RESUMEN
Blackfoot disease (BFD) is a peripheral arterial occlusive disease found among human inhabitants along the southwest coast of Taiwan. Well water used for drinking and cooking contains humic acid (HA), which may be a possible etiological factor. In this study, HA toxicity was investigated in human erythrocytes and was found to induce echinocytic formation. Morphological changes occurred in both a concentration- and time-dependent fashion. The presence of HA was also observed to facilitate the loading of erythrocytes with excess Ca(2+) (1 mM), which may have occurred following permeability changes in cell membranes, leading to echinocytic transformations. Sodium dodecyl sulfate (SDS) gel electrophoresis indicated that echinocyte formation was due to the oxidation of normal membrane proteins that were replaced by high-molecular-weight proteins. Humic acid also induced hemoglobin oxidation in erythrocytes. Data show that oxidative stress generated by HA as well as direct effects were exerted on the cytoskeleton of erythrocytes, and these may be significant factors in the etiology of BFD.
Asunto(s)
Quelantes/toxicidad , Deformación Eritrocítica/efectos de los fármacos , Sustancias Húmicas/toxicidad , Estrés Oxidativo/efectos de los fármacos , Anemia/inducido químicamente , Canales de Calcio/efectos de los fármacos , Membrana Celular/fisiología , Eritrocitos/efectos de los fármacos , Hemoglobinas/metabolismo , Humanos , Proteínas de la Membrana/metabolismo , Oxidación-Reducción , Enfermedades Vasculares Periféricas/inducido químicamente , PermeabilidadRESUMEN
Effects of acute exposure (2 h) to either 1.5% halothane or 0.5% methoxyflurane on chemical mediators of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated in male Sprague-Dawley rats immediately after exposure, after the righting reflex (4 h), or 24 h postexposure. Effects of these anesthetics on hippocampal corticotropin releasing factor (CRF) were also evaluated. Methoxyflurane caused significant elevations in pituitary adrenocorticotropin hormone (ACTH)-like immunoreactivities in all three of the experiment's time groups, yet halothane failed to cause the same response immediately after exposure. Serum ACTH-like immunoreactivities were significantly elevated immediately after exposure to both anesthetics, but were not elevated at 4 and 24 h postexposure. Corticosterone (CORT)-like immunoreactivities were significantly elevated by halothane in all experimental groups, and in the 2- and 24-h groups following methoxyflurane exposure. Hippocampal CRF-like immunoreactivities remained unaffected by either anesthetic. Results indicate that a 2-h exposure to either halothane or methoxyflurane results in significant activation of the rat hypothalamic-pituitary-adrenal axis, and that the activation appears to be sustained over a 24-h period.
Asunto(s)
Anestésicos por Inhalación/farmacología , Halotano/farmacología , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Metoxiflurano/farmacología , Sistema Hipófiso-Suprarrenal/efectos de los fármacos , Hormona Adrenocorticotrópica/sangre , Hormona Adrenocorticotrópica/metabolismo , Animales , Corticosterona/sangre , Hormona Liberadora de Corticotropina/metabolismo , Hipocampo/metabolismo , Sistema Hipotálamo-Hipofisario/metabolismo , Hipotálamo/metabolismo , Masculino , Hipófisis/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Radioinmunoensayo , Ratas , Ratas Sprague-DawleyRESUMEN
Effects of acute exposure (2 hr) to either 1.5% halothane or 0.5% methoxyflurane were investigated in the Sprague Dawley rat. Pituitary (PIT) and central nervous system (CNS) substance P (SP)-like and beta-endorphin (beta-end)-like immunoreactivities were evaluated immediately after anesthetic exposure (2 h), after righting reflex (4 h) or 24 hr postexposure (24 h). Only halothane significantly reduced SP-like immunoreactivity in olfactory bulbs in both the 2-h and 4-h groups. Halothane elevated SP-like immunoreactivity of hippocampus at all three time periods, and in the hypothalamus at 2 h. Both anesthetics significantly depleted thalamic concentrations of SP-like immunoreactivity. Methoxyflurane anesthesia resulted in a drastic decrease in SP-like immunoreactivity in PIT at all three time periods periods, while halothane elevated PIT concentrations of this peptide at 4 h. Both anesthetics significantly decreased beta-end-like immunoreactivity in the olfactory bulbs and thalami at 2, 4, and 24 h. However, halothane alone significantly elevated beta-end-like immunoreactivity in the spinal cord at 24 h. Halothane significantly elevated PIT beta-end-like immunoreactivity at 2 and 24 h, while methoxyflurane significantly lowered it in the 4-h group, but elevated the levels of the same in the 24-h group. Brain stem beta-end immunoreactivity were significantly reduced at 2 h by both anesthetics, and at 4 h by methoxyflurane. Results indicate that halothane and methoxyflurane may differ significantly in their actions on SP and beta-end secreting neurons in the CNS.
