Salmon calcitonin reduces food intake through changes in meal sizes in male rhesus monkeys

Amylinergic mechanisms are believed to be involved in the control of appetite. This study examined the effects of the amylin agonist, salmon calcitonin, on food intake and meal patterns in adult male rhesus monkeys. Fifteen minutes before the onset of their 6-h daily feeding period, monkeys received intramuscular injections of various doses of salmon calcitonin (0.032, 0.056, 0.1, 0.32, and 1 microg/kg) or saline. Salmon calcitonin dose dependently reduced total daily and hourly food intake, with significant decreases at the 0.1, 0.32, and 1 microg/kg doses. Daily food intake was reduced by approximately 35%, 62%, and 96%, at these doses, respectively. An analysis of meal patterns revealed that size of the first meal was significantly reduced across the dose range of 0.056 to 1 microg/kg, while average meal size was reduced with the 0.32 and 1 microg/kg doses. Meal number was only affected at the 1 microg/kg dose. Repeated 5-day administration of the 0.1 microg/kg dose resulted in a reduction in daily food intake only on injection day 2, while significant reductions in food intake were observed on all five injection days with a 0.32 microg/kg dose. Daily food intake was also reduced for 1 day after the termination of the 5-day injections of the 0.32 microg/kg salmon calcitonin dose. These sustained reductions in intake were expressed through decreases in meal size. These data demonstrate that salmon calcitonin acutely and consistently decreases food intake mainly through reductions in meal sizes in nonhuman primates.     

Dopamine does not limit fetal cerebrovascular responses to hypoxia.

Dopamine is used clinically to stabilize mean arterial blood pressure (MAP) in sick infants. One goal of this therapeutic intervention is to maintain adequate cerebral blood flow (CBF) and perfusion pressure. High-dose intravenous dopamine has been previously demonstrated to increase cerebrovascular resistance (CVR) in near-term fetal sheep. We hypothesized that this vascular response might limit cerebral vasodilatation during acute isocapnic hypoxia. We studied nine near-term chronically catheterized unanesthetized fetal sheep. Using radiolabeled microspheres to measure fetal CBF, we calculated CVR at baseline, during fetal hypoxia, and then with the addition of an intravenous dopamine infusion at 2.5, 7.5, and 25 microg.kg(-1).min(-1) while hypoxia continued. During acute isocapnic fetal hypoxia, CBF increased 73.0 +/- 14.1% and CVR decreased 38.9 +/- 4.9% from baseline. Dopamine infusion at 2.5 and 7.5 microg.kg(-1).min(-1), begun during hypoxia, did not alter CVR or MAP, but MAP increased when dopamine infusion was increased to 25 microg.kg(-1).min(-1). Dopamine did not alter CBF or affect the CBF response to hypoxia at any dose. However, CVR increased at a dopamine infusion rate of 25 microg.kg(-1).min(-1). This increase in CVR at the highest dopamine infusion rate is likely an autoregulatory response to the increase in MAP, similar to our previous findings. Therefore, in chronically catheterized unanesthetized near-term fetal sheep, dopamine does not alter the expected cerebrovascular responses to hypoxia.     

Repeated daily injections and osmotic pump infusion of isoproterenol cause similar increases in cardiac mass but have different effects on blood pressure

