Glycerol metabolism in the pregnant and virgin rats

The parameters of in vivo glycerol kinetic curves were determined after a single injection of glycerol-1-14 C in pregnant and in virgin rats. The half-life of glycerol was found to be 9 min in pregnant rats and 17 min in virgin rats. There was no significant difference between the absolute turnover rates. The glycerol plasma space cannot be appreciated. The distribution volume expressed in milliliter of plasma appeared to be very high indicating that glycerol was not distributed only in the plasma. Glycerol was found to be a precursor of glucose and this conversion seemed to proceed more rapidly in the pregnant rat than in the virgin rat.     

Effect of glycerol on triglyceride metabolism in the rat

Lipid metabolic studies were carried out on the male Wistar rats fed on glycerol-rich diet in order to elucidate the mechanism of glycerol-induced hypertriglyceridemia. No difference was found between the glycerol fed rats and the control rats in the rate of triglyceride secretion from the liver measured by the Triton WR-1339 method as well as in the rate of incorporation of labeled glycerol into liver triglyceride. The facts that the half-life of the intravenously injected Intralipid in the blood was significantly delayed in the glycerol fed rats and that the lipoprotein lipase activity released from epididymal adipose tissue of the glycerol fed rats was markedly decreased to 19% of that of the control rats seem to account for the serum triglyceride elevation induced by the glycerol feeding.     

VLDL triglyceride kinetics in Wistar fatty rats, an animal model of NIDDM: effects of dietary fructose alone or in combination with pioglitazone

The effects of dietary fructose alone or in combination with a new oral agent, pioglitazone, on VLDL-triglyceride (TG) turnover were studied in genetically obese Wistar fatty rats characterized by hyperinsulinemia (7,488 +/- 954 pmol/l), hyperglycemia, (22.5 +/- 1.4 mmol/l), and hypertriglyceridemia (4.39 +/- 0.54 mmol/l). They had an increased hepatic TG production (16.2 +/- 0.1 micromol/min; lean rats, 5.4 +/- 0.3 micromol/min) as well as a longer half-life of VLDL-TG from lean donors (8.8 +/- 1.4 min, lean recipients; 2.3 +/- 0.9 min). In addition, in lean recipients, the half-life of VLDL-TG from fatty donors was longer than that from lean donors (4.80 +/- 0.56 vs. 3.14 +/- 0.23 min). Although feeding fructose into fatty rats did not change plasma glucose and insulin levels, it produced a twofold increase in TG levels (8.74 +/- 1.15 mmol/l). This was associated with a 1.7-fold increase in TG production to 27.5 +/- 1.2 micromol/min, while no significant change was found in the half-life of lean VLDL-TG in fructose-fed fatty recipients (10.9 +/- 2.4 min) or in that of VLDL-TG from fructose-fed fatty donors in lean recipients (4.46 +/- 0.76 min). Daily administration of pioglitazone (3 mg/kg body weight) in fructose-fed fatty rats ameliorated glycemia and triglyceridemia to the level of lean rats (8.1 +/- 0.7 and 1.18 +/- 0.05 mmol/l, respectively) and insulinemia to a lesser extent (2,712 +/- 78 pmol/l). A fall in TG levels was associated with improvement of an impairment in the ability of fructose-fed fatty rats to remove lean VLDL-TG (half-fife: 2.6 +/- 0.6 min). Pioglitazone, however, produced no change in TG production (25.9 +/- 2.7 micromol/min), the half-life of VLDL-TG from fructose-fed fatty donors in lean recipients (4.17 +/- 0.38 min), or the activity of lipoprotein lipase and hepatic lipase in postheparin plasma. We conclude that in Wistar fatty rats 1) hypertriglyceridemia is attributed to TG overproduction and impaired TG catabolism, and the latter is due to changes in both VLDL, such that they are less able to be removed, and changes in the nature of Wistar fatty rats, such that they are less able to remove VLDL-TG; 2) fructose further increases hepatic TG production with a resultant deterioration in hypertriglyceridemia; 3) pioglitazone normalizes TG levels by altering the physiology of the Wistar fatty rats in a manner that increases their ability to remove VLDL-TG from the circulation.     

