RESUMO
The present study was designed to evaluate neurotensin as a hormonal regulator of gastric acid secretion in man. After a fat-rich meal, the strongest known stimulus of neurotensin release, plasma neurotensin-like immunoreactivity (NTLI) was elevated from 7.6 +/- 1.9 to 15.5 +/- 2.5 pM. Plasma NTLI was measured with antiserum L170, which requires the biologically active carboxyl-terminal hexapeptide of the neurotensin molecule for recognition and does not crossreact significantly with any known natural catabolite in human plasma. Intravenous infusion of neurotensin at 25 pmol X kg-1 h-1 resulted in a plasma level of 14.7 +/- 2.1 pM, similar to the maximal physiological level observed after the fat-rich meal. Intravenous infusion of neurotensin at 25 pmol X kg-1 h-1 during 2 h, however, failed to significantly inhibit peptone meal-stimulated gastric acid secretion measured by intragastric titration. The 2-h acid output to peptone was 40.8 +/- 6.2 and 41.3 +/- 6.9 mmol during the vehicle and the neurotensin infusion, respectively. Intravenous infusion of neurotensin at 100 or 400 pmol X kg-1 h-1 did not affect acid output, whereas at 1,600 pmol X kg-1 h-1, which resulted in a plasma neurotensin concentration of 725 +/- 80 pM, significantly reduced peptone meal-stimulated gastric acid secretion. The neurotensin-induced inhibition of acid output was independent of the hormone gastrin. The present results provide evidence against a hormonal role for neurotensin in the regulation of meal-stimulated gastric acid secretion in man.
Assuntos
Gorduras na Dieta/farmacologia , Ácido Gástrico/metabolismo , Neurotensina/fisiologia , Adolescente , Adulto , Alimentos , Gastrinas/sangue , Humanos , Soros Imunes , Masculino , Neuropeptídeos/sangue , PeptonasRESUMO
We investigated the effect of a novel gastrin-cholecystokinin-B receptor antagonist, L-365,260 [(3R)-3(N'-3-methylphenyl)ureido)-1,3-dihydro-5-phenyl- 2H-1,4-benzodiazepin-2-one], on gastric acid secretion in humans. In a double-blind, four-period crossover study, eight subjects received single oral doses of placebo or of 2.5, 10, or 50 mg L-365,260, followed by an intravenous infusion of pentagastrin at doses of 0.05, 0.4, and 2 micrograms/kg/hr for successive 30-minute periods. L-365,260 caused a dose-dependent inhibition of pentagastrin-stimulated gastric acid secretion. A single oral dose of 50 mg L-365,260 produced 50% inhibition of the gastric acid output response to pentagastrin (0.4 micrograms/kg/hr) when the mean (+/- SD) plasma L-365,260 concentration was 502 +/- 108 ng/ml. Plasma L-365,260 concentrations (all doses combined) and the inhibition of gastric acid output were correlated with a correlation coefficient of r = 0.45 (p < 0.05). Single oral doses of L-365,260 up to 50 mg did not inhibit basal gastric acid output or alter plasma gastrin concentrations. L-365,260 was well tolerated at oral doses up to 50 mg. These findings show that L-365,260 is an orally active antagonist at gastrin-cholecystokinin-B receptors in humans.
