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Biomedical subjects

S Klahr

Publications and source records attributed to S Klahr.

At least 163 records · Page 9Linked to original sources
PubMed1987

Role of hypertension and coagulation in the progressive glomerulopathy of rats with subtotal renal ablation.

Administration of heparin to rats with 1 3/4 nephrectomy prevents the development of glomerulosclerosis, hypertension and retards the decrease in renal function seen in these rats. To further define the role of hypertension and/or coagulation in the pathogenesis of the glomerulopathy seen in this model we studied several groups of rats with 1 3/4 nephrectomy: (1) a control group; (2) a group receiving a 'high dose' of acetylsalicylic acid (50 mg/kg) plus dipyridamole (10 mg/kg); (3) a group receiving a 'low' dose (5 mg/kg body weight) of acetylsalicylic acid alone; (4) a group receiving OKY 1581, an inhibitor of thromboxane synthesis; (5) a group treated with antihypertensive medications; (6) a group receiving heparin subcutaneously twice daily, and (7) a group given oral Coumadin. Drugs in all groups were administered daily for 4 weeks. All treated groups had a decrease in blood pressure (BP), in the ratio of heart weight to body weight, in BUN levels and had fewer abnormal glomeruli. The effects of acetylsalicylic acid alone, of acetylsalicylic acid plus dipyridamole, and OKY 1581 may be due to inhibition of platelet aggregation and intraglomerular thrombosis, with the fall in BP being the consequence of improved renal function. On the other hand, the decrease in BP may be related to a primary effect of these drugs. The lower BP in turn may play a role in slowing the progression of renal disease and improving the renal histology in the treated groups.

Animals↗
PubMed1986

Toxicity of parathyroid hormone in uremia.

The most significant complication of elevated parathyroid hormone (PTH) levels in uremia is the development of osteitis fibrosa cystica. The hormone also appears to play a role in soft-tissue and organ calcification, metabolic abnormalities (glucose, lipids), and electroencephalographic changes seen in uremic patients. Its role in the hematological abnormalities of uremia (anemia, bleeding) is controversial. A role for PTH in heart and skeletal muscle dysfunction in uremia has not been clearly established. Further studies are required to establish PTH as a "universal" toxin in uremia.

Anemia↗
PubMed1986

Glucose metabolism in epitrochlearis muscle of acutely exercised and trained rats.

Effects of insulin on glycogen synthesis (GS), glycolytic utilization (GU), and glucose uptake (GT) were studied in isolated epitrochlearis muscles from exercise-trained or sedentary rats during recovery from acute exercise or at rest. During the 1st h after acute exercise, the enhanced basal and insulin-stimulated GT was directed mainly toward replenishment of glycogen but basal GU was also increased. During the second through third hours after exercise, basal GS decreased but remained greater than rest and basal GU and GT returned to normal. Insulin sensitivity of these parameters was enhanced. Training alone reduced basal GS but enhanced insulin sensitivity of GT and GU. Training reduced the acute exercise-stimulated increase in basal and insulin sensitivity of GS during recovery from acute exercise, probably due to elevated glycogen stores. Thus recovery from acute exercise or training, either alone or in combination, enhances insulin stimulated GT in muscle; however, the increased glucose is primarily channeled toward GS after acute exercise, which is reduced by prior training and is directed to GU in trained animals either at rest or after acute exercise.

Animals↗
PubMed1986

Ureteral occlusion decreases phospholipid and cholesterol of renal tubular membranes.

Unilateral ureteral obstruction of 24 h duration in the dog results in a 20% decrease in the amount of total phospholipids present in basolateral membranes of renal tubular cells obtained from the experimental kidney as compared with the amount of phospholipid in basolateral membranes prepared from the contralateral kidney of the same dogs or from the kidneys of normal sham-operated dogs. There was also a decrease in the content of cholesterol and cholesterol esters of the basolateral membranes from the experimental kidney. By contrast, no significant change in lipid content was observed in brush border membranes obtained from the experimental kidney of dogs with unilateral ureteral obstruction. The decrease in phospholipid content of basolateral membranes was accompanied by a 40% fall in the content of phosphatidylcholine and a 12% fall in sphingomyelin. There was a small (12%) but significant increase in the content of phosphatidylethanolamine in basolateral membranes. The mechanisms responsible for the selective decrease in phospholipid content of basolateral membranes remain to be established. It is postulated that changes in solute transport and altered response to hormones observed in the postobstructed kidney of animals with unilateral ureteral obstruction may be explained, at least in part, by changes in the lipid composition of basolateral membranes.