Hypertriglyceridemia in nephrotic rats is due to a clearance defect of plasma triglyceride: overproduction of triglyceride-rich lipoprotein is not an obligatory factor

This study was conducted to determine whether overproduction of triglyceride-rich lipoprotein is an obligatory factor for experimental hypertriglyceridemia in nephrotic rats. Nephrosis was induced in male Wistar rats by administration of 150 mg/kg puromycin aminonucleoside. Nephrotic rats had slightly increased triglyceride secretion rate (TGSR) estimated using Triton WR1339 (0.53 +/- 0.05 vs. 0.45 +/- 0.04 mg/min, P < 0.05 vs. control rats) and marked hypertriglyceridemia (330.4 +/- 78.6 mg/dl). Rats made diabetic by 40 mg/kg streptozotocin were normotriglyceridemic (66.3 +/- 12.1 mg/dl) but had suppressed TGSR (0.33 +/- 0.09 mg/min). Experimental nephrosis was induced in diabetic rats. Their TGSR remained suppressed (0.35 +/- 0.06 mg/min) but they had marked hypertriglyceridemia (296.6 +/- 72.4 mg/dl) suggesting further impairment of triglyceride removal from the circulation in diabetic rats caused by nephrosis. Endogenously radiolabeled very low density lipoprotein (VLDL)-triglyceride from donor rats was reinjected into normal recipient rats. [3H]VLDL from the experimental groups (the rats with nephrosis, diabetes with nephrosis, and diabetes alone) were more slowly cleared by normal rats than VLDL from normal rats. These results suggest that circulating insulin is essential for increased triglyceride secretion in experimental nephrosis and that nephrotic hypertriglyceridemia can be induced only by a triglyceride removal defect. Therefore, hypersecretion of triglyceride-rich lipoprotein is not an obligatory factor for nephrotic hypertriglyceridemia.     

Four-week ethanol intake decreases food intake and body weight but does not affect plasma leptin, corticosterone, and insulin levels in pubertal rats

Long-term intake of ethanol decreases food intake and inhibits growth in experimental rats. The aim of this study was to determine the effect of 4-week oral ethanol ingestion on plasma leptin and adrenal function. Male 45-day-old Wistar rats were divided into three groups: absolute control (AC), ethanol (E) administered 10% (wt/vol) ethanol instead of tap water, and pair-fed (PF) given an amount of food corresponding to the food intake of E animals. E rats consumed less pelleted diet (74% cumulative total intake); however, this caloric deficit was compensated by ethanol ingestion. Net water intake in E animals was 76% of that in the control groups. The body growth of both E and PF rats was stunted compared with AC animals, but E rats were heavier than PF rats. The plasma leptin level was similar in E and AC and decreased in PF animals. There were no differences in plasma osmolality or glycemia among the three groups. Plasma insulin was decreased in PF compared with both AC and E rats. Plasma corticosterone was not affected by ethanol, but was increased in the food-restricted (PF) group. Although there were no differences in basal adrenal corticosterone production in vitro, there was a slightly higher response to corticotropin (ACTH) in E rats. We conclude that drinking 10% ethanol decreased the dietary intake and body growth. These changes were not mediated by plasma leptin changes. Although alcohol ingestion and its energy content theoretically normalized the total energy intake and prevented the decrease of plasma leptin, the growth of young rats was inhibited. Drinking 10% ethanol instead of tap water for 4 weeks did not stimulate basal adrenal activity.     

Induction of macrophage migration inhibitory factor messenger ribonucleic acid in rat forebrain by reperfusion

