RESUMEN
BACKGROUND: In blood vessels 5-HT stimulates sympathetic nerves, the endothelium and vascular smooth muscle cells. Triptans are specific anti-migraine drugs and they activate the serotoninergic 5HT1b/d receptors causing vasoconstriction of the cerebral vessels. AIM: To evaluate the effect of frovatriptan on isolated rat carotid artery. METHODS: Contractile activity of the preparations was registered isometrically. Krebs solution (pH = 7.4) was used for washing smooth muscle (SM) preparations aerated with 95% O2 and 5% CO2 at 37°C. The 60-minute adaptation of tone level of preparations was taken as a starting tone and the changes such as contraction or relaxation were calculated using it. RESULTS: Frovatriptan (1×10-6 mol/l - 1×10-5 mol/l) induced a contraction, but at higher concentrations it caused relaxation of the carotid artery. The L-norepinephrine contractile reaction was enhanced in the presence of frovatriptan. In the presence of 5-HT2 receptor antagonist, methysergide, frovatriptan increased the relaxation. In the presence of the specific α-1 receptor antagonist, prazosin, the frovatriptan-induced relaxation decreased. CONCLUSION: The observed contractile effect of frovatriptan is probably associated with the main effect of the drug - activation of the serotoninergic 5HT1B /1D receptors causing vasoconstriction of the cerebral vessels and their anti-migraine effect. At higher concentrations, frovatriptan, most likely via some non-specific mechanism, could activate the following intracellular chain reaction: stimulation of α1D could activate eNOS which may increase in the concentration of NO which results in the final effect of relaxation.
Asunto(s)
Carbazoles/farmacología , Arterias Carótidas/efectos de los fármacos , Contracción Muscular/efectos de los fármacos , Músculo Liso Vascular/efectos de los fármacos , Receptor de Serotonina 5-HT1B , Receptor de Serotonina 5-HT1D , Agonistas del Receptor de Serotonina 5-HT1/farmacología , Triptaminas/farmacología , Vasoconstricción/efectos de los fármacos , Vasodilatación/efectos de los fármacos , Antagonistas de Receptores Adrenérgicos alfa 1/farmacología , Animales , Técnicas In Vitro , Masculino , Metisergida/farmacología , Prazosina/farmacología , Ratas , Ratas Wistar , Antagonistas del Receptor de Serotonina 5-HT2/farmacologíaRESUMEN
BACKGROUND: Increased intra-abdominal pressure (IAP) causes tissue ischemia, subsequent hypoxia, and impairment of normal tissue metabolism. Elevation of IAP above 20 mmHg leads to progression of abdominal compartment syndrome (ACS) that is associated with organ dysfunction or failure not previously manifested. AIM: To evaluate the eff ects of diff erent grades and time of exposure to IAP on biochemical parameters and oxidative stress in organs aff ected by ischemia using previously developed rat model. RESULTS: Three experimental groups exposed to diff erent IAP and time frames were tested for liver, kidney, and pancreas injury by measuring the activities of tissue specifi c enzymes in blood serum. Elevated activities of aspartate aminotransferase, pancreatic amylase, lipase, and higher concentrations of D-lactate, urea, and creatinine were found in some of the experimental groups compared to a control group of animals not subjected to increased IAP. Increased levels of biomarkers of oxidative stress as well as decrease in concentration of the major cellular antioxidant glutathione indicated the presence of oxidative injury as a result of elevated IAP. CONCLUSIONS: The developed rat model is appropriate to study the mechanism and manifestation of tissue injury during diff erent grades of elevated IAP but also to test approaches aimed to attenuate the detrimental eff ects of ACS. This study also underlines the necessity of using not a single but a set of biochemical parameters in order to assess the severity of tissue injury during elevated IAP and progression to ACS.
