Celecoxib does not alter cardiovascular and renal function during dietary salt loading

1. Cyclo-oxygenase-2 (COX-2)-derived prostaglandins are important in controlling sodium excretion and renin release. In the present study, we tested the hypothesis that a clinical dose of celecoxib would impair urinary sodium excretion and elevate blood pressure (BP) during dietary salt loading. 2. Twelve normotensive individuals (mean (± SEM) age 35 ± 2 years) completed two separate 17 day dietary perturbations, one taking 200 mg/day celecoxib (CX2) and the other taking placebo (PL), randomized with a 1 month wash out. The controlled 17 day diet consisted of a 3 day run-in diet, 7 days of a low-salt (LS, 20 mmol sodium/day) diet and 7 days of a high-salt diet (HS, 350 mmol sodium/day) diet. The order in which the diets were applied was randomized. Data were collected on the last day of the LS and HS diets. 3. Plasma and urinary prostaglandins were modestly lower during celecoxib (P < 0.05). Urinary sodium excretion was greater (P < 0.01) during the HS diet (253 ± 10 vs 281 ± 27 mmol/24 h for PL vs CX2, respectively) compared with the LS diet (14 ± 3 vs 17 ± 7 mmol/24 h for PL vs CX2, respectively; P(drug) = 0.26). Celecoxib did not alter creatinine clearance (P > 0.50). Twenty-four hour mean arterial BP was similar during PL (87 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively) and CX2 (88 ± 2 vs 87 ± 2 mmHg for LS and HS, respectively; P = 0.85), with no effect of dietary salt (P > 0.80). Plasma renin activity, angiotensin II and aldosterone were all suppressed with dietary salt loading (P < 0.05), with no effect of drug (P > 0.35). 4. In conclusion, blood pressure and renal function were not adversely affected by celecoxib, even during dietary salt loading. These findings support current guidelines suggesting minimal cardiovascular risks associated with short-term, low-dose use of celecoxib in young to middle-aged adults.     

High dietary sodium blunts affects of angiotensin-converting enzyme inhibition on vascular angiotensin I-to-angiotensin II conversion in rats

High sodium intake blunts the efficacy of angiotensin (Ang)-converting enzyme (ACE) inhibition (ACEi), but the underlying mechanism is incompletely characterized. High sodium has been reported to increase vascular expression and vascular activity of ACE. To investigate whether high-dietary sodium-induced effects on vascular conversion of Ang I might be involved in the sodium-induced blunting of the response to ACEi, the authors studied the vasoconstrictor responses to Ang I and Ang II of isolated aortic rings from healthy rats on low dietary sodium (LS: 0.05% NaCl) and high dietary sodium (HS: 2.0% NaCl) after 3 weeks of ACEi (lisinopril 75 mg/L) or vehicle (CON). Blood pressure was similar in LS and HS in CON, but HS blunted the blood pressure response to ACEi. Functional conversion of Ang I was assessed as the difference in dose-response curves to Ang I and Ang II in parallel aortic rings. Sodium intake did not affect the dose-response curves to Ang I and Ang II in CON. In the ACEi groups, a significant difference was present between the curves for Ang I and Ang II on LS (deltaEC50, 6.7 nM; range, 2.2-13 nM; P < 0.01) but not on HS (deltaEC50: 1.3 nM; range, 0.0-4.1 nM, median [interquartile range], NS). Thus, HS blunts the ACEi-induced reduction of functional vascular Ang I conversion compared with LS. Whether the blunted functional vascular conversion is causally related to the blunted blood pressure response remains to be elucidated.     