Asunto(s)
Encéfalo/metabolismo , Halotano/farmacología , Metoxiflurano/farmacología , Médula Espinal/metabolismo , Sustancia P/metabolismo , betaendorfina/metabolismo , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Cinética , Masculino , Especificidad de Órganos , Postura , Radioinmunoensayo , Ratas , Ratas Sprague-Dawley , Reflejo/efectos de los fármacos , Sensibilidad y Especificidad , Médula Espinal/efectos de los fármacos , Factores de TiempoRESUMEN
The effects of nitrous oxide (N2O) on steady-state concentrations and turnover rates of catecholamines in the olfactory bulb, hypothalamus, brain stem, hippocampus, striatum, thalamus, cerebral cortex, and spinal cord were determined in rats. Animals were exposed for 2 h to either 60% N2O or air. Immediately following exposure, all animals were injected intraperitoneally with alpha-methylparatyrosine (alphaMPT), a competitive inhibitor of tyrosine hydroxylase, and sacrificed at 0, 30, or 90 min postinjection. Brain catecholamine concentrations were determined using high-performance liquid chromatography coupled with electrochemical detection (HPLC-EC). Results indicate that N2O exposure significantly elevates steady-state concentrations of norepinephrine (NE) in the hypothalamus and striatum yet decreases amine levels in the brain stem region. Steady-state levels of dopamine (DA) were not significantly altered in any region of the CNS by N2O exposure. Acute exposure to N2O also resulted in significant decreases in the turnover rate of NE in the brain stem, yet it increased turnover of this amine in the olfactory bulb, hypothalamus, and striatum. Acute exposure to N2O resulted in a decreased turnover rate of DA in the hippocampus and striatum. In contrast, N2O appears to increase DA turnover in the olfactory bulb. These results indicate that acute exposure to N2O in rats causes region-specific alterations in steady-state levels and turnover rates of DA and NE within the central nervous system.
Asunto(s)
Encéfalo/metabolismo , Dopamina/metabolismo , Óxido Nitroso/farmacología , Norepinefrina/metabolismo , alfa-Metiltirosina/farmacología , Análisis de Varianza , Animales , Encéfalo/efectos de los fármacos , Cromatografía Líquida de Alta Presión , Cinética , Masculino , Especificidad de Órganos , Ratas , Ratas Sprague-Dawley , Factores de TiempoRESUMEN
The endocrine pancreas is composed of nests of cells called the islets of Langerhans, which comprise only about 20% of pancreatic cell mass and secrete insulin, glucagon, somatostatin, and pancreatic polypeptide. Insulin is anabolic, increasing storage of glucose, fatty acids and amino acids, while glucagon namely stimulates hepatic glycogenolysis, gluconeogenesis, and ketogenesis. Somatostatin acts as a paracrine agent to inhibit both insulin and glucagon release, and, therefore, to modulate their output. This article explores factors controlling release of these hormones, as well as the way in which they affect fuel metabolism in the whole animal.
Asunto(s)
Insulina/fisiología , Islotes Pancreáticos/fisiología , Hígado/fisiología , Animales , Glucagón/biosíntesis , Glucagón/metabolismo , Insulina/biosíntesis , Insulina/metabolismo , Secreción de Insulina , Islotes Pancreáticos/metabolismo , Hígado/metabolismo , Somatostatina/fisiologíaRESUMEN
When insulin is withdrawn acutely from a severely diabetic patient, a sequence of intricately interconnected events begins which, without intervention, can result in coma and death. These events involve not only carbohydrate metabolism, but protein and lipid metabolism, electrolyte and fluid balance as well. Acute insulin withdrawal permits the unopposed action of the counter-regulatory hormones (which are attempting to elevate the plasma glucose concentration), namely glucagon, cortisol, growth hormone, and epinephrine. This article details interrelationships existing between the many biochemical and physiological events that are occurring more or less simultaneously in the animal following acute insulin withdrawal.
