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Santos, Rosimeire Ferreira Dos - One of the best experts on this subject based on the ideXlab platform.
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Partipation of cytosolic calcium in spasmolytic action of ent-7a-acetoxytrachyloban-18-oic acid and its hidroxylated derivated on guinea-pig ileum
Universidade Federal da Paraíba, 2010Co-Authors: Santos, Rosimeire Ferreira DosAbstract:Das cascas do caule da Xylopia langsdorfiana A. St.-Hil. & Tul. (Annonaceae), conhecida popularmente como pimenteira da terra foi isolado o diterpeno ácido ent-7a-acetoxitraquiloban-18-óico (traquilobano-360) que sofreu uma modificação estrutural do grupo acetoxi pelo hidroxi gerando o ácido ent-7a-hidroxitraquiloban-18-óico (traquilobano-318). O objetivo deste trabalho foi realizar um estudo comparativo de uma possível atividade espasmolítica dos diterpenos em aorta de rato, útero de rata, traquéia e íleo de cobaia. Foram realizadas medidas de contrações isotônicas e isométricas e do cálcio citosólico. Em aorta de rato e útero de rata nenhum dos diterpenos promoveu efeito espasmolítico significante até a concentração de 10-4 M. Já em traquéia de cobaia, apenas o traquilobano-318 relaxou este órgão pré-contraído com carbacol (CCh) na presença e na ausência de epitélio funcional, de maneira equipotente, sugerindo um possível efeito direto no músculo liso traqueal e que a modificação estrutural foi essencial para o efeito relaxante neste órgão. Por outro lado, em íleo de cobaia, ambos os diterpenos inibiram as contrações fásicas induzidas por CCh ou por histamina. No íleo pré-contraído com KCl, CCh ou histamina os diterpenos induziram relaxamento e este efeito não se dá por antagonismo competitivo dos receptores histaminérgicos, o que foi confirmado pelo desvio das curvas cumulativas induzidas pela histamina para a direita com redução dos Emax. Como o componente tônico da contração induzida por KCl, CCh ou histamina é mantido principalmente pela abertura dos CaV, hipotetizou-se que os traquilobanos poderiam estar agindo sobre estes canais. Hipótese confirmada com a observação de que ambos diterpenos antagonizaram as contrações induzidas por CaCl2 em meio despolarizante sem Ca2+ além de relaxarem o íleo pré-contraído por S-(-) Bay K 8644, agonista dos Cav1 (CE50 = 3,5 ± 0,7 x 10-5 e 5,5 ± 0,3 x 10-5 M, respectivamente) confirmando assim que o subtipo de Cav envolvido é o Cav1.2. Para investigar a participação dos canais para K+ no efeito dos diterpenos, observou-se que as curvas de relaxamento do traquilobano-360 (CE50 = 0,5 ± 0,04 x 10 -4 M) e do traquilobano-318 (CE50 = 2,0 ± 0,5 x 10-5 M) foram significantemente desviadas para a direita na presença de 5 mM de TEA+, bloqueador não seletivo dos canais para K+, sugerindo a participação destes canais no efeito dos diterpenos. O efeito do traquilobano-360 parece não envolver os subtipos de canais para K+ (KATP, SKCa, Kv e BKCa,) uma vez que o relaxamento não foi alterado na presença dos bloqueadores destes canais. Entretanto, o efeito do traquilobano-318 parece envolver a ativação dos canais do tipo KATP, SKCa e Kv mas não dos BKCa, fato este evidenciado pelos desvios da curva de relaxamento para direita na presença dos bloqueadores de canais para K+ como glibenclamida, apamina e 4-AP, respectivamente. Estes resultados sugerem que a modificação estrutural foi essencial para esses efeitos diferenciados, mas não para o envolvimento da via dos nucleotídios cíclicos, uma vez que na presença da aminofilina as curvas de relaxamento dos traquilobanos não foram alteradas. Os dois diterpenos reduziram a intensidade de fluorescência em miócitos intestinais de íleo de cobaia estimulados por histamina em conseqüência da redução da [Ca2+]c, o que explica os efeitos espasmolíticos destes diterpenos em nível funcional.From the stem bark of Xylopia langsdorfiana A. St.