Distinct regulation of inner medullary collecting duct nitric oxide production from mice and rats

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Sodium sensitivity and sympathetic nervous system in hypertension induced by long-term nitric oxide blockade in rats

1. Pharmacological inhibition of nitric oxide (NO) synthesis is known to produce acute and chronic hypertension in many animal species, but the underlying mechanisms mediating the hypertension are not completely understood. In particular, the pathogenetic roles of sodium sensitivity and the sympathetic nervous system in this model of hypertension are controversial. The present study was designed to test the hypothesis that long-term administration of the NO synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) to male Sprague-Dawley rats would produce a sodium-sensitive hypertension and that the enhanced activity of the sympathetic nervous system in this type of hypertension contributes to the sodium sensitivity. 2. NG-Nitro-L-arginine methyl ester was added to drinking fluid for 8 weeks at a concentration of 16 mg/dL. Rats received tap water for the first 4 weeks of the study and were then divided into two groups and placed on either a normal or high sodium intake (ingestion of either tap water or 0.9% NaCl, respectively). Awake systolic blood pressure was measured by the tail-cuff method every week. Urinary excretion rates of the stable NO metabolites and catecholamines during NO synthesis inhibition were examined. 3. Long-term administration of L-NAME produced a marked and sustained elevation in arterial pressure without altering urine flow, or sodium excretion rate. NG-Nitro-L-arginine methyl ester-induced hypertension was accompanied by a decreased urinary excretion of the stable NO metabolites NO2- and NO3- and was aggravated when rats drank 0.9% NaCl in place of tap water. Urinary excretion of adrenaline and noradrenaline, but not dopamine, in L-NAME-treated rats increased significantly within the first week of the study compared with control rats. L-Arginine (2 g/dL in drinking fluid) completely reversed the elevation of arterial pressure as well as the decrease in urinary NO2- and NO3- excretion and the increased urinary excretion of catecholamines associated with L-NAME treatment by 3 weeks of concomitant administration. 4. These results suggest that long-term inhibition of NO synthesis produces a sodium-sensitive hypertension and that changes in sympathetic nerve activity may, at least in part, contribute to the sodium sensitivity in this type of hypertension.     

The effect of saccharin ingestion on the excretion of microbial amino acid metabolites in rat and man

Low dietary levels of sodium saccharin (0-2%) fed to male rats for 6 weeks produced a dose-related increase in the urinary excretion of p-cresol, a major microbial metabolite of tyrosine. Some animals fed higher levels of saccharin (5-7.5%) for 6 weeks excreted increased amounts of p-cresol, but many excreted negligible amounts so that the overall dose-response relationship was bell shaped. After 20 weeks of exposure, all rats in the higher dose groups showed increased p-cresol excretion and by 26 weeks the 7.5% saccharin group showed a 36-fold increase over animals fed the 0% saccharin diet. The urinary excretion of phenol, another microbial amino acid metabolite, was constant in animals fed dietary levels of saccharin below 2% for 6 weeks, but was virtually abolished at higher levels. The excretion of indican (formed from indole, a microbial metabolite of tryptophan) was increased by saccharin in a dose-related fashion at all time points, but showed only a 3-fold increase at 7.5% compared with the 0% group. p-Cresol may therefore prove more sensitive than indican as an indicator of altered microbial metabolism due to saccharin. In a separate study the effect of 7.5% saccharin on p-cresol and indican excretion was shown to be largely reversible and the excretion of phenol increased rapidly when saccharin was withdrawn from the diet. Chronic saccharin administration to man at high doses (1 g/day for 4 weeks) had no perceptible effect on the excretion of these three metabolites.     

Chronic manipulation of dietary salt modulates renal physiology and kidney dopamine receptor subtypes: Functional and autoradiographic studies

• 1.1. Compared to rats maintained on the normal NaCI (0.33%) diet, animals maintained on the low NaCl (0%) diet for 4 weeks exhibited increased plasma aldosterone and chloride and decreased urinary sodium excretion.
• 2.2. Rats maintained on the high NaCl (8%) diet for 4 weeks showed increased systolic blood pressure, water intake, urine volume, sodium and dopamine excretion and decreased plasma aldosterone and glomerular filtration rate.
• 3.3. Administration of SCH 23390 (10mg/kg, po), but not domperidone to the high salt diet rats attenuated the diuretic effect, indicating the involvement of DA₁ rather than DA₂ receptors. The dopamine decarboxylase inhibitor, carbidopa (30 mg/kg, i.p.), also reduced the high salt-induced diuresis.
• 4.4. Kidney sections from rats fed the low NaCl diet showed a 63–100% decrease (P < 0.001−0.02) in cortical and medullary DA₁ and DA₂ binding sites, while rats fed the high NaCl diet demonstrated only a 70% decrease (P < 0.01−0.02) in cortical DA₁ binding, without affecting DA₂ binding.
• 5.5. These data indicate that chronic modification of dietary salt profoundly affects the sodium, water and dopamine excretion and leads to selective modulation of renal dopamine receptor subtypes.