Asunto(s)
Metabolismo de los Hidratos de Carbono , Diabetes Mellitus Tipo 1/metabolismo , Diabetes Mellitus/metabolismo , Insulina/deficiencia , Metabolismo de los Lípidos , Proteínas/metabolismo , Animales , Coma/etiología , Diabetes Mellitus Tipo 1/mortalidad , Cetoacidosis Diabética/metabolismo , Perros , HumanosRESUMEN
Rats were exposed to either oxygen (controls), 1.5% halothane in oxygen, or methoxyflurane (0.5%) in oxygen over a period of 2 h, then sacrificed at the end of exposure (2-h group), 4 h after removal from environmental chamber (4-h group), or at 24 h following anesthetic exposure (24-h group). Pituitary (excluding the neural lobe, Pit), brain, and spinal cord areas were isolated and processed with Met-enkephalin tissue concentrations determined. In halothane-exposed animals, Met-enkephalin concentrations in pit and across CNS areas studied were significantly lower at 2 h following anesthetic exposure than in control animals. Concentrations of Met-enkephalin in many areas of CNS and Pit of 4-h group approached control levels. Concentrations of Met-enkephalin in all areas studied except spinal cord returned to basal levels by 24 h following halothane exposure. Exposure to methoxyflurane resulted in less dramatic changes in Met-enkephalin concentrations across CNS regions examined. Exposure to methoxyflurane resulted in significant decreases in Met-enkephalin levels in olfactory bulb, thalamus, and hippocampus only. Met-Enkephalin levels did not change significantly in other areas of the central nervous system following methoxyflurane exposure. These results indicate that halothane and methoxyflurane may have differential effects on the endogenous opioid system.
Asunto(s)
Encéfalo/efectos de los fármacos , Encefalina Metionina/metabolismo , Halotano/farmacología , Metoxiflurano/farmacología , Médula Espinal/efectos de los fármacos , Animales , Masculino , Ratas , Ratas Sprague-DawleyRESUMEN
We examined the effects of chronic diethyldithiocarbamate (DDC) treatment on the concentrations of methionine-enkephalin, mature and unamidated forms (-Gly) of luteinizing hormone releasing hormone (LHRH) and substance P (SP) in various regions of the central nervous system (CNS). Chronic DDC treatment resulted in elevations of LHRH-Gly like immunoreactivity in the preoptic area (POA) and the medial basal hypothalamus (MBH), as well as elevations in SP-Gly like immunoreactivity in all areas of the CNS examined. Castration altered the ratios of SP-G-like/SP-like immunoreactivity in the pons, and LHRH-Gly like immunoreactivity in the MBH. Met-enkephalin concentrations were significantly elevated in the pons and medulla of intact DDC-treated animals, and in the POA of both intact- and castrated DDC-treated animals. Results demonstrate that it is possible to detect basal levels of unamidated LHRH and SP in many areas of the CNS, with ratios of unamidated/amidated peptides representing a unique and sensitive method for determining altered posttranslational processing of these transmitters, especially under altered endocrine states such as castration. Pharmacological blockade of terminal enzymatic processing of these peptides may be useful in studying upstream regulatory events in peptidergic neurons.
