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Biomedical subjects

J B Puschett

Publications and source records attributed to J B Puschett.

At least 19 recordsLinked to original sources
PubMed2006

Marinobufagenin impairs first trimester cytotrophoblast differentiation.

Preeclampsia is a pregnancy-specific syndrome that is the leading cause of maternal death during pregnancy in the developed world. In preeclampsia, a combination of immunological, genetic and environmental factors can lead to altered cytotrophoblast (CTB) invasion of the uterine wall, a process that is critical for normal placental development and pregnancy maintenance. Marinobufagenin (MBG) is an endogenous inhibitor of the sodium pump Na(+)/K(+) ATPase, and increased plasma MBG is associated with hypertension, chronic renal failure and preeclampsia. In the present study, the effects of MBG on CTB differentiation and invasion were investigated utilizing the first trimester extravillous CTB cell line SGHPL-4. MBG significantly inhibited SGHPL-4 proliferation in a dose-dependent manner. In addition, growth factor-induced migration and invasion were significantly inhibited by MBG treatment. These findings demonstrate that MBG impairs CTB differentiation along the invasive pathway. Elucidating the mechanisms by which MBG impairs placental development may increase our understanding of fetal and maternal pathologies associated with preeclampsia.

Bufanolides↗
PubMed1995

Phosphate transport inhibition by KW-3902, an adenosine A1 receptor antagonist, is mediated by cyclic adenosine monophosphate.

We have previously demonstrated that 1,3-dipropyl-8-(3-noradamantyl) xanthine (KW-3902) has an inhibitory effect on phosphate (Pi) transport with no effect on glucose transport in the rat renal proximal tubular cell, similar to that of parathyroid hormone (PTH). In the current studies we investigated the effect of KW-3902, rat PTH (1-34), and 1,3-dipropyl-8-cyclopentylxanthine (DPCPX), another selective adenosine A1 receptor antagonist, on Pi transport and the production of cyclic adenosine monophosphate (cAMP). We then compared these effects of KW-3902 with those of rat PTH in rat renal proximal tubule cells. The results showed that both KW-3902 (30 mumol/L) and rat PTH (1-34, 5 mumol/L) significantly inhibited Pi uptake in proximal cells from a control level of 61 +/- 3 to 19 +/- 3 (a reduction of 69%) and 46 +/- 4 picomoles phosphate/mg protein/min (a reduction of 25%), respectively (P < 0.01). The inhibitory effect of 30 mumol/L KW-3902 alone on Pi transport was more than twice that of 5 mumol/L rat PTH (1-34) alone (P < 0.01). KW-3902 stimulated the production of cAMP in a dose-dependent manner (r = 0.997, P < 0.01). Rat PTH (1-34; 5 mumol/L) also stimulated cAMP production, which was greater than that induced by 30 mumol/L KW-3902 alone. A significant increase in cAMP production by 30 mumol/L DPCPX was also observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Effect of KW-3902, a novel adenosine A1 receptor antagonist, on sodium-dependent phosphate and glucose transport by the rat renal proximal tubular cell.

KW-3902, 1,3-dipropyl-8-(3-noradamantanyl)xanthine, is a novel potent and selective adenosine A1-receptor antagonist. KW-3902 has been found to cause significant diuresis and natriuresis. To investigate the action of this adenosine A1-receptor antagonist on phosphate transport in renal proximal tubular cells, we studied its effect on the uptake of phosphate by the cultured rat renal proximal tubular cell. KW-3902 significantly inhibited sodium-dependent uptake of phosphate at 10 minutes. The inhibitory effect was dose-dependent with maximum effect achieved at a KW-3902 concentration of 3 x 10(-5) M in the uptake media. The half-maximal inhibitory concentration, IC50, of KW-3902 on phosphate uptake was 2 x 10(-6) M. Dixon plot analysis of the uptake data was consistent with pure non-competitive inhibition. The inhibition constant, Ki, of 6.2 x 10(-6) M for phosphate transport, derived from the Dixon plot, was in close agreement with the IC50 calculated from a semilog dose response curve. Sodium-dependent glucose transport was not affected by KW-3902. These findings reveal that KW-3902 has a direct and specific inhibitory effect on phosphate uptake in renal proximal tubules.

Animals↗
PubMed1994

Pharmacological classification and renal actions of diuretics.