     

High-salt diet and responses of the pressurized mesenteric artery of the dog to noradrenaline and acetylcholine

A high-salt diet in rats has been shown to result in enhanced vasoconstrictor and/or reduced vasodilator responses of isolated arteries to agonists. The present experiments were designed to investigate the effects of dietary salt on the responses of the pressurized mesenteric resistance artery of the dog to constrictor and dilator agents. Dogs were fed diets containing three different levels of salt with sodium concentrations (in mmol/kg per day) of 0.4 (low salt; LS), 3.0 (intermediate salt; IS) and 6.0 (high salt; HS) for a period of 4 weeks. At the end of the feeding period, animals were killed and lengths of third-order mesenteric artery were obtained and mounted in a perfusion myograph and changes in internal diameter were measured using a microscope and video-tracking device. The responses to noradrenaline (NA), acetylcholine (ACh) and sodium nitroprusside (SNP) were then determined. The vasoconstrictor responses to NA were identical in the three groups. However, the relaxation response of the vessels to ACh was attenuated in HS dogs compared with LS dogs (P < 0.05), but not with IS dogs. The application of N(G)-nitro-l-arginine methyl ester, an inhibitor of nitric oxide synthase, reduced the relaxation responses to ACh comparably in all three groups. The relaxation responses of the vessels to SNP were similar in all groups. These results indicate that, in the dog mesenteric resistance artery, a high-salt diet does not affect vasoconstrictor responses to NA, but does attenuate the vasorelaxant action of ACh, largely by inhibiting the production of endothelium-derived relaxing factor.     

Antagonistic actions of renal dopamine and 5-hydroxytryptamine: endogenous 5-hydroxytryptamine, 5-HT1A receptors and antinatriuresis during high sodium intake.