Asunto(s)
Amidas/metabolismo , Encéfalo/metabolismo , Ditiocarba/farmacología , Hormona Liberadora de Gonadotropina/metabolismo , Sustancia P/metabolismo , Animales , Cromatografía Líquida de Alta Presión , Encefalina Metionina/metabolismo , Inmunohistoquímica , Masculino , Orquiectomía , Radioinmunoensayo , Ratas , Ratas Sprague-DawleyRESUMEN
Glucagon and dibutyryl cyclic AMP (Bt2cAMP) stimulate Na+/taurocholate (TC) cotransport and increase the intracellular Ca2+ concentration ([Ca2+]i) of hepatocytes. Whether the effect of cAMP is mediated via increases in [Ca2+]i, cAMP-dependent protein kinase (PKA), and/or protein kinase C (PKC) was investigated in this study. TC uptake and [Ca2+]i were determined in isolated rat hepatocytes using [14C]TC and the fluorescent dye quin-2, respectively. Bt2cAMP, forskolin, and 8-bromo-cAMP stimulated Na(+)-dependent, but not Na(+)-independent TC uptake. Bt2cAMP increased the maximal rate of Na+/TC cotransport without affecting the apparent Km. Increases in TC uptake and [Ca2+]i by Bt2cAMP were inhibited in hepatocytes preloaded with bis-(2-amino-5-methylphenoxy)-ethane-N,N,N',N'-tetraacetic acid (MAPTA) or preincubated with 8-diethylaminooctyl 3,4,5-trimethoxybenzoate (TMB8). Calmodulin antagonists inhibited Bt2cAMP-induced increases in TC uptake, but not [Ca2+]i. Other Ca(2+)-mobilizing agents (thapsigargin, vasopressin, phenylephrine, and ionomycin) increased [Ca2+]i but failed to stimulate TC uptake, indicating that an increase in [Ca2+]i alone is not a sufficient stimulus for TC uptake. However, increases in TC uptake by 1 and 10 microM Bt2cAMP were further increased by thapsigargin, indicating a permissive role for Ca2+/calmodulin. Bt2cAMP-induced increases in TC uptake and [Ca2+]i were inhibited by known inhibitors of PKA and by an activator of PKC, but they remained unaffected by a specific inhibitor of PKC. Unlike thapsigargin, vasopressin inhibited Bt2cAMP-induced increases in TC uptake. Taken together these results indicate that stimulation of hepatic Na+/TC cotransport by cAMP 1) is mediated via PKA; 2) is potentiated, but not mediated, by Ca2+/calmodulin-dependent processes; and 3) may be down-regulated by PKC.
Asunto(s)
Calcio/metabolismo , AMP Cíclico/metabolismo , Hígado/metabolismo , Proteínas Quinasas/metabolismo , Sodio/metabolismo , Ácido Taurocólico/metabolismo , 8-Bromo Monofosfato de Adenosina Cíclica/farmacología , Animales , Bucladesina/farmacología , ATPasas Transportadoras de Calcio/antagonistas & inhibidores , Células Cultivadas , Colforsina/farmacología , Ionomicina/farmacología , Cinética , Hígado/efectos de los fármacos , Fenilefrina/farmacología , Inhibidores de Proteínas Quinasas , Ratas , Terpenos/farmacología , Acetato de Tetradecanoilforbol/farmacología , Tapsigargina , Vasopresinas/farmacologíaRESUMEN
It appears that different mechanisms responsible for fasting hyperbilirubinemia may be operative in different mammalian species (and subspecies). An increase in bilirubin production does not seem to occur in the horse, but a decrease in the hepatic uptake of bilirubin has been supported by a number of studies. Even though the delay in plasma elimination could also result from a decrease in hepatic blood flow, this possibility does not seem to play a major role since the hepatic uptake of compounds with low intrinsic hepatic clearance (e.g., ICG and bilirubin) appear to be affected more during fasting than those with higher clearances (e.g., BSP, bile acid, antipyrine, acetaminophen, and lidocaine) (Table I). Other possibilities such as a decrease in the affinity of hepatocellular membrane carriers involved in the uptake of these compounds or altered content of intracellular proteins involved in cellular transport or storage of bilirubin have not been investigated in horses. Competition with free fatty acids for these carrier-mediated events seems likely, particularly because horses and ponies experience high degrees of hyperlipidemia during fasting. However, studies that have explored the competition hypothesis, while not entirely negative, do not fully support it as being the sole mechanism responsible for this phenomenon. Hepatocellular UDPGT activities have not been adequately investigated in horses, but it is apparent that intraduodenal infusion of glucose is effective in reducing fasting hyperbilirubinemia and also in increasing biliary bilirubin excretion. It therefore seems possible that UDP-glucose and UDPGA levels in the livers of horses could be reduced during fasting, thus resulting in substrate depletion for the conjugating enzymes. As pointed out by Freedland et al. (1991), it is also possible that the horse, like the Bolivian squirrel monkey, might also have a relatively high apparent Km and low Vmax for UDPGT, thus resulting in high steady-state levels of plasma bilirubin, particularly during fasting. Although little is known about the cause of equine fasting hyperbilirubinemia and the subtle factors that may be modulating slight changes in the production, hepatocellular uptake, binding, conjugation, and/or biliary excretion of this pigment, it is known that it can be rapidly reversed by refeeding native hay. Perhaps one direction for future research could point toward more fully exploring what aspects of feeding are responsible for reversing this intriguing physiological phenomenon.
