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Biomedical subjects

J B Puschett

Publications and source records attributed to J B Puschett.

At least 37 records · Page 2Linked to original sources
PubMed1989

Modifications in proximal tubular function induced by nitrendipine in a rat model of acute ischemic renal failure.

Calcium channel blockers have been reported to preserve renal function when given prophylactically in animal models of acute renal failure (ARF), but the mechanism by which this effect occurs is unknown. We report that nitrendipine (NTR) ameliorates the decline in endogenous creatinine clearance when administered before to clamp-induced ischemia in rats (NTR + clamp, 0.21 +/- 0.06 ml/min; clamp alone, 0.13 +/- 0.04 ml/min, p less than 0.05). To determine whether this protective effect involves the proximal tubule, we compared the uptake of phosphate by brush border membrane (BBM) vesicles in NTR-pretreated ARF rats and in ARF rats pretreated with vehicle alone. A comparison of vehicle-pretreated/sham-operated and vehicle-pretreated/ARF rats served as a control. The initial uphill phase of Na+ gradient-dependent phosphate transport was significantly greater in NTR/ARF rats as compared with vehicle/ARF rats. Pretreatment with NTR did not affect BBM transport of D-glucose or proline. We conclude that NTR has a modest protective effect on overall renal function, and that preservation of proximal tubular function is probably part of this effect.

Acute Kidney Injury↗
PubMed1989

Elevated bone aluminum and suppressed parathyroid hormone levels in hypercalcemic dialysis patients.

We studied 21 dialysis patients who became hypercalcemic without vitamin D or calcium therapy and compared them to 28 dialysis patients who were not hypercalcemic. In the hypercalcemic group, the mean ionized-calcium level was elevated compared to normal subjects (5.4 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001), while the ionized-calcium level in the control dialysis patients was below normal (4.5 +/- 0.4 vs. 4.9 +/- 0.1; p less than 0.001). Bone biopsies were performed in all patients. Two thirds of the hypercalcemic patients had low-turnover osteodystrophy (LTO, predominantly osteomalacia), a fraction significantly higher than in the control dialysis patients (13/21 vs. 8/28, respectively; p less than 0.05). The hypercalcemic patients with LTO had markedly elevated surface bone aluminum (63 +/- 24% of all trabecular surfaces). In contrast, the nonhypercalcemic dialysis patients with LTO and all patients with osteitis fibrosa had minimal surface bone aluminum. Hypercalcemic patients with osteitis fibrosa had a significantly lower mean N-terminal parathyroid hormone (PTH) value than did nonhypercalcemic patients with osteitis fibrosa (149 +/- 81 vs. 278 +/- 135 pg/ml, respectively; p less than 0.005). Both mean values were markedly elevated in comparison with those obtained in normal subjects (16 +/- 5 pg/ml). In contrast, patients with LTO, irrespective of the calcium level, had mean PTH values that were not significantly different from those of normal subjects. A PTH level greater than 100 pg/ml was 95% sensitive and 87% specific for osteitis fibrosa, as demonstrated by histomorphometry in nonhypercalcemic dialysis patients. However, this level was only 62% sensitive and 77% specific for a diagnosis of osteitis fibrosa in hypercalcemic dialysis patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1989

Effects of selective oxidation of 1-34 bovine parathyroid hormone on its renal actions in the rabbit.

Oxidation of both of the methionine residues (positions 8 and 18) in parathyroid hormone (PTH) eliminates many of its biological effects. The present studies were performed to examine the actions of 1,34 bovine PTH and 1-34 bovine PTH oxidized selectively at Met 8, at Met 18, and at both sites on renal electrolyte handling and on adenylate cyclase (AC) stimulation. In clearance studies in anesthetized rabbits, PTH caused a phosphaturia and an anticalciuria. PTH also stimulated renal proximal tubular AC in vitro and increased renal cortical cAMP content in vivo. PTH oxidized at Met 18 was anticalciuric, but not phosphaturic, stimulated renal AC and increased cortical cAMP content. PTH oxidized at Met 8 also produced an anticalciuria without a phosphaturia, but only weakly stimulated AC and did not alter cortical cAMP content. PTH oxidized at both Met 8 and Met 18 was phosphaturic but not anticalciuric, was a weak agonist for AC and decreased cortical cAMP content. In the isolated perfused rabbit proximal straight tubule, PTH inhibited fluid and phosphate transport, whereas the doubly oxidized peptide was inactive. The data are consistent with the possibility that the effects of PTH on renal tubular phosphorus transport are mediated by more than one mechanism and are, in part, independent of the cAMP messenger system.