We found in mice that repeated single daily subcutaneous (s.c.) isoproterenol (ISO) injections, like constant infusions using osmotic minipumps, caused increased biventricular mass or weight relative to body weight (VW/BW). We found that 5 (1/d) s.c. injections of 2, 10, or 20 microg/g body weight caused equivalent VW/BW increases as compared with 5-d infusions at 20 microg/(g.d)). While it is often presumed that ISO elicits hypertrophy by a direct effect on the myocytes, growth may also be secondary to systemic hemodynamic effects. The 2 modes of ISO administration had different effects on mean arterial blood pressure (MABP) and heart rate. Using telemetry we observed that single injections of ISO (0, 0.5, 2, and 10 microg/g) were associated with hypotension and tachycardia with a duration but not a magnitude that was dose dependent. MABP dropped rapidly to 60 mm Hg for more than 2 h at the highest dose. Constant s.c. infusion of ISO at 20 microg/(g.d) initially lowered MABP to about 70 mm Hg for 24 h. At 48 h MABP was normal, but rose 10 mm Hg higher than baseline by day 5. Thus, different routes of administration of ISO that cause comparable increases in VW/BW had different effects on MABP. Thus when evaluating mouse models of ISO-induced cardiac hypertrophy, both repeated daily injections or infusions can cause similar increases in VW/BW, but the daily doses that are required are not the same. Furthermore, these different routes of administration have different hemodynamic sequelae and could potentially evoke different cardiac phenotypes.     

Oral artesunate prevents Plasmodium berghei Anka infection in mice

Artesunate, a semi-synthetic derivative of a naturally occurring anti-malarial artemisinin was compared with chloroquine in C57BL/6 mice infected with Plasmodium berghei Anka (PbA). A 7-day oral administration of artesunate prevented parasitaemia at 10 mg/kg/day. However, recrudescence of parasitaemia and cerebral malaria occurred upon cessation of treatment followed by death within 28 days. However, a 14-day course of artesunate (100 mg/kg/day) prevented completely the development of parasitaemia and cerebral malaria with a survival of more than 60-days as did 10 mg/kg/day chloroquine. These data demonstrate that oral artesunate inhibits PbA and prevents cerebral malaria, but needs to be administered at high dose and for prolonged time to eradicate PbA infection in mice.     

Cerebrovascular effects of intravenous dopamine infusions in fetal sheep.

Preterm infants are often treated with intravenous dopamine to increase mean arterial blood pressure (MAP). However, there are few data regarding cerebrovascular responses of developing animals to dopamine infusions. We studied eight near-term and eight preterm chronically catheterized unanesthetized fetal sheep. We measured cerebral blood flow and calculated cerebral vascular resistance (CVR) at baseline and during dopamine infusion at 2.5, 7.5, 25, and 75 microg x kg(-1) x min(-1). In preterm fetuses, MAP increased only at 75 microg x kg(-1) x min(-1) (25 +/- 5%), whereas in near-term fetuses MAP increased at 25 microg x kg(-1) x min(-1) (28 +/- 4%) and further at 75 microg x kg(-1) x min(-1) (51 +/- 3%). Dopamine infusion was associated with cerebral vasoconstriction in both groups. At 25 microg x kg(-1) x min(-1), CVR increased 77 +/- 51% in preterm fetuses and 41 +/- 11% in near-term fetuses, and at 75 microg x kg(-1) x min(-1), CVR increased 80 +/- 33% in preterm fetuses and 83 +/- 21% in near-term fetuses. We tested these responses to dopamine in 11 additional near-term fetuses under alpha-adrenergic blockade (phenoxybenzamine, n = 5) and under dopaminergic D(1)-receptor blockade (SCH-23390, n = 6). Phenoxybenzamine completely blocked dopamine's pressor and cerebral vasoconstrictive effects, while D(1)-receptor blockade had no effect. Therefore, in unanesthetized developing fetuses, dopamine infusion is associated with cerebral vasoconstriction, which is likely an autoregulatory, alpha-adrenergic response to an increase in blood pressure.     

