RESUMEN
Previous studies revealed pharmacological differences between human and guinea pig histamine H(2) receptors (H(2)Rs) with respect to the interaction with guanidine-type agonists. Because H(2)R species variants are structurally very similar, comparative studies are suited to relate different properties of H(2)R species isoforms to few molecular determinants. Therefore, we systematically compared H(2)Rs of human (h), guinea pig (gp), rat (r), and canine (c). Fusion proteins of hH(2)R, gpH(2)R, rH(2)R, and cH(2)R, respectively, and the short splice variant of G(salpha), G(salphaS), were expressed in Sf9 insect cells. In the membrane steady-state GTPase activity assay, cH(2)R-G(salphaS) but neither gpH(2)R-G(salphaS) nor rH(2)R-G(salphaS) showed the hallmarks of increased constitutive activity compared with hH(2)R-G(salphaS), i.e., increased efficacies of partial agonists, increased potencies of agonists with the extent of potency increase being correlated with the corresponding efficacies at hH(2)R-G(salphaS), increased inverse agonist efficacies, and decreased potencies of antagonists. Furthermore, in membranes expressing nonfused H(2)Rs without or together with mammalian G(salphaS) or H(2)R-G(salpha) fusion proteins, the highest basal and GTP-dependent increases in adenylyl cyclase activity were observed for cH(2)R. An example of ligand selectivity is given by metiamide, acting as an inverse agonist at hH(2)R-G(salphaS), gpH(2)R-G(salphaS), and rH(2)R-G(salphaS) in the GTPase assay in contrast to being a weak partial agonist with decreased potency at cH(2)R-G(salphaS). In conclusion, the cH(2)R exhibits increased constitutive activity compared with hH(2)R, gpH(2)R, and rH(2)R, and there is evidence for ligand-specific conformations in H(2)R species isoforms.
Asunto(s)
Agonistas de los Receptores Histamínicos/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Receptores Histamínicos H2/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Baculoviridae/genética , Línea Celular , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Perros , GTP Fosfohidrolasas/metabolismo , Subunidades alfa de la Proteína de Unión al GTP Gs/genética , Subunidades alfa de la Proteína de Unión al GTP Gs/metabolismo , Cobayas , Histamina/farmacología , Humanos , Ligandos , Metiamida/farmacología , Ratas , Receptores Histamínicos H2/genética , Proteínas Recombinantes de Fusión/metabolismo , Proteínas Recombinantes/metabolismo , Especificidad de la Especie , Spodoptera , TransfecciónRESUMEN
The effect of intracerebroventricular infusion of compound 48/80 (C48/80), a mast cell secretagogue, on adrenal cortisol secretion was investigated in dogs under pentobarbital sodium anesthesia. A marked increase in adrenal cortisol secretion was elicited by C48/80 along with a concomitant increase in the plasma levels of cortisol and immunoreactive ACTH, but neither arterial blood pressure and heart rate nor the plasma histamine level altered significantly. Pretreatment with either anti-CRF antiserum or pyrilamine maleate (H(1) histamine-receptor antagonist) significantly attenuated the C48/80-evoked increase in cortisol secretion, but pretreatment with metiamide (H(2)-receptor antagonist) significantly potentiated it. Significant attenuation of the C48/80-evoked increase in cortisol also occurred in dogs given ketotifen, a mast cell stabilizing drug, before pharmacologic challenge. In the pars tuberalis and median eminence (ME), mast cells were highly concentrated in close association with the primary plexus of the hypophysial portal system. Degranulated mast cells were extensively found in the ME of C48/80-treated animals. These results suggest that mast cells located in these regions liberated histamine within the brain as a result of degranulation induced by C48/80 and that this led to activation of the hypothalamic-pituitary-adrenocortical axis.