Adenylyl Cyclases↗
PubMed1988

An examination of the site and mechanism of action of torasemide in man.

Acute clearance studies were performed in normal subjects to determine the site and mechanism of action of torasemide (isopropyl-1-methyl-3 phenylamino-4 pyridil-3 sulphonyl-3-urea), a new diuretic agent, in the human kidney. The drug caused no change in glomerular filtration rate or effective renal plasma flow. Sodium excretion rose to 16% of filtered load, whereas there was a chloriuresis of 23%. During maximal water diuresis, the drug caused an increase in urine flow rate and a decrease in solute-free water clearance. Administration of the drug during hypertonic saline infusion into hydropenic subjects resulted in a marked decrease in water reabsorption from the collecting duct. Torasemide caused no change in phosphate excretion or in the percentage of filtered bicarbonate excreted, nor was urinary pH or net hydrogen ion excretion affected by the drug. The data suggest that the primary site of action of torasemide is the medullary portion of the ascending limb of the loop of Henle.

Acid-Base Equilibrium↗
PubMed1988

Chronic effects of nitrendipine on renal hemodynamics and tubular transport.

The effects of nitrendipine (10 mg, during acute clearance experiments) given both acutely and after 2 weeks of administration were examined in normal and hypertensive subjects. At the initiation of therapy, nitrendipine caused an increase in glomerular filtration rate and effective renal plasma flow in the hypertensive, but not in the normal, group. Percentage excretion rates of sodium (%ENa) and phosphate (%EPi) and free water clearance (CW) increased in both groups at the initiation of therapy. After 2 weeks of nitrendipine therapy repeat acute clearance studies showed that the drug no longer increased glomerular filtration rate or effective renal plasma flow in hypertensive subjects, the increases in %ENa and CW persisted in normal subjects and trended upward in hypertensive subjects, and the increase in %EPi persisted in both normal and hypertensive individuals. We conclude that nitrendipine is not sodium retentive after chronic therapy and the acute increase in %ENa, %EPi, and CW after its initial administration suggests a proximal tubular effect.

Adult↗
PubMed1988

Prostaglandin E2 is an inhibitor of adenylate cyclase in rabbit proximal tubule.

Prostaglandin E1 and E2 (PGE) antagonize the phosphaturic effect of parathyroid hormone (PTH), but do not alter the phosphaturia evoked by adenosine 3',5'-cyclic monophosphate (cAMP) analogues. These findings support the idea that PGE interfere with activation of adenylate cyclase in the renal proximal tubule. We tested this hypothesis in the rabbit renal proximal straight tubule (PST). In the PST, adenylate cyclase was activated by PTH (Km = 10(-9) M PTH), but not by PGE2, which attenuated the activation of adenylate cyclase by PTH. The inhibition by PGE2 of PTH action was prevented by pertussis toxin, which deactivates the regulatory aggregate, Ni. In the PST, PGE2 also attenuated the activation of adenylate cyclase by cholera toxin. The inhibitory effect of PGE2 was selective; PGE2 did not inhibit activation of adenylate cyclase in glomeruli, but it inhibited the enzyme in proximal convoluted tubules (PCT) and PST. We conclude that PGE2 inhibits adenylate cyclase in rabbit proximal tubule. We propose that this action may, in part, regulate transport function in vivo.

Adenylate Cyclase Toxin↗
PubMed1988

Variant of Bartter's syndrome with a distal tubular rather than loop of Henle defect.