Diuretics may be classified according to their chemical structure, their mechanism and site of action within the nephron, and their diuretic potency. Those agents with primary action in the proximal nephron include the carbonic anhydrase inhibitors, e.g. acetazolamide, a sulfonamide derivative. Other drugs containing the sulfonamido grouping, e.g. furosemide, chlorothiazide and metolazone, also have secondary effects on the proximal nephron. Those drugs which have their major pharmacologic activity within the ascending limb of the loop of Henle, inhibiting the sodium/potassium/2 chloride electroneutral transport system, include the sulfonamide agents furosemide, bumetanide, piretanide and torasemide, and the phenoxyacetic acid derivative, ethacrynic acid. In the early portion of the distal convoluted tubule, sodium chloride reabsorption is impaired by the thiazide group, indapamide and metolazone, as their primary site of action. In the late reaches of the distal convolution and in the collecting duct, agents that inhibit the exchange of sodium for that of hydrogen and potassium have their major sites of activity. These agents, spironolactone, amiloride and triamterene, differ not only chemically but in their mechanisms of action. Diuretics may also be grouped according to potency. The loop of Henle agents are the most powerful, causing the excretion of 20-25% of filtered sodium load. The thiazide group and metolazone are moderately potent, resulting in the excretion of 5-8% of filtered sodium, and the 'potassium-sparing' drugs are only mildly potent, causing the excretion of only 2-3% of filtered sodium.

Diuretics↗
PubMed1993

Parathyroid hormone transport effects and hormonal processing in primary cultured rat proximal tubular cells.

The development of satisfactory cell culture models for the study of parathyroid hormone (PTH)-induced inhibition of Pi transport has proven difficult. Using subcellular fractionation techniques we investigated the response of primary cultures of rat proximal tubular cells to PTH-(1-34). Specific binding of 125I-bPTH-(1-34) occurred at 2 degrees C. After 5 min of rewarming, trypsin-releasable radioactivity decreased from 90 to 50%, indicating internalization of the ligand. Cell disruption, followed by density centrifugation with 17% Percoll either directly after binding at 2 degrees C or post-rewarming for 20 min, showed a shift of 125I label from the plasma membrane (5'-nucleotidase) to lysosomal fractions (beta-D-glucosaminidase), confirming the sequential occurrence of cell surface binding, internalization and transport to lysosomes of 125I-bPTH-(1-34). Reculture at 37 degrees C revealed steady accumulation of trichloroacetic acid-soluble radioactivity in the medium, indicating degradation of 125I-bPTH-(1-34). Phosphate transport in the absence of sodium was minimal. Incubation of the cells with bPTH-(1-34) resulted in up to 50% inhibition of sodium-dependent phosphate transport. Prior phosphate depletion abrogated the response to PTH.

Animals↗
PubMed1993

Life-threatening hyperkalemia associated with captopril administration.

Angiotensin converting enzyme (ACE) inhibitors have become commonly used medications for hypertension and congestive heart failure. These agents are noted for their low incidence of adverse effects; but in certain cases, these effects can be life-threatening. Severe hyperkalemia is one of the potentially dangerous effects of the ACE inhibitors. While cases of life-threatening hyperkalemia associated with the use of ACE inhibitors have been described previously, in no instance was dialysis required. Herein, we report a case of acute hyperkalemia in a patient with congestive heart failure and renal insufficiency, the resolution of which required hemodialysis. The hyperkalemia in this case occurred without an increase in the patient's azotemia. In addition, the patient did not respond to attempts to effect the intracellular shift of potassium. This suggested that there may have been a defect in internal potassium homeostasis.

Aged↗
PubMed1992

Relationship of the renin-angiotensin system and systemic arterial pressure to sodium excretion during atrial natriuretic peptide infusion in men.

The goal of this study was to evaluate the relative contribution of the renin-angiotensin system and mean arterial pressure to sodium excretion and urine flow rate during an infusion of atrial natriuretic peptide (ANP) at physiologically relevant doses in humans. Eight normal volunteers were studied during five periods: (1) baseline in the supine position; (2) during an infusion of ANP at physiologic doses (0.01 micrograms/kg/min) in the supine position; (3) during ANP infusion and 60 degrees head-up tilt; (4) during ANP infusion, head-up tilt, and interruption of the renin-angiotensin axis with the angiotensin converting enzyme inhibitor (ACEI) enalaprilat; and (5) in the supine position during ANP infusion and ACEI. Infusion of ANP in the supine posture significantly increased urine flow rate and sodium excretion compared to baseline while mean arterial pressure and plasma renin activity were unchanged. During head-up tilt and ANP infusion, urine flow rate and sodium excretion were no longer significantly elevated over baseline while mean arterial pressure decreased and plasma angiotensin II levels increased. Addition of ACEI caused a marked diminution of urine flow rate and sodium excretion compared to baseline levels despite continued ANP infusion. Although mean arterial pressure after ACEI administration was lower than baseline, it was not significantly different from the non-ACEI head-up tilt state. Placing subjects in the supine position during ANP infusion and ACEI administration increased mean arterial pressure to levels that were no longer different from baseline, but urine flow rate and sodium excretion remained significantly depressed to the same degree as during head-up tilt with ACEI.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Diuretics in the therapy of hypertension: current status.