To evaluate the impact of uremia and associated caloric restriction on physiologically pulsatile growth hormone (GH) release, we used deconvolution analysis of spontaneous plasma GH profiles in 5/6-nephrectomized male rats (NX, N = 9). Three different normal renal function sham-operated groups were used: rats fed a normal diet ad libitum (SAL, N = 9); NX pair-fed rats (SPF, N = 6); NX rats pair-fed for protein ingestion but calorically supplemented up to the energy intake of SAL (SPF+, N = 8). Severe renal failure was confirmed by much higher (P < 0.001) BUN in NX than sham groups. NX rats were growth retarded as shown by reduced (P < 0.01) weight and length gains as compared with sham animals. Deconvolution analysis (mean +/- SEM) of plasma samples obtained every 10 minutes over 6 hours, and 14 to 16 days after second stage nephrectomy showed that NX rats had a longer GH t(1/2) (17.0 +/- 1.8 vs. 11.6 +/- 0.8 min), less GH mass secreted per burst (48 +/- 15 vs. 95 +/- 16 ng/ml/pulse), lower secretory pulse amplitude (1.9 +/- 0.5 vs. 5.8 +/- 0.9 ng/ml/min), and a reduced total GH secretion (240 +/- 69 vs. 400 +/- 56 ng/ml/6 hr) than SAL rats. Corresponding data were not significantly different between NX and SPF, or between SAL and SPF+ groups. In summary, stunted rats with chronic renal failure exhibit a prolonged GH t(1/2) and suppression of GH secretory pattern burst mass. Control data from rats with normal renal function suggest that the amplitude-specific depression of GH secretion may be attributed, at least in part, to chronic renal failure-associated calorie deficiency.     

SDZ 216-525, a selective 5-HT1A receptor antagonist, reverts zinc-induced inhibition of water intake in dehydrated rats

Zinc is found in many brain regions where it participates in important processes such as neurotransmission and neuromodulation. We previously demonstrated that acute third ventricle injection of zinc inhibits water intake in dehydrated rats. The present study was undertaken to explore a possible link between zinc-induced inhibition of water intake in dehydrated rats and serotonergic systems in the brain. Adult, male Wistar rats had the third ventricle cannulated a week before the experiments. After an overnight period of water deprivation, the animals (N = 12 per group) received acute intracerebroventricular injections (2 microliters) of Zn(Ac)2 (6.7, 67.1 and 671.6 ng/rat). Control animals (N = 12) received NaAc (671.6 ng/rat). Zinc-treated animals displayed a significant, dose-dependent reduction in water intake. Water intake after 120 min was 7.70 +/- 0.50 ml in control (NaAc-treated) dehydrated rats while animals treated with the highest dose of Zn(Ac)2 drank 2.63 +/- 0.73 ml. Third ventricle injections of SDZ 216-525, a selective 5-HT1A receptor antagonist, 45 min before zinc administration, generated a dose-dependent reversal of zinc-induced thirst blockade in water-deprived rats. At the highest dose used (10 micrograms/rat), the water intake of the animals after 120 min was 7.30 +/- 0.23 ml, a value equal to that of control animals. These data suggest that zinc may decrease water intake in dehydrated rats by activation of a 5-HT1A receptor-related mechanism.     

Effect of anaesthetizing the region of the paraventricular hypothalamic nuclei on energy metabolism during exercise in the rat

The ventromedial and posterior hypothalamic nuclei are known to influence glucoregulation during exercise. The extensive projections of the paraventricular hypothalamic nucleus (PVN) to the sympathetic nervous system suggest that the PVN also may be involved in glucoregulation during exercise. The region of the PVN was anaesthetized with bupivacaine before running (26 m min-1) or continued rest, via previously implanted bilateral brain cannulas aimed at the dorsal aspect of the PVN. Control rats were treated identically to PVN-anaesthetized rats, but were not infused. Blood, for determination of plasma concentrations of metabolites and hormones, was drawn from a tail artery, and 3H-glucose was infused in a tail vein for glucose turnover determinations. At rest, no significant changes in plasma concentrations of metabolites or hormones were induced by anaesthesia of the region of the PVN. During exercise, glucose production and utilization and plasma concentrations of glucose, lactate, glycerol, noradrenaline, adrenaline, corticosterone, and glucagon increased (P < 0.02) and plasma insulin decreased (P < 0.02) in all rats. However, initially in exercise, adrenaline (4.3 +/- 0.8 vs. 7.9 +/- 1.0 nmol l-1 in controls, P < 0.05, t = 6 min) and later corticosterone levels (1.37 +/- 0.06 vs. 1.69 +/- 0.10 nmol l-1 in controls, P < 0.05, t = 20 min) were attenuated by PVN anaesthesia. Initially during exercise, glucose utilization was higher and plasma glucose lower in PVN-anaesthetized rats compared to controls (16.6 +/- 0.8 vs. 12.7 +/- 0.6 mumol min-1 100 g-1 and 7.1 +/- 0.2 vs. 8.1 +/- 0.2 mmol l-1, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Monosodium glutamate (MSG)-obese rats develop glucose intolerance and insulin resistance to peripheral glucose uptake