Effects of midazolam (a benzodiazepine) on cerebral perfusion and oxygenation in dogs

Midazolam is a water-soluble benzodiazepine used for anesthetic induction. Its effects on the cerebral circulation are still controversial. We evaluated the effects of midazolam on the cerebral blood flow (CBF), cerebral vascular resistance (CVR), and cerebral oxygen consumption (CMRO2) in dogs (n = 6) using the cerebral venous outflow method. CVR was calculated as the quotient of mean arterial pressure (MAP) and CBF, CMRO2 was obtained from the measurements of CBF and arterio-venous O2 difference (A-V dO2). Midazolam was administered in sequential i.v. doses of 0.5, 1.0, and 2.0 mg/kg by bolus injection with an interval of 20 min. This agent significantly reduced the MAP, CBF and CMRO2, but did not affect the CVR. The maximal decreases in MAP, CBF, and CMRO2 from the control levels averaged 14.8%, 12.2%, and 9.3%, respectively, by 0.5 mg/kg; 18.9% 18.6% and 12.1% by 1.0 mg/kg; and 23.6%, 18.7% and 16.1% by 2.0 mg/kg. Although the increments in doses further depressed that MAP, CBF and CMRO2, the dose-dependent effects were slight. Only the values of reduction in CMRO2 were significantly different between the doses of 0.5 and 2.0 mg/kg. Therefore, a dose of 0.5 mg/kg produced nearly the maximal effects. The results indicate that midazolam causes a mild reduction (10-25%) in arterial pressure, brain perfusion and cerebral oxygenation. Cerebral vascular resistance is not significantly changed.     

Regular exercise enhances blood pressure lowering effect of acetylcholine by increased contribution of nitric oxide

This study is aimed to test the hypothesis, that short-term daily bouts of exercise alter the endothelial regulation of peripheral vascular resistance by nitric oxide. Rats ran on a treadmill once a day, 5 days a week, for an average of three weeks with gradually increasing intensity (EX), while a control group remained sedentary (SED). Dose dependent reductions in mean arterial blood pressure (resting MABP; SED: 120.0 +/- 3.4 and EX: 127.8 +/- 4.0 mm Hg) of pentobarbital anesthetized rats to intravenous endothelium independent dilator sodium nitropmsside (SNP; 0.6-3.0 microg/kg) were not different in EX and SED animals. In contrast, dose dependent reductions in MABP to endothelium dependent dilator acetylcholine (ACh) were significantly enhanced in EX compared to those in SED rats (at 0.5 and 1.0 microg/kg ACh: 60.3 +/- 2.4 and 66.5 +/- 1.8 vs 52.8 +/- 2.0 and 59.8 +/- 1.7 mmHg, respectively, p<0.01). There was no significant difference in the heart rate (HR) response to ACh and SNP in the two groups of rats. Intravenous administration of 20 mg/kg Nomega-nitro-L-arginine (L-NNA, a nitric oxide synthase inhibitor) elicited a similar increase (approximately 30%) in the MABP in the two groups and eliminated the difference between ACh-induced blood pressure lowering responses in EX and SED rats (at 0.5 and 1.0 microg/kg ACh: 44.6 +/- 4.7 and 56.3 +/- 4.4 vs 50.9 +/- 4.5 and 59.4 +/- 3.6 mm Hg, respectively). Thus, we suggest that the enhanced acetylcholine-induced decrease in systemic blood pressure following regular daily exercise is primarily due to the augmented synthesis of nitric oxide in the endothelium of peripheral vasculature. This change in the function of endothelium could be important in the adaptation of circulation to exercise training.     

Maternal and fetal distribution of a phosphorothioate oligonucleotide in rats after intravenous infusion

