Impaired intestinal calcium transport in the spontaneously hypertensive rat.
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Biomedical subjects
Publications and source records attributed to B Lacour.
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Serum lipoprotein disturbances were studied in 86 patients with primary (I), and 34 hemodialysis patients with severe secondary (II), hyperparathyroidism (HPTH) before and seven to 14 days after parathyroidectomy (PTx). In addition, a subset of patients had repeat studies more than 12 months after PTx. In patients with I as well as with II HPTH, mean +/- SEM fasting serum concentrations of total triglycerides (TG) (1.51 +/- 0.09 and 2.17 +/- 0.19 mmol/L, respectively) were significantly increased when compared with that of 22 age- and sex-matched healthy control subjects (1.01 +/- 0.09 mmol/L, P less than .001). No consistent anomalies of serum total cholesterol and lipoprotein cholesterol content were observed in Io HPTH patients. In uremic II HPTH patients, the cholesterol content of high-density lipoprotein (HDL) was significantly (P less than .01) depressed, compared with normal subjects. In the short term, PTx normalized serum total TGs (P less than .001) in Io HPTH patients from 1.50 +/- 0.11 to 1.19 +/- 0.07 mmol/L seven days after PTx. The surgical correction of II HPTH in dialysis patients was also followed by an improvement of hypertriglyceridemia from 2.22 +/- 0.21 to 1.46 +/- 0.08 mmol/L and 1.46 +/- 0.09 mmol/L seven and 14 days, respectively, after PTx (P less than .01). Long-term follow-up after PTx shows clearly a persistent decrease in serum TG concentration in I HPTH patients (1.17 +/- 0.11 mmol/L), as well as in II HPTH patients (1.61 +/- 0.18 mmol/L), 12 months after PTx by comparison with values determined before PTx.(ABSTRACT TRUNCATED AT 250 WORDS)
The renal effects of carbohydrates (CHO) were studied in two experiments. 1) The effects of CHO-energy restriction was evaluated by comparing uremic growing rats (initial weight: 80 g) fed "ad lib" (L rats) or CHO-restricted (starch and glucose) but receiving identical amounts of all other nutrients (R rats). R rats showed reduced growth, slower increase in plasma creatinine, lower mortality rate, and less histological renal damage than L rats. 2) Two types of CHO restriction, low glucose (R1 rats) or low starch (R2 rats) were compared to "ad lib" feeding (L1 rats) in adult rats (initial weight: 130 g). Growth was identically reduced in R1 and R2 rats. Mean plasma creatinine levels at week four was lower in R1 than in L1 rats. The overall rate mortality was higher for L1 and R2 than in R1 rats (79%, 81%, 53%) but included deaths from other causes than renal failure. Actuarial survival excluding these deaths was 27%, 83% and 10% in L1, R1 and R2 rats, respectively. Diffuse renal lesions were found in 25 of 30 L1, 5 of 15 R1, and 12 of 15 R2 rats (R1 vs. R1 and R2, P less than 0.01). The results show that CHO restriction may preserve the renal parenchyma, and suggest that restriction of "simple" rather than "complex" CHO restriction may be beneficial, a finding which could be of clinical importance if confirmed by further investigations.
Parathyroid hormone (PTH) has been shown to modify Ca2+ and Na+ transport in several epithelia. The molecular mechanisms of these effects are poorly understood. We investigated here whether PTH may modify Na+ and K+ transport across the human red blood cell membrane in vitro and ex vivo. Fourteen patients with severe primary or secondary hyperparathyroidism and hypercalcemia were studied before and 5-7 days after surgical parathyroidectomy. Erythrocyte ouabain-sensitive as well as furosemide-sensitive Na+ efflux rates of the patients were comparable to that of healthy volunteers and remained unchanged after parathyroidectomy. Moreover, erythrocyte Na+ fluxes of control subjects remained unchanged when red blood cells were incubated in the presence of 1.0 IU/ml of bovine PTH (1-85). However, erythrocytes from hyperparathyroid patients showed a significant increase in passive K+ permeability when compared to that of healthy controls (p less than 0.05). This abnormality could be corrected in vivo after parathyroidectomy and in vitro using quinine, respectively. It is concluded that hyperparathyroidism induces a moderate increase in Ca2+ dependent K+ permeability of erythrocytes ("Gardos effect") which is reversible after parathyroidectomy.