Different levels of insulin sensitivity have been described in several animal models of obesity as well as in humans. Monosodium glutamate (MSG)-obese mice were considered not to be insulin resistant from data obtained in oral glucose tolerance tests. To reevaluate insulin resistance by the intravenous glucose tolerance test (IVGTT) and by the clamp technique, newborn male Wistar rats (N = 20) were injected 5 times, every other day, with 4 g/kg MSG (N = 10) or saline (control; N = 10) during the first 10 days of age. At 3 months, the IVGTT was performed by injecting glucose (0.75 g/kg) through the jugular vein into freely moving rats. During euglycemic clamping plasma insulin levels were increased by infusing 3 mU.kg-1.min-1 of regular insulin until a steady-state plateau was achieved. The basal blood glucose concentration did not differ between the two experimental groups. After the glucose load, increased values of glycemia (P < 0.001) in MSG-obese rats occurred at minute 4 and from minute 16 to minute 32. These results indicate impaired glucose tolerance. Basal plasma insulin levels were 39.9 +/- 4 microU/ml in control and 66.4 +/- 5.3 microU/ml in MSG-obese rats. The mean post-glucose area increase of insulin was 111% higher in MSG-obese than in control rats. When insulinemia was clamped at 102 or 133 microU/ml in control and MSG rats, respectively, the corresponding glucose infusion rate necessary to maintain euglycemia was 17.3 +/- 0.8 mg.kg-1.min-1 for control rats while 2.1 +/- 0.3 mg.kg-1.min-1 was sufficient for MSG-obese rats. The 2-h integrated area for total glucose metabolized, in mg.min.dl-1, was 13.7 +/- 2.3 vs 3.3 +/- 0.5 for control and MSG rats, respectively. These data demonstrate that MSG-obese rats develop insulin resistance to peripheral glucose uptake.     

Leucine metabolism during chronic ethanol consumption

Chronic ethanol consumption is known to increase plasma concentrations of branched-chain amino acids (BCAA) in rats and man, but the mechanisms of this effect are not known. Chronic ethanol consumption may increase levels of BCAA by altering protein turnover and/or by affecting the oxidation of BCAA. These possibilities were investigated in rats pair-fed liquid diets containing either 0% or 36% of total calories as ethanol for 21 days. In the fed state, ethanol-treated rats had a plasma ethanol level of 20 +/- 5 mmol/L and twofold increases in BCAA concentrations in plasma. There were also significant increases (37% to 63%) in muscle, liver, and jejunal mucosa BCAA concentrations. Chronic ethanol consumption significantly increased whole-body rates (mumol/100 g/h) of leucine turnover (73.8 +/- 7.5 v 104 +/- 5.6, P < .01) and oxidation (12.0 +/- 1.7 v 17.7 +/- 1.1, P < .05). In contrast, it significantly decreased leucine incorporation (nmol/mg protein/240 min) into both muscle (0.61 +/- 0.07 v 0.35 +/- 0.05, P < .01) and liver (13.25 +/- 1.40 v 6.78 +/- 0.98, P < .01) proteins. Incorporation of leucine into the mucosal proteins of jejunum (17.42 +/- 1.42 v 15.85 +/- 1.90, P = NS) was not significantly altered by ethanol. These results suggest that reduced protein synthesis and/or increased protein breakdown may account for the elevated tissue BCAA concentrations in chronic ethanol consumption. The consequences of these increased tissue concentrations are increases in tissue oxidation and plasma concentrations of BCAA.     