1. The present study has examined the effect of (+)-WAY 100135, a selective antagonist of 5-HT1A receptors, and ketanserin, an antagonist of 5-HT2 receptors, on the urinary excretion of Na+, K+, dopamine, 5-hydroxytryptamine (5-HT) and their metabolites in rats treated with the selective type A monoamine oxidase (MAO-A) inhibitor, Ro 41-1049 (15 mg kg-1 day-1) in conditions of normal sodium (NS) and high sodium (HS; 1.0% NaCl in drinking water) intake. 2. Male Wistar rats were placed in metabolic cages and were given tap water (NS diet) in the first 4 days of the study and then challenged to a HS diet for another 7 days. Ro 41-1049 was given in drinking water only in the last 3 days of the HS diet, whereas (+)-WAY 100135 (5 and 10 mg kg-1 day-1, s.c.) or ketanserin (2 mg kg-1 day-1, s.c.) were administered in the last 4 days of the HS intake period. 3. Daily urinary excretion (in nmol kg-1 day-1) of dopamine (82 +/- 2), 3,4-dihydroxyphenylacetic acid (DOPAC; 198 +/- 9), homovanillic acid (HVA; 915 +/- 47), 5-HT (586 +/- 37) and 5-hydroxyindoleacetic acid (5-HIAA; 1035 +/- 64) in the HS intake period was similar or higher than that in NS diet (dopamine = 68 +/- 2, DOPAC = 197 +/- 4, HVA = 923 +/- 42, 5-HT = 539 +/- 132, 5-HIAA = 1286 +/- 95). The administration of Ro 41-1049 on 3 consecutive days reduced the urinary excretion of dopamine, DOPAC and HVA, respectively, by 35-51% (P < 0.05), 73-85% (P < 0.05) and 59-66% (P < 0.05); the urinary excretion of 5-HT increased 2 fold (P < 0.01) and the levels of 5-HIAA were reduced by 39-77% (P < 0.05). 4. During HS intake (7 days), daily urinary excretion of Na+ increased 5.5 fold (from 6.7 +/- 0.2 to 36.5 +/- 0.9 mmol kg-1 day-1), without changes in the urinary excretion of K+ (from 11.2 +/- 0.2 to 11.9 +/- 0.5 mmol kg-1 day-1) and urinary osmolality (from 1083.8 +/- 26.7 to 1117.7 +/- 24.1 mOsm kg-1 H2O). MAO-A inhibition during HS intake was found to produce a 47-68% decrease in Na+ excretion (from 39.1 +/- 0.7 to 15.1 +/- 2.5 mmol kg-1 day-1, n = 4; P < 0.02) and urine volume (from 160.4 +/- 3.3 to 43.8 +/- 9.0 ml kg-1 day-1, n = 4; P < 0.02) without changes in K+ (from 11.1 +/- 0.5 to 9.2 +/- 0.6 mmol kg-1 day-1, n = 4) and creatinine (from 29.1 +/- 2.3 to 28.4 +/- 2.1 mg kg-1 day-1) excretion; urine osmolality increased 2 fold (from 936.3 +/- 40.3 to 2210.7 +/- 157.4 mOsm kg-1 H2O, n = 4; P < 0.02). Administration of (+)-WAY 100135 (5 and 10 mg kg-1 day-1), but not of ketanserin (2 mg kg-1 day-1), was found to inhibit the antinatriuretic effect induced by Ro 41-1049 during HS intake. 5. It is suggested that MAO-A inhibition during HS intake leads to an increased availability of 5-HT in renal tissues, the effect of which is a decrease in the urinary excretion of Na+, involving the activation of tubular 5-HT1A receptors.     

Effect of food intake on blood lead concentration in workers occupationally exposed to lead

Results from a cross-sectional study showed the concentration of lead in the blood of male workers, aged 20-55 years, occupationally exposed to lead in a steel factory, to be negatively correlated with the daily nutritional content of dietary fiber, iron and vitamin B1 (thiamine) intake. Furthermore, in experiments with rats injected subcutaneously with lead acetate, lead levels in blood and femur of animals on a vitamin-rich laboratory chow were lower than those fed a general laboratory chow. Moreover, in the group fed the vitamin-rich chow, lead excretion in feces increased, while excretion in urine did not. These results suggest that lead excretion from the body may be increased by a high intake of nutrients such as thiamine, iron and fiber, that lead excretion in feces via bile may be enhanced by a large intake of vitamins such as thiamine and that accordingly the lead concentration in the blood of the workers is reduced.     

Altered levels of cyclic nucleotides in F344 rats fed sodium o-phenylphenate

Urinary c-AMP and c-GMP levels were measured in male and female F344/DuCrj rats during dietary treatment with 2% sodium o-phenylphenate (OPP-Na) for 136 days. At the end of the experiment, levels of the cyclic nucleotides in the plasma, kidney and liver, and of adenylate cyclase in the kidney and liver were also determined. Urinary c-AMP/creatinine in males decreased immediately after the start of OPP-Na treatment and recovered to the normal level within 1 wk. Such a biphasic change recurred intermittently until the end of the experiment. In the case of treated females, urinary c-AMP/creatinine also showed a decrease and recovery in 1 wk but no subsequent decrease was observed. As urinary c-GMP/creatinine in treated males was higher than that in control males, low c-AMP/c-GMP ratios persisted throughout the experiment. Although there was no significant difference of c-AMP or c-GMP levels in the liver or kidney between control and treated animals, c-AMP/c-GMP ratios in these tissues from treated rats decreased slightly. The c-AMP levels in plasma from treated males were significantly lower than those in the male controls, but no significant difference was observed between treated and control females. In the presence of activators (sodium fluoride, glucagon, epinephrine), adenylate cyclase activity in liver and kidney homogenates from treated rats was only about 70% of the control activity, except with the female kidney enzyme. This observed inhibition in treated rats suggests that the decreased excretion of urinary c-AMP in treated rats was not due to a decrease in renal clearance but to reduced production of c-AMP.     

