Effect of KRN4884 on lipid metabolism in hyperlipidemic rats

• 1.1. KRN4884 is a novel pyridinecarboxamidine type potassium channel opener.
• 2.2. To determine whether KRN4884 affects lipid metabolism, we investigated its effects on serum lipid levels by using two types of hyperlipidemic rats: genetically hyperlipidemic obese Zucker rats and diet-induced hyperlipidemic rats fed a high fat diet. KRN4884 dose dependently decreased systolic blood pressure in Zucker rats.
• 3.3. Oral administration of KRN4884 (1–10 mg/(kg day) for 14 days dose dependently reduced serum triglyceride levels in Zucker rats. The reductions in serum triglyceride were associated with reductions in triglyceride in chylomicron and very low density lipoprotein.
• 4.4. KRN4884 produced no change in serum insulin and glucose levels in Zucker rats.
• 5.5. KRN4884 exhibited a similar triglyceride lowering effect in diet-induced hyperlipidemic rats.
• 6.6. These results suggest that KRN4884 has a beneficial effect on serum triglyceride levels as well as a hypotensive effect.

     

Antihypertensive properties of KRN4884, a novel long-lasting potassium channel opener

The antihypertensive action of KRN4884 (5-amino-N-[2-(2-chlorophenyl)ethyl]-N'-cyano-3-pyridinecarboxamidine ), a newly synthesized 3-pyridine derivative was examined in conscious spontaneously hypertensive rats (SHRs). A single administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) produced a dose-dependent and long-lasting antihypertensive effect. The 7-day repeated administration of KRN4884 (0.5, 1.5 mg/kg, p.o.) did not diminish antihypertensive activity during the treatment period or induce rebound hypertension after the discontinuation of treatment. To examine the mechanism of the antihypertensive effect of KRN4884, we studied its vasorelaxing effects in rat isolated aortae precontracted with 25 mM KCl. Single application of KRN4884 showed a slower onset of inhibitory action than that of levcromakalim. KRN4884 was approximately 26-fold more potent than levcromakalim and 10-fold less potent than nilvadipine. KRN4884- and levcromakalim-induced vasorelaxation were antagonized by glibenclamide. Furthermore, we observed the recovery of the contraction inhibited by these drugs after repeated washing. The inhibitory effect of KRN4884 was restored only after four washes, whereas that of levcromakalim was completely restored after one wash. The nilvadipine-induced inhibitory effect was the most resistant to washing among these drugs. These results suggest that KRN4884 shows a long-lasting antihypertensive effect based on its potent potassium channel-opening action. The long-lasting action may be due to a slow association/dissociation with/from the binding sites on vascular smooth muscle.     

Triglyceride-lowering effect of a novel insulin-sensitizing agent, JTT-501.

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3, 5-isoxazolidinedione, is a novel insulin-sensitizing agent. We investigated the triglyceride-lowering activity of JTT-501 in a high-fat (HF) rat model. The HF rats showed insulin resistance with elevation of fasting insulin levels and reduction of insulin-stimulated glucose oxidation. There was also a tendency towards increased basal insulin and triglyceride levels. Oral administration of JTT-501 (3-30 mg kg(-1) day(-1) for 7 days) reduced basal triglyceride levels dose dependently with a minimum effective dose of 3 mg kg(-1) day(-1). Furthermore, regarding triglyceride metabolism, JTT-501 (30 mg kg(-1) day(-1) for 15 days, p.o.) decreased hepatic triglyceride output rate and serum triglyceride half-life (T1/2). In contrast, pioglitazone (30 mg kg(-1) day(-1) for 15 days, p.o.) reduced T1/2, but did not affect hepatic triglyceride output rate. We conclude that JTT-501 possesses potent triglyceride-lowering activity due to its inhibition of triglyceride secretion from the liver and enhancement of triglyceride disposal in peripheral tissues.     

