RESUMEN
The prostacyclin (IP) receptor agonists, treprostinil, iloprost and the selexipag metabolite, MRE-269 (ACT-333679) were evaluated in rat distal pulmonary blood vessels. Small pulmonary arteries and veins were pre-contracted with the thromboxane mimetic, U46619 (25 and 100nM, respectively), and relaxation determined with and without IP receptor antagonists, RO1138452 and RO3244794. In arteries, treprostinil was a more potent vasorelaxant than iloprost, while the efficacy of iloprost was greater. In pulmonary arteries, treprostinil-induced relaxation was essentially abolished by both IP antagonists (1µM), while responses to iloprost were partially inhibited. Both treprostinil and iloprost were equipotent, prominently relaxing pulmonary veins with responses being similarly and partially sensitive to IP antagonists. In contrast, RO1138452 failed to inhibit relaxations to MRE-269 in either pulmonary arteries or veins, suggesting no involvement of typical IP receptors. Thus, rat pulmonary tissues cannot be considered appropriate to assess classical IP receptors using the proposed highly selective non-prostanoid agonist MRE-269, contrasting with the IP receptor agonism profile of prostacyclin analogues, iloprost and treprostinil.
Asunto(s)
Acetamidas/metabolismo , Acetatos/metabolismo , Acetatos/farmacología , Epoprostenol/análogos & derivados , Iloprost/farmacología , Arteria Pulmonar/efectos de los fármacos , Venas Pulmonares/efectos de los fármacos , Pirazinas/metabolismo , Pirazinas/farmacología , Animales , Benzofuranos/farmacología , Compuestos de Bencilo/farmacología , Epoprostenol/farmacología , Femenino , Imidazoles/farmacología , Masculino , Propionatos/farmacología , Arteria Pulmonar/fisiología , Venas Pulmonares/fisiología , Ratas , Ratas Sprague-Dawley , Receptores de Epoprostenol/antagonistas & inhibidores , Vasodilatación/efectos de los fármacosRESUMEN
BACKGROUND AND PURPOSE: Leukotriene B(4) (LTB(4)), formed by the sequential actions of the 5-lipoxygenase (5-LO) and leukotriene A(4) hydrolase (LTA(4)H), is a pro-inflammatory mediator implicated in the pathogenesis of inflammatory bowel disease. However, inhibitors of 5-LO have not proved to be consistent in their therapeutic efficacy in colitis. Another approach to inhibiting LTB(4) synthesis is through the use of inhibitors of LTA(4)H, such as the novel, potent and selective compound, JNJ 26993135. EXPERIMENTAL APPROACH: The effect of oral administration of JNJ 26993135 has been evaluated in a rat model of colitis provoked by colonic instillation of trinitrobenzenesulphonic acid (TNBS). The extent and severity of the macroscopic inflammatory response, the colonic levels of myeloperoxidase (MPO) and LTB(4) and of the pro-inflammatory cytokines, tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) were measured. KEY RESULTS: Oral administration of JNJ 26993135 (5, 15 and 30 mg kg(-1), twice a day) dose-dependently reduced both the extent and intensity of the colonic inflammatory damage observed 3 days after TNBS challenge. JNJ 26993135 also dose-dependently reduced the elevated colonic levels of LTB(4), as well as the inflammatory biomarkers, MPO, IL-6 and TNF-alpha. This dosing regimen was supported by the pharmacokinetic profile of JNJ 26993135, along with the demonstration of the inhibition of ex vivo production of LTB(4) in whole blood following oral administration. CONCLUSIONS AND IMPLICATIONS: These results with JNJ 26993135 in the rat TNBS model support the role of LTB(4) in colitis and the potential value of targeting LTA(4)H for the treatment of inflammatory bowel diseases.
