperglycemic and glycogenolytic response; b) the H-2 blocker metiamide has little effect on the hyperglycemic response to exogenous histamine; and c) the H-1 blocker diphenhydramine may have antihyperglycemic properties.

The Influence of Pregnancy on the Blood Pressure Effects of Histamine in Normotensive and Spontaneously Hypertensive Rats

The blood pressure responses of normotensive (WKY) and hypertensive (SHR) rats to histamine injections were compared before and during pregnancy. A series of increasing doses of intravenous histamine was given before histamine receptor blockade, after H1 (pyrilamine) block, and after combined H1 and H2 (cimetidine) block. In both WKY and SHR nonpregnant rats, histamine caused dose-dependent decreases in blood pressure which were partially dependent on H1 and H2 receptors. In late pregnancy, the magnitudes of the hypotensive effects of histamine were significantly reduced and blocked only by combined H1 and H2 treatment but not by H1 treatment alone. Thus, the blood pressure effects of exogenous histamine in normotensive and hypertensive rats are modified in a similar way during late pregnancy with diminished hypotensive effects which are more dependent on H2 receptors than the effects in nonpregnant rats. This change in histamine responsiveness may play a role in the cardiovascular adjustments of pregnancy.

Effect of Histamine on Cyclic AMP Levels in Control and Antigen-Sensitized Guinea Pig Lungs

The effect of histamine on cyclic AMP was investigated in control and antigen-sensitized guinea pig lungs. Although histamine elevated the cyclic AMP levels in a dose-dependent manner in both groups, the response was consistently smaller in the sensitized lungs. In vivo pretreatment of control guinea pigs with histamine decreased the subsequent effect of exogenous histamine on cyclic AMP. Phosphodiesterase activity was not different in the two groups and it was not affected by histamine. These results indicate that the process of antigen sensitization results in an altered cyclic AMP response to histamine.

Influence of H1- and H2-receptor antagonists on the circulatory system and on the endogenous plasma histamine concentrations in dogs.

The effects of the H1-receptor antagonist dimethpyrindene and the H2-receptor antagonist burimamide on circulatory and respiratory parameters and on plasma histamine levels were tested in 21 mongrel dogs. Both drugs released histamine. The incidence for this effect was 10/11 in the case of dimethpyrindene and 5/10 in the case of burimamide. Following dimethpyrindene all animals showed arterial hypotension, pulmonal hypertension, decrease in peripheral resistance and hyperventilation. The portal venous pressure was increased in dogs reacting by a histamine release. Following burimamide both an initial arterial hypertension and a subsequent hypotension were observed the latter being more pronounced in the group with histamine release. In this group the portal venous pressure raised considerably. In the non-reacting animals cardiac output was elevated, probably due to a release of catecholamines. It seemed remarkable that the effect of exogenous histamine on portal venous pressure was completely blocked by dimethpyrindene, but not the action of histamine released by the drug itself. It is concluded that the effects of anti-histaminic drugs on possibly histamine-induced physiological and pathophysiological processes should be interpreted very carefully as far as their specificity is concerned.