BACKGROUND: Fetal uptake of an antisense oligonucleotide was evaluated after intravenous (i.v.) dosing of ISIS 2105, a 20-base phosphorothioate oligonucleotide, in timed-pregnant Sprague-Dawley rats. METHODS: To maximize the potential for fetal exposure, ISIS 2105 was administered as a 3-hr infusion at 6.6 mg/kg/hr with a total dose of 20 mg/kg, or as a continuous 7-day infusion at 0.35 mg/kg/hr with a total dose of 59 mg/kg. This dosing regime is higher than a patient would be expected to receive in the clinical use of oligonucleotides. Infusions were delivered through a jugular vein cannula by syringe pump on gestation day (GD) 19 (3-hr exposure) or by osmotic pumps implanted subcutaneously (s.c.) starting on GD 12 (7-day exposures). RESULTS: After a 3-hr infusion, maternal and fetal plasma concentrations of ISIS 2105 were >100 microg/ml and <0.07 microg/ml, respectively with a maternal fetal ratio of >1,000. Maternal regions of the placenta had twice the oligonucleotide concentration compared to fetal regions of the placenta (6 microg/g vs. 3 microg/g). After this acute exposure the concentrations in fetal kidney and liver were approximately 140- and 500-fold less than the maternal kidney and liver respectively. After 7-day infusion maternal plasma concentrations were 0.82 microg/ml and fetal concentrations were <0.22 microg/ml. By capillary gel electrophoresis (CGE) only the fetal liver consistently had quantifiable oligonucleotide concentrations (range=1.01-4.95 microg/g) compared to a mean concentration of 50.11+/-1.71 microg/g in the maternal liver a maternal to fetal ratio of approximately 10:50 after 7 days of infusion. CONCLUSIONS: There was a low level of transfer from dam to fetus, consistent with a slow equilibrium but the permeability of placenta to this 6 kDa polyanionic compound seemed to be limited even at supraclinical doses.     

Effects of capsaicin and nitric oxide synthase inhibitor on increase in cerebral blood flow induced by sensory and parasympathetic nerve stimulation in the rat.

Effects of electrical stimulation of the nerve bundles including sensory and parasympathetic nerves innervating cerebral arteries on cerebral blood flow (CBF) and mean arterial blood pressure (MABP) were investigated with a laser-Doppler flowmeter and a blood pressure monitoring system in anesthetized rats pretreated with and without capsaicin. The electrode was hooked on the nerve bundles including the distal nasociliary nerve from trigeminal nerve and parasympathetic nerve fibers from sphenopalatine ganglion. In control rats, the nerve stimulation for 30 s increased CBF in the ipsilateral side and MABP. Hexamethonium attenuated the increase in CBF and abolished that in MABP. Under treatment with hexamethonium, N(G)-nitro-L-arginine (L-NNA, 1 mg/kg) significantly attenuated the stimulation-induced increase in CBF, which was restored by the addition of L-arginine. Although the dose of L-NNA was raised up to 10 mg/kg, the stimulation-induced increase in CBF was not further inhibited and was never abolished. In capsaicin-pretreated rats, magnitudes of the stimulation-induced increases in CBF and MABP were lower than those in control rats. Hexamethonium attenuated the increase in CBF and abolished that in MABP. Under treatment with hexamethonium, L-NNA abolished the stimulation-induced increase in CBF in capsaicin-pretreated rats. In conclusion, nitric oxide released from parasympathetic nerves and neuropeptide(s) released antidromically from sensory nerves may be responsible for the increase in CBF in the rat. The afferent impulses by nerve stimulation may stimulate the trigeminal nerve and lead to the rapid increase in MABP, which partly contributes to the increase in CBF.     

Role of kappa- and delta-opioid receptors in the antinociceptive effect of oxytocin in formalin-induced pain response in mice