-Hil. & Tul. (Annonaceae), popularly known as pimenteria da terra , was isolated the diterpene ent-7-α-acetoxytrachyloban-18-oic acid (trachylobane-360) from which it was made a structural modification in which the acetoxy group was substituted by hydroxy generating the ent-7a-hidroxitrachyloban-18-oic acid (trachylobane-318). How there are some reports that show spasmolytic activity of some diterpenes, we aimed to investigate this activity on male rat aorta, rat uterus, guinea-pig trachea and ileum. On rat aorta and rat uterus nor trachylobane-360 or its derivative trachylobane-318 promoted significant spasmolytic effect until the concentration of 10-4 M. However on guinea-pig trachea, only the derivative relaxed this organ pre-contracted with carbachol (CCh) in the presence (EC50 = 3.3 0.9 ± 0.4 x 10-5 M) and absence (EC50 = 3.5 ± x 10-5 M) of functional epithelium, in a equipotent manner, suggesting a possible direct effect on tracheal smooth muscle and that the structural modification was essential for the relaxant effect in this organ. On the other hand, on guinea pig ileum, both diterpenes inhibited the phasic contractions induced by CCh or Histamine. When the ileum was pre-contracted with KCl, CCh or Histamine, the diterpenes induced relaxation and this effect is not by competitive antagonism of Histamine, which was confirmed by the shifted of the cumulative curves to Histamine to the right, in a non-parallel manner with reduction of the maximal effect (Emax). How the tonic component of contraction induced by KCl, CCh or Histamine is maintained mainly by the opening of CaV, we hypothesized that the trachylobanes could be acting on these channels. The hypothesis was confirmed with the observation that both diterpenes antagonized the CaCl2-induced contractions in depolarizing Ca2+-free solution also relaxed the ileum pre-contracted by S-(-) Bay K 8644, an Cav1 agonist (EC50 = 3.5 ± 0.7 x 10-5 e 5.5 ± 0.3 x 10-5 M, respectively) confirming that the Cav subtype involved is the L-type (Cav1.2). To investigate the involvement of K+ channels to the effect of diterpenes as observed that the relaxation curves of trachylobane-360 (EC50 = 0.5 ± 0.04 x 10-4 M) and trachylobane-318 (EC50 = 2.0 ± 0.5 x 10-5 M) were significantly shifted to the right in the presence of 5 mM TEA+, a non-selective channel blocker for K+, suggesting involvement of these channels in the effects of diterpenes. The effect of trachylobane-360 appears to involve the subtypes of K+ channels (KATP, SKCa, Kv and BKCa,) since the CE50 have not changed in the presence of blockers of these channels. Interestingly the effect of trachylobane-318 appears to involve the activation of the channel type KATP, Kv and SKCa but not BKCa, evidenced by shifts from the relaxation curves to the right in the presence of K+ channels blockers as glibenclamide, apamin and 4-AP, respectively. These results all together suggest that the structural change was essential for these differentiated effects, but not for the involvement of the cyclic nucleotides pathway, since that in the presence of aminophylline the relaxation curves of trachylobanes were not modified. Both diterpenes reduce the intensity of fluorescence on intestinal myocytes of guinea-pig ileum stimulated by Histamine which reflect reduction of [Ca2+]c, what would explain the spasmolytic effects of these diterpenes in functional level
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Partipation of cytosolic calcium in spasmolytic action of ent-7a-acetoxytrachyloban-18-oic acid and its hidroxylated derivated on guinea-pig ileum
UFPB, 2010Co-Authors: Santos, Rosimeire Ferreira DosAbstract:From the stem bark of Xylopia langsdorfiana A. St.-Hil. & Tul. (Annonaceae), popularly known as pimenteria da terra , was isolated the diterpene ent-7-α-acetoxytrachyloban-18-oic acid (trachylobane-360) from which it was made a structural modification in which the acetoxy group was substituted by hydroxy generating the ent-7a-hidroxitrachyloban-18-oic acid (trachylobane-318). How there are some reports that show spasmolytic activity of some diterpenes, we aimed to investigate this activity on male rat aorta, rat uterus, guinea-pig trachea and ileum. On rat aorta and rat uterus nor trachylobane-360 or its derivative trachylobane-318 promoted significant spasmolytic effect until the concentration of 10-4 M. However on guinea-pig trachea, only the derivative relaxed this organ pre-contracted with carbachol (CCh) in the presence (EC50 = 3.3 0.9 ± 0.4 x 10-5 M) and absence (EC50 = 3.5 ± x 10-5 M) of functional epithelium, in a equipotent manner, suggesting a possible direct effect on tracheal smooth muscle and that the structural modification was essential for the relaxant effect in this organ. On the other hand, on guinea pig ileum, both diterpenes inhibited the phasic contractions induced by CCh or Histamine. When the ileum was pre-contracted with KCl, CCh