Reduction of adipose tissue lipoprotein lipase activity as a result of in vivo administration of 2,3,7,8-tetrachlorodibenzo-p-dioxin to the guinea pig

Within 1 hr of intraperitoneal administration of 1 microgram 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)/kg, lipoprotein lipase (LPL) activity was reduced 38% from initial levels in the adipose tissue of the guinea pig. Maximal depression was observed after 2 days and persisted throughout the 10-day observation period. Oral administration of glucose restored LPL activity in TCDD-treated animals after 1 day but only partially after 2 and 5 days, and had no effect after 10 days of exposure. Although initial (2-day) serum insulin levels were depressed, the inability of glucose to restore LPL activity after prolonged exposure was not due to malabsorption of glucose nor to changes in serum thyroxine or insulin concentration. TCDD also inhibited the lipolytic pathway in the adipocyte, but had no effect on hormone sensitive lipase (HSL). Since HSL and LPL are reciprocally regulated, it was concluded that TCDD acts on the adipocyte to uncouple HSL-LPL reciprocity as well as to reduce LPL production.     

Attenuation of insulin resistance, metabolic syndrome and hepatic oxidative stress by resveratrol in fructose-fed rats

Metabolic syndrome and oxidative stress are common complications of type 2 diabetes mellitus. The present study was designed to determine whether resveratrol, a widely used nutritional supplement, can improve insulin sensitivity, metabolic complication as well as hepatic oxidative stress in fructose-fed rats. Male Sprague Dawley rats (180-200 g) were divided into four groups with 8 animals each. Fructose-fed insulin resistant group (Dia) animals were fed 65% fructose (Research diet, USA) for a period of 8 weeks, whereas control group (Con) animals were fed 65% cornstarch (Research Diet, USA). Resveratrol, 10 mg/kg/day (Dia+Resv) or metformin 300 mg/kg/day (Dia+Met) were administered orally to the 65% fructose-fed rats for 8 weeks. At the end of the feeding schedule, Dia group had insulin resistance along with increased blood glucose, triglyceride, uric acid and nitric oxide (NO) levels. Significant (p<0.05) increase in hepatic TBARS and conjugated dienes, and significant (p<0.05) decrease in hepatic SOD and vitamin C was observed in Dia group compared to Con group. Administration of metformin or resveratrol significantly (p<0.05) normalized all the altered metabolic parameters. However, a marked insulin sensitizing action was only observed in the Dia+Resv group. Similarly, while metformin administration failed to normalize the increased TBARS levels and decreased SOD activity, resveratrol showed a more promising effect of all oxidative stress parameters measured in the present study. Attenuation of hepatic oxidative stress in fructose-fed rat liver after resveratrol administration was associated with significant (p<0.05) increase in nuclear level of NRF2 compared with other groups. The present study demonstrates that resveratrol is more effective than metformin in improving insulin sensitivity, and attenuating metabolic syndrome and hepatic oxidative stress in fructose-fed rats.     

METABOLIC EFFECTS OF THIOCTIC ACID IN RODENT MODELS OF INSULIN RESISTANCE AND DIABETES

1. The antioxidant thioctic acid (TA) has been used in the treatment of diabetic neuropathy and recent studies have suggested that TA also has pancreatic and peripheral effects that improve glucose transport and metabolism. In the present study, the metabolic effects of TA were evaluated in rodent models of insulin resistance (fructose-fed Sprague-Dawley rat) and insulin deficiency (streptozotocin (STZ)-induced diabetic rat). Oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in conscious rats after treatment with 50 mg/kg per day TA or vehicle for 5 days. 2. Fructose feeding for 7 days induced insulin resistance and impaired glucose tolerance and hypertriglycerideaemia. Treatment of fructose-fed rats with TA had no significant effect on fasting or stimulated glucose levels or on fasting triglyceride concentrations (e.g. the area under the curve for glucose (AUC_glu) following OGTT was 1233 ± 67 and 1284 ± 59 in fructose-fed rats treated with either TA (n= 12) or vehicle (n= 12), respectively). Similarly, TA had no significant effect on IVGTT profiles in fructose-induced insulin resistance. 3. Low-dose STZ (80 mg/kg, i.p, over 2 days) induced hyper-glycaemia, but TA had no significant glucose-lowering effects in STZ-diabetic rats (AUC_glu (OGTT) following oral administration was 5507 ± 27 and 5450 ± 27 in TA (n= 12) and vehicle-treated (n= 12) rats, respectively). Nor did pretreatment with TA affect the diabetogenic response to STZ. 4. In contrast with previous in vitro studies reporting favourable metabolic effects of TA, the present study shows that after short-term oral therapy there are no significant improvements in glucose tolerance in rodent models of insulin resistance and insulin deficiency. Thioctic acid is unlikely to be of therapeutic benefit as an anti-diabetic drug in clinical practice.     