Assuntos
Benzodiazepinonas/farmacologia , Ácido Gástrico/metabolismo , Compostos de Fenilureia , Receptores da Colecistocinina/antagonistas & inibidores , Adolescente , Adulto , Análise de Variância , Benzodiazepinonas/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Gastrinas/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Pentagastrina/antagonistas & inibidores , Valores de ReferênciaRESUMO
Single subcutaneous doses of the somatostatin analogue, SMS 201-995, were evaluated for the degree and duration of effects on acid secretion, serum gastrin levels, and gastric emptying in eight human male subjects (mean age 44 years) over an 8-h period. All the subjects received subcutaneous 50-micrograms and 100-micrograms doses of SMS 201-995 and placebo on three separate days in a double-blind random order. Drug or placebo was administered at time 0 followed by peptone meals at time 0, 2, 4, and 6-h. Peptone meals were evacuated at time 1, 3, 5 and 7-h to create 'basal' conditions between alternate hours. Gastric acid secretion was determined hourly beginning at time--1. Both the 50-micrograms and 100-micrograms doses of SMS 201-995 significantly inhibited 'basal' and peptone meal-stimulated gastric acid secretion throughout the 8-h measurement period. The minimum effective plasma concentration of SMS 201-995 for inhibition of peptone meal-stimulated gastric acid secretion was approximately 1000 pg/ml. Peptone meal-stimulated plasma gastrin concentrations were inhibited for 5 and 7 h after 50-micrograms and 100-micrograms doses of SMS 201-995, respectively, whereas 'basal' plasma gastrins were inhibited for 4 and 6 h, respectively. Gastric emptying determined by marker dilution was not significantly enhanced compared to placebo. These results indicate prolonged and potent effects of single subcutaneous doses of SMS 201-995 on peptone-meal stimulated acid secretion and gastrin release.
Assuntos
Alimentos , Ácido Gástrico/metabolismo , Gastrinas/metabolismo , Octreotida/farmacologia , Adulto , Análise de Variância , Método Duplo-Cego , Esvaziamento Gástrico/efeitos dos fármacos , Gastrinas/sangue , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Octreotida/administração & dosagem , Octreotida/sangue , Peptonas/farmacologia , RadioimunoensaioRESUMO
Hypergastrinaemia induced by potent inhibitors of acid secretion is thought to occur as a result of the elimination of the inhibitory effects of intragastric acid on gastrin release. The present study was designed to determine if the mechanisms responsible for feedback inhibition of gastrin release and acid secretion by intragastric acid are preserved during four weeks of varying degrees of drug-induced acid inhibition. Forty-eight healthy male volunteers were randomly assigned to one of four treatments for four weeks: 10 mg omeprazole o.m., 20 mg omeprazole o.m., 40 mg omeprazole o.m. or 150 mg ranitidine b.d. Gastrin release and acid secretion in response to peptone meals maintained at pH 2.5 and pH 5.5 by intragastric titration, and 24-hour gastrin profiles in response to standard meals were determined before treatment, at the fourth week of treatment and two weeks after discontinuing treatment. As expected, omeprazole produced dose-related effects on acid secretion and gastrin concentrations that were largely reversed after treatment was discontinued. Gastrin release in response to pH 5.5 peptone meals remained significantly greater than gastrin release in response to pH 2.5 meals during treatment with all doses of omeprazole. The ratio of pH 5.5/pH 2.5 peptone meal-stimulated gastrin release was approximately 1.5, and remained constant for all treatment groups throughout the study period. These data indicate that four weeks of drug induced hypochlorhydria causes an apparent increase in overall G-cell function, but it does not interfere with normal feedback inhibition of gastrin release and acid secretion mediated by intragastric acidity.