Oxytocin has been implicated in the modulation of somatosensory transmission such as nociception and pain. The present study investigates the effect of oxytocin on formalin-induced pain response, a model of tonic continuous pain. The animals were injected with 0.1 ml of 1% formalin in the right hindpaw and the left hindpaw was injected with an equal volume of normal saline. The time spent by the animals licking or biting the injected paw during 0-5 min (early phase) and 20-25 min (late phase) was recorded separately. Oxytocin (25, 50, 100 microg/kg, i.p.) dose dependently decreased the licking/biting response, both in the early as well as the late phases. The antinociceptive effect of oxytocin (100 microg/kg, i.p.) was significantly attenuated in both the phases by a higher dose of the non-selective opioid receptor antagonist naloxone (5 mg/kg, i.p.), MR 2266 (0.1 mg/kg, i.p.), a selective kappa-opioid receptor antagonist and naltrindole (0.5 mg/kg, i.p.), a selective delta-opioid receptor antagonist but not by a lower dose of naloxone (1 mg/kg, i.p.) or beta-funaltrexamine (2.5 microg/mouse, i.c.v.), a selective mu-opioid receptor antagonist. Nimodipine, a calcium channel blocker (1 and 5 mg/kg, i.p.) produced a dose-dependent analgesic effect. The antinociceptive effect of oxytocin was significantly enhanced by the lower dose of nimodipine (1 mg/kg, i.p.) in both the phases. Chronic treatment with oxytocin (100 microg/kg/day, i.p. daily for 7 days) did not produce tolerance in both the phases of formalin-induced pain response. The results thus indicate that oxytocin displays an important analgesic response in formalin test; both kappa- and delta-opioid receptors as well as voltage-gated calcium channels seem to be involved in the oxytocin-induced antinociception.     

Protective effect of cerebrocrast on rat brain ischaemia induced by occlusion of both common carotid arteries

Diabetes mellitus is accompanied by several cardiovascular complications including atherosclerosis, cerebral ischaemia and stroke. We examined the neuroprotective effect of a 1,4-dihydropyridine derivative cerebrocrast (C, a new antidiabetic agent, synthesized in the Latvian Institute of Organic Synthesis) on the level of ATP in the brain, and on changes of the EEG and ECG, as well as blood pressure parameters in anaesthetized Wistar male rats before and during 10-min occlusion of both common carotid arteries. Cerebrocrast was administered i.v. at doses of 1.0 and 10 microg/kg in the v. femoralis 20 min prior to ischaemia. After 10-min ischaemia animals were decapitated and the brain was immediately frozen in liquid nitrogen and subsequently used for analysis of changes of ATP contention. Cerebrocrast, administered at doses of 1.0 and 10 microg/kg 20 min prior to occlusion of both common carotid arteries, completely prevented a fall in the ATP content of brain compared with the control rats. In control rats the content of ATP in brain during ischaemia decreased from 2.77 +/- 0.22 (basal level) to 1.74 +/- 0.20 micromol/g as a result of ischaemia. By administration of cerebrocrast 20 min before occlusion of the arteries, the content of ATP in the brain remained at the level of preischaemia (1.0 microg/kg C + ischaemia 2.82 +/- 0.36; 10 microg/kg C + ischaemia 2.42 +/- 0.22 micromol/g). Analysis of EEG parameters both before and during 10 min of occlusion showed that at a C dose of 1.0 microg/kg before occlusion produced a regular alpha rhythm during ischaemia and prevented cerebral bioelectric activity from significant changes. The depression of basal rhythm was observed at a C dose of 10 microg/kg during ischaemia in two rats out of six as well as an increase in the ECG ST segment above the isoelectric line. Blood pressure was decreased by about 10-20 mm Hg. We propose that pretreatment of rats with cerebrocrast at doses of 1.0 or 10 microg/kg 20 min prior to ischaemia can prevent ischaemic damage of rat brain, maintain necessary energy consumption, promote ATP production in brain cells, and prevent significant changes in EEG and ECG parameters. These properties are important in diabetes mellitus and its evoked cardiovascular complications as stroke, ischaemia, etc.     