Asunto(s)
Bilirrubina/metabolismo , Ayuno , Caballos/metabolismo , Hiperbilirrubinemia/etiología , Animales , Ácidos Grasos no Esterificados/metabolismo , Hígado/metabolismo , Especificidad de la EspecieRESUMEN
The objective of this study was to document, through comprehensive means, normal distribution and concentration of catecholamines in various regions of the CNS of pigs, an increasingly popular animal model used for transgenic manipulation of neural genes. The effects of gonadal steroidal status on this distribution were also assessed by comparing CNS catecholamine concentrations among mature male pigs (boars), immature (gilts) and mature female pigs (sows), and adult male pigs castrated prepuberally (barrows). Dissected tissue samples from the CNS were extracted in 2 N acetic acid, filtered through a 0.2 micron filter, then quantitated by reverse-phase high performance liquid chromatography using a C-18 reverse phase column with electrochemical detection. In both boars and sows the highest concentrations of norepinephrine (NE) were found in the diencephalic areas and brain stem. Gilts exhibited elevated concentrations of NE in the olfactory bulbs (OB), hypothalamus, pons, and corpus trapezoideum-locus ceruleus (LC) compared to lower concentrations in corresponding areas of sows. Prepuberal castration of the male was associated with significantly lower NE concentrations in the striatum, periaqueductal area (PAG), pons, LC, and spinal cord. The sow exhibited significantly lower NE concentrations in the mammillary area (Mam), PAG, pons, and spinal cord than those in corresponding areas of the boar. Dopamine concentrations appeared to be similar in all areas of the brain and spinal cord studied in the sow and boar. Results demonstrated that prepuberal castration of the male appears to significantly alter the DA content of the Mam and dorsal spinal cord, in contrast to gilts who possess significantly higher concentrations of DA. It is concluded from our studies that in general, catecholamine concentrations in various regions of the brain and spinal cord of sexually mature pigs parallel distributions of neuropeptides, substance P, and methionine enkephalin, as previously reported. In addition, significant association was found between gonadal activity and catecholamine concentrations in discrete areas of the pig brain.
Asunto(s)
Química Encefálica , Dopamina/análisis , Epinefrina/análisis , Norepinefrina/análisis , Médula Espinal/química , Animales , Cromatografía Líquida de Alta Presión , Femenino , Masculino , Orquiectomía , Especificidad de Órganos , Factores Sexuales , Maduración Sexual , PorcinosRESUMEN
The mechanism of cocaine-induced hepatotoxicity is not clearly understood. Recent studies show that fluctuations in intracellular Ca2+ ([Ca2+]i) and/or cyclic-AMP ([cAMP]) concentration play a major role in hormone action, and sustained elevations in [Ca2+]i may be involved in the initiation of hepatocellular damage. To evaluate the possible involvement of intracellular Ca2+ and/or cAMP, we investigated effects of cocaine and lidocaine on basal, epinephrine and dibutyryl cyclic-AMP (DBcAMP)-induced changes in [Ca2+]i and glucose efflux from isolated rat hepatocytes. [Ca2+]i was monitored continuously using a Ca2(+)-selective fluorescence indicator, Quin-2, and was calculated after correcting for autofluorescence. Neither cocaine nor lidocaine (0.1-5 mmol/l) affected basal [Ca2+]i, yet both agents decreased epinephrine (10 mumol/l) and DBcAMP (100 mumol/l)-induced increases in [Ca2+]i in a dose-dependent fashion. Half-maximal inhibition occurred at 0.75 mmol/l cocaine and 1.7 mmol/l lidocaine. Cocaine and lidocaine also decreased epinephrine and DBcAMP-induced glucose efflux. The dose-dependent effect on epinephrine-induced glucose efflux was similar to that of both anesthetics on epinephrine-induced increases in [Ca2+]i. However, 5 mmol/l cocaine or lidocaine decreased DBcAMP-induced glucose efflux by less than 50%, and [Ca2+]i by more than 80%. Taken together, these results indicate that cocaine and lidocaine decrease the ability of epinephrine to stimulate glucose efflux by interfering with the Ca2(+)-mediated, and not the cAMP-mediated intracellular pathway. It is therefore speculated that alterations in metabolic endocrine regulation may contribute to cocaine's hepatotoxic effect.