Acute hypotensive, natriuretic, and hormonal effects of nifedipine in salt-sensitive and salt-resistant black normotensive and hypertensive subjects.

In a randomized double-blind study, we compared the short-term effects of nifedipine (10 mg 3x daily for 1 day) versus placebo on 24-h blood pressure, diuresis, natriuresis, urinary excretion of dopamine and metabolites, and on plasma renin activity (PRA) and plasma aldosterone levels in 18 black hypertensive (HT) patients [eight salt-resistant (HT-SR) and 10 salt-sensitive (HT-SS)], and in 20 black normotensive (NT) subjects (12 NT-SR and eight NT-SS) who were studied randomly with both a high- (HS) and a low-salt (LS) diet. In comparison to placebo, nifedipine significantly decreased 24-h mean BP in all groups either with HS or LS diets (all p<0.05). With HS, greater hypotensive effects were achieved in NT-SS (-10+/-2 mm Hg) versus NT-SR (-3+/-1 mm Hg; p<0.05) and in HT-SS (-18+/-2 mm Hg) versus HT-SR (-12+/-2 mm Hg; p<0.05). In NT-SS and HT-SS, nifedipine induced greater (p<0.05) BP decrease with HS (-10+/-2 and -18+/-2 mm Hg) than with LS (-4+/-1 and -9+/-1 mm Hg, respectively), whereas in NT-SR and HT-SR, the hypotensive effect did not differ between HS and LS. Nifedipine versus placebo significantly increased natriuresis and fractional excretion of sodium in all groups only with HS (p<0.05) but not with LS diets. Only in HT-SS were the hypotensive and natriuretic effects of nifedipine significantly correlated (r = -0.77; p<0.01). Nifedipine produced a similar increase of the urinary excretion of dopamine, L-DOPA, and of DOPAC in all subjects, which did not correlate with hypotensive and natriuretic effects. Nifedipine did not modify plasma levels of renin and of aldosterone except in NT-SS with HS, in whom nifedipine increased PRA levels (p <0.05). We conclude that although nifedipine reduces BP in all groups of NT and HT with LS and HS diets, the effect is greater in salt-sensitive subjects with HS. Although in HT-SS with HS, the short-term natriuretic response to nifedipine may contribute to its hypotensive effects, the diuretic-natriuretic effect of nifedipine is not necessary for the expression of its hypotensive effect. Moreover, it is unlikely that any short-term effects of nifedipine either on the renal dopaminergic system or on the secretion of aldosterone explain nifedipine short-term hypotensive and diuretic-natriuretic effects.     

Sar1-Ile8-angiotensin II decreases urinary PGE2 and PGF2α excretion in rabbits on dietary sodium restriction

Urinary PGE₂ and PFG_2α excretion (U_PGV) were determined prior, during and after 48 h treatment with angiotensin-II-blocker, Sar¹-Ile⁸-angiotensin II (200 μg/kg/3 h), in rabbits maintained on chronic low (LS) or high (HS) salt diets. U_PGE2 V and F_2α were significantly (P < 0.001) higher in LS than in HS. Sar¹-Ile-⁸-angiotensin II decreased the elevated U_PGE2 V and U_PGF2α V in LS from 2.60 ± 0.084 μg/24 h to 1.13 ± 0.21 μg/24 h and from 6.63 ± 0.61 to 3.77 ± 0.86 μg/24 h respectively. In animals with HS intake, angiotensin II blockade failed to effect urinary prostaglandin excretion.     