Asunto(s)
Modelos Animales de Enfermedad , Hipertensión Intraabdominal/metabolismo , Animales , Glutatión/metabolismo , Estrés Oxidativo , Ratas , Ratas WistarRESUMEN
AIM: To find if tacrine exerts a sensitizing effect on the cholinergic receptors of gastric smooth muscles, and study some of the mechanisms inducing it and measure the relative intensity of tacrine's effects on contractile activity. MATERIAL AND METHODS: Isometric recording of the mechanical activity of gastric smooth muscle preparations; determination of acetyl-cholinesterase activity in smooth-muscle tissue homogenates using Ellman's method. RESULTS: We found that the threshold concentration for tacrine not reducing the acetylcholinesterase activity and not having an effect on the smooth muscle preparations was 1 x 10(-8) mol/l. This concentration, however, significantly increased the acetylcholine-induced contraction compared with the controls, after the smooth-muscle tissue was incubated for 60 or 100 min. Treating smooth-muscle preparations with tacrine in a concentration of 5 x 10(-6) mol/l triggered a contraction induced by the drug's anti-cholinesterase activity. A secondary contraction was induced after 38.6 +/- 5.6 min. There was no secondary contraction after the control acetylcholine-induced effect. Atropine (1 x 10(-6) mol/l) inhibits this effect. Preliminary treatment of smooth muscle preparations with hexamethonium (1 x 10(-6) mol/l) did not change significantly the intensity of the first phase of tacrine-induced contraction and shifted in time the appearance of the second contractile phase. CONCLUSION: Tacrine has a sensitizing effect on M-cholinergic receptors; it occurs after a long incubation of the gastric smooth muscles with the drug and is manifested as a secondary contraction which is shifted in time and is significantly inhibited by atropine.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Músculo Liso/efectos de los fármacos , Receptores Muscarínicos/efectos de los fármacos , Estómago/efectos de los fármacos , Tacrina/farmacología , Acetilcolina/farmacología , Animales , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/fisiología , Ratas , Ratas Wistar , Estómago/fisiologíaRESUMEN
AIM: The aim of the present study was to determine the nature and intensity of changes in the contractile activity and reactivity of gastrointestinal smooth muscle tissue in conditions of increased intra-abdominal pressure. METHODS: A method for recording isometric contractions of isolated smooth muscle preparations from gastric corpus, duodenum and sigmoid colon of rats was used. RESULTS: Two groups of rats were used in the study--control animals and animals with elevated abdominal pressure. It was established that pressure of 25 mmHg for 60 min did not cause statistically significant change in the tone and parameters of the spontaneous contractions in all preparation types, as well as in their reactivity to drotaverine (no-spa). Statistically significant increase in the strength of the tonic effects of galantamine (1.10(-6)-1.10(-3) mg/ml) was found in all types of smooth muscles preparations isolated from rats with increased abdominal pressure compared with preparations from the control rats. CONCLUSIONS: The statistically significant increase in the galantamine-induced effects on smooth muscle preparations is associated with increase in the contractile effectiveness of acetylcholine. M-type cholinergic receptors are predominantly involved in the processes, probably sensibilized from processes activated by the increased intra-abdominal pressure.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Síndromes Compartimentales/tratamiento farmacológico , Galantamina/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Contracción Isométrica/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Papaverina/análogos & derivados , Animales , Colon/efectos de los fármacos , Colon/fisiología , Síndromes Compartimentales/fisiopatología , Modelos Animales de Enfermedad , Duodeno/efectos de los fármacos , Duodeno/fisiología , Contracción Isométrica/fisiología , Masculino , Músculo Liso/fisiología , Papaverina/farmacología , Presión , Ratas , Estómago/efectos de los fármacos , Estómago/fisiología , Resultado del TratamientoRESUMEN
Water-soluble Maillard reaction products obtained from five different model systems were investigated for their effects upon the mechanical activity of rat gastric smooth muscle. Most of the total Maillard reaction products applied at concentration of 1.5 mg/ml evoked contractions; among them the product obtained from arginine and glucose (Arg-Glc) produced the most powerful contractions. The product obtained from glycine and ascorbic acid (Gly-AsA) was the only one that brought about relaxation response. The high molecular weight fractions (>3,500 Da) isolated from the reaction systems Arg-Glc and Gly-AsA demonstrated effects similar in type and amplitude to those evoked by non-fractioned reaction products. The results obtained suggest that moieties of molecules acting upon the muscle tonus originate mainly from lysine and arginine residues; that these structures are available in both low and high molecular pools in similar concentrations, and most likely these fragments act upon membrane-located cellular structures involved in calcium transport.