Asunto(s)
Corteza Suprarrenal/metabolismo , Degranulación de la Célula/efectos de los fármacos , Hormona Liberadora de Corticotropina/fisiología , Histamina/fisiología , Eminencia Media/citología , Eminencia Media/efectos de los fármacos , p-Metoxi-N-metilfenetilamina/farmacología , Corteza Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/farmacología , Animales , Cromatografía en Capa Delgada , Perros , Relación Dosis-Respuesta a Droga , Epinefrina/farmacología , Femenino , Hemodinámica/efectos de los fármacos , Histamina/sangre , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Hidrocortisona/sangre , Hidrocortisona/metabolismo , Inyecciones Intraventriculares , Cetotifen/farmacología , Masculino , Metiamida/farmacología , Pirilamina/farmacología , Circulación Esplácnica/fisiología , p-Metoxi-N-metilfenetilamina/administración & dosificación , p-Metoxi-N-metilfenetilamina/antagonistas & inhibidoresRESUMEN
Nerve growth factor (NGF) has been shown to stimulate the hypothalamic-pituitary-adrenocortical (HPA) axis. Since NGF induces the release of histamine from mast cells and in consideration of the fact that histamine is an HPA axis activator, we investigated whether NGF adrenocortical stimulation is mediated by histamine. To accomplish with it, the H1 histamine antagonist promethazine and the H2 antagonists metiamide and zolantidine were used in freely-moving cannulated rats. The increase in plasma corticosterone concentration induced by histamine administration was prevented completely by promethazine pretreatment but was unaffected by the H2 antagonists. Neither H1 nor H2 antagonists affected the adrenocortical stimulation induced by NGF administration. Moreover, since mast cells are reportedly present in the rat adrenal gland and the locally released histamine mediates the release of adrenaline which, in turn, stimulates glucocorticoid synthesis and secretion, we studied the effect of NGF on basal and ACTH-stimulated corticosterone release from in vitro isolated quartered adrenal glands and collagenase-dispersed adrenal cells. The results from these in vitro experiments have indicated that NGF modified neither spontaneous nor stimulated corticosterone release. Altogether these observations suggest that endogenous histamine is unlikely to be involved in HPA axis stimulation by NGF and reinforce the previously proposed concept of an active participation of NGF in the control of adrenocortical activity.
Asunto(s)
Histamina/fisiología , Sistema Hipotálamo-Hipofisario/fisiología , Factor de Crecimiento Nervioso/fisiología , Sistema Hipófiso-Suprarrenal/fisiología , Glándulas Suprarrenales/metabolismo , Animales , Benzotiazoles , Cateterismo , Corticosterona/metabolismo , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Masculino , Metiamida/farmacología , Ratones , Fenoxipropanolaminas , Piperidinas/farmacología , Prometazina/farmacología , Ratas , Ratas Wistar , Tiazoles/farmacologíaRESUMEN
Histamine and 2-methyl histamine caused dose-dependent aggregation of the integumental melanophores of Rana tigerina both in vitro and in vivo. The aggregating effects were antagonised by mepyramine and metiamide, specific H1 and H2 receptor blockers, respectively. Compound 48/80 and EDTA augmented the melanin-aggregating effects of exogenously applied histamine and 2-methyl histamine in in vivo experiments. 4-Methyl histamine, a specific H2 receptor agonist, dispersed the frog melanophores in in vitro studies, the dispersing effects were blocked by metiamide.
Asunto(s)
Melanóforos/metabolismo , Ranidae/metabolismo , Receptores Histamínicos/metabolismo , Piel/metabolismo , Animales , Ácido Edético/farmacología , Histamina/farmacología , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Técnicas In Vitro , Melaninas/metabolismo , Melanóforos/efectos de los fármacos , Metilhistaminas/farmacología , Metiamida/farmacología , Pirilamina/farmacología , Ranidae/anatomía & histología , Receptores Histamínicos/efectos de los fármacos , Piel/efectos de los fármacos , Pigmentación de la Piel/efectos de los fármacos , Pigmentación de la Piel/fisiología , p-Metoxi-N-metilfenetilamina/farmacologíaRESUMEN
H2- and B2-receptors concentrations and activity were measured in 12 adult (6-7-month-old) and 12 young (1.5-2-month-old) rabbits by vascular reactions to histamine and bradykinin with and without prior usage of relevant specific receptor blocker. The findings suggest that concentration and activity of H2- and B2-receptors in young animals are the highest in the larynx. In mature animals-partially in trachea. With aging these concentrations and activity diminish in the larynx and rise in the trachea, the changes of B2-receptors are more significant.
