RESUMO
Rat liver slices were employed as experimental model to characterise the system involved in the transport process which participates in liver tyramine uptake. The uptake of 0.4 micromol l-1of [3H]tyramine by rat liver slices was linear from 5 min up to the end of incubation. At 15 min the uptake was 4.58+/-0.18 pmol mg-1protein. The accumulation of [3H]tyramine was sensitive to temperature (69. 3+/-4.0% inhibition at 0 degrees C, P<0.001), to sodium omission replaced by 150 mmol l-1Tris or 110 mmol l-1Tris+40 mmol l-1choline (27.6+/-6.0%, P<0.01, and 24.6+/-3.8% inhibition, P<0.01, respectively), and the inhibition of Na+-K+-adenosine triphosphatase by 150 micromol l-1ouabain (20.4+/-2.6% decrease, P<0.01). Uptake of [3H]tyramine was cocaine- (10 micromol l-1) and desipramine- (1 micromol l-1) dependent (32.2+/-6.4%, P<0.05, and 31.6+/-4.0% inhibition, P<0.05, respectively). Uptake of [3H]tyramine in rat liver slices was not modified by 30 micromol l-1isoprenaline, 30 micromol l-1corticosterone, 30 micromol l-1normetanephrine and noradrenaline up to 4 micrometers at higher noradrenaline concentrations tyramine transport was diminished (P<0.05). Results achieved by incubation with increasing tyramine concentrations indicate that at the micromolar level hepatic uptake occurs by a combined passive diffusion and transport-mediated mechanism, whereas at greater tyramine concentrations passive transport predominates. These results suggest that both simple diffusion and a transport-mediated mechanism are involved in this uptake from hepatocytes, which presents features similar to those described for type 1 non-neuronal uptake systems.
Assuntos
Fígado/metabolismo , Simpatomiméticos/farmacocinética , Tiramina/farmacocinética , Corticosteroides/farmacologia , Inibidores da Captação Adrenérgica , Animais , Sobrevivência Celular/efeitos dos fármacos , Cocaína/farmacologia , Desipramina/farmacologia , Inibidores da Captação de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Técnicas In Vitro , Isoproterenol/farmacologia , Fígado/citologia , Fígado/efeitos dos fármacos , Masculino , Norepinefrina/farmacocinética , Normetanefrina/farmacologia , Ratos , Ratos Wistar , Sódio/farmacologia , Temperatura , Fatores de Tempo , TrítioRESUMO
Cardiovascular responses to several agents should be modified by glucocorticoid administration in the rat. We investigate the response to adrenergic agonists such as phenylephrine, noradrenaline, clonidine and isoproterenol and ganglionic blocking agent such as hexamethonium in conscious rats treated during 7 days with dexamethasone. Wistar rats were treated with either Dex (150 micrograms daily x 7 days, p.o.) or water. Mean arterial pressure were calculated from the intraarterial recordings of blood pressure. No differences in basal mean arterial pressure were seen between dexamethasone and control groups of rats. Phenylephrine and noradrenaline showed a pressor effect in control rats that was reduced by dexamethasone treatment. Clonidine showed similar pressor effect in both groups of rats but ten minutes after drug administration, a light hypotension was seen in dexamethasone rats. Isoproterenol and hexamethonium showed a similar hypotensive effect on control and dexamethasone rats. In conclusion, dexamethasone treatment should reduce the pressor responses to phenylephrine and noradrenaline. Moreover, the alpha adrenergic agonist clonidine showed a hypotensive effect in dexamethasone treated rats, although the response of isoproterenol and hexamethonium remains unchanged.
Assuntos
Agonistas Adrenérgicos/farmacologia , Sistema Cardiovascular/efeitos dos fármacos , Dexametasona/farmacologia , Animais , Pressão Sanguínea/efeitos dos fármacos , Clonidina/farmacologia , Feminino , Glucocorticoides/farmacologia , Isoproterenol/farmacologia , Masculino , Norepinefrina/farmacologia , Fenilefrina/farmacologia , Ratos , Ratos WistarRESUMO
1. The effect of paracetamol overdoses on its disposition was investigated in cholestatic rats. 2. Paracetamol plasma concentration and hepatic accumulation decrease about 70-80% in cholestatic rats. 3. Cholestatic rats intoxicated with paracetamol showed less hepatic damage as concluded from biochemical and histological findings. These data are correlated with liver and plasmatic paracetamol. 4. These results indicate a decrease in paracetamol toxicity related to stagnant bile.
Assuntos
Acetaminofen/intoxicação , Analgésicos não Narcóticos/intoxicação , Doença Hepática Induzida por Substâncias e Drogas , Colestase/induzido quimicamente , Fígado/efeitos dos fármacos , Acetaminofen/metabolismo , Analgésicos não Narcóticos/metabolismo , Animais , Overdose de Drogas , Hepatopatias/metabolismo , Masculino , Ratos , Ratos WistarRESUMO
The duodenal transfer and metabolism of [3H]tyramine from sacs and perfused segments of rat intestine were determined. In sacs, a linear relationship between the steady-state transfer rate of total tritium and the initial mucosal tyramine concentration was observed, suggesting that the clearance is the same at different concentrations. In duodenal perfusions, there was no significant difference in the amount of total tritium removed between control and everted tissues, whether the flow was 0.2 or 2.0 mL/min. The percentage of [3H]tyramine extracted from the gut lumen depended on the flow rate. About 30-40% of the extracted drug was metabolized; this value decreased to 20% when the rats were pretreated with pargyline. The data support the idea that the transfer mechanism for tyramine is simple diffusion.
Assuntos
Mucosa Intestinal/metabolismo , Tiramina/farmacocinética , Animais , Fenômenos Químicos , Físico-Química , Difusão , Duodeno/efeitos dos fármacos , Duodeno/enzimologia , Duodeno/metabolismo , Técnicas In Vitro , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/enzimologia , Intestinos/efeitos dos fármacos , Intestinos/enzimologia , Masculino , Monoaminoxidase/metabolismo , Pargilina/farmacologia , Perfusão , Ratos , Ratos Wistar , Tiramina/metabolismoRESUMO
Using hepatocytes isolated by collagenase perfusion, we studied the accumulation of 3H-noradrenaline. Cells incubated during 15 min in the presence of 0.4 mumol/l 3H-noradrenaline (without inhibition of noradrenaline metabolism) accumulated 8.32 +/- 1.77 pmol/10(6) cells (n = 3). The accumulation of 3H-noradrenaline in isolated parenchymal liver cells was sensitive to 10 mumol/l cocaine (inhibition 36.6 +/- 7.9%, n = 3) and 1 mumol/l desipramine (inhibition 27.2 +/- 6.9, n = 3). Accumulation of 3H-noradrenaline was temperature and sodium dependent (inhibition 33.2 +/- 9.4%, n = 9, when Na+ was replaced by Tris+) and was influenced by the inhibition of the membrane Na(+)-K(+)-adenosine triphosphatase (Na(+)-K(+)-ATPase) by 150 mumol/l ouabain (34.7 +/- 6.9% inhibition, n = 3). Accumulation of 3H-noradrenaline in the hepatocytes was not affected by the presence of uptake2 inhibitors, normetanephrine (30 mumol/l) and corticosterone (30 mumol/l), but was reduced by 30 mumol/l isoprenaline (76.3 +/- 5.0% inhibition, n = 6). Thus, the system that takes up and accumulates noradrenaline in the isolated rat liver cells possesses some characteristics of both, uptake1 and uptake2 systems and appears to be different from other extraneuronal cocaine-sensitive systems, such as the one reported for pulmonary endothelial cells.