Inhibition of dopamine release by methylenedioxymethamphetamine is mediated by serotonin

(+/-)-3,4-Methylenedioxymethamphetamine (MDMA), at doses of 0.1, 1 and 10 mg/kg, produced a long-lasting decrease in extracellular dopamine concentration in the neostriatum of anesthetized rats, as measured by in vivo voltammetry. Since MDMA has been shown to release serotonin from rat brain slices and synaptosomes, we examined the possibility that increased serotonin release might be the cause of the decrease in dopamine release. Rats were treated with d,l-p-chloroamphetamine seven days prior to acute MDMA administration. Rats pretreated with p-chloroamphetamine, which produced a marked decrease in serotonin content, showed no significant decrease in extracellular dopamine concentration when administered 10 mg/kg MDMA. These data suggest that MDMA produces a significant decrease in dopamine release when administered acutely, and that this decrease is an indirect effect mediated by an increase in serotonin release.     

Mitochondrial toxicity of 2-bromohydroquinone in rabbit renal proximal tubules

2-Bromohydroquinone (BHQ) is a nephrotoxic metabolite of bromobenzene and a model toxic hydroquinone. The primary goal of these studies was to determine whether BHQ produces toxicity in rabbit renal proximal tubules by inhibiting mitochondrial function. BHQ induces a specific sequence of cellular events. Initially there was decrease in tubular glutathione content followed by a decrease in nystatin-stimulated ouabain-sensitive respiration. A decrease in cell viability, as measured by a decrease in lactate dehydrogenase retention, was late event. Associated with the decrease in respiration was a decrease in intracellular ATP content. Probing of mitochondrial function in the tubule revealed that BHQ did inhibit mitochondrial function in a somewhat selective manner. State 3 respiration was inhibited prior to changes in the rate of electron flow through cytochrome c-cytochrome oxidase. It is postulated that BHQ may initially inhibit state 3 respiration by inhibiting the adenine nucleotide translocator and/or the F1-ATPase.     

Effects of DDT and triclosan on tumor‐cell binding capacity and cell‐surface protein expression of human natural killer cells

1,1,1‐trichloro‐2,2‐bis(4‐chlorophenyl)ethane (DDT) and triclosan (TCS) are organochlorine (OC) compounds that contaminate the environment, are found in human blood and have been shown to decrease the tumor‐cell killing (lytic) function of human natural killer (NK) cells. NK cells defend against tumor cells and virally infected cells. They bind to these targets, utilizing a variety of cell surface proteins. The present study examined concentrations of DDT and TCS that decrease lytic function for alteration of NK binding to tumor targets. Levels of either compound that caused loss of binding function were then examined for effects on expression of cell‐surface proteins needed for binding. NK cells exposed to 2.5 μM DDT for 24 h (which caused a greater than 55% loss of lytic function) showed a decrease in NK binding function of about 22%, and a decrease in CD16 cell‐surface protein of 20%. NK cells exposed to 5 μM TCS for 24 h showed a decrease in ability to bind tumor cells of 37% and a decrease in expression of CD56 of about 34%. This same treatment caused a decrease in lytic function of greater than 87%. These results indicated that only a portion of the loss of NK lytic function seen with exposures to these compounds could be accounted for by loss of binding function. They also showed that loss of binding function is accompanied by a loss of cell‐surface proteins important in binding function. Copyright © 2012 John Wiley & Sons, Ltd.     

Effects of prenatal and perinatal administration of phencyclidine on the behavioral development of rat offspring

The effects of prenatal and perinatal administration of a nonteratogenic dose of phencyclidine (PCP) on the behavioral development of Sprague-Dawley rats were examined. In the offspring prenatally treated with PCP (10 mg/kg) between days 7 and 17 of gestation, a decrease in maternal body weight in the gestation period, a decrease in fetal body weight and body length, a decrease in viability of offsprings, and a decrease in the body weights of the offspring in the nursing period were observed. Furthermore, PCP pups had difficulty performing the rota-rod task at 4 weeks and exhibited a decrease in sensitivity to challenged PCP at 5 weeks (female). In the offspring prenatally treated with PCP between days 7 and 21 of gestation, a decrease in the body weights of dams, fetuses and offspring, and a decrease in the viability of offsprings were observed. PCP pups showed an increase in the score for head-twitch response (male), a delay in the development of ambulation, negative geotaxis (male), bar holding and rope-descending behavior (female). However, the PCP administration during prenatal (between days 17 and 21 of gestation) and nursing periods showed only a decrease in viability and body weight of offspring, and a delay in the development of the separation of eyelids. These results suggest that more attention should be given to the developmental toxicity of PCP.     