High sodium intake increases the urinary excretion of L-3,4-dihydroxyphenylalanine but fails to alter the urinary excretion of dopamine and amine metabolites in wistar rats

• 1.1. The present study has examined the daily urinary excretion of L-DOPA, dopamine and its metabolites (DOPAC, 3-MT and HVA) during normal salt (NS) and high salt (HS) diets.
• 2.2. Daily urinary excretion of L-DOPA, DA, DOPAC, 3-MT and HVA during the 4-day period of NS diet averaged, respectively, 7.6±0.4, 71±5,217±22, 570±90and1217±110 nmol/kg/day. The slight increase in the urinary excretion of DA, DOPAC and 3-MT (16% to 42% increase), when rats were fed a HS diet, did not achieve statistical significance.
• 3.3. In contrast, the urinary levels of L-DOPA during the HS diet period (11 ± 1 nmol/kg/day) were found to be significantly higher than during the NS diet period; the maximal increase in the urinary excretion of L-DOPA (93% increase) was observed in the first day and then a progressive decline was observed towards the end of the HS intake period.
• 4.4. During the first 5 days of the HS intake period, the urine output of noradrenaline (NA) was found to increase (27% to 83%) and then to progressively decline to baseline values (13.5±0.7 nmol/kg/day).
• 5.5. Urinary excretion of adrenaline (AD) during the HS intake period was found to increase (72% to 146%); the mean daily urinary excretion of AD during the NS diet period averaged 2.5±0.4 nmol/kg/day. NA and DA contents in the kidney of rats on a NS diet were not significantly different from that of rats in a HS diet.
• 6.6. It is concluded that long-term HS intake in Wistar rats fails to change the urinary excretion of DA and of its metabolites (DOPAC, 3-MT and HVA). Furthermore, the discrepant profile in the urinary excretion of L-DOPA and DA during HS intake might be related to a reduction in the tubular uptake of the amino acid, rather than reflecting a decrease in its decarboxylation.

     

Noninvolvement of hypertriglyceridemia and hyperleptinemia in blood pressure increases induced by dietary lard in rats

We investigated whether hypertriglyceridemia and hyperleptinemia are involved in the development of increases in blood pressure induced by dietary lard. Rats received either chow alone or chow in which 50% of the energy content was from substituted lard. Each group was divided into two groups according to whether the diet included bezafibrate or not. In another series of experiments, rats were fed either chow alone or chow in which 50% of the energy content was from substituted lard, safflower oil, or sucrose. Systolic blood pressure (SBP) was measured every week during each 7-week feeding period. A steady-state plasma glucose method was used to determine insulin sensitivity after lard substitution with or without bezafibrate. After the 7-week feeding period, the plasma levels of glucose, immunoreactive insulin, triglyceride and leptin were measured. In rats fed with a high lard diet, SBP, plasma levels of immunoreactive insulin, triglyceride, leptin and steady-state plasma glucose concentrations significantly increased, compared with levels of these substances in controls. Bezafibrate treatment completely reversed these effects. In rats fed with a high safflower oil or a high sucrose diet, no significant change was seen in SBP and plasma immunoreactive insulin levels. However, the plasma triglyceride levels were increased by dietary lard or sucrose. Moreover, the plasma leptin level was also increased by dietary lard and safflower oil. Neither dietary hypertriglyceridemia nor hyperleptinemia were involved in the development of increases in blood pressure induced by dietary lard.     

Effects of nitrendipine on sodium balance during changes in sodium intake and low-dosage ANP.

We found previously that calcium entry blockade with nitrendipine enhanced the natriuretic effect of high-dose atrial natriuretic peptide (ANP). It is unknown whether nitrendipine also influences the effect of physiological changes in ANP. We therefore studied the effect of nitrendipine on cumulative sodium balance during changes in sodium intake as well as on natriuresis after low-dosage ANP infusion during low and high sodium (LS and HS, respectively) intake. In eight healthy volunteers, sodium balance was recorded after the switch from LS (20 mmol/day) to HS (300 mmol/day) diet. Cumulative sodium balance was equal with (441 +/- 45 mmol) or without (458 +/- 45 mmol) nitrendipine treatment. The body weight curves were also fully congruent. ANP (0.005 micrograms/kg/min for 3 h) was administered during maximal water diuresis on both sodium intake levels with and without nitrendipine. Infusion of ANP increased sodium excretion (mumol/min) from 30 +/- 7 to 81 +/- 12 (LS) and from 316 +/- 27 to 469 +/- 46 (HS). During nitrendipine, similar increments (from 36 +/- 7 to 98 +/- 24 mumol/min, HS) were found. ANP had no effect on inulin clearance and fractional excretion of lithium, but consistently depressed diluting segment reabsorption. This pattern was also similar during nitrendipine. Apparently, under the conditions of this study in normal subjects, nitrendipine has no effect on sodium balance. ANP, in physiological concentrations, increases natriuresis mainly by depressing sodium reabsorption in the distal nephron, an effect not enhanced by nitrendipine.     