Glucagon-like peptide-1 can reverse the age-related decline in glucose tolerance in rats

Wistar rats develop glucose intolerance and have a diminished insulin response to glucose with age. The aim of this study was to investigate if these changes were reversible with glucagon-like peptide-1 (GLP-1), a peptide that we have previously shown could increase insulin mRNA and total insulin content in insulinoma cells. We infused 1.5 pmol/ kg-1.min-1 GLP-1 subcutaneously using ALZET microosmotic pumps into 22-mo-old Wistar rats for 48 h. Rat infused with either GLP-1 or saline were then subjected to an intraperitoneal glucose (1 g/kg body weight) tolerance test, 2 h after removing the pump. 15 min after the intraperitoneal glucose, GLP-1-treated animals had lower plasma glucose levels (9.04+/-0.92 mmol/liter, P < 0.01) than saline-treated animals (11.61+/-0.23 mmol/liter). At 30 min the plasma glucose was still lower in the GLP-1-treated animals (8.61+/-0.39 mmol/liter, P < 0.05) than saline-treated animals (10.36+/-0.43 mmol/liter). This decrease in glucose levels was reflected in the higher insulin levels attained in the GLP-1-treated animals (936+/-163 pmol/liter vs. 395+/-51 pmol/liter, GLP-1 vs. saline, respectively, P < 0.01), detected 15 min after glucose injection. GLP-1 treatment also increased pancreatic insulin, GLUT2, and glucokinase mRNA in the old rats. The effects of GLP-1 were abolished by simultaneous infusion of exendin [9-39], a specific antagonist of GLP-1. GLP-1 is therefore able to reverse some of the known defects that arise in the beta cell of the pancreas of Wistar rats, not only by increasing insulin secretion but also by inducing significant changes at the molecular level.     

Short-term effects of a high-sucrose diet on plasma lipid, lipoprotein cholesterol, tissue lipoprotein lipase and hepatic triglyceride lipase in rats

Short-term (2 weeks) effects of a high-sucrose diet on plasma lipids, lipoproteins, tissue lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activities were investigated in rats. Three days of sucrose feeding significantly increased plasma TG (42 +/- 3 mg/dl vs. 56 +/- 2 mg/dl, p = 0.032), while TC increased significantly after 10 days of the diet (50 +/- 2 mg/dl vs. 62 +/- 2 mg/dl, p = 0.0001). HDL-C increased significantly after 3 days of sucrose feeding (36.2 +/- 0.9 mg/dl vs. 42.4 +/- 2.7 mg/dl, p = 0.011). Although LDL-C tended to decrease on days 3, 7 and 10, these changes were not significant. The plasma glucose level did not change during the study. Increased LPL activity in adipose tissue and decreased enzyme activities in skeletal and heart muscles were observed. Adipose tissue LPL returned to the baseline value after 14 days of the diet treatment, while LPL in skeletal and heart muscles remained at the decreased level. HTGL and HTGL/total liver lipase activities were significantly increased after 14 days of the diet. The different responses of lipase activities in various tissues may help to regulate serum lipid and lipoprotein levels in sucrose-fed rats.     

Prevention of diabetic glomerulopathy in streptozotocin diabetic rats by insulin treatment. Kidney size and glomerular volume

Kidney weight and glomerular volume have been studied in groups of insulin-treated streptozotocin diabetic rats maintained at high, or nearly normal plasma glucose levels. Kidney weight and glomerular volume in these groups were compared to a non-diabetic control group. --Rats with nearly normal plasma glucose levels (95 +/- 35 to 182 +/- 20 mg/100 ml) had the same kidney weight as the non-diabetic controls, 1.04 +/- 0.14 and 1.07 +/- 0.09 g, respectively. In the rats with constant high plasma glucose (338 +/- 71 to 555 +/- 86 mg/100 ml) kidney weight was significantly increased, 1.73 +/- 0.20 g, compared to each of the two other groups. Glomerular volume was 0.559 millimicron3 in the diabetic animals with nearly normal plasma glucose, a value very close to that of the non-diabetic controls, 0.587 milimicron3. In animals with high plasma glucose concentrations glomerular volume was 0.775 millimicron3, 2 p less than 0.03 compared with both other groups. --The study indicates that good diabetic control for 6 months prevents the development of large kidneys and large glomeruli in dibatic rats.     