The site of inhibition of porphyrin biosynthesis by an isomer of diazinon in rats

2-Isopropyl-6-methyl-4-S-pyrimidinyl diethyl thiophosphate (isodiazinon) has been synthesized by an unambiguous route. Rats treated with isodiazinon over a 100-day period show decreased levels of liver ferrochelatase. Rats treated with diazinon and isodiazinon in combination over the same period show a more marked decrease in liver ferrochelatase activity as well as a decrease in the activity of coproporphyrinogen oxidase. Treatment of rats with stabilised diazinon over the same period is not associated with a decrease in the activity of either enzyme. Neither diazinon nor isodiazinon causes a decrease in the activity of glutamate dehydrogenase, succinate dehydrogenase or kynurenine hydroxylase, suggesting that the effect is specific to the porphyrin biosynthesis pathway and not due to mitochondrial damage.     

Deterioration of baroreflex by transient global cerebral ischemia: its correlation with the degree of ischemia or post-ischemic hypoperfusion in the medulla oblongata

In a canine model of transient global cerebral ischemia, the correlation between the decrease in baroreflex sensitivity (BRS) following 5-min ischemia and the degree of ischemia or post-ischemic hypoperfusion was investigated. Although the medulla oblongata and the cerebral cortex suffered a similar degree of ischemia, the extent of post-ischemic decrease in BRS was inversely correlated with the residual blood flow during ischemia in the medulla, but not with that in the cerebral cortex. A similar degree of post-ischemic hypoperfusion occurred in the medulla and the cerebral cortex. However, the extent of decrease in BRS was not correlated with the degree of hypoperfusion, and the cortical EEG was not significantly affected. These results suggest that the decrease in BRS may be due to the functional damage in the medulla and that the selective decrease in BRS without concomitant impairment of the EEG cannot be ascribed to the regional difference in the degree of ischemia or post-ischemic hypoperfusion.     

Evaluation of the effect of food on the pharmacokinetics of avitriptan

Bioavailability of avitriptan was found to decrease significantly when administered 5 min after a standard high fat meal. The studies described herein were carried out to gain insight into the mechanism of this food effect. A series of studies were conducted in humans to assess the effect of timing of meal, type of meal, gastric pH, change in the formulation and dose on the bioavailability of avitriptan. Avitriptan was administered as a 50 mg capsule under fasted condition and at 30 min, 1, 2 and 4 h after a standard high fat meal. The reduction in avitriptan bioavailability persisted even at 4 h post high fat meal, although as the time interval between the meal and dose increased, the effect of meal tended to decrease. Bioavailability of avitriptan also decreased significantly when the drug was administered after a high protein and a high carbohydrate meal. Elevation in gastric pH caused by food was not found to be responsible for the food-related decrease in bioavailability of avitriptan since ranitidine pretreatment did not lead to a decrease in bioavailability. When administered as a 50 mg ¹⁴C-labeled solution after a standard high fat meal, bioavailability of avitriptan decreased although the decrease was less compared with that observed for a capsule dosage form. Plasma concentrations and cumulative urinary excretion of total radioactivity also decreased in the fed condition, indicating the absorption of avitriptan was affected. The decrease in avitriptan AUC was somewhat more pronounced than the decrease in the exposure to the total radioactivity suggesting a food-related increase in the first-pass metabolism of avitriptan. Effect of the standard high fat meal on avitriptan administered as a 150 mg capsule was similar to that observed at the 50 mg dose. Overall, the results indicate that bioavailability of avitriptan is significantly reduced irrespective of the type of meal, dose and dosage form and the effect persists for as long as 4 h post meal. Thus, it appears that avitriptan absorption and bioavailability are highly sensitive to presence of food in the stomach and any food-related changes in gastric emptying time and gastrointestinal motility. © 1998 John Wiley & Sons, Ltd.     