Assuntos
Ácido Gástrico/metabolismo , Gastrinas/sangue , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Método Duplo-Cego , Jejum , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/metabolismo , Gastrinas/química , Gastrinas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Omeprazol/farmacologia , Peptonas/farmacologia , Ranitidina/farmacologiaRESUMO
AIM: To compare acid inhibiting activity and duration of action of different doses of rabeprazole, a substituted benzimidazole characterized as a highly potent and irreversible H+, K+-ATPase inhibitor, administered for 7 days to subjects infected with Helicobacter pylori. METHODS: A total of 38 subjects (mean age 39.3 years) were enrolled in a single-centre, double-blind, randomized, crossover study. All subjects were confirmed positive for H. pylori by 14C urea breath test and ELISA serologies. Subjects were divided into two groups of 19 to receive two doses of rabeprazole, either 5 and 20 mg or 10 and 40 mg, and placebo, given in random order daily in the morning for 7 days. Peptone-stimulated acid, pH, and gastrin measurements were made for 24 h after the 1st dose and for 48 h after the 7th dose. RESULTS: Peptone-stimulated acid secretion rates were decreased from 12.5 to 6.7, 4.0, 1.5, and 0.26 h after initial 5, 10, 20, and 40 mg doses, respectively; to 7.3, 4.3, 2.1, and 1.2 mmol/h 23 h after the initial dose; and to 2.4, 2.6, 0.6, and 0.8 mmol/h 23 h after the 7th dose. After 48 h, stimulated acid secretion had recovered less than 40% for all treatment groups compared to placebo. Median intragastric pH also increased from 2.0 with placebo to 4.9, 6.2, 6.6 and 6.9 during the 24-h period after the 7th dose of 5, 10, 20, and 40 mg. The 20 mg dose of rabeprazole produced equivalent acid inhibition to the 40 mg dose with less increase in plasma gastrin. CONCLUSION: Rabeprazole in doses from 5 to 40 mg was a highly effective inhibitor of gastric acid secretion in subjects infected with H. pylori. The inhibition was rapid, dose-related, and long-acting, with less than 50% recovery of acid by 48 h after the 7th dose. The optimal acid inhibitory dose in these subjects appeared to be 20 mg daily, however 5 mg and 10 mg doses produced potent inhibition of gastric acid secretion.
Assuntos
Antiulcerosos/farmacologia , Benzimidazóis/farmacologia , Ácido Gástrico/metabolismo , Infecções por Helicobacter/complicações , 2-Piridinilmetilsulfinilbenzimidazóis , Administração Oral , Adolescente , Adulto , Idoso , Antiulcerosos/administração & dosagem , Antiulcerosos/uso terapêutico , Benzimidazóis/administração & dosagem , Benzimidazóis/uso terapêutico , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Determinação da Acidez Gástrica , Helicobacter pylori/patogenicidade , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/análogos & derivados , Peptonas/farmacologia , RabeprazolRESUMO
Somatostatin or its analogue octreotide (OCT) has previously been shown to modulate gastric emptying, intestinal motor activity and visceral sensation. In the current study we sought to determine the effect of a single dose of OCT (1.25 micrograms kg-1 s.c.), which has previously been shown to have both motor and sensory effects, on proximal gastric compliance and on conscious perception of gastric distention. Gastric distention was performed in 13 healthy male volunteers, by either slow ramp distention (60 ml min-1) or by intermittent pressure steps (phasic distention; 4-20 mmHg) using an electronic distention device. Compliance curves (pressure-volume relationship), and thresholds for innocuous (fullness) and noxious sensations (discomfort, pain) were determined following vehicle or OCT injection. OCT consistently and significantly reduced the rate of the gastric accommodation reflex by 50%, resulting in a reduced compliance at distention pressures greater than 10 mmHg during phasic distention. In contrast, no effect was observed on the compliance curve obtained during ramp distention. OCT selectively increased the threshold for fullness during both ramp and phasic distention. During phasic distention, OCT decreased the volume thresholds for noxious (pain) sensations experienced at volumes greater than 300 ml, without affecting the corresponding pressure threshold. These findings suggest that at low distension volumes, OCT in the dosage used has a direct inhibitory effect on afferents mediating innocuous gastric sensations. The hyperalgesic effect observed during phasic distention may be secondary to OCT's inhibitory effect on the gastric accommodation reflex.