Reversal of glucose intolerance by by pioglitazone in high fat diet-fed rats

The present study was undertaken to determine the effect of pioglitazone (3, 10 and 30 mg/kg p.o.), an insulin sensitizer, on glucose intolerance in high fat diet- (HFD) fed rats (a nongenetic model of insulin resistance). In addition, the effect of pioglitazone (3, 10 and 30 mg/kg p.o.) on diet-induced changes in body weight, plasma glucose, insulin, triglyceride and total cholesterol levels were also determined. The feeding of HFD for 4 weeks produced a significant increase in body weight, total fat pad weight, basal/fasting plasma glucose, insulin, basal triglyceride (TG) and total cholesterol (TC) levels in male rats. Furthermore, the rats fed HFD exhibited fasting hyperglycemia and hyperinsulinemia as well as enhanced glycemic response to exogenously administered glucose (2 g/kg p.o.) during an oral glucose tolerance test (OGTT) at the end of 4 weeks of dietary manipulation, indicating that the rats had developed insulin resistance and glucose intolerance. Treatment with pioglitazone (10 and 30 mg/kg p.o.) once daily for 2 weeks significantly diminished the elevated basal plasma insulin and TG levels in HFD-fed rats. In addition, a statistically significant reduction in TC level was observed only with the high dose of pioglitazone (30 mg/kg p.o.). However, pioglitazone had no significant effect on body weight, total fat pad weight and basal plasma glucose level. Pioglitazone (10 and 30 mg/kg p.o.) significantly reduced fasting hyperglycemia and reversed oral glucose intolerance to normal in HFD-fed rats compared with control normal rats. The above findings suggest that pioglitazone has potent insulin-sensitizing and lipid-lowering properties in a HFD-fed rat model. In conclusion, the present study demonstrates that the adult male rats on a HFD for 4 weeks exhibited the characteristic features of obesity, insulin resistance and glucose intolerance, namely increased body weight, increased total fat pad weight, mild basal/fasting hyperglycemia, hyperinsulinemia, hypertriglyceridemia, hypercholesterolemia and impaired oral glucose tolerance, that closely resemble the human prediabetic obese insulin-resistant and glucose-intolerant state. Further treatment with pioglitazone once daily for 2 weeks significantly ameliorated changes in basal plasma insulin, TG and TC, and reversed oral glucose intolerance to normal in HFD-fed rats, suggesting its potential in the treatment of insulin resistance and glucose intolerance associated with abnormal lipid metabolism.     

Safety,efficacy and toxicological evaluation of a novel,patented anti-diabetic extract of Trigonella Foenum-Graecum seed extract (Fenfuro)

Safety and anti-diabetic efficacy of a novel, proprietary Trigonella foenum-graecum seed extract [novel fenugreek extract (FE), Fenfuro?, CR0010810) enriched in furostanolic saponins (>60% w/w, HPLC) were assessed. Concerning safety, we undertook studies dealing with acute oral toxicity, 28-d sub-chronic toxicity and Ames’ bacterial reverse mutation assay that revealed no toxicity. Concerning efficacy, we examined beneficial effects of the extract on rats with type 2 diabetes (T2D). Male Sprague–Dawley rats received a high-fat diet for 2 weeks followed by streptozotocin (STZ, 35?mg/kg i.p.) to produce T2D. Seven days post-STZ, rats showing ≥300?mg/dl fasting plasma glucose level (PGL) were included in the study. FE (150- or 450- mg/kg p.o.) and glipizide (5?mg/kg p.o.) were administered once daily for 20?d and then twice daily for another 10?d (total 30?d). Blood samples were collected at 0, 10, 20 and 30?d of treatment and estimated for fasting plasma triglyceride (PTG), total cholesterol and insulin levels. After 30?d, FE and glipizide-treated diabetic animals were treated in combination with or without metformin (100?mg/kg) twice daily for another 10?d. FE did not influence body weight, feed and water intake. FE (150?mg/kg p.o.) reduced PTG levels in T2D rats by 22%, 24.6% and 29% at 10, 20 and 30?d of treatment, respectively, while glipizide (5?mg/kg p.o.) reduced the PTG levels by 57.4%, 46.2% and 39.4% at these time points. FE (450?mg/kg) treatment in STZ-induced diabetic rats produced significant hypoglycemic activity (approximately 31.5%) as compared to insulin (48.2% with 1 U/kg i.p.). FE (150?mg/kg p.o.) and metformin (100?mg/kg p.o.) combined produced significant reduction (20.7%) of PGL in T2D rats. No adverse effects were observed. We conclude after extensive in vitro and in vivo safety and efficacy studies that FE is safe and effective in treating T2D.     