Asunto(s)
Calcio/metabolismo , Cocaína/farmacología , Epinefrina/farmacología , Glucosa/metabolismo , Lidocaína/farmacología , Hígado/metabolismo , Animales , Bucladesina/farmacología , AMP Cíclico/metabolismo , Glucógeno/metabolismo , Hígado/citología , Hígado/efectos de los fármacos , RatasRESUMEN
The role of bile salt in biliary lipid excretion was studied in 3 healthy ponies with chronic external biliary fistulas. After endogenous bile salt pool depletion, micelle-forming taurocholate or taurochenodeoxycholate was infused to replace excreted bile salt. Enterohepatic circulations were held open (total biliary diversion) throughout each study. Results indicated that biliary lipid excretion in ponies (113 +/- 21 nmol/min/kg of body weight) is approximately 10 times less than that reported in rodents. Although the lipid composition (4.4% cholesterol, 5.6% phospholipid, and 90% bile salt) was within the predicted range for a single phase of micellar (or vesicular) liquid in solution, it was supersaturated with cholesterol because of low absolute concentrations of bile salt and phospholipid. Ponies, like guinea pigs, were determined to have a high bile salt-independent secretion of biliary lipid with little (or no) coupling to endogenous bile salt output. However, bile salt excretion induced by higher taurocholate infusion rates (ie, those greater than the physiologic range of 61 to 125 nmol/min/kg) was positively correlated with an increase in biliary phospholipid excretion, but not cholesterol excretion, thus indicating that a threshold intracellular bile salt concentration may be associated with enhanced biliary phospholipid excretion in ponies. The apparent cholerectic effects of endogenous bile salts, taurocholate, and taurochenodeoxycholate (that is, the increment in bile flow per increment in bile salt recovered) were greater in ponies than reported for any other mammal.
Asunto(s)
Ácidos y Sales Biliares/fisiología , Bilis/análisis , Caballos/fisiología , Lípidos/análisis , Animales , Bilis/fisiología , Ácidos y Sales Biliares/metabolismo , Ácidos y Sales Biliares/farmacología , Femenino , Factores de TiempoRESUMEN
Effects of bile acids on cystolic Ca++ activity and cell viability of isolated rat hepatocytes were studied to test the hypothesis that bile acids may produce hepatotoxicity by increasing cystolic Ca++ activity. Changes in cystolic Ca++ activity were calculated from time-dependent changes in fluorescence of quin-2 loaded hepatocytes. Release of lactate dehydrogenase and changes in propodium iodide fluorescence were used to assess cell viability. Bile acids studied were unconjugated and taurine-conjugated cholate, chenodeoxycholate (and taurochenodeoxycholate), deoxycholate (and taurodeoxycholate) and lithocholate (and taurolithocholate). With the exception of cholate and taurocholate, bile acids increased cystolic Ca++ activity within 10 to 30 sec in a concentration-dependent fashion (0.05 to 1.0 mM) and in the order lithocholate = taurolithocholate greater than chenodeoxycholate = taurochenodeoxycholate = deoxycholate = taurodeoxycholate. The initial increase in cystolic Ca++ activity by bile acids was not due to cell damage, since bile acid-induced decreases in cell viability were not significant until 2 to 3 min. At higher concentrations of unconjugated bile acid, there was a secondary increase in quin-2 fluorescence corresponding temporally to the increase in propodium iodide fluorescence, indicating cell damage after the initial increase in cystolic Ca++ activity. The ability of conjugated and unconjugated bile acids to increase cystolic Ca++ activity was abolished and decreased (60 to 90%), respectively, in the absence of extracellular Ca++, indicating that extracellular Ca++ is the major source of the bile acid-induced increase in cystolic Ca++ activity.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Ácidos y Sales Biliares/farmacología , Calcio/metabolismo , Hígado/metabolismo , Animales , Ácidos y Sales Biliares/toxicidad , Permeabilidad de la Membrana Celular , Supervivencia Celular/efectos de los fármacos , Citosol/metabolismo , Técnicas In Vitro , L-Lactato Deshidrogenasa/metabolismo , Hígado/efectos de los fármacos , Hígado/enzimología , Masculino , Ratas , Ratas EndogámicasRESUMEN
A neonatal lamb was admitted with icterus, hypoglycemia, increased liver enzyme activities, and delayed sulfobromophthalein clearance. Biliary and pancreatic duct atresia were documented in this lamb at necropsy. Hepatobiliary scintigraphy was useful in reaching an antemortem diagnosis of bile duct obstruction. Hepatobiliary scintigraphy, using 1.5 mCi of 99m technetium-labeled acid, was performed on the affected lamb and on an age-matched control lamb. Using a large field-of-view camera equipped with a low-energy parallel-hole collimator, right ventral oblique images of the thorax and abdomen were obtained. Images were simultaneously recorded on microdot film by use of a dedicated nuclear medicine computer. In the control lamb, there was rapid clearance of radioactivity from the blood pool, coincident with obvious accumulation of radioactivity in the liver and followed by sequential accumulation in the intrahepatic biliary system, gallbladder, common bile duct, and small intestine. Results of the study in the affected lamb were characterized by prolonged blood-pool radioactivity without appreciable hepatic uptake and by excessive renal and urinary bladder activity in the later phases of the study. Hepatobiliary scintigraphy was a safe and non-invasive procedure that provided quantitative information about the degree of bile duct obstruction in the affected lamb.