The effects of a high salt diet (8% NaCl) on blood pressure and intra-erythrocytic Na+ content were studied in Wistar rats. The ability of the plasma to inhibit the renal Na+,K+-ATPase activity and to cross-react with digoxin antibodies was also investigated. After 1 week, neither systolic blood pressure nor intra-erythrocytic Na+ content were modified, but plasma extracts slightly inhibited renal Na+,K+-ATPase (70.9 +/- 1.7 versus 76.3 +/- 2.1 mumol Pi/mg per h, P = 0.05). After 2 weeks, the plasma inhibitory activity, systolic blood pressure and intra-erythrocytic Na+ content were higher than corresponding values in control animals (65.5 +/- 1.6 versus 79.1 +/- 2.8 mol Pi/mg per h, P less than 0.001; 132 +/- 2 versus 114 +/- 4 mmHg, P less than 0.001, and 4.95 +/- 0.32 versus 3.81 +/- 0.36 mmol/l cells, P less than 0.05, respectively). After 3 months, the plasma digoxin-like immunoreactivity and its ability to inhibit the Na+ pump were elevated (68.7 +/- 7.9 versus 48.2 +/- 5.4 pg/ml, P less than 0.02; 57.8 +/- 1.8 versus 72.9 +/- 1.8 mumol Pi/mg per h, P less than 0.001, respectively) whereas intra-erythrocytic Na+ content had returned to control levels. The results demonstrated that this high salt intake led to simultaneous increases in systolic blood pressure and in the activity of a digitalis-like compound present in plasma. The inhibition of Na+,K+-ATPase was correlated with systolic blood pressure and digoxin-like immunoreactivity (r = 0.569, n = 76, P less than 0.001 and r = 0.414, n = 34, P less than 0.02, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
To define the role of insulin in lipid disturbances of chronic renal failure, chronically uremic rats (U+) were supplemented by continuous insulin infusion over a 35-day experimental period and compared with control ad libitum-fed rats (C) and uremic rats without insulin (U). Uremic rats were characterized by hypoinsulinemia, an increase in both circulating very low-density lipoprotein (VLDL) and their cholesterol concentration, a normal hepatic triglyceride secretion rate (TGSR) determined with Triton WR 1339, and a low adipose tissue lipoprotein lipase (LPL) activity. Chronic insulin infusion at low rate (0.5 IU/24 h) to U+ rats normalized serum insulin (from 17.0 +/- 0.6 mU/l in U rats to 23.4 +/- 1.7 mU/l in U+ rats), serum VLDL triglycerides (from 804 +/- 65 to 410 +/- 36 mg/l), and serum VLDL cholesterol (from 43 +/- 8 to 16 +/- 3 mg/l). Hepatic TGSR decreased significantly after insulin treatment (from 0.58 +/- 0.03 to 0.44 +/- 0.03 mumol/min). Moreover, adipose tissue LPL was restored to normal by insulin supplementation (from 460 +/- 60 to 860 +/- 150 mU per total epididymal fat in U and U+ rats, respectively). Correction of the disturbed VLDL metabolism was associated with multiple actions of insulin including 1) a decrease of peripheral lipolysis, 2) a decrease of hepatic TGSR, and 3) an increase of adipose tissue LPL activity. Because cholesterol-rich VLDL are potentially atherogenic, their normalization with insulin treatment in this animal model suggests a viable area of investigation for the prevention of accelerated atherogenesis in chronic renal failure.
The influence of chronic renal failure on pituitary content and on serum concentrations of growth hormone (GH), prolactin (PRL), and luteinizing hormone (LH) was studied in chronically uremic rats by comparison with control rats fed ad libitum and diet-restricted rats pair-fed with uremic rats. A decrease of pituitary GH content was found in uremic and diet-restricted rats, in association with a normal circulating GH level. A decrease of pituitary PRL and LH content with respectively high and normal serum values was observed in uremic but not in diet-restricted rats. These data strongly suggest that GH disturbances are related to malnutrition, whereas PRL and LH abnormalities are related to the uremic state per se. As hypoinsulinemia was observed in uremic rats, and as insulin is largely implicated in growth, we have investigated the effects of chronic infusion of insulin, using miniosmotic pumps, on pituitary hormone content. In spite of normalization of circulating insulin levels in uremic rats treated with insulin, pituitary GH, LH, and PRL contents were unaffected. Thus, insulin deficiency did not appear to be responsible for the diminished pituitary reserve of these hormones.