Effect of 4-(o-benzylphenoxy)-N-methylbutylamine hydrochloride (bifemelane hydrochloride, MCI-2016) on cerebral glucose metabolism

To predict the influence of MCI-2016 on cerebral energy metabolism, the activity of MCI-2016 on uptake of 2-deoxy-D-[14C]glucose ([14C]-DG) into the brain under normal or hypoxic conditions, formation of 14CO2 from 14C-glucose in the brain, and local cerebral glucose utilization (LCGU) were examined. Cerebral uptake of [14C]-DG in mice were significantly enhanced by 6 day repeated administration of MCI-2016 (25 mg/kg, i.p.) and Ca-hopantenate (100 mg/kg, i.p.). The two drugs showed a slight enhancing effect on [14C]-DG uptake after single administration. As an index of cerebral glucose metabolism, 14CO2 formation from 14C-glucose was also stimulated by 6 day repeated administration of MCI-2016 (100 mg/kg, p.o., mice and rats) and Ca-hopantenate (250 mg/kg, i.p., rats). MCI-2016 moderately attenuated the decreased [14C]-DG uptake under the hypoxic condition in rats after 6 day repeated administration (100 mg/kg, p.o.). In addition, local cerebral glucose utilization (LCGU) in rats was also significantly potentiated by MCI-2016 (100 mg/kg, p.o., 6 days) in the areas of the visual cortex, thalamus ventral nucleus and uvula. From these results, MCI-2016 may be suggested to have a moderate activating effect on cerebral energy metabolism.     

A study on the disulfiram-like reaction of T-2588. Influence of the consecutive administration of T-2588 on hepatic alcohol dehydrogenase and aldehyde dehydrogenase activities and blood levels of ethanol and acetaldehyde

A study on disulfiram-like reaction of T-2588 was carried out using Sprague-Dawley male rats. A 500 mg/kg/day dose of T-2588 was given orally to 14 male rats once daily for 7 days. Disulfiram (200 mg/kg/day X 3 days, p.o.), cephalexin (CEX) (500 mg/kg/day X 7 days, p.o.) and cefmetazole (CMZ) (500 mg/kg/day X 7 days, i.v.) were used as the positive control and 2 comparative controls, respectively. The results obtained were summarized below. Each parameter (aldehyde dehydrogenase activity and the blood aldehyde level) in the disulfiram-like reaction was not affected by the T-2588 administration. A marked inhibition of aldehyde dehydrogenase activity (low-Km ALDH, Enzyme I) and a significant increase of the blood aldehyde level were observed in the rats receiving disulfiram. No drug-related disulfiram-like reaction was induced in the male rats receiving CEX, while alterations similar to the disulfiram action were recognized in rats receiving CMZ.     

Hepatic lipase activity and high density lipoproteins in familial hypercholesterolemia: adaptational mechanisms for LDL-receptor deficient state

With a view toward elucidating the poorly understood high density lipoprotein (HDL) metabolism in familial hypercholesterolemic (FH) patients, the activities of the plasma enzymes involved in HDL metabolism; hepatic triglyceride lipase (HTGL), lipoprotein lipase (LPL) and lecithin-cholesterol acyltransferase (LCAT) with concomitant determination of HDL particle size, were analyzed in 50 age-matched hypercholesterolemic patients (26 FH and 24 non-FH patients). The activity of HTGL in FH patients was significantly higher (p less than 0.02) than in non-FH patients. The analysis of HDL size by gradient gel electrophoresis showed significantly smaller HDL particles in FH patients. Analysis of the correlation between HTGL activity and HDL particle size confirmed that the variation in HDL particle size was related to HTGL activity. Those results suggest that the differences in HTGL activity and HDL size between the familial and non-familial types of hypercholesterolemia may be due to differences in their pathophysiology. The high HTGL activity and small HDL particles in FH probably are the consequences of an adaptational mechanism used by LDL-receptor-deficient hepatocytes to increase the intracellular pool of cholesterol.     