Asunto(s)
Aminoácidos/química , Aminoácidos/farmacología , Carbohidratos/química , Carbohidratos/farmacología , Reacción de Maillard , Músculo Liso/efectos de los fármacos , Estómago , Animales , Arginina/análogos & derivados , Arginina/química , Arginina/farmacología , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/química , Ácido Ascórbico/farmacología , Glucosa/análogos & derivados , Glucosa/química , Glucosa/farmacología , Glicina/análogos & derivados , Glicina/química , Glicina/farmacología , Técnicas In Vitro , Lisina/análogos & derivados , Lisina/química , Lisina/farmacología , Masculino , Peso Molecular , Contracción Muscular/efectos de los fármacos , Tono Muscular/efectos de los fármacos , Músculo Liso/fisiología , Polímeros/química , Polímeros/aislamiento & purificación , Polímeros/farmacología , Ratas , Ratas Wistar , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier , Xilosa/análogos & derivados , Xilosa/química , Xilosa/farmacologíaRESUMEN
Tacrine, a non-competitive reversible acetylcholinesterase and butyrylcholineserase inhibitor, caused a concentration-dependent tonic contraction of gastric smooth muscle preparations in the concentration range 1 x 10(-7) mol/L - 1 x 10(-5) mol/L, whereas concentrations higher than 2 x 10(-5) mol/L induced a biphasic effect; a short-time contraction was followed by a prolonged relaxation. To shed some light on the mechanism underlying this untypical relaxation, the amplitude of mechanical reactions caused by tacrine were compared with those of tacrine in the presence of atropine, ipratropium, metrifonate, TTX, nifedipine, D-600, caffeine, apamin, and charybdotoxin. The results obtained revealed that the relaxation was neither cholinergic in nature, nor mediated by the influence of the drug on intramural neuronal structures. It was not influenced by processes inducing changes in cytosolic Ca2+ levels. This assumption was confirmed by experiments with permeabilized muscle preparations that were pre-contracted in a solution with pCa 5.5. Tacrine relaxed the smooth muscles in spite of the constant intracellular Ca2+ concentration resulting from the permeabilization. These findings argue that tacrine at concentrations higher than 2 x 10(-5) mol/L has a desensitizing effect on the contractile apparatus of gastric corpus smooth muscle preparations towards Ca2+.
Asunto(s)
Calcio/metabolismo , Inhibidores de la Colinesterasa/farmacología , Relajación Muscular/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Estómago/efectos de los fármacos , Tacrina/farmacología , Acetilcolina/metabolismo , Animales , Cafeína/farmacología , Bloqueadores de los Canales de Calcio/farmacología , Antagonistas Colinérgicos/farmacología , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/metabolismo , Técnicas In Vitro , Masculino , Contracción Muscular/efectos de los fármacos , Músculo Liso/metabolismo , Potasio/metabolismo , Bloqueadores de los Canales de Potasio/farmacología , Ratas , Sodio/metabolismo , Bloqueadores de los Canales de Sodio/farmacología , Factores de TiempoRESUMEN
INTRODUCTION: Tacrine is an acetylcholinesterase inhibitor. It has an indirect cholinomimetic effect inducing contractions of the gastric smooth muscles. The contractions are related to the effect of the accumulated acetylcholine in tissues on the respective choline receptors. There is a well defined direct correlation between tacrine concentrations and the inhibition of cholinesterase activity. That suggest simultaneous increase of the strength of tacrine-induced contractions. Instead, at concentrations above 1 x 10(-5) mol/l, tacrine causes permanent relaxation with yet unknown causing mechanism. AIM: The aim of this study was to investigate if tacrine induces reduction of calcium ions through chelation and/or inhibits directly calmodulin's participation in the contractile processes, thus causing smooth muscle relaxation which is not characteristic of a typical acetylcholinesterase blocker. METHODS: The contractile activity of smooth muscle preparations was measured isometrically with a Microtechna (Czech Republic) amplifier and recorded by a Linseis (Germany) recorder. The absorption electron spectrum of tacrine (1 x 10(-4) mol/l) was determined with a Cary 1 (Varian, Australia) spectrophotometer. The concentration of ionized CaCa2+ was measured with the ISE-block of a clinical-chemical analyzer Konelab 60 (Finland). RESULTS: The presence of Ca2+ (10(-2) mol/l) does not alter tacrine characteristic absorption spectrum at pH values corresponding to the SM cell cytosolic pH. The presence of 1 x 10(-4) mol/l tacrine does not affect Ca2+ concentration in the Krebs solution (pH = 7.4). In the presence of trifluoperazine (a calmodulin blocker) 1 x 10(-4) mol/l tacrine causes relaxation which is commensurable with that in the controls. CONCLUSIONS: Tacrine-induced smooth muscle relaxation is not a result of the reduction of the effective Ca2+ concentrations as a result of chelation between tacrine and Ca2+ and it is not related to the tacrine effects on calmodulin.