or Histamine, the diterpenes induced relaxation and this effect is not by competitive antagonism of Histamine, which was confirmed by the shifted of the cumulative curves to Histamine to the right, in a non-parallel manner with reduction of the maximal effect (Emax). How the tonic component of contraction induced by KCl, CCh or Histamine is maintained mainly by the opening of CaV, we hypothesized that the trachylobanes could be acting on these channels. The hypothesis was confirmed with the observation that both diterpenes antagonized the CaCl2-induced contractions in depolarizing Ca2+-free solution also relaxed the ileum pre-contracted by S-(-) Bay K 8644, an Cav1 agonist (EC50 = 3.5 ± 0.7 x 10-5 e 5.5 ± 0.3 x 10-5 M, respectively) confirming that the Cav subtype involved is the L-type (Cav1.2). To investigate the involvement of K+ channels to the effect of diterpenes as observed that the relaxation curves of trachylobane-360 (EC50 = 0.5 ± 0.04 x 10-4 M) and trachylobane-318 (EC50 = 2.0 ± 0.5 x 10-5 M) were significantly shifted to the right in the presence of 5 mM TEA+, a non-selective channel blocker for K+, suggesting involvement of these channels in the effects of diterpenes. The effect of trachylobane-360 appears to involve the subtypes of K+ channels (KATP, SKCa, Kv and BKCa,) since the CE50 have not changed in the presence of blockers of these channels. Interestingly the effect of trachylobane-318 appears to involve the activation of the channel type KATP, Kv and SKCa but not BKCa, evidenced by shifts from the relaxation curves to the right in the presence of K+ channels blockers as glibenclamide, apamin and 4-AP, respectively. These results all together suggest that the structural change was essential for these differentiated effects, but not for the involvement of the cyclic nucleotides pathway, since that in the presence of aminophylline the relaxation curves of trachylobanes were not modified. Both diterpenes reduce the intensity of fluorescence on intestinal myocytes of guinea-pig ileum stimulated by Histamine which reflect reduction of [Ca2+]c, what would explain the spasmolytic effects of these diterpenes in functional level.Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPESDas cascas do caule da Xylopia langsdorfiana A. St.-Hil. & Tul. (Annonaceae), conhecida popularmente como pimenteira da terra foi isolado o diterpeno ácido ent-7a-acetoxitraquiloban-18-óico (traquilobano-360) que sofreu uma modificação estrutural do grupo acetoxi pelo hidroxi gerando o ácido ent-7a-hidroxitraquiloban-18-óico (traquilobano-318). O objetivo deste trabalho foi realizar um estudo comparativo de uma possível atividade espasmolítica dos diterpenos em aorta de rato, útero de rata, traquéia e íleo de cobaia. Foram realizadas medidas de contrações isotônicas e isométricas e do cálcio citosólico. Em aorta de rato e útero de rata nenhum dos diterpenos promoveu efeito espasmolítico significante até a concentração de 10-4 M. Já em traquéia de cobaia, apenas o traquilobano-318 relaxou este órgão pré-contraído com carbacol (CCh) na presença e na ausência de epitélio funcional, de maneira equipotente, sugerindo um possível efeito direto no músculo liso traqueal e que a modificação estrutural foi essencial para o efeito relaxante neste órgão. Por outro lado, em íleo de cobaia, ambos os diterpenos inibiram as contrações fásicas induzidas por CCh ou por histamina. No íleo pré-contraído com KCl, CCh ou histamina os diterpenos induziram relaxamento e este efeito não se dá por antagonismo competitivo dos receptores histaminérgicos, o que foi confirmado pelo desvio das curvas cumulativas induzidas pela histamina para a direita com redução dos Emax. Como o componente tônico da contração induzida por KCl, CCh ou histamina é mantido principalmente pela abertura dos CaV, hipotetizou-se que os traquilobanos poderiam estar agindo sobre estes canais. Hipótese confirmada com a observação de que ambos diterpenos antagonizaram as contrações induzidas por CaCl2 em meio despolarizante sem Ca2+ além de relaxarem o íleo pré-contraído por S-(-) Bay K 8644, agonista dos Cav1 (CE50 = 3,5 ± 0,7 x 10-5 e 5,5 ± 0,3 x 10-5 M, respectivamente) confirmando assim que o subtipo de Cav envolvido é o Cav1.2. Para investigar a participação dos canais para K+ no efeito dos diterpenos, observou-se que as curvas de relaxamento do traquilobano-360 (CE50 = 0,5 ± 0,04 x 10 -4 M) e do