Effects of aging, diet, and sex on plasma glucose, fructosamine, and lipid concentrations in barrier-raised Fischer 344 rats

We studied the relationships of plasma glucose, fructosamine, triglycerides, and cholesterol as a function of age, gender, and diet in barrier-raised Fischer 344 rats aged 5 to 26 months, fed a diet either ad libitum or restricted to 60% of the ad libitum caloric intake. The complex relationships of these plasma levels to age, gender, and diet led to the development of a model with age, diet, and sex as covariates. Overall, fasting plasma glucose concentrations were reduced by approximately 25% in rats on the restricted diet, compared to ad libitum-fed animals. There was a significant age-dependent decline in glucose levels in male animals, whereas in females there was an increase in plasma glucose with aging. Plasma fructosamine levels in calorie-restricted animals, overall, were reduced by 7% compared to levels in animals fed ad libitum. There was a significant positive correlation between plasma glucose and fructosamine levels. Mean plasma triglyceride content was decreased by 50% in calorie-restricted rats compared to ad libitum-fed animals. A significant decrease in triglyceride levels with increasing age was seen in male animals, and an increase with aging in females. There was a significant positive correlation between plasma glucose and triglyceride levels. Plasma cholesterol levels in calorie-restricted animals were reduced by 7% compared to levels in ad libitum-fed animals. An increase of cholesterol concentration with aging was significant in both males and females. Analysis of the data showed that there were significant differences between male and female Fischer 344 rats in the response of plasma glucose and fructosamine to aging and calorie restriction. Changes of plasma triglyceride and cholesterol with aging and dietary calorie restriction were also different in males and females. Studies of the effect of aging on glycemia and blood lipid content should take into account the contributions of animal sex.     

Benfluorex normalizes hyperglycemia and reverses hepatic insulin resistance in STZ-induced diabetic rats

We have examined the effect of chronic (20 days) oral administration of benfluorex (35 mg/kg) in a rat model of NIDDM, induced by injection of STZ 5 days after birth and characterized by frank hyperglycemia, hypoinsulinemia, and hepatic and peripheral insulin resistance. We assessed the following: 1) basal blood glucose and insulin levels, 2) glucose tolerance and glucose-induced insulin release in vivo and in vitro, and 3) basal and insulin-stimulated in vivo glucose production and glucose utilization, using the insulin-clamp technique in conjunction with isotopic measurement of glucose turnover. The in vivo insulin response of several individual tissues also was evaluated under the steady-state conditions of the clamp, using the uptake of the glucose analogue 2-deoxy-D-glucose as a relative index of glucose metabolism. In the benfluorex-treated diabetic rats, postabsorptive basal plasma glucose levels were decreased (8.1 +/- 0.2 mM compared with 10.5 +/- 0.5 mM in the pair-fed untreated diabetic rats and 6.1 +/- 0.2 mM in the benfluorex-treated nondiabetic rats), whereas the basal and glucose-stimulated intravenous glucose tolerance test plasma insulin levels were not improved. Such a lack of improvement in the glucose-induced insulin release after benfluorex treatment was confirmed under in vitro conditions (perfused pancreas). In the pair-fed untreated diabetic rats, the basal glucose production and overall glucose utilization were significantly increased, and during hyperinsulinemia both liver and peripheral tissues revealed insulin resistance. In the benfluorex-treated diabetic rats, the basal glucose production and basal overall glucose utilization were normalized. After hyperinsulinemia, glucose production was normally suppressed, whereas overall glucose utilization was not significantly improved.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of dopamine receptor and adrenoceptor blockade on the hemoconcentrating and hypotensive actions of atrial natriuretic peptide