Embryotoxicity studies of norfloxacin in cynomolgus monkeys: I. Teratology studies and norfloxacin plasma concentration in pregnant and nonpregnant monkeys

Norfloxacin, a new orally active antibiotic, was investigated in cynomolgus monkeys for potential developmental toxicity. Fifty-seven monkeys were administered a control vehicle or norfloxacin by nasogastric gavage during the major period of organogenesis on gestational days (GD) 21 through 50 at doses of 0, 50, 100, 150, or 200/300 mg/kg/day. There was no evidence of teratogenicity at any dose level. Maternotoxicity and a significant increase in embryolethality occurred following doses of 200/300 mg/kg/day. The maternotoxicity was not expected based on range-finding studies in nonpregnant female monkeys, which showed no signs of toxicity in doses up to 500 mg/kg/day. Additional studies were conducted to determine if norfloxacin caused similar toxicity later in gestation. Forty-six pregnant monkeys were dosed with a control vehicle or 200 mg/kg/day norfloxacin for one of three 10-day periods on GD 36-45, 71-80, or 111-120. There were no maternotoxic, embryotoxic, or fetotoxic effects observed. Plasma concentrations of norfloxacin in five cynomolgus monkeys following 50 and 200 mg/kg oral doses were not dose-proportionate. However, at a given dose, administered in cross-over fashion, plasma concentrations of norfloxacin were higher in nonpregnant females (approximately 20-40%) than during pregnancy when the same subject was compared. At the no-observed-effect dose for maternal and embryotoxicity (50 mg/kg), peak plasma concentrations of norfloxacin in pregnant cynomolgus monkeys are approximately threefold higher than those observed in human volunteers receiving norfloxacin at the maximum recommended therapeutic dose of 400 mg (5.7 mg/kg based on 70 kg body weight) twice per day.     

Hypoglycemic effect of methanol extract of Phyllanthus amarus Schum & Thonn on alloxan induced diabetes mellitus in rats and its relation with antioxidant potential

Methanolic extract of P. amarus was found to have potential anti-oxidant activity as it could inhibit lipid peroxidation, and scavenge hydroxyl and superoxide radicals in vitro. The amount required for 50% inhibition of lipid peroxide formation was 104 microg/ml and the concentrations needed to scavenge hydroxyl and superoxide radicals were 117 and 19 microg/ml respectively. The extract was found to reduce the blood sugar in alloxan diabetic rats at 4th hr by 6% at a dose level of 200 mg/kg body wt and 18.7% at a concentration of 1000 mg/kg body wt. Continued administration of the extract for 15 days produced significant (P < 0.001) reduction in blood sugar. On 18th day after alloxan administration values were almost similar to normal in the group taking 1000 mg/kg body wt.     

Effect of adrenalectomy and corticosterone on cocaine-induced sensitization in rats.

Effects of adrenalectomy (ADX) and corticosterone (CORT) on the development and expression of sensitization to the locomotor effect of cocaine (COC) were studied in rats. Sensitization was evoked by 5 daily injections of COC (10 mg/kg) and measured after a challenge dose of the drug (10 mg/kg) after a 5-day withdrawal (on day 10 of the experiment). ADX, performed before the start of COC administration, completely blocked the manifestation of COC-induced sensitization. In contrast, ADX performed on animals already sensitized to COC did not affect the sensitized locomotor activity response to a challenge dose of COC (on day 18). Pretreatment with CORT, 10 mg/kg, but not 5 mg/kg, before each of the 5 daily COC injections facilitated the development of COC sensitization, tested after a 5-day withdrawal. When pretreated with CORT alone (10 mg/kg), the challenge dose of COC administered on day 10 induced cross-sensitization to CORT. CORT (10 mg/kg) injected acutely before COC on day 10, potentiated the expression of COC sensitization. When given alone, on day 10 CORT (5-10 mg/kg) induced an increase in the locomotor activity of rats pretreated daily (5 injections) with COC. No drug treatment induced conditioned locomotion, as measured after saline challenge on day 8. Our results indicate that CORT facilitates the development and expression of COC sensitization, while ADX blocks the initiation of the behavioral phenomenon only. Moreover, there takes place cross-sensitization between CORT and COC, which indicates a close relationship between the drug-related mechanism and behavioral sensitization.     