Assuntos
Octreotida/farmacologia , Sensação/efeitos dos fármacos , Estômago/efeitos dos fármacos , Adulto , Cateterismo , Complacência (Medida de Distensibilidade) , Relação Dose-Resposta a Droga , Fármacos Gastrointestinais/farmacologia , Humanos , Masculino , Pessoa de Meia-Idade , Limiar Sensorial/efeitos dos fármacos , Estômago/fisiologia , Vísceras/efeitos dos fármacos , Vísceras/fisiologiaRESUMO
Corticotropin-releasing factor (CRF) released in the gastrointestinal mucosa from immune cells or enterochromaffin cells may play a role in the modulation of rectal afferent function. In the current study we evaluated the effects of peripherally administered CRF on afferent mechanisms in the human rectum. We used rectal balloon distention in seven healthy volunteers to evaluate the effect of CRF (1 microgram/kg) on visceral afferents originating in the rectum which are involved in the following functions: thresholds and intensity of conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum using a volume ramp (40 and 400 mL/min), or by intermittent phasic distention. CRF decreased the thresholds and increased the intensity for the sensation of discomfort in response to both ramp and phasic distention. During slow ramp distention, CRF also lowered the stool threshold. CRF increased rectal compliance during slow ramp distention without affecting the rate of receptive relaxation or the inflection point of the compliance curve. CRF had no effect on viscerosomatic referral patterns, or on the rectoanal inhibitory reflex. These findings are consistent with a dual effect of CRF on afferent pathways mediating perception of aversive rectal sensations, and on rectal smooth muscle.
Assuntos
Hormônio Liberador da Corticotropina/farmacologia , Neurônios Aferentes/efeitos dos fármacos , Reto/inervação , Adulto , Cateterismo , Complacência (Medida de Distensibilidade) , Eletromiografia/efeitos dos fármacos , Humanos , Masculino , Mecanorreceptores/efeitos dos fármacos , Mecanorreceptores/fisiologia , Pessoa de Meia-Idade , Contração Muscular/efeitos dos fármacos , Contração Muscular/fisiologia , Reto/anatomia & histologia , Reto/efeitos dos fármacos , Limiar Sensorial/efeitos dos fármacosRESUMO
An evening oral dose of nizatidine, a new H2-receptor antagonist, was tested for its ability to suppress nocturnal gastric acid secretion and to inhibit food stimulated acid secretion the following day. Using a double-blind, randomized, cross-over design, nizatidine 30, 100, and 300 mg and placebo were compared in 8 male subjects with basal acid secretion greater than or equal to 3 mmol/h. Continuous nasogastric suction was started 2 h after oral dosing, and acid secretion was measured hourly overnight. Phenol red was used to determine the completeness of gastric aspiration. The following day, food stimulated acid secretion in response to 8% peptone meals was measured by intragastric titration to determine the carry-over effect of nizatidine. Serum gastrin levels were measured by RIA. Nizatidine inhibited overnight acid secretion in a dose-related manner with 30, 100, and 300 mg producing 57, 73, and 90% suppression. The effect was long-lasting, with nizatidine 300 mg decreasing acid secretion by 52% 10 h after administration. Peptone stimulated acid secretion on the following day was not inhibited by nizatidine. Gastrin levels did not differ significantly among the treatment groups. Nizatidine's effects on nocturnal acid secretion therefore resemble other H2-receptor antagonists.
Assuntos
Ácido Gástrico/metabolismo , Gastrinas/metabolismo , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Tiazóis/administração & dosagem , Adulto , Relação Dose-Resposta a Droga , Método Duplo-Cego , Esquema de Medicação , Humanos , Masculino , Pessoa de Meia-Idade , Nizatidina , Peptonas , Distribuição AleatóriaRESUMO
The aim of the present study was to determine whether the association between Helicobacter pylori infection and increased concentrations of gastrin in serum is independent of chronic duodenal ulcer disease and whether the mechanism of this association involves a disturbance of feedback inhibition of gastrin release by intragastric acid. Of 48 subjects evaluated, 26 (54%) were seropositive for H. pylori by ELISA. Fasting and peptone meal-stimulated gastrin release at pH 2.5 and pH 5.5 as well as integrated 24-hour plasma gastrin concentrations were significantly higher in the seropositive group, even when subjects with a history of duodenal ulcer were excluded. The inhibitory effect of low pH on the release of gastrin was not attenuated in subjects with positive results in the ELISA. These data indicate that the association between seropositivity for H. pylori and enhanced release of gastrin is independent of a history of duodenal ulcer and is not caused by a disturbance of the normal feedback inhibition of gastrin release by intragastric acid.