Asunto(s)
Benzotiazoles/farmacología , Colitis/tratamiento farmacológico , Inhibidores Enzimáticos/farmacología , Epóxido Hidrolasas/antagonistas & inhibidores , Inflamación/tratamiento farmacológico , Piperidinas/farmacología , Administración Oral , Animales , Benzotiazoles/administración & dosificación , Benzotiazoles/farmacocinética , Colitis/inducido químicamente , Colitis/fisiopatología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Sistemas de Liberación de Medicamentos , Inhibidores Enzimáticos/administración & dosificación , Inhibidores Enzimáticos/farmacocinética , Inflamación/etiología , Interleucina-6/metabolismo , Masculino , Peroxidasa/efectos de los fármacos , Peroxidasa/metabolismo , Piperidinas/administración & dosificación , Piperidinas/farmacocinética , Ratas , Ratas Wistar , Índice de Severidad de la Enfermedad , Ácido Trinitrobencenosulfónico , Factor de Necrosis Tumoral alfa/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Nitric oxide (NO) synthase activity, which converts arginine to citrulline and NO, is present in homogenates of rat gastric mucosal cells. The aims of this study were to identify the form of NO synthase expressed in gastric cells isolated from fed rats, and to investigate the metabolism of arginine by suspensions of intact mucosal cells. Antibodies directed against the neuronal form of NO synthase recognised a protein of 160 kDa on immunoblots of extracts of gastric cells, and stained isolated cells of approx. 8 microm in diameter. NO synthase was enriched in a cell fraction which banded at high-density in a Percoll gradient, and was inhibited (IC50) by N(G)-nitro-L-arginine (0.8 microM), N(G)-monomethyl-L-arginine (12.6 microM), L-canavanine (147 microM), trifluoperazine (140 microM) and by phosphorylation involving protein kinase C. Intact gastric cells converted exogenous arginine to ornithine and citrulline. Arginase was present in the cells, and was predominantly responsible for arginine metabolism because formation of ornithine and citrulline was reduced by the arginase inhibitors, N(G)-hydroxy-L-arginine and L-ornithine, but not by NO synthase inhibitors such as N(G)-nitro-L-arginine. In conclusion, NO synthase that resembles the neuronal isoform is present in gastric mucosal cells, but a pathway involving arginase seems to be largely responsible for citrulline formation from exogenous arginine in intact mucosal cells.
Asunto(s)
Arginasa/análisis , Mucosa Gástrica/enzimología , Óxido Nítrico Sintasa/análisis , Animales , Arginasa/antagonistas & inhibidores , Arginina/metabolismo , Separación Celular , Citrulina/metabolismo , Mucosa Gástrica/citología , Immunoblotting , Inmunohistoquímica , Óxido Nítrico Sintasa/antagonistas & inhibidores , RatasRESUMEN
1 The mechanisms by which -he bile salt, sodium taurocholate, potentiates the formation of gastric mucosal erosions induced by indomethacin has been investigated in the rat. 2 Systemic administration of indomethacin lowered resting mucosal blood flow but had no effect on the acid back-diffusion across the mucosa. 3 Gastric perfusion of taurocholate in acid solution increased acid back-diffusion and lowered the potential differences. This was accompanied by an increase in mucosal blood flow, which may represent a protective mechanism in the mucosa. 4 Administration of indomethacin during acid-taurocholate perfusion reduced this elevated mucosal blood flow without any further change in acid back-diffusion. 5 The results suggest that although a decrease in mucosal blood flow or an increase in acid back-diffusion can lead to a low incidence of erosions, a combination of both produces extensive mucosal damage. 6 The (15S)-methyl analogue of prostaglandin E2 reduced erosion formation induced by indomethacin and acid-taurocholate administration. 7 It is suggested that this protective action of the prostaglandin analogue may be linked to changes in gastric mucosal permeability and in mucosal blood flow.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Indometacina/farmacología , Prostaglandinas E/farmacología , Ácido Taurocólico/farmacología , Ácidos/metabolismo , Animales , Difusión , Interacciones Farmacológicas , Mucosa Gástrica/irrigación sanguínea , Mucosa Gástrica/metabolismo , Técnicas In Vitro , Potenciales de la Membrana/efectos de los fármacos , Prostaglandinas Sintéticas/farmacología , Ratas , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
Subcutaneous administration of anti-inflammatory doses of aspirin, indomethacin, naproxen and flurbiprofen inhibited prostacyclin formation ex vivo in the luminally-perfused gastric mucosa of anaesthetized rats. These doses of anti-inflammatory compounds potentiated the formation of gastric mucosal erosions following 3 h luminal perfusion of the topical irritant, acidified sodium taurocholate (2 mM in 100 mM HCl). The increase in luminal acid-loss during gastric perfusion of acidified taurocholate was not significantly enhanced by these anti-inflammatory agents. A correlation was found between the increase in gastric erosion formation and the inhibition of mucosal prostacyclin formation ex vivo by intravenous injection of aspirin or ketoprofen during acid-taurocholate perfusion. BW755C, which failed to inhibit mucosal prostacyclin formation ex vivo, did not significantly augment acid-taurocholate induced gastric damage. The present findings support the potentiating interactions between topical irritation and inhibition of gastric cyclo-oxygenase in the genesis of the gastric lesions.