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Abnormalities of intestinal calcium absorption and the vitamin D axis in the spontaneously hypertensive rat (SHR) are controversial. The present report documents a reduction in circulating 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in the 12-14-wk-old male SHR with evidence of its functional significance. Both plasma 1,25(OH)2D3 and mucosa-to-serosa duodenal calcium flux (Jm-s), measured by the Ussing chamber, were significantly lower (approximately 60% of value in Wistar-Kyoto rats [WKY]) in SHR on both normal (1%) and low (0.1%) calcium diets than in corresponding control WKY. Low dietary calcium increased both 1,25(OH)2D3 and Jm-s by approximately 80% in SHR and WKY, with levels of both parameters rising in the SHR to levels found in the WKY under baseline conditions. The latter fact suggests the improbability of intestinal resistance to the action of 1,25(OH)2D3 in the SHR. Plasma 25-hydroxyvitamin D3 (25(OH)D3) was not significantly different between the strains. Intraperitoneal 1,25(OH)2D3 increased Jm-s in 12-14-wk-old SHR to levels observed in equivalent WKY. In 20-24-wk-old SHR, calcium deprivation was associated with significantly reduced Jm-s compared with equivalent WKY. Bone density and bone calcium content in 20-30-wk-old SHR were significantly reduced. In summary, we provide evidence that the SHR was unable to sustain appropriate circulating levels of 1,25(OH)2D3, an impairment which resulted in reduced duodenal calcium absorption.
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In the present work we studied rapid in vitro effects of calcitriol (1,25(OH)2 vitamin D3) on the intestinal transport of inorganic phosphate (Pi). Enterocytes from vitamin D replete (D+) as well as vitamin D depleted (D-) rats were isolated mechanically from the duodeno-jejunum. In this model, Pi uptake was a temperature and Na+-dependent phenomenon. The in vitro-addition of calcitriol (1 pM) resulted in a significant enhancement of initial Pi uptake rate by enterocytes from D+ (P less than 0.01) and D- (P less than 0.05) rats. This effect which was Na+-dependent, was observed within the time of 20 min, but not before. A similar effect on Pi uptake rates of D+ or D- enterocytes could be elicited by the in vitro addition of the methyl ester of cis-vaccinic acid (MCVA) which is thought to increase membrane fluidity by modifying the lipid composition of the cell membrane. The stimulatory effect of calcitriol on Pi uptake rate was blunted in the presence of the methyl ester of transvaccinic acid (MTVA) thought to decrease membrane fluidity. Enterocyte Pi efflux rate constant (oKPi) remained unchanged in the presence of calcitriol (1 pM). In conclusion, the study demonstrates a rapid in vitro effect of calcitriol on Pi uptake by isolated enterocytes from D+ and D- rats. It suggests, but does not prove, that the hormone may act via an action independent of genomic nuclear activation.
Vitamin K promotes the formation of gamma-carboxylated glutamate (GLA) in several protein species. GLA residues have a high affinity for the Ca ion. In the present study, we tested the hypothesis that experimental vitamin K deficiency in rats could induce changes in Ca metabolism. Vitamin K depletion, which was associated with a reduction in urinary GLA excretion, induced within 7 days a significant increase in cumulative urinary Ca excretion that persisted throughout the 21 days of study. The hypercalciuria of vitamin K-deficient rats was corrected on vitamin K supplementation. No concomitant changes were observed in intestinal Ca absorption determined by a balance technic or of skeletal resorption and apposition rates determined by bone histomorphometry. Plasma Ca, but not total protein concentration, of vitamin k-depleted rats showed a transient decrease at day 15 that disappeared at day 21. plasma sodium, phosphate and 1,25(OH)2 vitamin D concentration, and urinary phosphate, sodium, and creatinine excretion remained unchanged. In conclusion, vitamin k deficiency in the rat induced hypercalciuria that could be of renal origin. Its possible relationship to vitamin K-dependent renal GLA protein remains to be clarified.