traquilobano-318 (CE50 = 2,0 ± 0,5 x 10-5 M) foram significantemente desviadas para a direita na presença de 5 mM de TEA+, bloqueador não seletivo dos canais para K+, sugerindo a participação destes canais no efeito dos diterpenos. O efeito do traquilobano-360 parece não envolver os subtipos de canais para K+ (KATP, SKCa, Kv e BKCa,) uma vez que o relaxamento não foi alterado na presença dos bloqueadores destes canais. Entretanto, o efeito do traquilobano-318 parece envolver a ativação dos canais do tipo KATP, SKCa e Kv mas não dos BKCa, fato este evidenciado pelos desvios da curva de relaxamento para direita na presença dos bloqueadores de canais para K+ como glibenclamida, apamina e 4-AP, respectivamente. Estes resultados sugerem que a modificação estrutural foi essencial para esses efeitos diferenciados, mas não para o envolvimento da via dos nucleotídios cíclicos, uma vez que na presença da aminofilina as curvas de relaxamento dos traquilobanos não foram alteradas. Os dois diterpenos reduziram a intensidade de fluorescência em miócitos intestinais de íleo de cobaia estimulados por histamina em conseqüência da redução da [Ca2+]c, o que explica os efeitos espasmolíticos destes diterpenos em nível funcional
Gianni Marone - One of the best experts on this subject based on the ideXlab platform.
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Milestones in the biology and pharmacology of Histamine H1-receptor antagonists
Allergy, 1997Co-Authors: Gianni MaroneAbstract:Daniele Bovet's pioneering discovery that a series of compounds possessing anti-Histamine activity reduced the symptoms of anaphylaxis provided the proof that Histamine plays a pivotal role as a mediator of allergic reactions. Basophils and mast cells are the major sources of Histamine in man and they are thus one of the primary effector cells of allergic inflammation. Some H1-receptor antagonists posseses a variety of antiinflammatory activity to H1-- antagonism in vitro and in vivo. This promising area should be explored further and much remains to be done in the evaluation of the immunodulatory effects of anti-Histamines.
Y Zopf - One of the best experts on this subject based on the ideXlab platform.
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circadian profiling reveals higher Histamine plasma levels and lower diamine oxidase serum activities in 24 of patients with suspected Histamine intolerance compared to food allergy and controls
Allergy, 2018Co-Authors: Theresa C Pinzer, Esther Tietz, Elisabeth Waldmann, Monic Schink, Markus F Neurath, Y ZopfAbstract:Background Histamine intolerance is thought to trigger manifold clinical symptoms after ingesting Histamine-rich food due to reduced activity of diamine oxidase (DAO). No study has hitherto systematically assessed daily fluctuations of Histamine levels and DAO activities in symptomatic patients. The aim of the study was to investigate the presence of Histamine intolerance, to therefore establish day profiles of Histamine levels and DAO activities, and to compare the results between patients with suspected Histamine intolerance, food allergy and healthy controls. Methods We determined day profiles of Histamine plasma levels and DAO serum activities in 33 patients with suspected Histamine intolerance, in 21 patients with proven food allergy and in 10 healthy control patients. Clinical symptoms, food intolerances and further clinical and laboratory chemical parameters were evaluated. Results Twenty-four percent (8 of 33) suspected Histamine-intolerant patients showed elevated Histamine levels during the day. That might be caused by constantly and significantly reduced DAO activities in these patients compared to food-allergic and control patients. The remaining 25 patients presented normal Histamine levels and DAO activities, but an increased prevalence of multiple food intolerances compared to the other subgroup of suspected Histamine-intolerants. There was no correlation between subjective complaints and serological Histamine parameters in patients with suspected Histamine intolerance. Conclusions We determined by daily profiling that decreased DAO activities correlated with elevated Histamine levels in a subgroup of suspected Histamine-intolerants. This finding discriminates these patients from food intolerant individuals with similar clinical symptoms and strongly suggests the presence of Histamine intolerance.