A 19-year-old normotensive patient had all of the clinical features of Bartter's syndrome: hypokalemia, elevated renin and aldosterone levels and increased excretion of prostaglandin E. In contrast to the patients described by Bartter, the patient had a normal capacity to form solute-free water, suggesting intact loop of Henle function. Baseline potassium and chloride excretion rates were higher than those observed in 5 normal subjects, but the response to intravenous chlorothiazide, a drug which acts in the early distal convolute tubule, was abnormal. While chloride excretion rose by only 61% in this patient, it increased sixfold in the normal subjects. Sodium excretion quadrupled in the controls but less than doubled in this patients. Roughly equivalent increments in potassium excretion occurred in normals and controls, suggesting that the patient's distal potassium-secretory mechanism was intact. Review of the literature indicates that whether the site of the abnormal renal tubular potassium (chloride) leak is the proximal tubule, the loop of Henle or the distal convoluted tubule, patients may achieve features indistinguishable from those previously reported as characteristic for Bartter's syndrome. If loop of Henle malfunction is required to diagnose classical Bartter's syndrome, then our patient (and several reported elsewhere) has a variant form.

Adult↗
PubMed1988

Inhibitory effects of volume expansion performed in vivo on transport in the isolated rabbit proximal tubule perfused in vitro.

To examine the renal tubular sites and mechanisms involved in the effects of hypooncotic volume expansion (VE) on renal electrolyte excretion, we performed clearance and isolated tubular perfusion studies using intact and thyroparathyroidectomized (TPTX) rabbits. We also examined the effect of VE on luminal brush border transport. In the microperfusion studies, proximal convoluted (PCT) and straight (PST) tubules were taken from rabbits without prior VE or after 30 min of 6% (body wt) VE. Acute VE increased the percentage excretion of Na, Ca, and P in TPTX animals and the percentage and absolute excretions of these ions in intact rabbits. In PST from VE animals, fluid flux (Jv) was depressed compared with Jv in PST from nonVE rabbits: Jv = 0.18 +/- 0.03, (VE) vs. 0.31 +/- 0.03 nl/mm.min, (nonVE) P less than 0.02. Phosphate transport (Jp) in the PST from VE animals was also depressed: JP = 1.58 +/- 0.10 (VE) vs. 2.62 +/- 0.47 pmol/mm.min, (nonVE) P less than 0.05. Similar results were obtained with TPTX animals. In the PCT from VE animals, Jv was decreased (0.49 +/- 0.10 (VE) vs. 0.97 +/- 0.14 nl/mm.min, (nonVE) P less than 0.02), but JP was not affected significantly. Transport inhibition was stable over approximately 90 min of perfusion. In the brush border vesicle studies, sodium-dependent phosphate transport was inhibited compared with that in control animals, at the 9-, 30-, and 60-s time points. These findings indicate that the inhibition of renal ionic transport by VE occurs in both PCT and PST and is, in part, the result of a direct effect of VE on tubular transport mechanisms.

Animals↗
PubMed1988

Hyperparathyroidism and 1,25-dihydroxyvitamin D deficiency in mild, moderate, and severe renal failure.

It has been postulated that hyperparathyroidism in chronic renal failure results from hypocalcemia, occurring, in part, from phosphate retention and/or deficient 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] synthesis. However, many studies have failed to demonstrate hyperphosphatemia or low 1,25-(OH)2D levels in patients with mild renal failure. We measured creatinine clearance (CCr), fractional excretion of phosphorus (FEP), and serum phosphorus, ionized calcium, and plasma N-terminal PTH, and 1,25-(OH)2D concentrations in 21 normal subjects and 51 patients with renal failure. Patients with mild renal failure (Ccr, greater than 40 mL/min.1.73 m2) had normal mean serum phosphorus and ionized calcium and decreased mean 1,25-(OH)2D levels compared with those in normal subjects. In patients with moderate renal failure (CCr, 20-40), the mean ionized calcium level was normal, plasma PTH levels and FEP were elevated, and the decrement in 1,25-(OH)2D was more pronounced. The mean ionized calcium level was decreased only in the group of patients with severe renal failure (CCr, less than 20). The 1,25-(OH)2D values correlated positively with CCr and negatively with the log of plasma PTH and serum phosphorus concentrations. Log of plasma PTH correlated negatively with CCr and positively with FEP. The ionized calcium concentration correlated very weakly with CCr and the log of the plasma PTH level. These data demonstrate the presence of hyperparathyroidism, normocalcemia, and 1,25-(OH)2D deficiency in renal failure and are consistent with a role for 1,25-(OH)2D in the suppression of parathyroid activity through as yet unidentified mechanisms.

Adult↗
PubMed1987

Volume expansion-induced changes in renal tubular membrane protein phosphorylation.