Decline of histidine decarboxylase activity and histamine levels in rat stomach after reserpine

The previously reported reduction of rat gastric histamine following reserpine administration was investigated. It was observed that there was a rapid decrease in the histidine decarboxylase activity in the glandular portion of rat stomach after the administration of reserpine. This decrease in histidine decarboxylase activity preceded a decrease in the histamine content of the rat stomach. The effect of reserpine on histidine decarboxylase activity was seen only in the intact animal; reserpine had no action on histidine decarboxylase activity in vitro. The reduction of histidine decarboxylase activity by reserpine was not abolished by vagotomy or atropine treatment nor by treatment with agents producing sympathetic blockade. However, the administration of the sympatholytic agents alone reduced gastric histidine decarboxylase activity. It was concluded that the decrease in histidine decarboxylase activity in the stomach following reserpine treatment might be one factor contributing to the decrease in gastric histamine after administration of this drug.     

糙海参多糖纯化工艺优选及其产物的药理活性比较

通过正交实验发现糙海参多糖粘度和脱色时的温度，时间，多糖浓度和H2O2浓度有关。温度升高，时间延长，多糖浓度减小和H2O2浓度增大使产物粘度减小，并且不同粘度的糙海参多糖对小鼠急性脑缺血死亡时间的影响不同，在一定的范围内，随粘度减小，死亡时间延长，因此在生产中对多糖生产工艺的控制至关重要。     

Sex-related effect of hemin on cytochrome P450 and drug-metabolizing enzymes in rat liver

We examined the effect of hemin on rat hepatic microsomal cytochrome P450 (P450) and its molecular species (P450 2E1, 3A2, 2C11 and 2C12) under the induction of heme oxygenase activity in male and female rats. Hemin produced an inverse relationship between the induction of heme oxygenase activity and the decrease of P450 content in a dose-dependent manner. A time course study revealed that hemin produced a significant decrease in total P450 content in male rats to about 37% that of the controls at 24 hr after its administration. Western and Northern blot analyses revealed that the increase in both heme oxygenase-1 (HO-1) protein and HO-1 mRNA reached a maximum at 24 hr and returned to control levels within 120 hr in both sexes. With respect to P450-dependent monooxygenase activities, we found that there was a significant decrease of aniline p-hydroxylase activity to about 30% of the control animals, but not in erythromycin N-demethylase activity at various time intervals. Immunoblot analysis revealed that P450 2E1 in male rat liver was dramatically decreased at 24 hr to about 20% of the controls, but not P450 3A2. Parallel to the decrease of androstenedione 16 alpha-hydroxylase activity, there was a marked decrease of P450 2C11 or 2C12 in male or female rats, respectively, at 72 hr after the treatment; however, hemin did not decrease androstenedione 16 alpha-hydroxylase activity in phenobarbital-pretreated rat liver. These findings suggest that hemin predominantly affects constitutively expressed isozymes rather than inducible P450 species in rat liver.     

Cisplatin-induced lipid peroxidation and decrease of gluconeogenesis in rat kidney cortex: different effects of antioxidants and radical scavengers

The present in vitro study was performed to investigate the effect of the nephrotoxic anticancer agent cisplatin (CP) on lipid peroxidation, on pyruvate-stimulated gluconeogenesis and on p-aminohippurate (PAH) accumulation in rat renal cortical slices. In addition, the inhibitory effects of the antioxidants and radical scavengers N,N'-diphenyl-p-phenylenediamine (DPPD), (+)-cyanidanol-3 or alpha-tocopherol on CP-induced lipid peroxidation and CP-induced decrease of gluconeogenesis and the inhibitory effect of DPPD on CP-induced decrease of PAH accumulation were evaluated. Slices were incubated in a CP-containing medium for different periods of time (7.5-300 min) and at different concentrations (0.025-1.5 mg/ml). Lipid peroxidation was monitored by measuring the production of malondialdehyde (MDA). Accumulation of PAH was expressed as slice to medium concentration ratio. Pyruvate-stimulated gluconeogenesis, measured as glucose production, was determined after a subsequent 60- or 15-min incubation in a pyruvate-containing, CP-free medium. CP led to a time- and concentration-dependent increase in MDA production, a time- and concentration-dependent decrease of pyruvate-stimulated gluconeogenesis and a time-dependent decrease of PAH accumulation in renal cortical slices. Decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation. Antioxidants reduced CP-induced MDA production and CP-induced decrease of accumulation of PAH, but did not reverse CP-induced decrease of gluconeogenesis. This might indicate, that the generation of free radicals and subsequent lipid peroxidation may play a role, at least in part, in inducing CP nephrotoxicity. There could be more than one mechanism of CP-induced nephrotoxicity, since decrease of gluconeogenesis preceded MDA production and decrease of PAH accumulation and could not be inhibited by antioxidants and radical scavengers.     