Asunto(s)
Antiinflamatorios/toxicidad , Inhibidores de la Ciclooxigenasa , Mucosa Gástrica/efectos de los fármacos , Ácido Taurocólico/farmacología , Animales , Aspirina/toxicidad , Sinergismo Farmacológico , Epoprostenol/biosíntesis , Ácido Gástrico/metabolismo , Mucosa Gástrica/metabolismo , Masculino , Norepinefrina/farmacología , Ratas , Ratas EndogámicasRESUMEN
The effect of the endogenous vasoconstrictor peptide, endothelin, on gastric mucosal integrity has been investigated in the rat. Local intra-arterial infusion of endothelin, in picomole doses, dose-dependently induced haemorrhagic and necrotic damage in the gastric mucosa. Such injury was not prevented by atropine, cimetidine, adrenoceptor antagonists, indomethacin, or the 5-lipoxygenase inhibitor BW A4C. These results suggest a potential pro-ulcerogenic role of endothelin in the pathogenesis of gastric damage and ulceration.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Péptidos/farmacología , Animales , Endotelinas , Endotelio Vascular/fisiología , Mucosa Gástrica/patología , Hemorragia Gastrointestinal/inducido químicamente , Masculino , Necrosis , Péptidos/fisiología , Ratas , Ratas Endogámicas , Úlcera Gástrica/inducido químicamente , Vasoconstrictores/farmacologíaRESUMEN
1. A technique for the close-arterial administration of substances to the rat stomach in vivo has been developed. 2. Intra-arterial infusion of platelet-activating factor (Paf, 10-50 ng kg-1 min-1 for 10 min) induced macroscopically assessed damage in the corpus mucosa, characterized as vasocongestion and necrosis. 3. The threshold intra-arterial doses of Paf that induced histologically assessed damage in the antrum and corpus of the stomach (10 and 5 ng kg-1 min-1, respectively) produced minimal systemic hypotension (less than 20 mmHg) suggesting a dissociation between these events. 4. Pretreatment with the Paf-antagonist, L-652,731 (2.5 mg kg-1 i.v.) prevented the gastric damage induced by local infusion of Paf. 5. Intravenous infusion of Paf (25 ng kg-1 min-1) did not significantly damage the gastric mucosa, in contrast to the same dose infused locally, yet Paf administered by either route produced a comparable degree of hypotension. Such findings suggest minimal metabolism of Paf during its passage through the gastric circulation. 6. Local intra-arterial infusion of Paf in doses as low as 0.25 ng kg-1 min-1, which had no systemic hypotensive actions, significantly induced gastric damage in the presence of intragastric 20% ethanol. 7. These observations support a local role for Paf in the pathogenesis of gastric irritation and ulceration, such as that observed during endotoxin shock or bacterial infection. The present technique is thus useful for the study of locally administered substances on gastric function and integrity.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Factor de Activación Plaquetaria , Animales , Presión Sanguínea/efectos de los fármacos , Furanos/farmacología , Mucosa Gástrica/citología , Infusiones Intravenosas , Inyecciones Intraarteriales , Masculino , Perfusión , Factor de Activación Plaquetaria/antagonistas & inhibidores , Ratas , Ratas EndogámicasRESUMEN
The effects of pretreatment with 16,16-dimethyl prostaglandin E2 (DmPGE2) on the recovery of gastric mucosal 'barrier' parameters after ethanol-induced damage were studied using an ex vivo chamber preparation in the rat. DmPGE2 (4-40 micrograms kg-1) significantly reduced the extent of haemorrhagic damage to the gastric mucosa induced by the topical application of 50% ethanol followed by 0.05 M hydrochloric acid. The lowest dose of DmPGE2 tested (4 micrograms kg-1) had no effect on the ethanol-induced changes in transmucosal potential difference (PD) or K+ efflux. However, DmPGE2 at doses at 20 or 40 micrograms kg-1 significantly reduced the changes in these indices of epithelial integrity. The recovery of PD and K+ efflux to control levels after ethanol-injury was accelerated by DmPGE2. With the two higher doses of DmPGE2 (20 and 40 micrograms kg-1) there was a significantly (P less than 0.001) lower level of epithelial discontinuity, measured histologically, in samples taken at the end of the experiment. These results suggest that at the higher doses, DmPGE2 confers some protection to the gastric epithelium as well as accelerating the recovery of epithelial integrity after damage induced by ethanol.
Asunto(s)
16,16-Dimetilprostaglandina E2/farmacología , Etanol/antagonistas & inhibidores , Mucosa Gástrica/efectos de los fármacos , Prostaglandinas E Sintéticas/farmacología , Administración Tópica , Animales , Etanol/toxicidad , Mucosa Gástrica/metabolismo , Mucosa Gástrica/patología , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/prevención & control , Masculino , Potenciales de la Membrana/efectos de los fármacos , Necrosis , Potasio/metabolismo , Ratas , Ratas EndogámicasRESUMEN
The anti-aggregatory prostanoid, prostaglandin D2 (PGD2) does not completely inhibit ADP-induced aggregation of guinea-pig platelets and thus produces a bell-shaped dose-inhibition curve. The nature of this bell-shaped curve has now been investigated in guinea-pig platelet-rich plasma. Two selective thromboxane receptor antagonists, 13-aza-prostanoic acid (13-AZA; 16-64.4 microM) and BM 13.177 (5.9-29.8 microM), converted PGD2 to a full inhibitor of aggregation in a dose-related manner. The putative platelet PGD2 receptor antagonist, N-0164 (75 microM) also converted PGD2 to a full inhibitor of platelet aggregation. In contrast to 13-AZA and BM 13.177, higher concentrations of N-0164 (380 and 760 microM) caused a dose-related rightward shift of the PGD2 dose-inhibition curve. The thromboxane receptor antagonism of N-0164 was confirmed in studies in which the dose-aggregation curve to U-46619, a thromboxane mimetic, was competitively antagonized with a pA2 value of 4.67 and a slope of 1.13, comparable to that of 13-AZA. The results show that N-0164 acts as both a platelet PGD2 and thromboxane-receptor antagonist in both human and guinea-pig platelet-rich plasma. The results further indicate that PGD2 can interact at thromboxane receptors in guinea-pig platelets.