Asunto(s)
Atresia Biliar/veterinaria , Sistema Biliar/diagnóstico por imagen , Hígado/diagnóstico por imagen , Enfermedades de las Ovejas/diagnóstico por imagen , Animales , Atresia Biliar/diagnóstico por imagen , Femenino , Cintigrafía , OvinosRESUMEN
Adult female ponies (130-225 kg) with chronically implanted external biliary fistulas (T-tubes) participated in three-way cross-over studies using either i.v. lorazepam (10 mg) or acetaminophen (2 g), two model drugs biotransformed mainly by hepatic conjugative reactions. The objectives were to determine the systemic pharmacokinetics, urinary and biliary excretion and degree of enterohepatic circulation (EHC) of these compounds. Trial conditions were: A: EHC intact, with blood and urine, but not bile, collected after i.v. drug administration; B: EHC interrupted, with blood, urine and bile collected after i.v. drug administration; and C: bile infused, EHC open, without i.v. drug administration, with bile collected from trial B (containing biliary excreted drug) infused into the duodenum via the T-tube, followed by collection of blood, urine and bile. At least 2 weeks elapsed between trials. Interruption of the EHC caused lorazepam plasma half-life to shorten (3.4 vs. 2.3 hr with the EHC intact, P less than .1), clearance to increase (9.2 vs. 12.3 ml/min/kg, P less than .1) and total area under the plasma concentration curve for lorazepam glucuronide to decrease (210 vs. 310 ng/ml X hr, P less than .06). Recovery of lorazepam as its glucuronide in bile was 24.5% of the i.v. injected dose. Urinary elimination of lorazepam glucuronide was reduced from 41 to 36% of the dose due to bile collection. Subsequent duodenal infusion of collected bile, containing an average of 2.45 mg of lorazepam as glucuronide, was followed by urinary excretion of 0.48 mg of lorazepam as glucuronide in urine and 0.36 mg re-excreted into bile.(ABSTRACT TRUNCATED AT 250 WORDS)
Asunto(s)
Acetaminofén/farmacocinética , Circulación Enterohepática , Lorazepam/farmacocinética , Animales , Bilis/metabolismo , Femenino , Glucuronatos/farmacocinética , Semivida , Caballos , Técnicas In Vitro , Sulfatos/farmacocinéticaRESUMEN
This article addresses clinical problems that present in equine liver disease. It also discusses the variety of laboratory tests available to the clinician that can differentiate the type and degree of liver dysfunction. This is followed by a more specific discussion regarding unique features of equine bilirubin and bile acid metabolism.