Animals↗
PubMed1986

Citrate transport in rabbit nephron.

Citrate is an important renal metabolic substrate and urinary inhibitor of calcium stone formation. Our purpose was to characterize citrate reabsorption in the rabbit nephron using isolated perfused tubules. Citrate reabsorption, measured by luminal disappearance of [14C]citrate, was found only in the proximal tubule, not in the cortical thick ascending limb or the cortical collecting tubule. In the proximal convoluted tubule, the collected fluid was also analyzed by thin-layer chromatography and by measurements of chemical citrate concentration using an ultramicroassay. Luminal disappearance of [14C]citrate was determined to accurately represent citrate reabsorption; no significant citrate secretion was found. The absolute magnitude of citrate reabsorption was approximately 3.4 pmol X mm-1 X min-1 using either 1 or 3 mM citrate in the perfusate. This rate of citrate reabsorption in the rabbit proximal tubule could account for all of renal citrate reabsorption but was severalfold lower than glucose reabsorption, which was studied for comparative purposes. In contrast, the magnitude of succinate transport (which probably occurs via the same transport system as citrate) was comparable with that of citrate. Citrate reabsorption was inhibited approximately 80% by 10(-5) M ouabain. This characterization of citrate transport in the intact proximal tubule should provide a useful model to study regulation of urinary citrate excretion.

Absorption↗
PubMed1986

Thromboxane synthesis and blood pressure in spontaneously hypertensive rats.

The present study examines effects of administration of OKY 046, an inhibitor of thromboxane synthesis, for 100 days on systemic blood pressure and renal function in spontaneously hypertensive rats and in normotensive control rats. Untreated spontaneously hypertensive rats had higher values for thromboxane excretion in the urine and higher values for blood pressure than did normotensive control rats. Administration of OKY 046 decreased systolic and mean arterial blood pressure and urinary excretion of thromboxane and protein in spontaneously hypertensive rats. Administration of OKY 046 decreased thromboxane excretion in the urine of normotensive control rats but had no effect on blood pressure or protein excretion. Renal function, as assessed by the clearances of inulin and p-aminohippuric acid, was greater in spontaneously hypertensive rats treated with OKY 046 than in those receiving vehicle alone. In normotensive control rats, OKY 046 administration did not affect renal function. These results suggest that increased renal synthesis of thromboxane may play a role in the pathogenesis of the elevated blood pressure of spontaneously hypertensive rats.

Acrylates↗
PubMed1986

Differential biological effects of calcitonin and parathyroid hormone on isolated perfused bone.

These studies examine the release of 3',5'-cyclic adenosine monophosphate (cyclic AMP) from isolated perfused canine bones in response to synthetic bovine parathyroid hormone (syn b-PTH 1-34) and human calcitonin (hCT). Bones for perfusion were obtained from three groups of dogs: control (n = 11); thyroparathyroidectomized (n = 7), and mithramycin-treated thyroparathyroidectomized animals (n = 5). The results indicate that PTH causes a greater release of cyclic AMP from adult bones than CT; the addition of the two hormones simultaneously results in a synergistic rather than an additive effect; mithramycin inhibits the cyclic AMP response to calcitonin; and thyroparathyroidectomy decreases the cyclic AMP release in response to CT stimulation, suggesting that the cells (osteoclast-like) that respond to CT have an impaired response in the absence of PTH; acute TPTX does not affect the response of the cell populations of adult bones to PTH.

Animals↗
PubMed1985

Long-term effects of 24-hr unilateral ureteral obstruction on renal function in the rat.