The influence of volume expansion (VE) on the in vitro phosphorylation of membrane protein in the proximal brush border membrane (BBM) of the thyroparathyroidectomized (TPTX) rat was studied in the presence and absence of cyclic AMP and the results were compared to those obtained in control TPTX and intact animals. The results indicate that the cyclic AMP-independent phosphorylation of a protein band (Mr = 72,000) was stimulated both by VE and by the presence of parathyroid hormone in the circulation, whereas the cyclic AMP-dependent phosphorylation of membrane proteins (Mr = 40,000, 52,000 and 87,000) was inhibited by the same maneuvers. These findings, taken together with data previously available, which demonstrate inhibition of BBM phosphate transport following VE, may provide a link between alterations in phosphate transport in renal BBM vesicles and the phosphorylation of membrane proteins. The results further suggest that membrane protein phosphorylation may be a common mechanism by which a number of agents and maneuvers induce an inhibition of renal tubular phosphate transport.

Animals↗
PubMed1987

Early and late forms of cyclosporine nephrotoxicity: studies in cardiac transplant recipients.

To characterize the two forms of cyclosporine nephrotoxicity, we examined renal function in the immediate and late postoperative periods after cardiac transplantation. Moderate azotemia occurred during the first postoperative week in 58% of 43 cyclosporine-treated recipients, but in only 34% of 41 azathioprine-treated recipients, and 4% of 25 patients undergoing cardiopulmonary bypass for nontransplant surgery (both P less than .01 v cyclosporine). Acute renal failure developed in an additional 12% of the cyclosporine-treated group. Late postoperative renal dysfunction also occurred with a high prevalence. Life-table analysis indicated that at 6 months 55%, at 12 months 17%, at 24 months 4%, and at 36 months no cyclosporine-treated recipients retained normal renal function. Three renal biopsies performed in subjects with late nephrotoxicity demonstrated prominent interstitial fibrosis. Although one patient subsequently required chronic dialysis, reduction of cyclosporine dosage from a mean of 5.3 +/- 0.7 mg/kg/d to a mean of 2.3 +/- 0.3 mg/kg/d 9 to 21 months after transplantation with concurrent initiation of azathioprine therapy to prevent rejection led to an improvement of renal function in the five patients so treated. These data indicate that there are two distinct forms of cyclosporine nephrotoxicity. Although both occur with high prevalence, the early form does not appear to be a specific risk factor for the late form.

Acute Kidney Injury↗
PubMed1987

Do calcium channel blockers protect against renal ischemia?

Data from several studies have indicated that calcium channel blockers may prevent acute renal damage caused by ischemia. If this is true, then the obvious clinical application of this premise would be in surgical cases requiring cross-clamping of the aorta, or in patients experiencing prolonged hypotension. Evidence for the mechanism by which calcium channel blockers mitigate injury include the prevention or amelioration of renal vasoconstriction and/or their ability to inhibit calcium entry into cells, thereby possibly preventing toxic calcium 'overload'. Studies of animal models examining ischemic acute renal failure produced either by infusion of vasoconstrictors or by interrupting renal artery blood flow have provided conflicting results. Certain calcium channel blockers afford some degree of protection only when administered prior to the ischemic episode, while others may protect even if given after the insult. Several investigations have been carried out to determine the mechanism(s) of this protective effect. The results indicate cellular calcium accumulation occurs in cells during the anoxic period; this is most pronounced during reflow. This accumulation of calcium appears to be temporally related to both mitochondrial dysfunction and cell death. The ability of the calcium channel blockers to prevent calcium entry into cells may explain their role in protecting the cell and ameliorating ischemic injury.

Acute Kidney Injury↗
PubMed1987

The effects of atrial natriuretic peptide on whole-kidney and proximal straight tubular function in the rabbit.