Asunto(s)
Envejecimiento/metabolismo , Laringe/metabolismo , Receptores de Bradiquinina/metabolismo , Receptores Histamínicos H2/metabolismo , Tráquea/metabolismo , Factores de Edad , Animales , Antagonistas de los Receptores de Bradiquinina , Antagonistas de los Receptores H2 de la Histamina/farmacología , Hipolipemiantes/farmacología , Laringe/irrigación sanguínea , Laringe/efectos de los fármacos , Metiamida/farmacología , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , Piridinolcarbamato/farmacología , Conejos , Receptores Histamínicos H2/efectos de los fármacos , Tráquea/irrigación sanguínea , Tráquea/efectos de los fármacosRESUMEN
Histamine and 2-methyl histamine caused dose-dependent aggregation of melanophores in toad B. melanostictus. The effects were effectively antagonised by mepyramine, a specific H1 histamine receptor antagonist, and metiamide a specific H2 receptor antagonist. On the other, hand 4-methyl histamine, a specific H2 receptor agonist dispersed the melanophores. The results suggest that adult Bufo melanophores have H1 histamine receptors which mediate melanophore aggregation, however, dispersion of melanophores may be controlled by undifferentiated histamine receptors of H2 type.
Asunto(s)
Histamínicos/farmacología , Melanóforos/efectos de los fármacos , Animales , Bufonidae , Agregación Celular/efectos de los fármacos , Histamina/farmacología , Técnicas In Vitro , Melanóforos/metabolismo , Metilhistaminas/farmacología , Metiamida/farmacología , Pirilamina/farmacologíaRESUMEN
1. The role of the vascular endothelium in the relaxant and contractile responses to histamine of the isolated rabbit aorta; common carotid, mesenteric, renal, and femoral arteries; as well as receptor types mediating these responses were analyzed. 2. Histamine (10(-8) to 10(-4) mol/l) contracted resting rings and caused a further concentration-dependent contraction of rings of the arteries precontracted by phenylephrine. 3. Pyrilamine abolished the contractile response to histamine in resting rings of the arteries, whereas it reversed that response into a concentration-dependent relaxant response in precontracted rings of the arteries. The relaxant effect of histamine was abolished by metiamide, but it was not affected by sotalol and atropine. Moreover, in control experiments, the phenylephrine-induced contractions and acetylcholine-induced relaxations were not changed by pyrilamine and metiamide, respectively. 4. Endothelial removal did not influence the contractile and relaxant responses of the arteries to histamine. 5. These findings indicate that, in the isolated rabbit aorta and common carotid, mesenteric, renal, and femoral arteries, the contractile effect of histamine resulting from the activation of H1 receptors overcomes its relaxant effect resulting from the activation of H2 receptors. The effects of histamine are neither mediated nor modulated by the endothelial cells.
