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D Marver

Publications and source records attributed to D Marver.

At least 19 recordsLinked to original sources
PubMed1991

Long term observations in a patient with pseudohypoaldosteronism.

This paper describes a patient with severe pseudohypoaldosteronism (PHA) for over 12 years. The patient presented at 10 days of age with a serum sodium of 118 mEq/l and potassium of 12 mEq/l. After failing to maintain normal fluid and electrolyte status with standard therapy, including maximal mineralocorticoid stimulation, he was given a special formula containing minimal potassium plus salt supplements which normalized his electrolyte status. However, when he was 4.5 years of age, an acute gastrointestinal illness led to severe volume depletion, hyperkalemia, and cardiopulmonary arrest. This resulted in significant neurological impairment. At 12.5 years of age, the patient continues to require massive sodium supplements and his diet contains less than 0.5 mEq/kg potassium daily; his height and weight are at the 95th percentile, thus demonstrating that normal growth may be achieved with strict dietary manipulation in a patient with persistent, severe PHA. Serial studies to further define the lesion in this patient have demonstrated: (1) normal binding of aldosterone to aldosterone binding globulin (5.1% bound); (2) normal mineralocorticoid "activity"; (2) suppressible renin and aldosterone levels; (4) increased prostaglandin excretion (3.15 micrograms/g creatinine); (5) lack of benefit of prostaglandin inhibition with indomethacin; (6) normal proximal tubule function (CNa + CH2O = 18.0 ml/100 ml glomerular filtration rate; (7) impaired distal tubule function (CH2O/CNa + CH2O = 79.8%) during water diuresis.

Aldosterone↗
PubMed1991

Role of adenosine triphosphate (ATP) and NaK ATPase in the inhibition of proximal tubule transport with intracellular cystine loading.

Cellular cystine loading with cystine dimethyl ester inhibits volume absorption, transepithelial potential difference, glucose transport, and bicarbonate transport in proximal convoluted tubules perfused in vitro. This study examined the roles of ATP and NaK ATPase in this in vitro model of the Fanconi syndrome of cystinosis. Intracellular ATP was measured using the luciferin-luciferase assay. Intracellular ATP was reduced by 60% in proximal convoluted tubules incubated with 0.5 mM cystine dimethyl ester for 15 min at 37 degrees C (P less than 0.001). Incubation of cystine loaded tubules with 1 mM exogenous ATP increased intracellular ATP to levels not significantly different than that of controls. On the other hand, Vmax NaK ATPase activity was unchanged even though the incubation times and the concentration of cystine dimethyl ester were doubled to 30 min and 1 mM, respectively. In proximal convoluted tubules perfused in vitro, 0.5 mM cystine dimethyl ester resulted in an 89% inhibition in volume absorption (0.81 +/- 0.14 to 0.09 +/- 0.09 nl/mm.min), while there was only a 45% inhibition in volume absorption (P less than 0.01) due to cellular cystine loading in the presence of 1 mM lumen and bath ATP (0.94 +/- 0.05 to 0.52 +/- 0.11 nl/mm.min). These data demonstrate that proximal tubule cellular cystine loading decreases cellular ATP concentration, but does not directly inhibit NaK ATPase activity. The inhibition in transport and decrease in intracellular ATP due to cellular cystine loading was ameliorated by exogenous ATP. These data are consistent with cellular ATP depletion playing a major role in the inhibition of proximal tubule transport due to intracellular cystine loading.

Adenosine Triphosphate↗
PubMed1990

Aldosterone.

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Aldosterone↗
PubMed1989

Chronic indomethacin increases rabbit cortical collecting tubule Na+-K+-ATPase activity.