Atrial natriuretic peptide (ANP) lowers mean arterial pressure (MAP) and increases hematocrit through reduction in plasma volume caused by a transcapillary shift of plasma fluid and protein toward the interstitium. We examined the consequences of blockade of the dopaminergic and adrenergic systems on the hypotensive and hemoconcentrating responses to ANP. Changes in MAP, hematocrit, and plasma protein concentration (PPC) were measured in anesthetized acutely binephrectomized rats, during infusion of ANP alone (1 microgram.kg-1.min-1 for 45 min) or in the presence of haloperidol (20 micrograms.kg-1.min-1), phentolamine (15 micrograms.kg-1.min-1), or propranolol (10 micrograms.kg-1.min-1). Infusion of ANP reduced MAP by 8.6 +/- 1.3% and increased hematocrit by 9.0 +/- 0.6% (both p < 0.005 vs. vehicle). PPC increased (4.4 +/- 0.6%; p < 0.005 vs. vehicle) significantly less than hematocrit, indicating extravasation of proteins. The ANP-evoked reduction in MAP was not affected in haloperidol- or phentolamine-treated rats (-8.8 +/- 2.3 and -10.5 +/- 2.4%, respectively; both p < 0.005 vs. vehicle) but was abolished in propranolol-treated rats (+3.2 +/- 1.3%; p = ns vs. vehicle). The ANP-induced increase in hematocrit was slightly attenuated in haloperidol-, phentolamine-, and propranolol-treated rats (7.5 +/- 0.7, 7.3 +/- 0.8, and 6.0 +/- 1%, respectively). In addition, the coefficient of reflection, an index of the permeability to proteins, was higher in these three groups (0.41 +/- 0.06, 0.49 +/- 0.08, and 0.57 +/- 0.14, respectively) than in control rats infused with ANP (0.27 +/- 0.03), indicating an attenuation of the ANP-induced extravasation of proteins. Thus, in binephrectomized rats, the hypotensive activity of ANP requires a beta-adrenergic component, whereas its hemoconcentrating action is, at least in part, dependent upon dopaminergic and adrenergic activation.     

Effects of chronic di(2-ethylhexyl) phthalate intake on the secretion and removal rate of triglyceride-rich lipoproteins in rats

This work intends to characterize the nature of the plasma triglyceride level decrease in male Wistar rats fed with diets supplemented with 2% (w/w) di(2-ethylhexyl) phthalate (DEHP), a packaged-food chemical contaminant. After being fed for 21 days, the animals were assessed to determine plasma and liver lipids or to quantify the in vivo hepatic secretion and in vitro plasma removal of triglyceride-rich lipoproteins. The liver cholesterol and triglyceride contents in DEHP-fed rats were closely similar to those found in controls, co-existing with a decrease in plasma cholesterol (19%), phospholipid (14%) and triglyceride (36%) levels. The decrease of the plasma triglyceride pool size was not associated with a reduction in hepatic secretion of triglyceride. The total triglyceride lipase activity rose (32%) due to a remarkable increase (100%) of the extrahepatic lipoprotein lipase activity. We can conclude that extrahepatic lipoprotein lipase activity accounts for the hypotriglyceridaemic effect of DEHP through an increase of triglyceride removal rate.     

Potassium citrate/citric acid intake improves renal function in rats with polycystic kidney disease

Polycystic kidney disease (PKD) has been shown to be exacerbated by acidosis or a low potassium intake, and there is evidence that administration of alkali might have a beneficial effect. This study determined whether ingestion of potassium citrate and citric acid would ameliorate PKD. Healthy normal and heterozygous littermate Han:SPRD rats with autosomal dominant PKD were provided with either tap water or 55 mM K3citrate/67 mM citric acid solution (KCitr) to drink starting at the age of 1 mo. Renal clearance measurements and histologic assessments were performed when the rats were 3 mo old. KCitr intake did not affect body weight or urine flow, but completely prevented the decline in GFR found in untreated rats with PKD. In rats that drank tap water, left kidney GFR averaged (in microliter/min per 100 g body wt) 503 +/- 78 (n = 9) in normal animals and 242 +/- 56 (n = 6) in rats with PKD. In rats that drank KCitr, GFR averaged 562 +/- 123 (n = 7) in normal animals and 534 +/- 103 (n = 7) in rats with PKD. Kidneys of rats with PKD were approximately double normal size. KCitr treatment did not affect kidney size, but led to fewer interstitial abnormalities and smaller cysts in cystic kidneys. KCitr ingestion led to a significantly lower (P < 0.001) plasma [K+] in rats with PKD (3.3 +/- 0.2 versus 4.1 +/- 0.2 mEq/L in rats on tap water). Chronic KCitr intake in the young heterozygous Han:SPRD rat with PKD yields a modest improvement of kidney histology and a dramatic improvement in GFR. The mechanism of action of KCitr and the long-term effects of this treatment on renal structure and function in PKD deserve further study.     