Asunto(s)
Arterias/efectos de los fármacos , Endotelio Vascular/fisiología , Histamina/farmacología , Músculo Liso Vascular/efectos de los fármacos , Animales , Femenino , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Técnicas In Vitro , Masculino , Metiamida/farmacología , Contracción Muscular/efectos de los fármacos , Relajación Muscular/efectos de los fármacos , Pirilamina/farmacología , ConejosRESUMEN
Classic physiological and pharmacological experiments were made on 33 rabbits under hexenal anesthesia to determine the presence, topical concentration and activity of H2 and B2-receptors. These parameters were inferred by edema and other vascular responses of the mucosa to local application of histamine and bradykinin prior to and after usage of specific blocker of each receptor type. Both mediators and receptor blockers were applied to laryngeal and tracheal mucosa for 10 min (histamine 10(-4) and 10(-3) g/ml, H2-receptor blocker metiamide 0.1 and 1 mmol, bradykinin 10(-5) and 10(-4) g/ml, B2-receptor blocker pyridinolcarbamate 10(-2) and 10(-1) g/ml). The larynx and trachea were found to contain H2- and B2-receptors the concentrations of which were greater in the subvocal part of the larynx than in the vestibular part and trachea. B2-receptor activity and concentrations in the subvocal part of the larynx were 10 times while in the trachea 1.5-2 times greater than those of H2-receptors. These regularities were not influenced by individual varieties of receptor topical concentrations. The blocker density in the receptors and the duration of their binding were not universally proportional. This is also true for the relations mediator-receptor. Concentrations and activity of H2- and B2-receptors are thought important in pathogenesis and location of acute inflammatory and allergic conditions in the upper respiratory tract.
Asunto(s)
Laringe/metabolismo , Receptores de Bradiquinina/análisis , Receptores Histamínicos H2/análisis , Tráquea/metabolismo , Animales , Bradiquinina/farmacología , Antagonistas de los Receptores de Bradiquinina , Histamina/farmacología , Antagonistas de los Receptores Histamínicos/farmacología , Técnicas In Vitro , Laringe/efectos de los fármacos , Laringe/fisiología , Metiamida/farmacología , Membrana Mucosa/efectos de los fármacos , Membrana Mucosa/metabolismo , Piridinolcarbamato/farmacología , Conejos , Receptores de Bradiquinina/fisiología , Receptores Histamínicos H2/fisiología , Tráquea/efectos de los fármacos , Tráquea/fisiologíaAsunto(s)
Inflamación/fisiopatología , Leucotrienos/metabolismo , Pulmón/fisiopatología , Animales , Cobayas , Leucotrieno B4/antagonistas & inhibidores , Pulmón/efectos de los fármacos , Pulmón/inmunología , Masculino , Metiamida/farmacología , Ovalbúmina/inmunología , Pirilamina/farmacología , Quinolinas/farmacologíaRESUMEN
Histamine and the guanosine 3',5'-cyclic monophosphate (cGMP)-inducing agent sodium nitroprusside both increased serotonin (5-HT) uptake and cGMP levels in isolated human platelets in vitro. Histaminergic stimulation was observed at concentrations ranging from 10 nM to 0.25 microM [mean effective concentration (EC50) = 0.1 microM histamine]. The inhibition produced by the H2-receptor antagonists tiotidine, metiamide, and cimetidine was 10-10(5) times more potent on histamine receptors regulating 5-HT uptake and cGMP generation in human platelets than on the histaminergic receptors H1, HIC, H2, and H3 in other tissues. The in vitro histamine-induced 5-HT uptake was prevented by preincubation of isolated human platelets in the presence of the nitric oxide synthase inhibitor NG-monomethyl-L-arginine or the cGMP-lowering agent LY-83583. Histamine was ineffective in stimulating cAMP generation in human platelets and did not interact with effector sites known to downregulate 5-HT uptake, including imipramine, gamma-aminobutyric acid A, peripheral type benzodiazepine-binding sites, and V1a vasopressin receptors inducing human platelet shape change and aggregation. These atypical human platelet histaminergic receptors differ from the previously classified histamine receptors by their apparent high affinity to histamine H2-receptor antagonists and their apparent link with the soluble, nitric oxide-dependent guanylate cyclase. These findings suggest that human platelets express a new subtype H2h of histamine receptors.