Diuretics were the first effective oral agents for treating hypertension. They have proven to be safe and effective. Recently, they have been scrutinized as possibly being responsible for certain side effects that may increase risk for cardiovascular morbidity and mortality. A careful review of the literature suggests this class of agents warrants continued use as first-line therapy of hypertension, especially in certain demographic groups. However, monitoring of potential baleful effects and a general reduction in dosage are appropriate. Furthermore, selection of other (alternative) agents for monotherapy is advised in certain clinical circumstances.

Diuretics↗
PubMed1991

Differential effects of atrial natriuretic peptide infusion at physiological doses in different postures in humans.

To evaluate potential physiological actions of atrial natriuretic peptide (ANP) in humans, normal male volunteers were studied in the supine and head-up tilt positions both in the absence and presence of an ANP infusion at a rate which increased plasma ANP levels to ranges observed during physiological stimuli such as volume expansion. Infusion of ANP in the supine position provoked a significant natriuresis and diuresis and suppressed aldosterone secretion. Head-up tilt alone caused expected decreases in urine flow rate and the absolute and fractional excretion rates of sodium and increases in plasma renin activity and aldosterone levels. The combination of head-up tilt and ANP infusion resulted in a less marked decrease in urine flow rate and sodium excretion and a similar increase in plasma renin activity. However, there was a significant decrease in plasma aldosterone levels. These data support a physiologic action of ANP on renal and adrenal function.

Adult↗
PubMed1991

Acid-base disturbances in cardiogenic pulmonary edema.

Eighty-one consecutive cases of uncomplicated cardiogenic pulmonary edema (CPE) were retrospectively graded for severity of chest roentgenogram (CXR) changes and grouped according to primary acid-base abnormalities, either single or mixed. Mean age was 72, 50 male, 31 female. Twenty-three percent had no acid-base disturbances (ABD). Isolated respiratory alkalosis was most common (41%), followed by metabolic acidosis, 22%; metabolic alkalosis, 10%, and respiratory acidosis, 9%. Age, sex, race distribution, morbidity and mortality were not significantly different between the groups. Overall mortality was 17%. Significantly higher mortality was associated with age over 70, pH less than 7.4, and presence of acute myocardial infarction. CXR scores did not correlate with pH, pCO2 or pO2, mortality or morbidity. Some patients with the most severe ABDs recovered while others, who had no ABD on presentation, eventually died. Thus, in 81 consecutive episodes of uncomplicated CPE, isolated respiratory alkalosis was the commonest ABD, occurring in 41%. No correlation was found between ABD and severity of CPE, morbidity or mortality.

Acid-Base Imbalance↗
PubMed1991

Iatrogenic hypercalcemia in hemodialysis patients.

Calcium carbonate is frequently used in large doses as a phosphorus binder in hemodialysis patients, which often results in hypercalcemia. In most studies in which calcium carbonate is prescribed to control serum phosphorus levels the patients are not given calcitriol. However, calcitriol may be necessary for suppression of parathyroid hormone. The risk of hypercalcemia when calcium supplements are used in conjunction with calcitriol has not previously been examined in detail. We reviewed the charts of 74 hemodialysis patients (119 patient dialysis years) to determine the relationship of serum calcium to calcitriol, calcium therapy, and PTH levels. Twenty-eight patients (38%) were hypercalcemic at some point. Calcitriol therapy significantly increased the risk of hypercalcemia, independently of calcium therapy (p = 0.032). However, patients on a low dose of calcitriol were more than twice as likely to be hypercalcemic than patients on higher doses. Mean PTH levels were lower in the patients on the lower doses of calcitriol, indicating less severe hyperparathyroid disease. We conclude that hypercalcemia is a common complication in hemodialysis patients on calcitriol and calcium carbonate. Whether lowering the dialysate calcium, as suggested by other investigators, will successfully decrease the risk of hypercalcemia without worsening hyperparathyroidism remains to be determined.

Adult↗
PubMed1990

Cyclosporine nephrotoxicity in cardiac allograft patients--a seven-year follow-up.

Renal function was observed retrospectively in a population of 228 adults who underwent a cardiac allograft at the University of Pittsburgh from June 1980 through June 1987, survived a minimum of one year, and received cyclosporine. Renal function was determined by serial measurement of serum creatinine concentration. Serum creatinine rose from 1.2 +/- 0.0 mg/dl at time of hospital discharge to 2.0 +/- 0.0 mg/dl at two and four years and 3.3 +/- 0.1 mg/dl at seven years. The fall in renal function was biphasic, with a rapid decline (reciprocal creatinine slope -0.018 dl/mg-mo) through 24 months and a slower decline thereafter -0.0036 dl/mg/month). This occurred despite a progressive decrease in cyclosporine levels from 668 +/- 23 ng/ml (whole blood RIA) to 380 +/- 12 ng/ml at seven years. Three of 222 patients (1.6%) developed end-stage renal disease within 18 months of initiation of cyclosporine therapy. Only one additional patient of 26 followed through 54 months (3.8%) developed end-stage disease thereafter. The decline in renal function seen with cyclosporine is rapid in the first 18 months, with a slower but continuing decline seen with later follow up. At least in heart transplantation, the risk of end-stage renal disease is significant, but not prohibitive.