To characterize the pattern of recovery following release of unilateral ureteral obstruction of 24-hr duration, rats were studied with whole kidney clearance techniques, 3 hrs, 8, 14, and 60 days after release. The single nephron glomerular filtration rate (SNGFR) of superficial and juxtamedullary nephrons was estimated with a modification of Hanssen's technique in rats studied 8 and 60 days after ureteral release. The whole kidney glomerular filtration rates (GFR) were decreased markedly 3 hrs after relief of obstruction, but gradually increased and by 14 days, the GFR of the postobstructed kidney (POK) and the contralateral kidney (CK) were comparable. This recovery of GFR was not a consequence of a homogeneous improvement in SNGFR. At 8 days, more than 15% of superficial and juxtamedullary nephrons were not filtering in the POK. This decrease in the percent of filtering nephrons persisted to 60 days post release, indicating a permanent loss of nephron units. The SNGFR of the residual nephrons of the POK was significantly greater than that of the CK at 8 and 60 days following ureteral release. Thus, acute unilateral ureteral obstruction results in a permanent loss of filtering nephrons, which is offset by hyperfiltration of those remaining. Abnormalities in renal tubule function persisted beyond the time (14 days) when whole kidney GFR had returned to normal. These abnormalities were in distal tubule function. Urine osmolality was consistently lower at all time intervals post release, as was net acid excretion. The results of the present study suggest that these abnormalities are a consequence of the reduction in the number of filtering juxtamedullary nephrons and/or to abnormalities in collecting duct function.

Animals↗
PubMed1985

Inhibition of thromboxane synthesis ameliorates the progressive kidney disease of rats with subtotal renal ablation.

Ablation of greater than 70% of renal mass in the rat results in hypertension, proteinuria, and glomerular sclerosis of the remnant kidney. Rats with a remnant kidney have increased excretion of thromboxane in the urine when compared with normal rats. Chronic oral administration of OKY 1581, an inhibitor of thromboxane synthesis, in rats with a remnant kidney increases renal blood flow and glomerular filtration rate (GFR), decreases protein and thromboxane excretion in the urine, lowers blood pressure and cardiac index, and improves renal histology. The degree of hypertrophy of the remnant kidney was unaffected by administration of OKY 1581. Calculated values for single nephron plasma flow and GFR were significantly greater in rats with remnant kidneys given OKY 1581 than in rats given saline. Acute i.v. administration of OKY 1581 increased renal plasma flow and GFR in rats with a remnant kidney but not in normal rats or rats with a remnant kidney previously treated with acetylsalicyclic acid. OKY 1581 markedly inhibited platelet aggregation. We suggest that in this model of renal disease platelet aggregation and intraglomerular thrombosis play a key role in the development of glomerulosclerosis. Inhibition of platelet aggregation prevents development of glomerulosclerosis, hypertension, and cardiac hypertrophy. We suggest that hyperperfusion and hyperfiltration per se occurring in remnant glomeruli are not directly responsible for the development of glomerulosclerosis.

Acrylates↗
PubMed1985

Muscle protein turnover: effects of exercise training and renal insufficiency.

Chronic renal failure is associated with an enhanced catabolism of muscle protein. To determine the effect of exercise training and moderate renal insufficiency on net protein catabolism and protein synthesis in isolated epitrochlearis muscles, three-fourth nephrectomized and control rats were exercise trained or remained sedentary. Net muscle protein degradation was determined by measuring the rates of release of phenylalanine and tyrosine. Protein synthesis was determined by measuring the incorporation of [U-14C]phenylalanine into muscle protein. Exercise training reduced the elevated protein degradation of uremia to control levels. In control rats, exercise training had no effect on protein degradation. Exercise training increased alanine release in control rats but did not further increase the elevated alanine release of uremia. Protein synthesis was unaffected by both uremia and exercise training. Exercise training in control and uremic rats moderately increased the responsiveness of muscle to insulin by reducing net protein degradation but did not further enhance the insulin-stimulated increase in protein synthesis. Thus exercise training ameliorates the enhanced muscle protein degradation of moderate renal insufficiency.

Alanine↗
PubMed1985

NH4Cl inhibition of transport in the rabbit cortical collecting tubule.

Ammonium has previously been found to inhibit transport in a number of tissues. The present experiments were designed to evaluate the effect of ammonium chloride on transepithelial voltage (VTE) and cation transport in the isolated rabbit cortical collecting tubule perfused in vitro. Peritubular NH4Cl (2-10 mM) inhibited VTE in these tubules independent of bath or lumen pH. Luminal NH4Cl had a similar effect. However, VTE did not change with bath NH4Cl in tubules treated with amiloride or ouabain. Furthermore, when bath PCO2 was lowered simultaneously with the addition of NH4Cl to the bath, little change in VTE occurred, raising the possibility that intracellular pH falls after addition of NH4Cl to the bath. Consistent with the voltage effects, 5 mM NH4Cl in the bathing solution inhibited net sodium reabsorption by 36% and potassium secretion by 44%. Unidirectional lumen-to-bath tracer fluxes were consistent with predominant inhibition of the sodium reabsorptive flux and the potassium secretory flux. These findings may have relevance to metabolic acidosis in vivo because ionic ammonium concentrations attain the levels used in this study.