To help determine whether prostaglandin-mediated inhibition of transport in the isolated rabbit cortical collecting tubule (CCT) is related to a suppression of sodium pump activity, adrenalectomized rabbits on replacement dexamethasone were treated for 3 days with vehicle or the prostaglandin inhibitor, indomethacin. On the day of death, rabbits treated with indomethacin had a significantly reduced urinary prostaglandin E2 (PGE2) excretion rate compared with vehicle-treated animals (107 +/- 7 vs. 415 +/- 129 ng.kg body wt-1.day-1, indomethacin vs. vehicle, P less than 0.05). In addition, CCTs obtained from indomethacin-treated rabbits had a significantly higher Na+-K+-ATPase activity than controls (2.66 +/- 0.33 vs. 1.17 +/- 0.33 mol Pi.kg dry wt-1.h-1, 37 degrees C, P less than 0.005); Mg-ATPase activity was invariant. Despite the elevated CCT Na+-K+-ATPase activity, there was no evidence of a sustained increase in Na reabsorption and/or K excretion by the kidney. Thus at death, the fractional excretions of Na and K, urinary Na/K ratios and plasma K values in rabbits given indomethacin were not significantly different from control values. There was also no evidence for a direct effect of either indomethacin or PGE2 on Na+-K+-ATPase activity when added directly to CCT broken-cell assays. Therefore in vivo chronic indomethacin administration leads to a rise in CCT Na+-K+-ATPase activity, which is coincident with a fall in urinary PGE2, suggesting that endogenous PGE2 may suppress the activity of this enzyme by a cell-mediated process.

Adrenal Glands↗
PubMed1989

Protein intake and cation transport in the loop of Henle.

High-protein intake enhances maximal urinary concentrating ability and suppresses tubuloglomerular feedback activity in a manner that correlates with enhanced salt reabsorption in the loop of Henle. In this article we describe studies designed to localize the site at which protein intake alters loop sodium uptake (JNa) in rats fed diets containing either 6% or 40% protein for approximately 8 to 10 days. In vivo microperfusion demonstrated that luminal bumetanide (10(-5) mol/L) fully reversed the stimulation of JNa by high-protein intake, thus suggesting that high-protein intake stimulates salt transport in the thick ascending limb. In vitro studies supported this possibility, showing that high-protein intake significantly increased sodium-potassium adenosine triphosphatase (NaK ATPase) activity in homogenates of outer renal medulla (68%) and in dissected medullary thick ascending limbs (87%). This effect was partly selective, since high-protein intake did not alter NaK ATPase activity in superficial renal cortex, had a smaller and statistically insignificant effect on NaK ATPase activity in dissected pars rectae, and did not affect magnesium ATPase activity in any tissue. Furthermore, this effect did not appear to require hypertrophy, since high-protein intake for approximately 8 days did not detectably alter the relative amounts of tissue protein and DNA in either medulla or cortex. A last series of studies demonstrated that high-protein intake increased plasma aldosterone levels. We conclude that increased protein intake stimulates salt reabsorption predominantly in the thick ascending limb, an effect that is partly selective; does not appear to require hypertrophy; and may be related to increased plasma aldosterone levels.

Aldosterone↗
PubMed1986

ATPase activity in macula densa cells of the rabbit kidney.

Na-K- and Mg-activated ATPase activities were determined in maculae densae and glomeruli dissected from both superficial and juxtamedullary nephrons of normal rabbits, using an ultramicro method including a cycling reaction. Activities were expressed as Pi generated per macula densa or per glomerulus and normalized for tissue volume. Results indicate that the mean volume of superficial and juxtamedullary macula densa samples was not statistically different, while glomeruli from deep nephrons had sample volumes that were 29% larger than those from superficial nephrons (P less than 0.001). Correcting for volume both superficial and juxtamedullary macula densa samples had an Na-K-ATPase activity of 0.37 +/- 0.21 fmol X h-1 X (micron3)-1 X Mg-ATPase activity in both pools was also similar [0.41 +/- 0.07 and 0.52 +/- 0.1 fmol X h-1 X (micron3)-1]. Na-K-ATPase activity in macula densa cells is estimated to be about 1/40th the activity of surrounding cortical thick ascending limb cells. Total glomerular ATPase per unit volume was significantly higher in glomeruli from superficial than from deep nephrons [0.41 +/- 0.04 vs. 0.28 +/- 0.04 fmol X h-1 X (micron3)-1, P less than 0.05]. There was no statistically significant activity of Na-K-ATPase in either superficial or deep glomeruli. These results suggest that in contrast to previous reports, the macula densa contains Na-K-ATPase, but at a low level relative to surrounding tubular cells. Further, in normal rabbits, this activity is invariant in superficial and juxtamedullary samples.

Animals↗
PubMed1986

Cyclic AMP-dependent stimulation of Na,K-ATPase in shark rectal gland.