Adult↗
PubMed1990

Acute and chronic renal failure in liver transplantation.

We have performed a retrospective review of the incidence and etiologies of acute renal failure (ARF) in 105 adult patients receiving liver transplants. The prevalence of chronic renal failure was also determined. ARF occurred in 94.2% of these patients. Acute tubular necrosis was the leading cause of ARF and was associated with the highest mortality. Factors associated with increased mortality included: (1) peak serum creatinine greater than 3 mg/dl, (2) multiple liver transplants and (3) the need for dialysis. Pretransplant renal failure did not increase mortality. Chronic renal failure developed in 83% of patients at latest follow-up (mean: 30.5 +/- 7.9 months).

Acute Kidney Injury↗
PubMed1990

Acid excretion and serum electrolyte patterns in patients with advanced chronic renal failure.

Hyperchloremic metabolic acidosis can be seen in advanced chronic renal failure (CRF). To study this further, we measured acid excretion under controlled conditions in 19 patients with severe but stable CRF. Twelve patients had a hyperchloremic metabolite acidosis, 3 had an elevated anion gap acidosis ('delta acidosis'), while the 4 remaining patients had a slightly decreased tCO2 with a normal anion gap and serum chloride level ('mild acidosis'). Ammonium excretion was markedly reduced in CRF patients (11 +/- 1 vs. 32 +/- 2 mEq/day in normal subjects, p less than 0.005), and likewise urinary titratable acid was diminished (18 +/- 2 mEq/day in patients, vs. 28 +/- 3 mEq/day in normal subjects; p less than 0.005). When expressed per 100 ml GFR, ammonium and titratable acid excretion were markedly increased in all groups of patients compared to normal subjects. The Tm for bicarbonate was 22.5 +/- 3.7 mEq/l for all CRF patients and 24 +/- 1 mEq/l for the patients with a hyperchloremic metabolic acidosis. We conclude that the hyperchloremic metabolic acidosis in advanced renal failure is due to diminished excretion of ammonium and titratable acid and is not due to an increased bicarbonate leak. As renal failure advances and renal mass declines, the remaining functioning nephrons hypersecrete acid.

Acidosis↗
PubMed1989

Inhibition by volume expansion of phosphate uptake by the renal proximal tubule brush border membrane.

Clearance studies and examination of brush border membrane (BBM) vesicle transport were performed in rats that had been volume expanded by 10% of body weight. The results were compared to those obtained in control animals. The data indicate that the phosphaturia which resulted from the expansion procedure was accompanied by an inhibition of proximal BBM phosphate uptake. The BBM uptake of proline and glucose was unchanged. Furthermore, since plasma calcium did not change, the findings are compatible with the view that the membrane transport changes resulted from alterations induced by the saline loading itself, rather than (or in addition to) any changes caused by parathyroid hormone excretion.

Animals↗
PubMed1989

Characterization of primary cell cultures derived from rat renal proximal tubules.

Proximal tubules were prepared from rat kidney cortex by collagenase digestion and purified by Percoll gradient centrifugation. Their enrichment was estimated by comparing the specific activities of various cell-specific enzymes in homogenates of renal cortex and of the isolated tubules. The tubules were cultured in a 50:50 mixture of Dulbecco's modified Eagle's and Ham's F12 media supplemented with insulin, transferrin, epidermal growth factor, hydrocortisone, and prostaglandin E1. After 2 to 3 d an extensive outgrowth of epithelial cells developed from the attached tubules. After 5 to 7 d near confluent monolayers were obtained. Hormonal responsiveness, marker enzyme activities, and transport properties were determined to further characterize the primary cultures. The cultured cells exhibited increased cyclic AMP production in response to parathyroid hormone but not calcitonin or vasopressin, consistent with the absence of cells derived from distal and collecting tubules. The cells also retained significant levels of 25-hydroxyvitamin D3-1 alpha-hydroxylase, alkaline phosphatase, and gamma-glytamyl-transpeptidase, three enzymes that are primarily associated with the proximal tubule. The cultured epithelial cells also exhibit a Na+-dependent phosphate and glucose transport systems. Therefore, the cells retain many functional properties that are characteristic of proximal tubules. Thus, the primary cultures should be suitable for the study of processes that occur specifically within this segment of the rat nephron.

Animals↗