Asunto(s)
Plaquetas/metabolismo , Organofosfonatos , Prostaglandinas D/sangre , Receptores de Superficie Celular/metabolismo , Receptores de Prostaglandina/metabolismo , Ácido 15-Hidroxi-11 alfa,9 alfa-(epoximetano)prosta-5,13-dienoico , Adenosina Difosfato/farmacología , Animales , Plaquetas/efectos de los fármacos , Cobayas , Masculino , Compuestos Organofosforados/farmacología , Agregación Plaquetaria/efectos de los fármacos , Prostaglandina D2 , Endoperóxidos de Prostaglandinas Sintéticos/farmacología , Ácidos Prostanoicos/farmacología , Receptores de Tromboxanos , Sulfonamidas/farmacologíaRESUMEN
The effects of several inhibitors of arachidonic acid metabolism on gastric necrosis, hypotension, haemoconcentration, leukopenia and plasma exudation induced by platelet-activating factor (Paf) were studied in the rat. A 10 min intravenous infusion of Paf (100 ng kg-1 min-1) caused extensive gastric damage and a marked fall in systemic blood pressure which had not recovered to basal levels 30 min after the infusion had been terminated. Paf also caused significant haemoconcentration, plasma exudation and transient leukopenia. Pretreatment with dexamethasone (0.2 or 2 mg kg-1 s.c.) or prednisolone (20 mg kg-1 s.c.) two hours before Paf significantly reduced the gastric damage and accelerated the recovery of blood pressure after the Paf infusion. Likewise, BW755C (50 mg kg-1 p.o.) significantly reduced the gastric damage. Acute pretreatment with dexamethasone (2 mg kg-1 i.v.) 15 min before Paf, or with indomethacin (5 mg kg-1 s.c.), acetylsalicylic acid (10 mg kg-1 i.v.) or 1-benzylimidazole (50 mg kg-1 s.c.) did not significantly affect the gastric damage induced by Paf. The Paf-induced haemoconcentration and plasma exudation were significantly reduced by pretreatment with prednisolone (20 mg kg-1 s.c.) or BW755C (50 mg kg-1 p.o.), while Paf-induced leukopenia was unaffected by either drug. These studies indicate that cyclo-oxygenase products of arachidonic acid are unlikely to contribute significantly to the gastric damage or the prolonged hypotension induced by Paf. The ability of corticosteroids and BW755C to reduce the gastric damage, haemoconcentration and plasma exudation suggests that lipoxygenase products of arachidonic acid may contribute to these actions of Paf.
Asunto(s)
Ácidos Araquidónicos/metabolismo , Mucosa Gástrica/patología , Factor de Activación Plaquetaria/toxicidad , 4,5-dihidro-1-(3-(trifluorometil)fenil)-1H-pirazol-3-amina , Animales , Ácido Araquidónico , Ácidos Araquidónicos/antagonistas & inhibidores , Aspirina/farmacología , Presión Sanguínea/efectos de los fármacos , Dexametasona/farmacología , Hematócrito , Masculino , Necrosis , Factor de Activación Plaquetaria/sangre , Prednisolona/farmacología , Pirazoles/farmacología , Ratas , Ratas EndogámicasRESUMEN
1. The interactions between local intra-arterial infusion of endothelin-1 (ET-1) and rat alpha-calcitonin gene-related peptide (alpha-CGRP) on gastric mucosal damage and blood flow have been investigated in the pentobarbitone-anaesthetized rat. 2. Close-arterial infusion of ET-1 (2-200 pmol kg-1 min-1) induced a significant and dose-dependent increase in gastric mucosal haemorrhagic injury. 3. Close-arterial infusion of the higher doses of ET-1 (100 and 200 pmol kg-1 min-1) resulted in a biphasic effect on mucosal blood flow, as determined by laser Doppler flowmetry (LDF). This consisted of an initial transient increase followed by a pronounced and sustained fall in LDF. 4. Local microvascular constriction may thus contribute to the mechanisms underlying the gastric injury induced by these higher doses of ET-1. 5. However, close-arterial infusion of lower doses of ET-1 (2-50 pmol kg-1 min-1), that also provoked substantial mucosal damage, induced only a sustained and significant mucosal hyperaemia, which may be secondary to microvascular injury. 6. Concurrent dose-arterial administration of rat alpha-CGRP (50 pmol kg-1 min-1) significantly inhibited the extent of gastric mucosal injury induced by ET-1 (5 pmol kg-1 min-1). 7. Furthermore, concurrent close-arterial infusion of this dose of alpha-CGRP, which itself increased mucosal LDF, significantly inhibited the hyperaemic response induced by close-arterial infusion of ET-1 (5 pmol kg-1 min-1). 8. These results indicate a damaging action on the gastric mucosa by low doses of ET-1 which is independent of local vasoconstriction, that may involve a direct injury of the microvascular endothelium. The protective action of alpha-CGRP thus seems unlikely to be due to a local vasodilator effect but may reflect protective actions on the microvascular endothelium