Scatchard analysis of 3H ouabain bound to isolated rectal gland cells as a function of increasing ouabain concentrations produced a concave curvilinear plot that was resolved into two specific sites with either a high (I) or low (II) affinity for ouabain. Cyclic cAMP/theophylline (+/- furosemide, 10(-4) M) increased the amount of 3H ouabain bound to the high-affinity site I. Vanadate, a phosphate congener which promotes formation of the ouabain-binding state of the enzyme, mimicked the effects of cAMP/theophylline at low concentrations of ouabain, suggesting that cAMP/theophylline increases binding to site I by enhancing the rate of turnover of resident enzyme. Enhanced 86Rb uptake seen following cAMP/theophylline administration was primarily associated with increased flux through the high-affinity ouabain site, and this stimulation was not obliterated by the co-administration of furosemide. A model was presented which suggested the presence of two noninteracting pools of enzyme or isozymes which exhibit either a high or low affinity for ouabain. Cyclic AMP both stimulated turnover via site I, and modified the kinetics of binding of 3H ouabain to site II. The (ave) Kd of 3H ouabain for site II was increased from 3.6 microM (controls) to 0.5 microM (cAMP/theophylline) and the Hill coefficient was modified from 0.45 (controls) to 1.12 (cAMP/theophylline), suggesting a transition from a negative- to a noncooperative binding state. While furosemide reversed the effects of cAMP/theophylline on site II kinetics, it did not obliterate cAMP/theophylline effects on site I. This suggests that cAMP may alter the intrinsic turnover rate of this particular pool of Na,K-ATPase in shark rectal gland.

Animals↗
PubMed1985

Alpha2-adrenoceptors and cellular cAMP levels in single nephron segments from the rat.

A functional role for the numerically predominant renal alpha2-adrenoceptors, which in other tissues inhibit adenylate cyclase, remains undefined. We therefore examined the effect of alpha2-adrenoceptor stimulation with (-)-epinephrine (E) on cell cAMP content in the isolated proximal convoluted tubule (PCT), medullary and cortical thick ascending limb of Henle, and collecting tubule (MTAL, CTAL, MCT, and CCT, respectively). Parathyroid hormone (1-34 PTH), in PCT or CTAL, or arginine vasopressin (AVP), in MTAL, CTAL, MCT, or CCT, was used to activate adenylate cyclase in intact cells from these microdissected nephron segments in the presence of 3-isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and propranolol. Alpha2-Adrenoceptors were activated using varying concentrations of E (37 degrees C, 2 min). Alpha2-Adrenoceptor activation with E (5 X 10(-7) to 5 X 10(-6) M) suppressed cellular cAMP stimulation by PTH by 35% in PCT and stimulation by AVP in CCT by 50%. This suppression by E in PCT and CCT was inhibited by 5 X 10(-6) M yohimbine or 5 X 10(-7) M phentolamine but not by 5 X 10(-6) M prazosin. E also suppressed cAMP stimulated by AVP in MCT, but it did not suppress the PTH-or AVP-stimulated increase in cellular cAMP in CTAL and MTAL. These studies show that there are alpha2-adrenoceptors in the rat nephron. Activation of these alpha 2-adrenoceptors can inhibit cAMP formation stimulated by PTH in PCT and by AVP in the CCT and MCT but not in the CTAL and MTAL. A pathophysiological role of altered regulation of these receptors is yet to be described.

Adenylyl Cyclases↗
PubMed1979

The mineralocorticoid antagonist activity of an 11 beta,18-oxidopregnane.

Removal of the 18-hydroxy group of the hemiacetal form of aldosterone transforms its activity from that of pure agonist to predominant antagonist. The 18-deoxy derivative possesses one third of the binding affinity of aldosterone for the cytoplasmic mineralocorticoid receptor of rat kidney and exhibits an approximate 2:1 antagonist to agonist ratio in both toad bladder and adrenalectomized rat bioassay systems. The promising properties of the 11 beta,18-oxidopregnane tested included very low androgen receptor affinity and approximately equal effectiveness in vitro and in vivo in displacing aldosterone from mineralocorticoid-binding sites in the rat.

Aldosterone↗
PubMed1976

Photoaffinity site-specific covalent labeling of human corticosteroid-binding globulin.