Effect of feeding aqueous extract of Pterocarpus marsupium on glycogen content of tissues and the key enzymes of carbohydrate metabolism

The Indian traditional system of medicine prescribed plant therapies for diseases including diabetes mellitus called madhumeh in Sanskrit. One such plant mentioned in Ayurveda is Pterocarpus marsupium (PM). In the present study, aqueous extract of PM (1 g/kg PO) was assessed for its effect on glycogen levels of insulin dependent (skeletal muscle and liver), insulin-independent tissues (kidneys and brain) and enzymes such as glucokinase (GK), hexokinase (HK), and phosphofructokinase (PFK). Administration of PM led to decrease in blood glucose levels by 38 and 60% on 15th and 30th day of the experiment. Liver and 2-kidney weight expressed as percentage of body-weight was significantly increased in diabetics (p < 0.0005) vs. normal controls and this alteration in the renal weight (p < 0.0005) but not liver weight was normalized by feeding of PM extract. Renal glycogen content increased by over 10 fold while hepatic and skeletal muscle glycogen content decreased by 75 and 68% in diabetic controls vs. controls and these alteration in glycogen content was partly prevented by PM. Activity of HK, GK and PFK in diabetic controls was 35, 50 and 60% of the controls and PM completely corrected this alteration in PFK and only partly in HK and GK.     

Research for the effect of octylphenol on spermatogenesis and proteomic analysis in octylphenol-treated mice testes

OP (octylphenol), an environmental oestrogen was administered, and differentially expressed proteins were analysed in mice testes to clarify its mechanism of action in male sterility. Male Kunming suckling mice (10 days old) were subcutaneously injected with OP at a dose of 10 μg/kg per day, 50 μg/kg per day and 100 μg/kg per day as low-, medium- and high-dose groups, respectively, for 35 days. Animals in the control group received subcutaneous injections of olive oil at a dose of 10 μl/mouse per day. Serum oestradiol, testosterone, FSH (follicle stimulating hormone) and LH (luteinizing hormone) levels were measured on day 45. The left testes were removed for tissue analysis, and the right testes were analysed for differentially expressed proteins by using two-dimensional gel electrophoresis and MS. Tissue analysis showed that mice spermatogenesis was blocked at the round spermatid stage in the high-dose group, whereas no such changes were found in the medium- and low-dose groups. Higher serum oestradiol (P<0.05) and lower testosterone (P<0.05) levels were found in the medium- and high-dose groups. There was no significant difference in serum oestradiol and testosterone levels in the low-dose and control groups. No significant influence of OP was seen on serum FSH and LH levels in all OP-treated animals. The results from four differentially expressed proteins such as PPIA (peptidyl-prolyl cis-trans isomerase A), PEBP1 (phosphatidylethanolamine-binding protein1), TPI (triose-phosphate isomerase) and TCP-1 (T-complex protein 1) in the high-dose and control groups showed up-regulation of PPIA expression and down-regulation in PEBP1, TPI and TCP-1 expressions. These findings will contribute to clarify the mechanism of male sterility by environmental oestrogens.     

The acute and the chronic effects of imipramine on the spontaneous motility in chick embryos

The effect of imipramine on the spontaneous motility and development of chick embryos was studied from the 4th to the 19th day of incubation. On acute administration (a single dose of 12.5 of 25 mg/kg egg weight), imipramine already induced significant depression of spontaneous motility in 11-day embryos--an effect which increased significantly after the 15th day of incubation. The similar effect of imipramine in spinal embryos testifies to its direct action on the spinal cord and draws attention to certain details of the role of supraspinal structures of the CNS in the acute effect of imipramine. The chronic administration of imipramine showed that it had an almost 100% lethal effect from 4th to the 7th day of incubation. Between the 8th and the 10th day it caused longlasting depression of spontaneous motility. When it was administered between the 11th and 16th day of incubation, no significant effect on the development of spontaneous motor activity was found in chick embryos.     