Asunto(s)
Péptido Relacionado con Gen de Calcitonina/farmacología , Endotelinas/farmacología , Mucosa Gástrica/irrigación sanguínea , Animales , Mucosa Gástrica/efectos de los fármacos , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/prevención & control , Flujometría por Láser-Doppler , Masculino , Microcirculación/efectos de los fármacos , Ratas , Ratas Wistar , Flujo Sanguíneo Regional/efectos de los fármacosRESUMEN
1. Bolus intravenous injection of prostaglandin D2 (PGD2, 1-160 micrograms kg-1), the hydantoin prostanoid BW245C (0.25-160 micrograms kg-1) or prostacyclin (PGI2, 0.05-0.5 microgram kg-1) caused a dose-dependent fall in systemic arterial blood pressure (BP) in the anaesthetized rat, lasting 2-4 min. 2. Intravenous infusion of the novel 3-benzyl substituted hydantoin, BW A868C (1-10 micrograms kg-1 min-1), in doses that had no direct effect on BP, dose-dependently reduced the vasodepressor action of PGD2. 3. Bolus injection of BW A868C (30 and 100 micrograms kg-1, i.v.) likewise dose-dependently antagonized the vasodepressor responses to PGD2, causing a 3.4 and 13.2 fold rightward shift of the dose-response curve. 4. The thromboxane-receptor antagonist, BM 13.177 (2.5 mg kg-1 i.v.) had little effect on the PGD2 vasodepressor responses, suggesting minimal contribution of a PGD2 interaction at thromboxane receptor-sites in the systemic vasculature of this species. 5. BW A868C (10 micrograms kg-1 min-1 i.v.) caused a rightward shift (59 fold) of the dose-response relationship for BW245C, the putative PGD2-receptor agonist. This antagonism lasted for at least 1h after termination of the BW A868C infusion. Higher doses of BW A868C (20-100 micrograms kg-1 min-1) caused no further antagonism of the vasodepressor responses to BW245C, suggesting that this prostanoid also acts at vascular receptors other than of the DP-type. 6. BW A868C (10 micrograms kg-1 min-1, i.v.) failed to alter the vasodepressor actions of prostacyclin. 7. These findings in the rat in vivo support the characterization of BW A868C as a potent and selective antagonist of the cardiovascular actions of PGD2 at the DP-receptor.
Asunto(s)
Presión Sanguínea/efectos de los fármacos , Hidantoínas/farmacología , Prostaglandina D2/antagonistas & inhibidores , Receptores de Prostaglandina/efectos de los fármacos , Animales , Epoprostenol/antagonistas & inhibidores , Epoprostenol/farmacología , Infusiones Intravenosas , Masculino , Prostaglandina D2/farmacología , Ratas , Ratas Endogámicas , Sulfonamidas/farmacologíaRESUMEN
1. The role of endothelial dysfunction in the gastric microcirculatory responses during local endothelin-1 (ET-1) infusion has been investigated in the pentobarbitone-anaesthetized rat. Furthermore, the involvement of prostanoids or nitric oxide (NO) in these actions has been investigated by the use of indomethacin to inhibit cyclo-oxygenase and NG-nitro-L-arginine methyl ester (L-NAME) to inhibit NO synthase. 2. Close-arterial infusion of ET-1 (1-10 pmol kg-1 min-1 for 10 min) induced a dose-dependent increase in the gastric leakage of radiolabelled albumin, used as an index of endothelial cell dysfunction. 3. Close-arterial infusion of a submaximal dose of ET-1 (5 pmol kg-1 min-1 for 10 min) significantly increased gastric albumin leakage after 2 min infusion, which reached maximal levels after 10 min, and only slowly declined during the 30 min observation period. 4. By contrast, gastric blood flow, as assessed by laser Doppler flowmetry, did not significantly increase until after 5 min of infusion of ET-1 (5 pmol kg-1 min-1 for 10 min), reaching a maximum after 17 min, and was sustained for the 30 min observation period. 5. Pretreatment with L-NAME (2 mg kg-1, i.v.) or indomethacin (5 mg kg-1, i.v.) significantly reduced both the hyperaemic response to ET-1 and the increase in gastric albumin leakage, and in combination abolished these responses. 6. These results suggest that locally released NO and prostanoids mediate the gastric vasodilator response to close arterial infusion of ET-1. This hyperaemia is preceded by changes in gastric albumin extravasation and hence may be initiated as a response to direct endothelial injury by ET-1.