Adverse effects of antiepileptic drugs on bone mineral density in children

Bone mineral content (BMC) or density (BMD) may be decreased in children with epilepsy either as a consequence of the epilepsy, the condition that caused the epilepsy or the treatment for epilepsy. This paper investigates the effects of antiepileptic drugs (AEDs) on BMD in children. A systematic search of Pubmed resulted in 14 papers that described changes in BMD in children on AEDs. For phenytoin, one study failed to show a decrease in femur BMD, whereas another study reported a decrease in total body and spine BMD, but only with the use of phenytoin for > 2 years. With phenytoin combined with a ketogenic diet, a decrease in forearm BMC was seen. For phenobarbital, one study showed a decrease in spine and total body BMD, but only among those who had used phenobarbital for > 2 years. Six studies were available for carbamazepine, and none of these showed a decrease in BMD in any skeletal site. For valproate, results were diverse; two studies reported a decrease in spine BMD, whereas two other studies did not. Two studies reported a decrease in hip BMD with valproate, whereas one did not. All three studies on forearm BMD in users of valproate described a decrease. Three studies reported an improvement in BMC with vitamin D supplementation in children on AEDs. No reports on changes in BMD among users of newer AEDs are available. In conclusion, more evidence is needed for the effects on BMD in children, especially for newer AEDs. The available studies have all been cross-sectional, and longitudianal studies are needed along with studies on potential interventions in children with decreased BMD.     

Decrease in insulin secretion related to hypocalcemia induced by a high dose of zinc in rats

A single oral administration of zinc (Zn), sufficient to induce hypocalcemia, caused a decrease in glucose tolerance in fasted rats. This decrease resulted from reduction of insulin secretion. The restoration of Zn-induced hypocalcemia completely prevented the decrease in glucose tolerance and insulin secretion. These results suggest that the effect of Zn administration on insulin secretion in rats is a consequence of hypocalcemia.     

The effects of acute and chronic morphine administration on GABA receptor binding

The effect of acute and chronic morphine administration and naloxone-precipitated withdrawal on the binding of [3H]GABA to its receptor sites in rat brain membranes was investigated. Acute morphine (25 mg/kg) administration produced a decrease in the GABA binding in cerebellum, cortex and striatum. This decrease appears to be due to a selective decrease in the number of high-affinity GABA receptor binding sites. In contrast, rats chronically treated with morphine by pellet implantation did not exhibit any changes in GABA receptor binding, except for an increase in pons medulla. However, in rats which were physically dependent, as indicated by naloxone-precipitated withdrawal, GABA binding was decreased significantly in cerebellum and striatum, relative to chronic morphine treatment or placebo pellet controls. This decrease was due to a decrease in the number of low affinity GABA receptor binding sites. Both chronic morphine and naloxone-precipitated withdrawal treatments produced an increase in GABA binding in the pons medulla. These results suggest that morphine may produce some of its effects by modulating GABAergic systems and that high and low affinity GABA receptor sites may play a differential role during various morphine treatments.     

Effect of betaxolol on aspartate aminotransferase activity in hypoxic rat retina in vitro

We investigated the effect of betaxolol on the decrease of mitochondrial aspartate aminotransferase (mAAT) activity in rat retinas induced by hypoxia in vitro. It is reported that mAAT decreases in ischemic or hypoxic retina and that the decrease is caused by Ca(2+)-dependent proteases such as calpain. Betaxolol is a compound that has beta(1)-adrenergic receptor blocking and voltage-dependent calcium channel blocking properties. The rat eye cups were maintained with Locke's solution saturated with 95% air - 5% CO(2). The eye cups were immersed in glucose-free Locke's solution saturated with 95% N(2) / 5% CO(2) (hypoxic solution). Ninety minutes of hypoxia caused a 20% decrease in mAAT activity. The eye cups incubated with the hypoxic solution containing 1 mM EGTA, 10 micro M MK-801 or 100 micro M betaxolol were protected from the decrease in mAAT activity, so that the residual mAAT activity was 50%, 45% or 40%, respectively, compared to the eye cups incubated in hypoxic solution alone, which had a 100% decrease in mAAT activity. In addition, co-incubation with EGTA and betaxolol had a greater protective effect against the mAAT decrease than a single application. This additive effect of betaxolol was dose-dependent. These results suggested that betaxolol had a protective effect against the decrease of mAAT caused by hypoxia and indicated that betaxolol might inhibit the Ca(2+) release from intracellular Ca(2+) stores.     