Asunto(s)
Calcio/metabolismo , Calmodulina/metabolismo , Inhibidores de la Colinesterasa/farmacología , Citosol/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Tacrina/farmacología , Animales , Quelantes , Citosol/metabolismo , Relación Dosis-Respuesta a Droga , Mucosa Gástrica/efectos de los fármacos , Mucosa Gástrica/metabolismo , Técnicas In Vitro , Contracción Muscular/efectos de los fármacos , Contracción Muscular/fisiología , Relajación Muscular/efectos de los fármacos , Relajación Muscular/fisiología , Músculo Liso/metabolismo , Músculo Liso/fisiopatología , Ratas , Ratas Wistar , Trifluoperazina/farmacologíaRESUMEN
INTRODUCTION: Tacrine is a cholinesterase inhibitor used for the treatment of Alzheimer's disease. The drug also has an effect on a number of tissues and organs that are not targets of its therapeutical action in this disease. The gastrointestinal tract is one such affected organ. AIM: To investigate the in vitro effects of tacrine on rat stomach smooth muscles and determine the correlation between the anticholinesterase activity of the drug and the provoked smooth muscle mechanical responses. METHODS: The acetylcholinesterase activity was determined spectrophotometrically in tissue homogenates by the Ellman's method. Spectrophotometer "Cary 1" was used. The contraction activity of smooth muscle strips (11-12 mm long and 1.5-2 mm wide) from the gastric corpus was measured isometrically with Microtechna (Czech Republic) amplifier and recorded by Linseis (Germany) recorder. RESULTS: The results showed significant increase in the tacrine-induced contractions concurrent with reduction of the acetylcholinesterase activity within the concentration range of 10(-7)-10(-5) mol/l. The tendencies of development of both processes showed a high level of correlation (>0.99). Tacrine-induced contractions were inhibited significantly with atropine, ipatropium and hexametonium. They had a cholinergic character and most likely were due to endogenous acetylcholine accumulated as a result of inhibition of cholinesterase activity. An opposite tendency (correlation = - 0.98) was observed at tacrine concentrations of > or = 5.10(-5) mol/l: the decrease in the enzyme activity coincided with relaxation of muscle preparations. CONCLUSIONS: The analysis of the results suggests that the observed relaxation is non-anticholinesterase and non-cholinergic.
Asunto(s)
Inhibidores de la Colinesterasa/farmacología , Tracto Gastrointestinal/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Tacrina/farmacología , Análisis de Varianza , Animales , Masculino , Contracción Muscular/efectos de los fármacos , Ratas , Ratas WistarRESUMEN
Galantamine is efficacious for vascular dementia and Alzheimer's disease. Its application leads to some negative gastrointestinal side effects. The present study observes galantamine-induced influence on gastrointestinal motility of rats and its effects on isolated gastrointestinal smooth muscles. The gastrointestinal tract was studied by X-ray contrast examination. Functional disturbances were observed: hypertonia, increased stomach and ileal peristalsis activity, accelerated intestinal passage. In vitro, the drug caused tonic contractions in smooth muscle preparations and increased the gastric and ileal phasic amplitude. The jejunal smooth muscle strips demonstrated an opposite tendency. The reactions were a result of the interaction of galantamine-accumulated endogenic acetycholine with M- and N-acetylcholine receptors. The tonic effects were influenced in varying degree by atropine and ipratropium, whereas the phasic by atropine, ipratropium, hexametonium and methysergide. In conclusion, the in vitro effects registered satisfactorily explain in vivo examined galantamine-induced changes in the gastrointestinal tract of the treated rats and can be considered as main cause for development of such changes.