Asunto(s)
Plaquetas/metabolismo , Antagonistas de los Receptores Histamínicos/farmacología , Histidina/farmacología , Receptores Histamínicos/fisiología , Serotonina/sangre , Adulto , Aminoquinolinas/farmacología , Transporte Biológico/efectos de los fármacos , Plaquetas/efectos de los fármacos , Cimetidina/análogos & derivados , Cimetidina/metabolismo , Cimetidina/farmacología , AMP Cíclico/sangre , Dimaprit/farmacología , Famotidina/farmacología , Femenino , Histidina/análogos & derivados , Humanos , Imipramina/farmacología , Impromidina/farmacología , Técnicas In Vitro , Masculino , Metiamida/farmacología , Persona de Mediana Edad , Modelos Biológicos , Agregación Plaquetaria/efectos de los fármacos , Receptores Histamínicos/efectos de los fármacosRESUMEN
The activation of mast-cells in situ induces angiogenesis in normally vascularized, adult mammalian tissue. Since the secreting mast-cell characteristically releases histamine, we studied the possible role of histamine in the outcome of mast-cell mediated angiogenesis using the rat mesenteric window assay. One H1-receptor antagonist, brompheniramine maleate (BPA), and one H2-receptor antagonist, metiamide, were separately administered systemically (s.c.) at non-toxic doses during the period of angiogenesis induction. Angiogenesis was effected by i.p. injections of the mast-cell secretagogue compound 48/80 for 5 consecutive days. The animals were killed 14 days after the start of the i.p. and s.c. treatment, close to the middle of the expanding angiogenic phase of the angiogenic reaction studied. Angiogenesis was quantified in terms of (a) the number of vessel profiles per unit tissue length (No/UL), which reflects mainly the degree of branching and/or tortuosity, (b) the relative vascularized area (VA), which is a measure of spatial extension, and (c) the vascular density (VD), a measure of vessel density per unit area of vascularized tissue. Whereas BPA significantly suppressed No/UL, metiamide significantly reduced No/UL and VD in statistical terms suggesting that endogenous mast-cell histamine is angiogenic through both H1- and H2-receptors. This appears to be the first paper to report that the occupancy of H2-receptors is angiogenic.
Asunto(s)
Histamina/fisiología , Mastocitos/metabolismo , Neovascularización Patológica/metabolismo , Receptores Histamínicos H1/fisiología , Receptores Histamínicos H2/fisiología , Animales , Antagonistas de los Receptores Histamínicos H1/farmacología , Antagonistas de los Receptores H2 de la Histamina/farmacología , Liberación de Histamina/fisiología , Masculino , Mesenterio/irrigación sanguínea , Metiamida/farmacología , Neovascularización Patológica/patología , Ratas , Ratas Sprague-DawleyRESUMEN
We characterized the kinetics of and determined the mediators involved in antigen-induced contraction of pulmonary arteries (PA) and lung parenchyma isolated from actively sensitized guinea pigs. Ovalbumin (10(-2) mg/ml) induced contractions of PA rings, which reached maximum amplitude by 2 min and decayed to 50% of maximum by 4-6 min. Pyrilamine (10(-6) M) delayed the onset of contraction and decreased the peak of the response by > 50%. Metiamide (10(-4) M) partially reversed this effect. The addition of indomethacin (10(-6) M) to the combination of pyrilamine and metiamide had no significant effect. The further addition of the leukotriene (LT) D4/LTE4 receptor antagonist SKF 104353 (10(-5) M) reduced the contraction by > 80%. The maximum amplitude of antigen-induced contraction of parenchymal strips was reached by 15 min and was sustained for > 60 min. In these tissues, SKF 104353 inhibited the contraction by approximately 35%, but the histamine receptor antagonists and indomethacin had no significant effect. These results suggest that both histamine and sulfidopeptide LTs mediate antigen-induced contraction of PA, whereas sulfidopeptide LTs, but not histamine, are involved in the parenchymal response.