The determination of cellulase activity by viscometry

The enzymatic activity of cellulase has been estimated by the decrease of viscosity of a hydroxyethylcellulose solution as a function of incubation time. This decrease is a function of the applied shear stress. It is proposed that the viscosity be measured in an ordinary Ostwald viscometer under conditions where the viscosity is Newtonian, that is, the decrease of viscosity by enzymatic activity is independent on the shear stress.     

Central inhibitory effect of alpha-methyldopa on blood pressure, heart rate and body temperature of renal hypertensive rats.

The central inhibitory effect of alpha-methyldopa on blood pressure, heart rate and body temperature was studied in conscious renal hypertensive rats. Systemic administration of alpha-methyldopa decreased mean arterial blood pressure and body temperature and caused a short lasting increase in heart rate followed by a long lasting decrease. Inhibition of central decarboxylase activity prevented the decrease in blood pressure, heart rate and body temperature but not the initial increase in heart rate. Inhibition of peripheral decarboxylase activity blocked the increase in heart rate and partially reduced the decrease in heart rate and body temperature but did not affect the decrease in blood pressure. Alpha-Methyldopa also decreased blood pressure at an ambient temperature of 30 degrees C, but the decrease of body temperature was absent and the heart rate remained elevated for 7 hr. Similar results were obtained in normotensive rats. The decrease in heart rate was correlated with the decrease in body temperature in normotensive and renal hypertensive rats. These findings suggest that in the renal hypertensive rat the decrease in blood pressure and in body temperature depends on a central action of alpha-methyldopa metabolites.     

Comparison of renal excretion of chloramphenicol in patients with chronic pyelonephritis, glomerulonephritis and polycystic kidneys.

In patients with chronic pyelonephritis, glomerulonephritis and polycystic kidneys, decrease in renal clearance of chloramphenicol (CCHL) is related to a decrease in the clearance of inulin (Cin). The rate of decrease of CCHL is relatively slower than that of Cin. The findings attest to an increased excretion of chloramphenicol by residual nephrons. The groups investigated did not display any significant differences in the relation between CCHL and Cin. The findings indicate that changes in the excretion of chloramphenicol by residual nephrons are not related to the primary pathological process responsible for the impairment of the renal parenchyma.     

Cimetidine interaction with liver microsomes in vitro and in vivo. Involvement of an activated complex with cytochrome P-450

The O-deethylation of 7-ethoxycoumarin was inhibited in a mixed type manner by cimetidine in vitro and in microsomes isolated from rats treated with cimetidine in vivo. It was found that the inhibition was even greater if cimetidine was preincubated with the microsomal suspension in the presence of an NADPH-generating system prior to the addition of substrate. In vitro the decrease in activity was accompanied by a decrease in cytochrome P-450 content. This decrease was unaffected by the addition of EDTA to the microsomal suspensions, eliminating the possibility that free radical production was responsible for the decrease in cytochrome P-450. The decrease in activity and cytochrome P-450 content following preincubation of microsomal suspensions with cimetidine could be attenuated if potassium ferricyanide was added to the suspensions. The deethylation activity and cytochrome P-450 content of liver microsomes prepared from cimetidine-treated rats was decreased compared to control animals. The activity and cytochrome P-450 content of microsomes from cimetidine-treated rats could also be restored if microsomes were washed with potassium ferricyanide prior to incubation with substrate. It is proposed that an intermediate complex of cimetidine and cytochrome P-450 could be involved in the inhibition of microsomal metabolism by cimetidine.     

The role of the sodium pump in the plasma membrane potential changes during mast cell activation

The role of the sodium pump in the plasma membrane potential changes induced by compound 48/80 and by antigenic challenge has been investigated using a fluorescent potential sensitive probe, bis-oxonol. Compound 48/80 induced a fast decrease of the fluorescence of bis-oxonol followed by a delayed decrease. The antigenic stimulation induced only a delayed decrease of fluorescence. Zinc gluconate inhibited the first decrease but did not alter the second one. The delayed decrease was inhibited by ouabain or by the absence of potassium. These results suggest that compound 48/80 induced mast cell secretion via a zinc-sensitive mechanism followed by activation of the sodium pump. The changes in the plasma membrane potential during the antigenic stimulation are due to the activation of the sodium pump but occur after the secretion process.