Asunto(s)
Endotelinas/farmacología , Endotelio Vascular/fisiología , Mucosa Gástrica/irrigación sanguínea , Óxido Nítrico/fisiología , Prostaglandinas/fisiología , Albúminas/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Permeabilidad Capilar/efectos de los fármacos , Hiperemia/inducido químicamente , Hiperemia/fisiopatología , Indometacina/farmacología , Flujometría por Láser-Doppler , Masculino , Microcirculación/efectos de los fármacos , NG-Nitroarginina Metil Éster , Óxido Nítrico/antagonistas & inhibidores , Ratas , Ratas WistarRESUMEN
1. The effects of depletion of sensory neuropeptides from primary afferent neurones by capsaicin pretreatment, on the changes in resting gastric mucosal blood flow following administration of inhibitors of nitric oxide biosynthesis have been investigated in the pentobarbitone-anaesthetized rat. 2. Bolus administration of the NO-synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME; 0.8-12.5 mg kg-1 i.v.), induced a dose-dependent increase in systemic arterial blood pressure (BP) and a reduction in resting mucosal blood flow, as determined by laser Doppler flowmetry. 3. Concurrent administration of L-arginine (300 mg kg-1 i.v.) attenuated the effects of L-NAME (6.25 mg kg-1) on resting mucosal blood flow and BP. The enantiomer, D-NAME (50 mg kg-1 i.v.), which does not inhibit NO biosynthesis, had no effect on either parameter. 4. The fall in mucosal blood flow induced by submaximal doses of L-NAME (0.8-3.2 mg kg-1) was substantially augmented in rats pretreated 2 weeks earlier with capsaicin. 5. The fall in resting mucosal blood flow induced by the less potent NO-synthase inhibitor, NG-monomethyl-L-arginine (L-NMMA; 1.6-25 mg kg-1 i.v.) was likewise significantly augmented in capsaicin-pretreated rats. 6. Pretreatment (15 min) with indomethacin (5 mg kg-1 i.v.) did not augment further the microvascular actions of L-NAME or L-NMMA in capsaicin-pretreated rats, suggesting the lack of interaction of endogenous prostanoids with these other mediators in regulating local blood flow. The effects of L-NAME on BP were not altered by capsaicin and indomethacin administration.7. These findings indicate that endogenous sensory neuropeptides and NO can interact in the regulation of the gastric microcirculation.
Asunto(s)
Mucosa Gástrica/irrigación sanguínea , Neuronas Aferentes/metabolismo , Neuropéptidos/metabolismo , Óxido Nítrico/metabolismo , Animales , Arginina/análogos & derivados , Arginina/farmacología , Presión Sanguínea/efectos de los fármacos , Capsaicina/farmacología , Mucosa Gástrica/efectos de los fármacos , Indometacina/farmacología , Masculino , Microcirculación/efectos de los fármacos , Microcirculación/fisiología , NG-Nitroarginina Metil Éster , Ratas , Ratas Endogámicas , omega-N-MetilargininaRESUMEN
1. The effects of reactive oxygen metabolites on the rat gastric mucosa following close-arterial infusion into the left gastric artery have been determined by macroscopic and histological assessment. 2. Local intra-arterial infusion of hydrogen peroxide (0.6-1.3 mumol kg-1 min-1) induced mucosal injury, characterised by areas of pronounced disruption and haemorrhage, which was prevented by concurrent intravenous administration of catalase. 3. Local infusion of the superoxide generating system xanthine-oxidase and hypoxanthine likewise induced extensive haemorrhagic damage and necrosis of the mucosa. Prolonged incubation of this mixture (10 min) before administration, significantly reduced the degree of injury, indicating the lability of the products so formed. 4. The gastric mucosal injury induced by the superoxide generating system was inhibited by concurrent local infusion of superoxide dismutase (96 u kg-1 min-1), as was the associated increase in mucosal permeability to radiolabelled albumin. 5. Administration of catalase did not inhibit the gastric mucosal damage induced by infusion of xanthine oxidase-hypoxanthine, yet augmented the protective effects of a low dose of superoxide dismutase (46 u kg-1 min-1 i.a.). 6. These findings directly confirm that reactive oxygen metabolites can induce extensive gastric mucosal injury, supporting their role in the pathogenesis of gastric damage following ischaemia and hypotensive shock.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Oxígeno/toxicidad , Animales , Mucosa Gástrica/anatomía & histología , Peróxido de Hidrógeno/administración & dosificación , Peróxido de Hidrógeno/toxicidad , Hipoxantinas/metabolismo , Infusiones Intraarteriales , Radioisótopos de Yodo , Masculino , Ratas , Ratas Endogámicas , Superóxido Dismutasa/administración & dosificación , Superóxido Dismutasa/toxicidad , Superóxidos/metabolismo , Xantina Oxidasa/metabolismoRESUMEN