The possible mechanisms of the increase in serum triglycerides (TG) and TG-rich lipoproteins were studied in chronically uremic (U) rats by comparison with either ad-lib fed control (C) rats or diet-restricted (DR), sham-operated pair-fed control rats. A first series of animals was studied in the fed state and a second series after a 16-hr fast. In U animals the concentration of serum TG and TG-rich particles was lower than that of C rats in the fed state but significantly higher than that of C and DR rats after a 16-hr fast. Serum glucose and lactate concentrations in the fed or fasted state were unchanged by uremia. Serum insulin concentration was significantly decreased in U rats as compared to C and DR rats in both series. The fast did not increase the concentration of serum nonesterified fatty acids (NEFA) in U or DR animals to the same extent as in C rats, whereas the serum concentration of beta-hydroxybutyrate (BOB), which was higher than that of C rats in the fed state, was significantly lower after a 16-hr fast. In U animals, as compared to control rats of either series, a significant decrease of epididymal lipoprotein lipase (LPL) activity was observed during both nutritional states when expressing the enzymic activity per number of cells. In conclusion, our data provide evidence against hepatic over-production of TG-rich lipoproteins in rats with chronic renal failure and strongly point to an LPL-mediated defect of their peripheral catabolism, probably related to the insulin deficiency state.
The present studies were designed to explore the possibility that, in addition to its well-known steroidlike action, 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the active vitamin D3 metabolite, modulates inorganic phosphate (Pi) transport across the intestinal mucosa through more rapid membrane effects. Enterocytes were mechanically isolated from the duodenojejunum of vitamin D-replete rats. In this model enterocyte Pi uptake was a temperature-dependent as well as a Na+-dependent process. In vitro addition of 1,25(OH)2D3 (1 pM) led to a significant increase in Na+-dependent initial Pi uptake velocity (iVpi) within 20 min (P less than 0.001). No effect was seen for shorter incubation times (5 and 15 min). Incubation of the cells with cycloheximide did not inhibit the hormone-mediated increase of iVpi. 25-Hydroxyvitamin D3 significantly increased iVPi (P less than 0.05) at a concentration of 1 nM but not 1 pM. Vitamin D3 at a concentration of 1 microM had no effect on iVPi. Enterocyte Pi efflux rate constant was not modified by the presence of 1,25(OH)2D3(1pM). Thus, the early in vitro effect of 1,25(OH)2D3 on Pi uptake by isolated enterocytes suggests a nongenomic action of the hormone, possibly by modifying the lipid structure of the plasma membrane.
In the present review, the role of lipid disturbances is evaluated as a risk factor in the pathogenesis and the potential acceleration of atherosclerosis in uremic patients undergoing long-term hemodialysis. The alteration in high density lipoprotein composition with a decrease in high density lipoprotein cholesterol but a normal apoprotein AI content may have relevance to the atherogenetic process. Moreover, the accumulation of cholesterol-rich, very low density lipoproteins and intermediate density lipoproteins may play a major role in atherosclerosis since these degradation products of triglyceride-rich particles are considered as atherogenic. The hypothesis should be tested whether a correction of the abnormal catabolism of triglyceride-rich lipoproteins in uremic patients leads to a decrease in ischemic vascular events.
In the present study, the role of factors was investigated that could possibly lead to changes in plasma and tissue aluminum (A1) concentrations following oral A1 exposure. In chronically uremic rats that received an oral A1 supplementation of 150 mumol/g diet during 4 weeks, a significant increase in mean (+/- SEM) liver A1 content was observed when compared to sham-operated, pair-fed control rats (9.9 +/- 2.0 versus 4.8 +/- 0.65 nmol/g wet weight, p less than 0.02). No such difference was found in non-A1-supplemented rats. Plasma A1 and the A1 content of other organs studied except muscle were not increased in uremic as compared to control animals. In rats with hyperparathyroidism secondary to a calcium-poor diet, mean liver and bone A1 content was significantly decreased when not A1-exposed (2.5 +/- 0.13 and 62 +/- 5.5 nmol/g, respectively) and normal when A1-supplemented (4.7 +/- 0.59 and 120 +/- 23 nmol/g, respectively) as compared to normal control rats without A1 supplementation (5.1 +/- 1.5 and 170 +/- 17 nmol/g, respectively). However, in the hyperparathyroid rats, mean plasma A1 concentration was higher than in control, euparathyroid rats. In rats with exogenous hyperparathyroidism (parathyroid extract) a significant increase in liver A1 content was observed when compared to control rats (8.1 +/- 0.95 versus 5.3 +/- 0.53 nmol/g, p less than 0.05). In A1-supplemented normal rats treated with 1,25(OH)2 vitamin D3 during 4 weeks, liver A1 content was significantly lower than in control rats receiving vehicle solution only (2.9 +/- 0.76 versus 5.7 +/- 0.59 nmol/g, p less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)