Asunto(s)
Enfermedades de las Vías Biliares/veterinaria , Enfermedades de los Caballos/diagnóstico , Hepatopatías/veterinaria , Animales , Enfermedades de las Vías Biliares/diagnóstico , Pruebas Enzimáticas Clínicas/veterinaria , Caballos , Hepatopatías/diagnóstico , Pruebas de Función Hepática/veterinariaRESUMEN
The pharmacokinetics of dantrolene sodium were investigated in horses following both intravenous (2 mg/kg) and intragastric (4 mg/kg) administration. Two ponies also received dantrolene sodium intravenously (2 mg/kg) in a pilot study to obtain preliminary kinetic data and to determine urinary and biliary excretion of the intact drug. Distribution and elimination of dantrolene was rapid, resulting in an elimination half-life of 129 +/- 8 (SEM) min and a whole body clearance of 4.16 +/- 0.52 ml/min/kg. Following intragastric administration, dantrolene rapidly acheived peak concentrations within 1.5 h, but was incompletely absorbed, with a bioavailability of 39 +/- 10%. Small amounts of intact drug were recovered in urine and bile. Based upon disposition kinetics of dantrolene in these studies, intravenous and intragastric dosage regimens were determined which would maintain blood dantrolene concentrations within the predicted clinically effective range.
Asunto(s)
Dantroleno/farmacocinética , Caballos/metabolismo , Animales , Bilis/metabolismo , Dantroleno/administración & dosificación , Dantroleno/sangre , Dantroleno/orina , Femenino , Inyecciones Intravenosas , Intubación GastrointestinalRESUMEN
Previous studies demonstrated that plasma clearance of organic anions such as bilirubin, bile acid, sulfobromophthalein (BSP) and indocyanine green (ICG), was reduced from 36% (bile acid) to 55% (ICG) in fasted (3 days) horses. It is believed that a general decline in carrier-mediated hepatic uptake may have accounted for those changes. However, fasting may also affect hepatic blood flow, thereby contributing to reduced clearance of these compounds. In order to test this hypothesis, plasma clearance of antipyrine, acetaminophen and lidocaine, drugs known to be cleared by the liver yet not suspected of undergoing carrier-mediated hepatic uptake, were investigated in nine healthy adult mares (three horses/drug group) before and following a 3-day fast. Results demonstrate that fasting decreased clearance of organic anions from previous studies more than clearance of drugs used in these studies. In addition, clearance of lidocaine, the drug with the highest plasma clearance and therefore the drug most likely to be affected by reduced hepatic blood flow, was affected least by fasting. Therefore, reductions in clearance of these compounds due to fasting must not be due entirely to reductions in hepatic blood flow, but must also involve reductions in intrinsic hepatic clearance.
Asunto(s)
Acetaminofén/metabolismo , Antipirina/metabolismo , Caballos/metabolismo , Lidocaína/metabolismo , Animales , Ayuno , Femenino , Cinética , Hígado/metabolismoRESUMEN
The following studies were designed to evaluate plasma elimination kinetics of intravenously administered antipyrine, acetaminophen and lidocaine among 9 healthy adult horses and 9 healthy drug-free humans (3 each per drug group), in order to compare potential species differences in drug-metabolizing ability. Acetaminophen is largely biotransformed in humans by hepatic glucuronide and sulfate conjugation, whereas both antipyrine and lidocaine are oxidized by hepatic microsomal mixed-function oxidases. Thus, plasma clearances of these drugs are thought to reflect differences in hepatic oxidative and conjugative activity, and possibly hepatic blood flow in the case of lidocaine. Results showed that mean (+/- SD, n = 3) acetaminophen clearance was similar in both horses (4.84 +/- 0.637 ml/min/kg) and humans (4.68 +/- 0.691 ml/min/kg). However, antipyrine clearance was 10 times greater in horses (5.83 +/- 2.21 ml/min/kg) than in humans (0.536 +/- 0.110 ml/min/kg), which may reflect enhanced hepatic microsomal activity in horses. Although lidocaine clearance in humans was similar to estimated hepatic blood flow (20.6 +/- 5.81 ml/min/kg), clearance in horses was more than 2 times greater (52.0 +/- 11.7 ml/min/kg). The cause of the higher clearance of lidocaine in horses (like dogs) remains unexplained, and may involve significant metabolism of lidocaine at extrahepatic, extravascular sites, for intravascular degradation and renal excretion of intact lidocaine in horses was negligible. Although precise biochemical mechanisms underlying pharmacokinetic parameters for these drugs in horses were not determined, it is nonetheless concluded from antipyrine results that horses may have an enhanced ability (compared with humans) to clear drugs from the circulation that are primarily metabolized in the liver by phase I oxidative reactions.(ABSTRACT TRUNCATED AT 250 WORDS)