1. The interactions between endogenous and exogenous sensory neuropeptides on gastric mucosal injury induced by endothelin-1 (ET-1) have been investigated in the anaesthetized rat. 2. Close intra-arterial infusion of ET-1 (4-20 pmol kg-1 min-1) dose-dependently induced vasocongestion and haemorrhagic necrosis in the gastric mucosa. 3. Capsaicin-pretreatment, two weeks earlier to deplete sensory neuropeptides from primary afferent neurones, augmented the mucosal damage induced by ET-1, as assessed by both macroscopic and histological examination. 4. The damage induced by threshold doses of ET-1 alone or in capsaicin-pretreated rats was further enhanced by administration of indomethacin (5 mg kg-1, i.v.), indicating a modulatory influence of endogenous prostanoids. 5. Morphine administration (3 mg kg-1, i.v.), which can prevent neuropeptide release, augmented the damage induced by threshold doses of ET-1, this effect being reversed by naloxone (1 mg kg-1, i.v.). 6. Concurrent local intra-arterial infusion of rat alpha-calcitonin gene-related peptide (10-50 pmol kg-1 min-1) dose-dependently reduced the mucosal injury induced by ET-1. 7. These findings suggest interactions between ET-1 and sensory neuropeptides, which may reflect an important influence of these peptide mediators in the regulation of mucosal integrity.
Asunto(s)
Endotelinas/farmacología , Neuropéptidos/farmacología , Úlcera Gástrica/inducido químicamente , Animales , Péptido Relacionado con Gen de Calcitonina/farmacología , Capsaicina/farmacología , Mucosa Gástrica/patología , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/patología , Indometacina/farmacología , Masculino , Morfina/farmacología , Necrosis/inducido químicamente , Necrosis/patología , Ratas , Ratas Endogámicas , Úlcera Gástrica/patologíaRESUMEN
1. The effects of neuropeptide Y (NPY) and noradrenaline on rat gastric mucosal blood flow, as estimated by laser Doppler flowmetry (LDF), have been examined. In addition, the ability of NPY and noradrenaline to induce acute mucosal haemorrhagic damage has also been assessed. 2. Close-arterial infusion of NPY (0.05-0.2 nmol kg-1 min-1) for 10 min in the anaesthetized rat induced a dose-dependent fall in LDF, but had minimal effects on systemic arterial blood pressure. Higher doses of NPY did not produce any further reduction in LDF. 3. Close-arterial infusion (0.1-0.4 nmol kg-1 min-1) of the structurally related peptide YY (PYY) or pancreatic polypeptide (PP), had inconsistent actions in decreasing LDF. 4. Close-arterial infusion of noradrenaline (30-90 nmol kg-1 min-1) dose-dependently reduced gastric LDF. 5. Local infusion of NPY (0.1 and 0.2 nmol kg-1 min-1) or noradrenaline (45 and 60 nmol kg-1 min-1) resulted in dose-related increases in the area of mucosal hemorrhagic damage. 6. Pretreatment with the alpha 1-adrenoceptor antagonist, prazosin (0.1 mg kg-1, i.v.) significantly reduced the effect of noradrenaline, but not NPY, on both LDF and mucosal damage. 7. These findings indicate that NPY and noradrenaline act directly on the gastric microvasculature to induce vasoconstriction and both can induce acute mucosal damage. Therefore endogenous NPY, like noradrenaline could play a modulatory role in regulating vascular tone and may influence mucosal integrity.
Asunto(s)
Mucosa Gástrica/irrigación sanguínea , Neuropéptido Y/farmacología , Norepinefrina/farmacología , Anestesia , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/efectos de los fármacos , Hemorragia Gastrointestinal/inducido químicamente , Hemorragia Gastrointestinal/patología , Técnicas In Vitro , Masculino , Neuropéptido Y/toxicidad , Norepinefrina/toxicidad , Polipéptido Pancreático/farmacología , Prazosina/farmacología , Ratas , Ratas Endogámicas , Flujo Sanguíneo Regional/efectos de los fármacos , Úlcera Gástrica/inducido químicamenteRESUMEN
1. The effects of aminoguanidine on neutrophil adherence to venules and on the diameter of arterioles in the mesenteric vascular bed of the pentobarbitone-anaesthetized rat have been compared with those of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). 2. Administration of L-NAME (1-10 mg kg-1, i.v.) caused a dose-dependent increase in leukocyte adherence and a reduction in leukocyte rolling velocity in postcapillary venules of the rat mesentery over 1 h. 3. Likewise, aminoguanidine (10-100 mg kg-1, i.v.) dose-dependently increased leukocyte adherence and decreased leukocyte rolling velocity over 1 h. 4. Both L-NAME and aminoguanidine caused a dose-dependent reduction in mesenteric arteriolar diameter and an increase in systemic arterial blood pressure. 5. The effects of aminoguanidine (50 mg kg-1, i.v.) on leukocyte adherence, arteriolar diameter and on blood pressure were significantly reversed by pretreatment with L-arginine (300 mg kg-1, i.v.). 6. These findings indicate that, like L-NAME, aminoguanidine can acutely promote leukocyte adherence to the mesenteric venular wall and reduce arteriolar diameter. Moreover, these acute effects were reversed by L-arginine, suggesting they are mediated through inhibition of constitutive NO synthase.