Acid-Base Equilibrium↗
PubMed1985

Dietary protein intake conditions the degree of renal vasoconstriction in acute renal failure caused by ureteral obstruction.

Whole kidney inulin (CIn) and PAH (CPAH) clearances were measured after unilateral release of bilateral ureteral obstruction (BUO) of 24-h duration in rats fed for 4 wk isocaloric diets containing either 40% casein (high protein diet) or 6% casein (low protein diet). Values for CIn and CPAH were markedly depressed in both groups but to a greater extent in high protein-fed rats, averaging less than 60% of values measured in low protein-fed animals. Captopril, an inhibitor of the angiotensin I converting enzyme, increased CIn and CPAH markedly but comparably in high or low protein fed rats. Micropuncture studies performed after unilateral release of BUO in another group of rats fed a high or a low protein diet revealed lower levels of glomerular plasma flow rate (QA) and single nephron glomerular filtration rate (SNGFR) in rats fed a high protein diet. Values for renal arteriolar resistances were nearly twofold in high as compared with low protein-fed animals. Infusion of OKY-1581, an inhibitor of thromboxane A2 synthetase, increased both QA and SNGFR, decreased arteriolar resistances, and increased glomerular capillary ultrafiltration coefficient in high but not in low protein-fed rats. Urinary thromboxane B2 excretion per milliliter of GFR was greater in rats fed a high protein diet than in those fed a low protein diet after release of BUO but not in normal rats. In normal rats infusion of OKY-1581 did not increase CIn or CPAH.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Kidney Injury↗
PubMed1985

Hydraulic water permeability and transepithelial voltage in the isolated perfused rabbit cortical collecting tubule following acute unilateral ureteral obstruction.

Ureteral obstruction affects the kidney's ability to conserve water and sodium. Using the isolated perfused tubule technique, we studied cortical collecting tubules (CCT) taken from rabbits subjected to a sham operation or to 4 h of unilateral ureteral obstruction (UUO). Tubules were perfused in the presence of an osmotic gradient directed to promote water movement from lumen to bath, and volume flux (Jv), hydraulic water permeability (Lp), and transepithelial voltage (V1) were determined. In tubules from sham-operated and UUO animals, basal (before exposure to vasopressin) J, and Lp were not different from zero. After addition of 200 microU . ml-1 of arginine vasopressin (aVP) to the bath, Jv and Lp increased to 1.64 +/- 0.23 nl . mm-1 . min-1 and 127.9 +/- 19.8 cm . s-1 . atm-1 x 10(7), respectively, in tubules from sham-operated animals, but not only 0.27 +/- 0.09 nl . mm-1 . min-1 an 18.8 +/- 6.2 cm . s-1 . atm-1 . 10(7) in tubules from UUO animals. Pretreatment with desoxycorticosterone acetate (DOCA) or indomethacin in vivo did not prevent the blunted vasopressin response seen in tubules taken from UUO animals. The Jv and Lp responses to the cyclic AMP (cAMP) analogue, 8-Br-cAMP, were also diminished in tubules taken from UUO animals compared with shams. V1, measured during the basal period, was diminished in tubules from UUO kidneys (-5.0 +/- 2.1 mV) compared with shams (-21.9 +/- 4.1 mV), and pretreatment with DOCA did no prevent the effects of UUO on V1. In contrast, tubules taken from animals that received indomethacin prior to UUO developed voltages not different from voltages in tubules taken from sham-operated animals (-17.3 +/- 1.7 mV). We conclude that, although CCT from UUO animals can maintain osmotic gradients, their ability to respond to vasopressin by increasing Lp is impaired by an intrinsic defect located at a step beyond the generation of cAMP, and that prostaglandin inhibition or DOCA pretreatment do not reverse the decreased responsiveness of Lp to aVP. UUO also diminished V1, and this abnormality was prevented by previous treatment with indomethacin, suggesting that prostaglandins may mediate the effect of UUO on V1.

Adrenal Cortex Hormones↗
PubMed1985

Impaired parathyroid hormone receptor-adenylate cyclase system in the postobstructed canine kidney.