Asunto(s)
Antígenos/administración & dosificación , Pulmón/fisiología , Arteria Pulmonar/fisiología , Animales , Ácidos Dicarboxílicos/farmacología , Cobayas , Técnicas In Vitro , Indometacina/farmacología , Pulmón/efectos de los fármacos , Pulmón/inmunología , Masculino , Metiamida/farmacología , Contracción Muscular/efectos de los fármacos , Contracción Muscular/inmunología , Ovalbúmina/inmunología , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/inmunología , Pirilamina/farmacología , SRS-A/antagonistas & inhibidores , Vasoconstricción/efectos de los fármacos , Vasoconstricción/inmunologíaRESUMEN
We evaluated the serum gastrin response to feeding and increasing age in swine. In addition, metiamide (SKF 92058) and the more potent H2 receptor antagonist, SKF 93479, were administered in the feed after which, serum was evaluated for changes in gastrin. We also measured metiamide clearance from the blood after an intravenous bolus infusion of the drug. Gastrin levels measured 15 minutes after feeding decreased as a consequence of increasing animal age (P less than 0.0001). Postprandial serum gastrin levels increased to maximal levels by approximately 60 minutes postfeeding and declined slowly during the subsequent 60 minutes. There were no differences in the postprandial gastrin responses during the morning or evening feeding, although evening levels tended to be higher (P greater than 0.10). Metiamide fed at 50 or 500 mg/kg of feed caused a significant increase (P less than 0.02) in gastrin 15 minutes postfeeding (31.0 and 39.7%, respectively). Metiamide in serum decreased to undetectable levels by 120 minutes after an intravenous infusion of 10 mg/kg in two pigs. Metiamide fed at 162 mg/kg and SKF 93479 fed at 54 mg/kg of ration resulted in similar elevations in gastrin, indicating that SKF 93479 was as potent as metiamide in eliciting a gastrin response by using only one-third of the concentration in the feed. These results provide evidence for similarities between swine and humans in serum gastrin responses.
Asunto(s)
Gastrinas/sangre , Antagonistas de los Receptores H2 de la Histamina/farmacología , Factores de Edad , Animales , Humanos , Masculino , Tasa de Depuración Metabólica , Metiamida/administración & dosificación , Metiamida/farmacocinética , Metiamida/farmacología , Pirimidinonas/farmacología , Especificidad de la Especie , PorcinosRESUMEN
We examined the response of tracheal mucosal blood flow normalized for systemic arterial pressure (Qtrn), water content (VH20) and luminal dead space (Vtr) to nebulized histamine in intact, lightly anesthetized sheep. Nebulized histamine produced rapid increases in mean Qtrn (+84%) and VH2O (+85%), and a decrease in mean Vtr (-17%) (P less than 0.05) within 5 min post completion of challenge. Mean Vtr rapidly returned to baseline, while mean Qtrn and VH2O remained elevated for 60 and 90 min after challenge, respectively. Pretreatment with chlorpheniramine (H1-antagonist) blocked the changes in Vtr and VH2O, and attenuated the increase in Qtrn. Metiamide (H2-antagonist) pretreatment abolished the increase in Qtrn and blunted the increase in VH2O, but had no effect on the decrease in VTR. 2-methylhistamine (H1-agonist) decreased mean Qtrn and Vtr (P less than 0.05) and dimaprit (H2-agonist) increased mean Qtrn (P less than 0.05) without changing Vtr. Neither 2-methylhistamine nor dimaprit significantly altered VH2O. Atropine blocked histamine induced decreases in Vtr and slightly attenuated the increases in Qtrn and VH2O. Thus, histamine increased airway smooth muscle tone and mucosal water content principally via H1 receptors, and mucosal perfusion via H2 receptors. The airway smooth muscle contraction involved muscarinic pathways.