The nephrotoxic potential of styrene in sprague-dawley rats

Pre-fasted (16 h) Sprague-Dawley male rats were treated i.p. with 0, 0.2, 0.4, 0.8 and 1.2 g/kg of styrene in corn oil. Renal functions were assessed at 0–24, 242-48 and 48–72 h after the exposure. Urinary creatinine was decreased at 0.8 g/kg of styrene during 0–24 h after the treatment compared to control, whereas such a decrease was noticed in 1.2 g/kg styrene-treated rats when compared to control groups during 0–24 and 0–48 h after the dose. Urine pH and urinary contents of sodium, potassium and chloride were all decreased in a dose-dependent manner at 0.8 and 1.2 g/kg of styrene compared to both control animals during 0–24 h, whereas urinary proteins were not affected significantly. In another experiment, groups of pre-fasted (16 h) rats were treated i.p. with 0, 0.8 and 1.2 g/kg of styrene in corn oil and were then fasted for another 24 h to induce more stress prior to collection of blood and urine. Urinary pH and excretions of sodium and potassium were all decreased in styrene-treated rats 24 h after the dose. Urinary proteins were elevated and relative kidney weights were increased in 1.2 g/kg styrene-treated rats only compared to both control and 0.8 g/kg styrene-treated groups. A significant increase in serum creatinine and an increase close to significant in blood urea nitrogen were observed at 1.2 g/kg dose. These results suggest an impairment of renal functional parameters due to acute styrene exposure and further demonstrate a possible dose-dependent nephrotoxic potential of styrene in rats.     

Growth, liver lipid and blood amino acids in rats fed ethanol with an adequate diet

The weight, histology and RNA, DNA, protein and lipid content of the liver and arterial and portal plasma amino acid concentrations were determined in male Sprague-Dawley rats fed a liquid diet which met AIN-76A standards with 36% of the calories supplied by ethanol. The dietary components of the dry mixture in percentages by weight included 20% casein, 22% sucrose, 43% dextrin, 5% corn oil, vitamins, minerals and other dietary factors. For feeding these were suspended in distilled water containing 2.5% xanthan gum with or without ethanol to supply 1 kcal/ml. The feeding method employed perforated neoprene discs floated on top of the suspended diet to control evaporative losses. Animals were pair fed or ad libitum fed for 8-10 weeks. Gain/feed ratios were virtually identical for ethanol-fed rats and their pair-fed controls. Ethanol intake of ad libitum fed rats averaged 14.8, 10.3 and 7.4 g/kg BW/day after 1, 5 and 10 weeks, respectively. No chemical or histological evidence of liver fat accumulation or significant differences in arterial or portal amino acid concentrations were detected in animals fed ethanol. The lack of apparent ethanol toxicity is discussed in relation to the results of others and to our earlier report of increased orotic acid excretion by ethanol-fed rats.     

Effects of taurine on neutrophil function in hyperlipidemic rats

In dietary hyperlipidemic rats, an increase in serum lipid level may cause an increase in membrane lipid level of the neutrophils, and phagocytosis and bactericidal capacity may be thereby lowered. Treatment with taurine (470 mg/kg/day, p.o.) strengthened the bactericidal capacity of neutrophils which was decreased by cholesterol diet feeding, as the capacity was stronger on the 40th day than that in animals fed laboratory chow. The results suggest that taurine may play an important role in the mechanism of host defense through the neutrophil function.     