The mechanisms by which atrial natriuretic peptide (ANP) produces a diuresis and natriuresis remain unclear. It has been suggested that the major if not sole mediator of ANP's renal effects is a hemodynamically induced increase in glomerular filtration rate (GFR). Data from clearance studies in anesthetized rabbits demonstrate that ANP administration can produce a significant increase in absolute and percentage sodium excretion (42.0 +/- 5.9----64.6 +/- 10.2 mu eq/min, P less than 0.01, and 1.97 +/- 0.28----3.12 +/- 0.35%, P less than 0.001, respectively) without increasing GFR (16.8 +/- 2.1----16.1 +/- 2.5 cc/min, P greater than 0.30). The natriuresis occurred despite a fall in renal plasma flow (RPF) (56.7 +/- 7.0----44.5 +/- 9.4 cc/min, P less than 0.01), a rise in filtration fraction (0.33 +/- 0.01----0.46 +/- 0.05, P less than 0.01), and an unchanged filtered load of sodium (2.28 +/- 0.27----2.16 +/- 0.32 mu eq/min, P greater than 0.10). Isolated tubular microperfusion studies demonstrated that ANP, present as a 10(-9) M concentration in the solution bathing perfused proximal straight tubules (PST), did not affect fluid flux (Jv) (0.38 +/- 0.07----0.41 +/- 0.07 nl/mm/min, P greater than 0.30) or phosphate reabsorption (Jp) (1.50 +/- 0.5----1.38 +/- 0.36 pmole/mm/min, P greater than 0.50). When ANP was infused into rabbits prior to harvesting the PSTs for isolated tubular microperfusion and the results were compared to tubules taken from control animals, there was again no effect on Jv (0.37 +/- 0.05 vs 0.42 +/- 0.05 nl/mm/min, P greater than 0.50) or Jp (2.41 +/- 0.27 vs 2.42 +/- 0.44 pmole/mm/min, P greater than 0.90). These findings suggest that ANP can inhibit sodium transport without increasing whole-kidney GFR or RPF, but does not directly inhibit transport in the proximal straight tubule.

Animals↗
PubMed1987

Effect of nitrendipine in a rat model of ischemic acute renal failure.

An increase in intracellular calcium has been identified as an etiologic factor in acute renal failure (ARF) and blockade of slow calcium channels has been successful in its amelioration. Diuretics may also prevent or mitigate the effects of renal ischemia. We examined the actions of a new calcium channel blocker, nitrendipine (NTR), given intravenously to rats prior to bilateral clamping of the renal pedicle for 45-60 min. Four groups of rats were studied. Group I: Rats given the vehicle only and subjected to sham surgery had a creatinine clearance (Ccr) of .93 +/- .05 ml/min (n = 20). Group II: Rats given NTR (1 or 3 mg/kg) and subjected to sham surgery had a Ccr of .65 +/- .03 ml/min (n = 17). Group III: The infusion of the vehicle alone 10-15 min before clamping resulted in a Ccr of .12 +/- .02 ml/min (n = 23, p less than .001 vs. group I). Group IV: Rats given NTR and then clamped had a Ccr of .30 +/- .04 ml/min (n = 31, p less than .001 vs. group III, p less than .001 vs. group II). Higher doses of NTR did not improve the results. We concluded that NTR partially protects against ARF, but NTR lowered Ccr compared to control rats (p less than .001, group I vs. group II).

Acute Kidney Injury↗
PubMed1986

Clinical pharmacologic implications in diuretic selection.

Logical and comprehensive diuretic therapy is based on a sound knowledge of renal physiologic principles. Knowledge of the sites within the nephron at which the currently available diuretics work and their modes of action provide the clinician with a basis upon which to arrive at therapeutic decisions. True diuretic resistance is uncommon, but when it occurs, sequential nephron blockade can frequently reverse the refractoriness initially exhibited by the patient.

Bicarbonates↗
PubMed1986

In vivo bone lead measurements: a rapid monitoring method for cumulative lead exposure.

Lead concentrations (microgram/g wet weight) in human bone (tibia) were measured noninvasively in vivo employing an X-ray fluorescence technique. Forty-five workers who had been subjected to chronic industrial exposure were found to have a mean bone lead content of 52.9 micrograms/g wet weight (0 to 198 micrograms/g). In addition to bone lead content, blood lead, body burden of lead as assessed by urinary lead excretion after EDTA chelation, zinc protoporphyrin, and unstimulated urinary lead excretion were evaluated. The results suggest that the in vivo measurement of tibia lead content may serve as an acceptable indicator of body lead burden and provide a practical technique for lead screening purposes. The correlation coefficient between X-ray fluorescence findings and lead excretion following Ca-EDTA administration is 0.69; p less than 0.001.

Bone and Bones↗