Assuntos
Úlcera Duodenal/complicações , Alimentos , Gastrinas/sangue , Infecções por Helicobacter/metabolismo , Helicobacter pylori , Adulto , Anticorpos Antibacterianos/sangue , Testes Respiratórios , Ensaio de Imunoadsorção Enzimática , Infecções por Helicobacter/complicações , Helicobacter pylori/imunologia , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Peptonas/administração & dosagem , Valor Preditivo dos Testes , RecidivaRESUMO
H. pylori infection is associated with acid-peptic disease, although its role in the pathogenesis is unclear. The purpose of this study was to determine if chronic infection in asymptomatic subjects impairs the inhibition of meal-stimulated gastrin and acid secretion that is observed normally at low intragastric pH. Presence of infection was determined by both C-14 urea breath test and serology. Acid secretion was measured under basal conditions and in response to peptone meal stimulation and pentagastrin. Plasma gastrin concentrations were determined by radioimmunoassay under basal conditions and during peptone meal stimulation. Intragastric titration with 1% peptone during the first hour, and 8% peptone during the second hour, was performed at both pH 7.0 and 2.5 on different days to compare the inhibition of gastrin and acid secretion. Compared to noninfected subjects, asymptomatic individuals infected with H. pylori had significantly increased: (1) basal gastrin values (P < 0.005); (2) 8% peptone-stimulated gastrin responses at both pH 7.0 and 2.5 (P < 0.05); and (3) 8% peptone-stimulated acid output at pH 2.5 (P = 0.01). During the second hour of peptone-stimulation, subjects infected with H. pylori had significantly decreased inhibition of gastrin (52% vs 95%) (P = 0.002) and acid (30% vs 81%) (P = 0.01) secretion from pH 7.0 to 2.5. Thus, chronic infection with H. pylori results in impaired inhibition of gastrin and acid secretion at low intragastric pH during the second hour of peptone meal stimulation. These defects may be unrelated to the pathogenesis of acid-peptic disease, since they occur in asymptomatic subjects infected with H. pylori.
Assuntos
Ácido Gástrico/metabolismo , Gastrinas/metabolismo , Infecções por Helicobacter/fisiopatologia , Helicobacter pylori , Adulto , Idoso , Úlcera Duodenal/fisiopatologia , Retroalimentação , Alimentos , Suco Gástrico/química , Gastrinas/sangue , Gastrinas/efeitos dos fármacos , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Peptonas/farmacologiaRESUMO
The present study was designed to evaluate somatostatin as a hormonal inhibitor of gastric functions in humans. Seven healthy volunteers were investigated on 6 separate days. Peptone meal-stimulated gastric acid secretion was measured by intragastric titration for 2 h and gastric emptying was estimated with a dye-dilution technique. The effect of intravenous administration of somatostatin at 0, 12.5, 50, 100, and 200 pmol/kg.h was investigated and related to the effect of intragastric administration of 100 ml of vegetable oil. Plasma somatostatinlike immunoreactivity was elevated during intravenous administration of somatostatin at 100 and 200 pmol/kg.h, whereas no increase was detected in response to the oil. Somatostatin infusion at 100 and 200 pmol/kg.h significantly inhibited the acid secretion by 25% and 65%, and the oil reduced the acid output by 41%. Somatostatin at 100 and 200 pmol/kg.h significantly enhanced gastric emptying, whereas the oil inhibited gastric emptying. These observations suggest that somatostatin may not be an important hormonal messenger of fat-induced inhibition of acid secretion or gastric emptying.