Antidiabetic and hypolipidemic effects of a novel dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, E3030, in db/db mice and beagle dogs

We investigated the antidiabetic effects of E3030, which is a potent dual activator of peroxisome proliferator-activated receptor (PPAR) alpha and PPARgamma, in an animal model of diabetes, C57BL/KsJ-db/db mice (db/db mice), and the lipidemic effects of E3030 in beagle dogs, whose PPARalpha and PPARgamma transactivation responses to E3030 were similar to those of humans. E3030 activated human PPARalpha, mouse PPARalpha, dog PPARalpha, human PPARgamma, mouse PPARgamma, and dog PPARgamma with EC(50) values of 65, 920, 87, 34, 73, and 34 nM, respectively, in the chimeric GAL4-PPAR receptor transactivation reporter assay. In db/db mice orally administered E3030 decreased blood glucose, triglyceride (TG), non-esterified fatty acids (NEFA), and insulin levels and increased blood adiponectin levels during a 14-day experimental period. Significant effects on blood glucose and adiponectin levels were observed at a dose of 3 mg/kg or greater. Furthermore, significant effects on blood TG, NEFA, and insulin levels were observed at doses of 1 mg/kg or more. An oral glucose tolerance test (OGTT) performed on Day 15 showed that E3030 at 3 mg/kg improved glucose tolerance in this model. Fourteen days of oral treatment with E3030 at a dose of 0.03 mg/kg or greater showed remarkable TG- and non high-density lipoprotein (non-HDL) cholesterol-lowering effects in beagle dogs. These results were similar to those observed for the PPARalpha agonist fenofibrate. E3030 also reduced apo C-III levels on Days 7 and 14, and elevated lipoprotein lipase (LPL) levels on Day 15. These results indicate that the TG- and non-HDL cholesterol-lowering actions of E3030 involve combined effects on reduction of apo C-III and elevation of LPL, resulting in increased lipolysis. The experimental results in animals suggest that E3030 has potential for use in the treatment of various aspects of metabolic dysfunction in type 2 diabetes, including dyslipidemia, hyperglycemia, hyperinsulinemia, and impaired glucose disposal.     

Improvement in insulin sensitivity by losartan in non-insulin-dependent diabetic (NIDDM) rats.

The present investigation was undertaken to study the effects of chronic treatment with losartan (2 mg kg(-1)/ day P.O) in neonatal non-insulin-dependent diabetes mellitus (NIDDM) rats. To induce NIDDM single-dose injection of STZ (70 mg kg(-1); i.p.) was given to 5 day old pups. The animals were weaned at 30 days and after a period of 3 months, they were checked for fasting and fed glucose levels to confirm the status of NIDDM. Losartan (2 mg kg(-1); p.o.) was administered for 6 weeks into the confirmed diabetic rats. A group of control animals were also maintained and this group received saline 5 days after birth. Fasting and fed glucose levels in NIDDM rats were significantly higher than control rats. Treatment with losartan in the NIDDM rats caused a significant decrease in insulin levels and reduction in elevated fasting and fed glucose levels. Results of the oral glucose tolerance test (OGTT) showed a significant increase in AUC(glucose)and AUC(insulin)values in NIDDM control rats. Losartan treatment significantly decreased both AUC(glucose)and AUC(insulin)values. Insulin sensitivity (K(ITT)) index of NIDDM control was significantly low as compared to Wistar control animals followed by significant increase in T(1/2)glucose value. Losartan treatment significantly reversed both K(ITT)and T(1/2)glucose value. Our data indicates that losartan increases insulin sensitivity in NIDDM rats.     

Effect of K+ channel openers, KRN2391 and Ki1769, and nitroglycerin on the urinary tract of rats in vivo.

The effects of KRN2391 (N-cyano-N'-(nitroxyethyl)-3-pyridine carboximidamide methane-sulfonate), which possesses ATP-sensitive potassium (K+) channel opening (KCO) activity and nitrate activity; Ki1769 (N-cyano-N'-(phenylethyl)-3-pyridinecarboximidamide methanesulfonate), which possesses only KCO activity; and nitroglycerin (NG) were determined on the motility of the ureter, urinary bladder and urethra of rats. Bladder contraction was induced by infusion of fluid into the bladder of conscious rats and recorded on a cystometrogram. KRN2391 and Ki1769 (both 0.3 mg/kg, i.v.) prolonged the micturition interval immediately after the injection, but NG (5 mg/kg, i.v.) did not. Peristaltic movement of the ureter, recorded in anesthetized rats, was inhibited by i.v. injection of KRN2391 and Ki1769 (both 0.03 mg/kg). However, when NG, NaNO2, N-nitro L-arginine methylester and methylene blue were applied directly to the ureter, no change in movement of the ureter was detected. KRN2391 (0.03 mg/kg, i.v.) and Ki1769 (0.3 mg/kg, i.v.) reduced the resistance to fluid infusion through the urethral lumen in anesthetized rats, whereas NG (0.5 mg/kg, i.v.) only reduced this resistance transiently. These results indicate that KCO activity had an inhibitory effect on the motility of the ureter, bladder and urethra. On the other hand, nitrate activity had an inhibitory effect on urethral tonus, corresponding to that induced by KCO activity.     