Arsenic induced free radical toxicity in brain of mice

The present study was designed to investigate the in vivo effects of oral administration of arsenic trioxide (As2O3; 0.5 and 1 mg/kg body weight/day for 45 days) on cerebral hemispheres and cerebellum in male mice, Mus musculus. Arsenic reduced the concentration of glutathione (GSH) in cerebral hemisphere and cerebellum at both the dose levels; while increased lipid peroxidation (LPO) in cerebral hemisphere and cerebellum regions. Further, the activities of antioxidant enzymes viz., superoxide dismutase and catalase also declined in these two regions with dose indicating oxidative stress. This effect is caused by the action of reactive oxygen species (ROS) induced by arsenic exposure.     

The hemodynamic and metabolic profiles of Zucker diabetic fatty rats treated with a single molecule triple vasopeptidase inhibitor, CGS 35601

CGS 35601 is a triple vasopeptidase inhibitor (VPI) of angiotensin converting enzyme (ACE), neutral endopeptidase (NEP), and endothelin (ET) converting enzyme-1 (ECE-1), with respective IC(50) values of 22, 2, and 55 nM. The aim of the present study was to establish the hemodynamic profile of Zucker diabetic fatty (Zdf)-Fatty rats, a high-fat diet gene-prone model developing spontaneous Type 2 diabetes (T2D) and the effects of CGS 35601. Male Zdf-Fatty (14 weeks, n = 17-23), Zdf-Lean (14 weeks, n = 8-10), and Wistar (14 weeks, n = 9-10) rats on distinct diets were implanted with a catheter in the left carotid and placed individually in a metabolic cage for 30 days. The hemodynamic profile and some metabolic biomarkers were assessed daily. After a 7-day stabilization period, the Zdf-Fatty rats were divided into two groups: Group 1, controls (n = 7-10) receiving vehicle-saline (250 microl/hr) and Group 2, (n = 10-13) receiving increasing doses of CGS 35601 (0.1, 1, and 5 mg/kg/day x 6 days each, intra-arterially) followed by a 5-day washout period. Mean arterial blood pressure (MABP) of young Zdf-Fatty rats was compared with age-matched Zdf-Lean and Wistar rats, which were found similar. MABP decreased by 5.9% (from baseline at 102 +/- 5 to 96 +/- 4 mmHg), 12.7% (to 89 +/- 6 mmHg) and 21.6% (to 80 +/- 4 mmHg), at 0.1, 1, and 5 mg/kg/day, respectively, in CGS 35601-treated Zdf-Fatty rats. Systolic and diastolic blood pressures were similarly reduced. The heart rate was not affected. Hyperglycemic status and insulin-resistance were not modulated by short-term treatment. CGS 35601 presented an excellent short-term safety profile. This novel molecule and class of VPI may be of interest for lowering vascular tone. Further long-term studies, once cardiovascular and renal complications have developed in this T2D rat model are warranted to define the efficacy of this class of VPI.     

Effect of fentanyl and morphine on local blood flow and tissue oxygen tension in cortical frontal-parietal area and nucleus accumbens in albino rats

The aim of this study was to examine effects of i.p. injected Fentanyl (0.005 mg/kg) and Morphine (1 mg/kg) on local cerebral blood flow (ICBF) and tissue pO2 level in frontal-parietal area of the cortex and nucleus accumbens of the rat's brain. Either fentanyl or morphine injection resulted in significant increase of local blood flow in the n.accumbens and its decrease in frontal-parietal area of cortex. Measurement of oxygen partial pressure revealed the opposite (to ICBF) changes: a decrease in n.accumbens and its increase in cortical area of the brain. Analysis of this data and electrical activity recorded from both said structures allow to conclude that they are conditioned by respective changes in functional-metabolic activity induced by intraperitoneal injection either fentanyl or morphine: its suppression in frontal-parietal area of the cortex and development of seizure-like activity in the n.accumbens.