A method was developed for the synthesis of high-specific-activity 21-diazo-21-[6,7-(3)H]deoxycorticosterone, an analog of corticosterone. This analog was used as a photoaffinity label of a high affinity steroid-binding protein, human corticosteroid-binding globulin. Based on direct binding studies and crosscompetition experiments, this diazo derivative exhibited the requisite affinity (within a factor of 1.5 times that of corticosterone) and site specificity to qualify as an affinity labeling legand. Irradiation of corticosteroid-binding globulin with the 21-diazo derivative resulted in irreversible binding to corticosteroid-binding globulin, identified by polyacrylamide gel electrophoresis. Specificity of covalent binding to corticosteroid-binding globulin was established by competition analysis with various steroids. Irreversibility of photodependent binding was shown by persistence of the complex on electrophoresis (in contrast to the noncovalently linked complex), and resistance to exchange with corticosterone or pregnanediol and to solvent extraction. Site specificity of covalent binding was inferred from the effects of a scavenger, Tris-HC1, and fluorescence quenching of a neighboring tryptophan.

Affinity Labels↗
PubMed1975

Autoradiographic localization of corticosterone receptors (type III) to the collecting tubule of the rat kidney.

Recently, a class of receptors exhibiting high affinity for corticosterone was described in rat kidney (Feldman, D. et al., Endocrinology 92: 1429, 1973). These receptor sites exhibited negligible affinity for dexamethasone and aldosterone and were designated Type III to distinguish them from sites having high affinity for aldosterone (Type I), and sites with high affinity for dexamethasone and corticosterone (Type II). To visually localize Type III sites in the kidney and demonstrate whether or not they represent intracellular steroid receptors, we used an autoradiographic procedure for diffusible substances. Male adrenalectomized rats were injected intravenously with the following combination of steroids per 100 g body weight: 4 x 10(-9) mol [3H]corticosterone, 4 x 10(-9) mol unlabeled aldosterone, and 4 x 10(-9) mol unlabeled dexamethasone. To differentiate "nonspecific" binding, each experimental animal was paired with a control animal that received the same steroids plus 250-fold unlabeled corticosterone. At 3 min, 10 min, and 30 min, kidneys were removed, cut into quadrants, and frozen in isopentane cooled by liquid nitrogen. For autoradiography, 4 mum frozen sections were cut, pressed into contact with emulsion precoated slides at -30 C, melted and simultaneously dried under a jet of dry nitrogen gas, and exposed at 4 C for 2 to 6 weeks. At all three time intervals, silver grains representing [3H]corticosterone binding sites, were concentrated over collecting tubules, only in the outer medulla and cortex (those in the inner medulla and papilla were not labeled). In the labeled segments of the nephron, some of the cells showed an apparent high ratio of cytoplasmic to nuclear grains and in others nuclear labeling was more prominent. A small population of cells within labeled collecting tubules (possibly dark cells) were not labeled. Although no function can yet be ascribed to Type III receptors in the kidney, they may represent an important steroid-mediated renal mechanism.

Animals↗
PubMed1974

Renal aldosterone receptors: studies with (3H)aldosterone and the anti-mineralocorticoid (3H)spirolactone (SC-26304).

In vivo, a spirolactone (SC-26304) inhibited the effects of aldosterone on urinary K(+):Na(+) ratios and the binding of [(3)H]aldosterone to renal cytoplasmic and nuclear receptors. Cytoplasmic binding of [(3)H]aldosterone and [(3)H]spirolactone (SC-26304) was similar in magnitude and involved the same set of sites. Under three sets of conditions-(i) in the intact rat, (ii) in kidney slices, and (iii) in reconstitution studies (mixing prelabeled cytoplasm with either purified renal nuclei or chromatin), [(3)H]spirolactone (SC-26304) did not yield specific nuclear complexes in contrast to the reproducible generation of these complexes with [(3)H]aldosterone. In glycerol density gradients, cytoplasmic [(3)H]aldosterone receptor complexes sedimented at 8.5 S and 4 S in low concentrations of salt and at 4.5 S in high concentrations of salt. Cytoplasmic [(3)H]spirolactone (SC-26304) receptor complexes sedimented at 3 S in low concentrations of salt and 4 S in high concentrations of salt. These results are discussed in terms of an allosteric model of the receptor system.

Adrenalectomy↗