Assuntos
Gorduras na Dieta/farmacologia , Ácido Gástrico/metabolismo , Esvaziamento Gástrico , Somatostatina/fisiologia , Adulto , Feminino , Gastrinas/sangue , Humanos , Pessoa de Meia-Idade , Peptonas/administração & dosagem , Peptonas/farmacologia , Óleos de Plantas/administração & dosagem , Taxa Secretória/efeitos dos fármacos , Somatostatina/sangue , Somatostatina/farmacologiaRESUMO
The prevalence of sleep disturbances was studied in patients with severe non-ulcer dyspepsia. It was also considered if the change in sleep pattern was associated with changes in the rhythmic fasting motor activity of the gastrointestinal tract, and if motor events correlate with the patient's symptoms. Motor activity in the duodenum was monitored over a 24 hour period under freely ambulatory conditions in 10 healthy controls and in 10 patients with severe non-ulcer dyspepsia using a transnasally placed catheter with six solid state pressure transducers connected to a digital data logging device. Symptoms and sleep disturbance were assessed by questionnaire and diary. Based on their symptoms, the patients were separated into two groups: those with dyspepsia symptoms only (non-ulcer dyspepsia; n = 5) and those with dyspepsia and additional functional symptoms thought to arise from the lower gastrointestinal tract (non-ulcer dyspepsia+irritable bowel syndrome; n = 5). When compared with either the control or the non-ulcer dyspepsia+irritable bowel syndrome group, non-ulcer dyspepsia patients had a considerably decreased number of migrating motor complexes during the nocturnal period (0.7 v 4.6), a decreased percentage of nocturnal phase I (5.2% v 78.0%), and an increased percentage of the nocturnal period in phase II (94% v 15.4%). Patients with non-ulcer dyspepsia+irritable bowel syndrome were not different from normal controls. Four of the non-ulcer dyspepsia patients and all of the non-ulcer dyspepsia+irritable bowel syndrome patients reported difficulties with sleep. Clusters of high amplitude tonic and phasic activity, not accompanied by subjective reports of discomfort were noted in several patients in both groups during the study. In eight of 10 patients, abdominal pain was reported during normal motor activity, while in one patient, pain correlated with phase III of the migrating motor complex. In contrast with previous reports in patients with irritable bowel syndrome, our findings suggest an abnormality of diurnal rhythmicity--shown in changed sleep and changed rhythmic duodenal motor activity--in patients with chronic abdominal pain thought to arise from the upper gastrointestinal tract.
Assuntos
Duodeno/fisiopatologia , Dispepsia/complicações , Motilidade Gastrointestinal/fisiologia , Transtornos do Sono-Vigília/complicações , Dor Abdominal/fisiopatologia , Adulto , Ritmo Circadiano , Doenças Funcionais do Colo/fisiopatologia , Dispepsia/fisiopatologia , Feminino , Humanos , Masculino , Manometria , Pessoa de Meia-Idade , Monitorização Fisiológica , Prevalência , Transtornos do Sono-Vigília/fisiopatologiaRESUMO
Somatostatin (Som) administered intrathecally to humans has been shown to exert potent analgesic effects on somatic pain, and anecdotal evidence suggests that Som may also relieve visceral pain. In the current study, we used rectal balloon distension in seven healthy volunteers to evaluate the effect of the Som analogue octreotide (Oct; 1.25 microgram/kg sc) on four pathways mediated by different visceral afferents that originate in the rectum: conscious perception, receptive relaxation, reflex inhibition of internal anal sphincter, and a viscerosomatic reflex. Rectal mechanoreceptors were stimulated either by distending the rectum tonically (volume ramp at 20-40 and 400 ml/min) or phasically (intermittent pressure steps of 60 s duration). Pressure thresholds for nonnoxious and noxious sensations in response to slow tonic distension were increased in the presence of rectal lidocaine (20 ml of 2% solution), whereas those to phasic distension were unaffected. Oct significantly increased pressure and volume thresholds for nonnoxious and noxious sensations in response to slow tonic distension but did not further increase thresholds in the presence of intrarectal lidocaine. In contrast, no effect of Oct on rectal sensations was observed during rapid tonic or phasic distension. Oct had no effect on any of the monitored reflex responses. The effect of Oct on rectal sensation in the concentration used in this study was not associated with changes in the rectal wall pressure-volume relationship during any distension protocol. These findings indicate that the inhibitory effect of Oct on rectal sensation is likely to represent a direct effect on a subset of extrinsic primary afferent neurons, with receptive fields in the mucosa.