Asunto(s)
Histamina/farmacología , Músculo Liso/efectos de los fármacos , Ovinos/fisiología , Tráquea/irrigación sanguínea , Agua/metabolismo , Animales , Atropina/farmacología , Clorfeniramina/farmacología , Dimaprit , Femenino , Mediciones del Volumen Pulmonar , Metiamida/farmacología , Membrana Mucosa/irrigación sanguínea , Membrana Mucosa/metabolismo , Membrana Mucosa/ultraestructura , Músculo Liso/fisiología , Músculo Liso/ultraestructura , Receptores Colinérgicos/efectos de los fármacos , Receptores Colinérgicos/fisiología , Receptores Histamínicos H1/efectos de los fármacos , Receptores Histamínicos H1/fisiología , Receptores Histamínicos H2/efectos de los fármacos , Receptores Histamínicos H2/fisiología , Flujo Sanguíneo Regional/efectos de los fármacos , Ovinos/metabolismo , Tiourea/farmacología , Tráquea/metabolismo , Tráquea/ultraestructuraRESUMEN
Epinephrine, histamine and prostaglandin E1 stimulated adenylate cyclase activity in lung membranes and their stimulation of the enzyme activity was completely blocked by propranolol, metiamide and indomethacin, respectively. A partially-purified activator from the adult rat lung also enhanced adenylate cyclase activity in membranes. However, stimulation of adenylate cyclase by the rat lung activator was not abolished by the above receptor antagonists. Further, epinephrine, NaF and Gpp(NH)p stimulated adenylate cyclase activity rather readily, whereas stimulation of the enzyme activity by the lung activator was evident after an initial lag phase of 10 min. Also, the lung activator produced additive activation of adenylate cyclase with epinephrine, NaF and Gpp(NH)p. These results indicate that the lung activator potentiates adenylate cyclase activity in membranes by a mechanism independent from those known for epinephrine, NaF and Gpp(NH)p. Incubation of lung membranes for 30 min at 40 degrees C resulted in a loss of adenylate cyclase activation by NaF and Gpp(NH)p. Addition of the released proteins to the heat-treated membranes did not restore the enzyme response to these agonists. However, heat treatment of lung membranes in the presence of 2-mercaptoethanol or dithiothreitol prevented the loss of adenylate cyclase response to NaF and Gpp(NH)p. N-ethylmaleimide abolished adenylate cyclase activation by epinephrine, NaF, Gpp(NH)p and the lung activator. These results indicate that the sulfhydryl groups are important for adenylate cyclase function in rat lung membranes.
Asunto(s)
Adenilil Ciclasas/metabolismo , Activación Enzimática/efectos de los fármacos , Pulmón/enzimología , Proteínas de Neoplasias/química , Animales , Membrana Celular/enzimología , Citoplasma/química , Citoplasma/enzimología , Citoplasma/metabolismo , Epinefrina/farmacología , Guanilil Imidodifosfato/farmacología , Histamina/farmacología , Técnicas para Inmunoenzimas , Indometacina/farmacología , Pulmón/química , Masculino , Metiamida/farmacología , Proteínas de Neoplasias/metabolismo , Propranolol/farmacología , Prostaglandinas E/farmacología , Ratas , Ratas Endogámicas , Fluoruro de Sodio/farmacologíaRESUMEN
The influence of histaminergic sites in the preoptic-anterior hypothalamic area (POA-AHA) on the basal release of luteinizing hormone (LH) under a continuous regimen of estradiol, progesterone, or both was studied in ovariectomized rats. Different groups of animals were subjected to the following experimental schedule: at day 1, rats received a s.c. silastic implant filled with oil, estradiol, progesterone, or estradiol plus progesterone. Seven days later (day 7), animals were implanted into the POA-AHA with microinjection cannulae. At day 8 and 9, the different groups of rats were microinjected with 1 microliter of saline solution containing 35 nMol of pyrilamine or metiamide, or 20 nMol of alpha-fluoro-methyl-histidine. At day 10, blood samples were taken through a permanent jugular cannulae implanted in situ the day before. LH concentrations