Antidiabetic activity of ethanolic extract of tubers of Dioscorea alata in alloxan induced diabetic rats

Objective:

To evaluate the antidiabetic activity of ethanolic extract of Dioscorea alata in glucose loaded and alloxan induced diabetic rats.

Materials and Methods:

The authenticated tubers of D. alata (DA) (JSSCPDP/2008/157) were collected from Dharmapuri, Tamil Nadu. The ethanol extract was tested for hypoglycemic activity in normal rats. In oral glucose tolerance test, glucose (3 g/kg, p.o.) was administered to non diabetic control, metformin (250 mg/kg, p.o.) and DA extract (100 and 200 mg/kg, p.o.) to treat treated rats. Diabetes mellitus was induced by alloxan monohydrate (120 mg/kg, i.p.) in physiological saline after overnight fasting for 18 hours. DA extract (100 and 200 mg/kg, p.o.) and standard drug metformin (250 mg/kg, p.o.) were administered to diabetic rats for 21 days. Fasting blood glucose level and changes in body weight were measured on days 0, 7, 14, and 21. At the end of 21^st day, serum lipid profile, total protein, albumin, and creatinine were assessed.

Results:

In glucose loaded normal rats, the treatment with the extract of DA had shown a highly significant reduction (P < 0.001) in blood glucose levels at the doses of 100 and 200 mg/kg, respectively. The extract did not produce hypoglycemic activity at both the dose levels in normal, fasted rats. In alloxan induced diabetic rats, the body weight of the DA extract treated animals had shown a significant increase (P < 0.001) after 21 days treatment. The blood glucose level was reduced significantly by 47.48% and 52.09% after 21 days treatment at dose levels 100 and 200 mg/kg, respectively. Serum lipid levels, total protein, albumin, and creatinine were reversed toward near normal in treated rats as compared to diabetic control.

Conclusion:

The results indicate that ethanol extract of DA tubers possesses significant antidiabetic activity.     

Chronic N-acetylcysteine prevents fructose-induced insulin resistance and hypertension in rats

We examined if administration of an antioxidant compound protects against the development of insulin resistance and hypertension. Male rats were assigned randomly into four groups, and treated for 12 weeks with normal chow, normal chow plus N-acetylcysteine (1.5 g/day/kg), fructose (60% of diet), and fructose plus N-acetylcysteine. After 10 weeks, plasma triglyceride and 15-F2t-isoprostane, and insulin sensitivity were measured, and after 12 weeks, pressor response to methoxamine (15-60 microg/kg min) was assessed. Relative to normal chow-fed controls, the fructose-fed rats had increased blood pressure, plasma insulin, triglyceride and 15-F2t-isoprostane, and decreased insulin sensitivity; these changes were inhibited by N-acetylcysteine. Maximal pressor response to methoxamine was attenuated in the fructose-fed rats given N-acetylcysteine relative to the other three groups. Therefore, chronic treatment with N-acetylcysteine increases insulin sensitivity and prevents the blood pressure increase associated with fructose feeding in rats, the mechanism may involve the decrease of oxidative stress and alpha-adrenoceptor-mediated vasoconstriction.     

Levels of insulin in the brains of rats modified by chronic administration of amphetamine, haloperidol and sulpiride

Rats treated with two classic neuroleptic drugs at therapeutic doses, haloperidol (0.05 mg/kg/day i.p.) and sulpiride (3 mg/kg/day i.p.) showed a marked decline in cerebral levels of insulin (0.085 +/- 0.02 ng/g and 0.120 +/- 0.04 ng/g wet weight respectively) compared to the control group (0.383 +/- 0.05 ng/g wet weight), while rats given D-amphetamine bitartrate chronically (20 mg/kg/day p.o.) showed an increase in cerebral insulin (0.55 +/- 0.04 ng/g wet weight). Combining treatment with each neuroleptic drug and amphetamine, at the same doses, produced a significant decrease in cerebral levels of insulin (P less than 0.001) as in the amphetamine animals. In the groups of rats treated with haloperidol, sulpiride and both of these drugs combined with amphetamine, there was a slight increase in levels of serum insulin, more so in the neuroleptic groups. Serum glucose values did not vary.     