N-acetylcysteine in high-sucrose diet-induced obesity: Energy expenditure and metabolic shifting for cardiac health

To study the effects of N-acetylcysteine (NAC, C₅H₉–NO₃S) on high-sucrose diet-induced obesity and its effects on energy metabolism and cardiac oxidative stress, male Wistar 24 rats were divided into four groups (n = 6): (C) given standard chow and water; (N) receiving standard chow and 2 g/l N-acetylcysteine in its drinking water; (HS) given standard chow and 30% sucrose in its drinking water, and (HS-N) receiving standard chow, 30% sucrose and N-acetylcysteine in its drinking water.After 30 days of the treatment, obesity was evidenced in HS rats from enhanced body weight, respiratory quotient, hypertriglyceridemia. As well depressed resting metabolic rate, and oxygen consumption per surface area. HS rats had triacylglycerol accumulation, oxidative stress and metabolic shifting in cardiac tissue. NAC enhanced fat oxidation and energy expenditure, normalizing these adverse effects, comparing HS-N and HS rats. The beta-hydroxyacyl coenzymne-A dehydrogenase activity was higher in HS-N animals, indicating higher heart fatty acid degradation than in HS. NAC normalized myocardial glycogen and lactate dehydrogenase activity, comparing HS-N and HS rats, but had no effects on calorimetric and biochemical parameters in standard-fed rats, comparing N and C groups.In conclusion, N-acetylcysteine offers promising therapeutic value in prevention of high-sucrose induced-obesity and its effect on cardiac tissue. N-acetylcysteine reduced the oxidative stress and prevented the metabolic shifting in cardiac tissue, enhancing fatty acid oxidation and reducing anaerobic metabolism in high-sucrose-fed conditions. The application of this agent in food system via exogenous addition may be feasible and beneficial for antioxidant protection and energy metabolism in cardiac tissue.     

Metabolism and pharmacokinetic profile of vinylidene chloride in rats following oral administration

Male rats (normally fed or previously fasted for 18 hr) were given a single oral dose of 1 or 50 mg/kg of [¹⁴C]vinylidene chloride (VDC) in corn oil and the routes and rates of elimination of ¹⁴C activity were then followed for 72 hr. After a single oral dose of 1 mg/kg of [¹⁴C]VDC, 78% of the dose was metabolized and excreted in urine and feces as nonvolatile metabolites of VDC. The remainder was exhaled as ¹⁴CO₂ (21%) and unchanged [¹⁴C]VDC (1–3%). Fasting prior to [¹⁴C]VDC administration did not significantly affect the fate of the 1-mg/kg dose of [¹⁴C]VDC. Conversely, after a 50-mg/kg dose of [¹⁴C]VDC, excretion of the parent compound via the lungs accounted for 19 and 29% of the dose in fed and fasted rats, respectively. Elimination of nonvolatile metabolites of VDC was slightly greater in fed than in fasted rats indicating a reduced capacity for metabolism of VDC in fasted rats. Fasting also resulted in an increased concentration of covalently bound [¹⁴C]VDC metabolites in the livers of rats given 50 mg/kg of [¹⁴C]VDC. Urinary radioactivity was separated by high-pressure liquid chromatography into four major metabolites. Two of the four urinary metabolites were identified as S-(2-hydroxyethyl)-N-acetylcysteine and thiodiglycolic acid by gas chromatography-mass spectrometry, indicating that a major pathway for detoxification of VDC is via conjugation with glutathione (GSH). The fate of VDC following oral administration to rats is depedent upon both the dose administered and the nutritional status of the animal. The diminished ability of fasted animals to metabolize the high dose of VDC correlates well with the previously observed enhancement of VDC-induced hepatotoxicity in fasted animals. Both the hepatotoxic response to VDC and the extent of its detoxification appear to be dependent on the concentration of GSH in the liver. When hepatic GSH is depleted (i.e., in fasted animals or at higher doses of VDC) a toxic response to VDC is elicited.