Natalija Novak - One of the best experts on this subject based on the ideXlab platform.
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Histamine and Histamine intolerance
The American Journal of Clinical Nutrition, 2007Co-Authors: Laura Maintz, Natalija NovakAbstract:Histamine intolerance results from a disequilibrium of accumulated Histamine and the capacity for Histamine degradation. Histamine is a biogenic amine that occurs to various degrees in many foods. In healthy persons, dietary Histamine can be rapidly detoxified by amine oxidases, whereas persons with low amine oxidase activity are at risk of Histamine toxicity. Diamine oxidase (DAO) is the main enzyme for the metabolism of ingested Histamine. It has been proposed that DAO, when functioning as a secretory protein, may be responsible for scavenging extracellular Histamine after mediator release. Conversely, Histamine N-methyltransferase, the other important enzyme inactivating Histamine, is a cytosolic protein that can convert Histamine only in the intracellular space of cells. An impaired Histamine degradation based on reduced DAO activity and the resulting Histamine excess may cause numerous symptoms mimicking an allergic reaction. The ingestion of Histamine-rich food or of alcohol or drugs that release Histamine or block DAO may provoke diarrhea, headache, rhinoconjunctival symptoms, asthma, hypotension, arrhythmia, urticaria, pruritus, flushing, and other conditions in patients with Histamine intolerance. Symptoms can be reduced by a Histamine-free diet or be eliminated by antiHistamines. However, because of the multifaceted nature of the symptoms, the existence of Histamine intolerance has been underestimated, and further studies based on double-blind, placebo-controlled provocations are needed. In patients in whom the abovementioned symptoms are triggered by the corresponding substances and who have a negative diagnosis of allergy or internal disorders, Histamine intolerance should be considered as an underlying pathomechanism.
Carina Shayo - One of the best experts on this subject based on the ideXlab platform.
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Involvement of Histamine H1 and H2 receptor inverse agonists in receptor's crossregulation.
European Journal of Pharmacology, 2019Co-Authors: Antonela Díaz Nebreda, Federico Monczor, Carlos Davio, Natalia Fernández, Carlos Daniel Zappia, Angela Rodríguez González, Ana Sahores, Máximo H. Sosa, Valeria Burghi, Carina ShayoAbstract:Abstract Histamine [2-(4-Imidazolyl)-ethylamine] modulates different biological processes, through Histamine H1 and H2 receptors, and their respective blockers are widely used in treating allergic and gastric acid-related disorders. Histamine H1 and H2 receptor crossdesensitization and cointernalization induced by its agonists have been previously described. In this study, we show how this crosstalk determines the response to Histamine H1 and H2 receptor inverse agonists and how Histamine H1 and H2 receptor inverse agonists interfere with the other receptor's response to agonists. By desensitization assays we demonstrate that Histamine H1 and H2 receptor inverse agonists induce a crossregulation between both receptors. In this sense, the Histamine H1 receptor inverse agonists desensitize the cAMP response to amthamine, a Histamine H2 receptor agonist. In turn, Histamine H2 receptor inverse agonists interfere with Histamine H1 receptor signaling. We also determine that the crossdesensitization induced by Histamine H1 or H2 receptor agonists alters the Histamine inverse agonists receptor response: activation of Histamine H1 receptor affects cAMP response induced by Histamine H2 receptor inverse agonists, whereas Histamine H2 receptor agonist induces a negative regulation on the anti-inflammatory response of Histamine H1 receptor inverse agonists. Binding studies revealed that Histamine H1 and H2 receptors cointernalize after stimulus with Histamine receptor inverse agonists. In addition, the inhibition of the internalization process prevents receptor crossregulation. Our study provides new insights in the mechanisms of action of Histamine H1 and H2 receptors that explain the effect of Histamine H1 and H2 receptor inverse agonists and opens up new venues for novel therapeutic applications.