Insulin sensitivity in familial hypercholesterolemia

Insulin resistance is found in association with obesity, non-insulin-dependent diabetes mellitus, and essential hypertension, which are all risk factors for atherosclerotic cardiovascular disease. Furthermore, hyperinsulinemia has been reported in familial combined hyperlipoproteinemia and endogenous hypertriglyceridemia. Finally, relatively high serum triglyceride and low high-density lipoprotein (HDL) cholesterol concentrations invariably accompany hyperinsulinemia. Whether insulin sensitivity is affected by the isolated presence of high levels of serum low-density lipoprotein (LDL) cholesterol has not been clearly established. We studied 13 subjects with heterozygous familial hypercholesterolemia (FHC) and 15 normocholesterolemic subjects selected to be free of any other known cause of insulin resistance. Thus FHC patients and controls had normal body weight and fat distribution, glucose tolerance, blood pressure, and serum triglyceride and HDL cholesterol concentrations, but were completely separated on plasma LDL cholesterol concentrations (6.05 +/- 0.38 v 3.27 +/- 0.15 mmol/L, P < .0001). Fasting plasma levels of glucose, insulin, free fatty acids (FFA), and potassium and fasting rates of net carbohydrate and lipid oxidation were superimposable in the two study groups. During a 2-hour euglycemic (approximately 5 mmol/L) hyperinsulinemic (approximately 340 pmol/L) clamp, whole-body glucose disposal rates averaged 30.4 +/- 2.3 and 31.1 +/- 3.0 mumol.kg-1 x min-1 in FHC and control subjects, respectively (P = 0.88). The ability of exogenous hyperinsulinemia to stimulate carbohydrate oxidation and energy expenditure and suppress lipid oxidation and plasma FFA and potassium levels was equivalent in FHC and control subjects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Physiological indirect effect modeling of the antilipolytic effects of adenosine A1-receptor agonists

The relationship between blood concentrations of the adenosine A1-receptor agonist N6-(p-sulfophenyl) adenosine (SPA) and its effect on both plasma nonesterified fatty acid (NEFA) and glycerol release was described on the basis of an integrated pharmacokinetic-pharmacodynamic model. An indirect response model rather than a hypothetical "link" model was used to account for the delayed response. For that purpose an empirical solution to the differential equation describing the physiological indirect response model is presented. The model-estimated rate constant for the output of the glycerol response was compared to the elimination rate constant after exogenous administration of glycerol. In a crossover designed study, chronically cannulated male Wistar rats were subjected to either SPA administration (120 microgram/kg for 15 min) for measurement of the effects on glycerol, or glycerol administration for determination of glycerol pharmacokinetics. Glycerol pharmacokinetics was determined in the presence of a stable level of SPA (171 +/- 6 ng/ml) to suppress endogenous glycerol levels completely. The indirect response model adequately described the relationship between SPA concentrations and plasma glycerol levels. The PD parameter estimates for EC50, EMAX, and Hill factor were 23 +/- 2 ng/ml, 74 +/- 3% (change from baseline), and 3.3 +/- 0.5, respectively. These values were not different from those obtained when analyzing the data on basis of the differential equation directly. Furthermore, the EC50 values for the reduction in glycerol or NEFA levels were identical (23 +/- 2 and 21 +/- 3 ng/ml, respectively) indicating that both PD endpoints reflect the same physiological process. The concentration-time profile after administration of glycerol could be described best on the basis of a biexponential function. The value for kout in the PK/PD model (0.19 +/- 0.03 min-1) corresponded very well to the terminal elimination rate constant determined after i.v. administration of glycerol (0.25 +/- 0.03 min-1). In conclusion, the antilipolytic effects of adenosine A1-receptor agonists can be described by the indirect suppression model. The rate constant describing the delay between concentration and glycerol effect was shown to be a true reflection of the removal of glycerol.