The present studies examine the initial events in the action of PTH, namely receptor binding and adenylate cyclase activation in the postobstructed canine kidney. Both kidneys were removed from five mongrel dogs 2 h after relief of unilateral ureteral obstruction (UUO) of 42 h duration. Basolateral membranes (BLM) were prepared from both the UUO and contralateral (control) kidneys. Maximal activation of adenylate cyclase by PTH was 35% lower (P less than 0.01) in BLM from UUO than control kidneys (3869 +/- 200 vs. 5978 +/- 425 pmol cAMP/mg protein X 30 min). The concentration of PTH required for half-maximal activation of the enzyme was unchanged. Addition of 1 mM GTP failed to correct the decreased enzyme activity in response to PTH of BLM from kidneys with UUO. NaF activation, a measure of interaction of the nucleotide regulatory component (G/F) with the catalytic unit of the adenylate cyclase was similar in BLM from UUO and control kidneys. Similarly, activation of the catalytic unit of the enzyme by Mn2+ was not different. Specific binding of [125I]Nle8, Nle8, Tyr34-bovine PTH NH2 was markedly reduced (P less than 0.01) in BLM from UUO vs. control (6.37 +/- 1.20 vs. 2.43 +/- 0.09 fmole bound/microgram protein). There was no change in hormone affinity for the binding site. These data indicate that there is decreased activation of adenylate cyclase by PTH as a consequence of apparent loss of receptors for the hormone in the BLMs of renal tubular cells of postobstructed kidneys. These abnormalities may play a role in the abnormal regulation of phosphorus excretion after ureteral obstruction.

Adenylyl Cyclases↗
PubMed1984

Effect of 24,25(OH)2D3 on PTH levels and bone histology in dogs with chronic uremia.

Controversy exists as to whether 24,25(OH)2D3 has a direct inhibitory effect on parathyroid hormone (PTH) secretion. Therefore, the present investigation examined the effect of long-term administration of 24,25(OH)2D3 on immunoassayable PTH levels (iPTH) and bone histology in dogs with chronic renal failure. Chronic renal failure was produced in 16 dogs, half of which served as controls whereas the other half received 2.5 micrograms/day of 24,25(OH)2D3, orally. Serum iPTH, serum total, ionized calcium, serum phosphorus, and creatinine were followed at weekly or biweekly intervals in both groups. Also, creatinine clearances, serum levels of 25(OH)D3, 24,25(OH)2D3, and 1,25(OD)2D3 and the intestinal absorption of calcium were measured. After 1 year of chronic renal failure the dogs were sacrificed and rib biopsy specimens were obtained for histological examination and measurement of mineral content. Serum iPTH increased equally in the two dog groups with no effect at any time of 24,25(OH)2D3 treatment, despite a significant increase in the serum levels of 24,25(OH)2D3 and a concomitant decrease of the 1,25(OH)2D3 levels. There was no difference in the levels of serum calcium or in the calcium content of bone. Furthermore, after 8 months of uremia three control dogs were switched to the group treated with 24,25(OH)2D3 and followed for another 7 months. No suppressive effect of administering 24,25(OH)2D3 on the iPTH levels could be demonstrated in these three dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

24,25-Dihydroxyvitamin D 3↗
PubMed1984

Glutamine transport in renal basolateral vesicles from dogs with metabolic acidosis.

To determine whether the increased ammonia production per nephron in chronic metabolic acidosis is accompanied by augmented L-glutamine transport across the basolateral membrane of the renal cortical cell and consequent increased availability of this ammoniagenic amino acid, we measured L-[3H]glutamine transport in basolateral membrane vesicles (BLMV) isolated from kidneys of normal and acidotic dogs. Na+ -dependent electrogenic transport of L-[3H]glutamine was demonstrated in BLMV from kidneys of normal dogs that exhibited saturability over the concentration range of 25 microM to 2 mM L-glutamine. The apparent Km was 416 +/- 114 microM and Vmax was 536 +/- 129 pmol X mg protein-1 X 15 s-1. The initial rate of Na+ -dependent L-[3H]glutamine transport was increased in BLMV from kidneys of acidotic dogs, as reflected by an increased apparent Vmax. We conclude that an adaptation resulting in greater uptake of L-glutamine across the basolateral membrane of the renal cortical cell may underlie, in part, the increased rate of ammonia production per nephron seen in chronic metabolic acidosis.

Acidosis↗