Asunto(s)
Inhibidores Enzimáticos/farmacología , Guanidinas/farmacología , Venas Mesentéricas/efectos de los fármacos , Venas Mesentéricas/enzimología , Neutrófilos/efectos de los fármacos , Óxido Nítrico Sintasa/antagonistas & inhibidores , Animales , Arginina/análogos & derivados , Arginina/farmacología , Arteriolas/anatomía & histología , Arteriolas/efectos de los fármacos , Arteriolas/enzimología , Presión Sanguínea/efectos de los fármacos , Adhesión Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/enzimología , NG-Nitroarginina Metil Éster , Neutrófilos/citología , Neutrófilos/fisiología , Ratas , Ratas Wistar , Vénulas/anatomía & histología , Vénulas/efectos de los fármacos , Vénulas/enzimologíaRESUMEN
1. Nitric oxide (NO) and the superoxide anion can interact to form the cytotoxic moiety, peroxynitrite. The involvement and potential source of superoxide in the gastric mucosal damage induced by local infusion of NO donors, has now been investigated in the pentobarbitone-anaesthetized rat. 2. Local intra-arterial infusion of the NO donor, sodium nitroprusside (40 micrograms kg-1 min-1) for 10 min induced macroscopically apparent gastric mucosal injury. 3. This mucosal damage was dose-dependently reduced by prior administration of a systemically acting form of superoxide dismutase conjugated with polyethylene glycol (500-2000 iu kg-1, i.v.). 4. Likewise, the mucosal damage induced by nitroprusside was dose-dependently reduced by prior administration of the xanthine oxidase inhibitor, allopurinol (20-100 mg kg-1, i.p. or 100 mg kg-1, p.o.). 5. Pretreatment with allopurinol (100 mg kg-1, i.p.) also reduced the mucosal injury induced by local intra-arterial infusion of the nitrosothiol, S-nitroso-N-acetyl-penicillamine (40 micrograms kg-1 min-1), but not that induced by local infusion of endothelin-1 (5 pmol kg-1 min-1), indicating specificity of action. 6. Prior administration (4h) of rabbit anti-rat neutrophil serum (0.4 ml kg-1, i.p.), which reduced circulating neutrophils by 90%, did not significantly protect against mucosal injury induced by nitroprusside. 7. Intravenous administration of the platelet-activating factor receptor antagonists, WEB 2086 (1 mg kg-1) or BN 52021 (10 mg kg-1), or the thromboxane synthase inhibitor, OKY 15181 (25 mg kg-1), did not modify mucosal damage induced by nitroprusside, showing lack of involvement of these neutrophil-derived mediators. 8. These findings indicate the involvement of superoxide in the injurious actions of the NO donors, implicating a cytotoxic role of peroxynitrite. Xanthine oxidase, but not neutrophils, appears to be a source of the superoxide.
Asunto(s)
Mucosa Gástrica/efectos de los fármacos , Óxido Nítrico/toxicidad , Superóxidos/farmacología , Xantinas/farmacología , Alopurinol/toxicidad , Animales , Relación Dosis-Respuesta a Droga , Masculino , Nitratos/toxicidad , Nitroprusiato/farmacología , Ratas , Ratas Wistar , Superóxido Dismutasa/toxicidad , XantinaRESUMEN
1 The non-steroid anti-inflammatory drugs, indomethacin, flufenamate and meclofenamate, inhibited the release of histamine from rat peritoneal mast cells induced by pharmacological or immunological challenge in vitro. 2 Anti-inflammatory steroids had little effect on histamine release from the mast cells. 3 Th inhibition of histamine release by the aspirin-like drugs was not prevented by incubation with glucose, unlike the inhibition of 2,4,dinitrophenol or antimycin-A. This suggests that the non-steroid anti-inflammatory compounds do not act by preventing the energy production from oxidative metabolism, required for histamine release. 4 The inhibition of the calcium ionophore A23187-induced histamine release by the aspirin-like drugs was reversed by an increase in the calcium concentration of the incubation medium. 5 The results suggest that the non-steroid anti-inflammatory compounds inhibit histamine release by actions on calcium influx into the mast cell, or on calcium mobilization or utilization within the mast cell.