were determined in plasma by RIA. Results showed that the increase of LH plasma levels induced by the ovariectomy was inhibited by the estrogen implant, as expected. Treatment of metiamide or alpha-fluoro-methyl-histidine did not affect the pattern of LH secretion. Nevertheless, treatment of metiamide induced a transient increase in the gonadotropin concentrations that extended for two hours (16:00 and 17:00 H). No change in LH plasma levels was observed in rats bearing the progesterone implant. Treatments (pyrilamine, metiamide, or alpha-fluoro-methyl-histidine into the POA-AHA) had no effect. The transient increase in the hormone levels observed in rats treated with pyrilamine in the estrogen-implanted rats was absent in rats bearing the estrogen-progesterone implant.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Estradiol/farmacología , Histamina/fisiología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Hipotálamo Anterior/efectos de los fármacos , Hormona Luteinizante/metabolismo , Adenohipófisis/metabolismo , Progesterona/farmacología , Receptores Histamínicos/fisiología , Animales , Interacciones Farmacológicas , Femenino , Metilhistidinas/farmacología , Metiamida/farmacología , Ovariectomía , Pirilamina/farmacología , Ratas , Tasa de Secreción/efectos de los fármacosRESUMEN
Suspensions of rat liver hepatocytes exposed to oxmetidine rapidly lose viability, an event preceded by a marked and rapid inhibition of cell respiration and depletion of ATP. In isolated rat liver mitochondria (RLM), oxmetidine inhibits pyruvate/malate- but not succinate-supported, ADP-stimulated oxygen consumption (state 3). The purpose of this investigation was to determine the exact molecular site of oxmetidine-induced inhibition of RLM electron transport. Oxmetidine did not significantly inhibit succinate-supported, ADP-stimulated state 3 oxygen consumption in isolated RLM at concentrations up to 0.5 mM. In contrast, oxmetidine significantly inhibited beta-hydroxybutyrate- or isocitrate-supported mitochondrial state 3 oxygen consumption at concentrations above 10 microM and 25 microM, respectively. In RLM electron transport particles (ETP), oxmetidine inhibited NADH-oxidase and NADH-CoQ reductase activity (IC50 of 3.4 microM and 2.6 microM, respectively). However, oxmetidine did not significantly affect NADH-Fe3(CN)6 reductase activity (at concentrations up to 200 microM). SK&F 92058, a thiourea analog of oxmetidine approximately 24-fold less toxic to hepatocytes, produced a similar pattern of inhibition of respiration, although far less potent (IC50 of 0.8 mM and 0.6 mM for NADH-oxidase and NADH-CoQ reductase, respectively). SK&F 92058 did not significantly inhibit NADH-Fe3(CN)6 reductase activity at concentrations up to 3.0 mM. Studies with [14C]oxmetidine failed to show any specific, saturable binding to rat liver ETP.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Antagonistas de los Receptores H2 de la Histamina/toxicidad , Imidazoles/toxicidad , Mitocondrias Hepáticas/efectos de los fármacos , Consumo de Oxígeno/efectos de los fármacos , Animales , Transporte de Electrón/efectos de los fármacos , Antagonistas de los Receptores H2 de la Histamina/metabolismo , Imidazoles/metabolismo , Metiamida/farmacología , Mitocondrias Hepáticas/metabolismo , Oxidación-Reducción , RatasAsunto(s)
Mucosa Gástrica/metabolismo , Receptores de Superficie Celular/fisiología , Animales , Atropina/farmacología , Perros , Alimentos , Jugo Gástrico/efectos de los fármacos , Jugo Gástrico/metabolismo , Mucosa Gástrica/efectos de los fármacos , Gastrinas/inmunología , Histamina/farmacología , Sueros Inmunes/farmacología , Metiamida/farmacología , Células Parietales Gástricas/efectos de los fármacos , Células Parietales Gástricas/metabolismo , Pentagastrina/farmacología , Receptores de Superficie Celular/efectos de los fármacosRESUMEN
Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.