Influence of ACTH on the effects of imipramine, desipramine and lithium on duration of immobility of rats in the forced swim test.

We examined the effects of adrenocorticotropic hormone (ACTH) on the immobilization of rats in the forced swim test with the administration of imipramine, desipramine, or lithium. A single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) significantly decreased the duration of immobility in normal rats in a dose-dependent manner. Lithium (10-100 mg/kg, p.o.), however, had no affect on the performance of rats in the forced swim test. ACTH (100 microg/day), administered subcutaneously to rats for 1, 3, 7, and 14 days, had no apparent effect on the duration of immobility in this test. The immobility-decreasing effect induced by a single administration of either imipramine (10-30 mg/kg, i.p.) or desipramine (30 mg/kg, i.p.) was blocked by chronic administration of ACTH for 3-14 days. The reduction of immobility, induced by chronic administration of imipramine (10 mg/kg, i.p.) for 15 days, was blocked by treatment with ACTH for 14 days. When lithium (100 mg/kg, p.o.) was administered for 15 days concurrently with imipramine (10 mg/kg, i.p.), we observed a significant decrease in immobility in rats treated with ACTH for 14 days. We suggest that chronic treatment of rats with ACTH may prove to be an effective model of tricyclic antidepressants-treatment-resistant depression.     

Effect of N-(3-aminopropionyl)-L-histidinato zinc (Z-103) on healing and hydrocortisone-induced relapse of acetic acid ulcers in rats with limited food-intake-time

In the healing test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., at doses of 3 and 10 mg/kg, twice a day, for 14 consecutive days from the day after acetic acid injection not only reduced the size and depth of the ulcers, but also promoted the regeneration of the defective mucosa. In the hydrocortisone-induced relapse test of acetic acid ulcers in rats with limited food-intake-time, Z-103 given, p.o., twice a day, at doses of 3 and 10 mg/kg for 20 consecutive days from the 40th day after the acid injection strongly prevented the exfoliation of the regenerated mucosa. Cimetidine (100 mg/kg x 2/day, p.o.), like Z-103, showed a marked relapse-preventive action in addition to the healing-promoting action. However, it was more effective on the healing. Gefarnate (300 mg/kg x 2/day, p.o.) markedly reduced the size and depth of the ulcers and strongly prevented the steroid-induced relapse, but showed no apparent effect on the regeneration of the defective mucosa. These results suggest that Z-103 may be a new therapeutic agent sharing both healing-promoting and relapse-preventive actions on gastric ulcers.     

Comparison of the effects of efaroxan and glibenclamide on plasma glucose and insulin levels in rats.

The effect of efaroxan (1 and 5 mg/kg p.o.; a selective alpha 2-adrenoceptor antagonist) was compared to glibenclamide (1 and 5 mg/kg p.o.; a standard sulphonylurea) on basal plasma glucose levels of fed and fasted rats. In addition, the effect of efaroxan (5 mg/kg p.o.) and glibenclamide (2 or 5 mg/kg p.o.), alone and in combination, on the hyperglycaemia and hyperinsulinaemia induced by glucose challenges, were investigated. An intra-arterial (250 mg/kg i.a.) and a subcutaneous (1 g/kg s.c.) glucose challenge were used to stimulate the fast and slow release phases of insulin secretion. Efaroxan increased plasma insulin levels in both conscious fed and fasted rats without greatly affecting plasma glucose levels. Glibenclamide also elevated insulin levels, but was associated with marked hypoglycaemia. Efaroxan and glibenclamide potentiated the slow and fast release of insulin secretion, but glibenclamide had a tendency to produce hypoglycaemia in these test situations, a property not shared by efaroxan. A combination of efaroxan and glibenclamide produced a greater elevation in the slow and fast insulin release phases than either compound alone, but did not enhance the hypoglycaemia seen with glibenclamide alone. These results provide further evidence that pancreatic alpha 2-adrenoceptors are involved in the regulation of insulin secretion.