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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↗
PubMed1984

Influence of adrenalectomy and steroid replacement on heart citrate synthase levels.

Aldosterone-dependent changes in citrate synthase (CS) activity have been used as an index of mineralocorticoid target sites. However, adrenalectomy (ADX) resulted in a fall in activity of CS and several other enzymes in rabbit heart, a tissue with glucocorticoid-but not mineralocorticoid-specific receptors. The enzymes included CS (2.03-1.36 U/mg protein, normal----ADX, P less than 0.001), isocitrate dehydrogenase-NADP+ (1.10-0.80 U/mg, P less than 0.002), isocitrate dehydrogenase-NAD+ (0.034-0.020 U/mg, P less than 0.01), and hydroxymethylglutaryl-CoA lyase (0.072 to 0.035 U/mg, P less than 0.001); in contrast, mitochondrial malate dehydrogenase levels were not significantly reduced by adrenal loss. There was also a decrease after surgery in sarcolemmal Na-K-(17.30-12.31 mumol Pi . mg protein-1 . h-1, P less than 0.002) and Mg-ATPase activities (14.16-12.11 mumol Pi . mg protein-1 . h-1, P less than 0.05). However, ADX did not result in a significant change in heart weight per kilogram body weight or recovery of mitochondrial protein per gram heart. CS was also assayed in hearts from ADX animals following acute (90 min) and chronic (3 day) steroid replacement. Although neither acute intravenous aldosterone (10 micrograms/kg) nor dexamethasone (100 micrograms/kg) increased activity, exposure to multiple subcutaneous injections of either steroid over a 3-day period significantly elevated CS above ADX values. The coordinate changes in the levels of several myocardial enzymes associated with energy metabolism is discussed in terms of an adaptation to chronic alterations in energy demands as opposed to specific mineralocorticoid or glucocorticoid receptor-mediated processes.

Adenosine Triphosphatases↗
PubMed1984

Evidence of corticosteroid action along the nephron.

The kidney contains three classes of corticosteroid-binding proteins receptors. They include a mineralocorticoid-specific (Type I), a glucocorticoid-specific (Type II), and a corticosterone-specific (Type III) site. The Type I and Type III sites roughly parallel each other along the nephron, with maximal binding occurring in the late distal convoluted or connecting segment and the cortical and medullary collecting ducts. Type II sites occur throughout the nephron, with maximal concentrations appearing in the proximal tubule and the late distal convoluted-cortical collecting duct region. The function of the Type I sites in the connecting segment is unclear since chronic mineralocorticoid therapy does not influence the potential difference in this segment as it does in the cortical collecting tubule. Furthermore, the specific role of Type II versus Type III sites in the distal nephron is unknown. Finally, the possible influence of sodium on both latent and steroid-induced renal cortical and medullary Na-K-ATPase is discussed.

Adrenal Cortex Hormones↗
PubMed1984

Assessment of mineralocorticoid activity in the rabbit colon.

Analyses of [3H]corticosteroid binding sites in distal colon indicated high-affinity binding sites or receptors for both [3H]aldosterone (Type I, Kd = 6.5 X 10(-9) M) and [3H]dexamethasone (Type II, Kd = 5.5 X 10(-8) M). The relative affinity of dexamethasone (D) was 1/20 that of aldosterone (A) for Type I sites and the affinity of A for Type II sites was 1/50 that of D at 37 degrees C. Citrate synthase (CS) activity was assayed and found to be reduced in enterocytes harvested from adrenalectomized (ADX) vs. normal colon segments (0.24 vs. 0.44 U/mg protein, P less than 0.025). Aldosterone (10 micrograms/kg body wt) increased CS at 2 h to a level intermediate between normal and ADX animals and thus not significantly different from either group, but was significantly increased over ADX + D values. Transmural potential difference was increased by 10(-8) M A but not by 10(-8) M D. Since both steroids enhanced short-circuit current at this concentration, the dichotomy of the glucocorticoid vs. mineralocorticoid results can be best explained by the pronounced effect of D on resistance (R) across the tissue (R at 4 h + D was 50% that of paired controls). These findings would suggest that the rabbit distal colon is a target segment for both mineralocorticoids and glucocorticoids. Furthermore, as in the kidney, the two steroids may play coordinated but, perhaps in some way, unique roles in the regulation of transport.

Adrenalectomy↗
PubMed1981

Secondary effect of aldosterone on Na-KATPase activity in the rabbit cortical collecting tubule.

The possibility that mineralocorticoids have a direct influence on renal Na-K ATPase activity has been the focus of intense research effort and some controversy for a number of years. Early studies were hindered by an inability to differentiate between possible glucocorticoid vs. mineralocorticoid effects on this enzyme within the multitude of cells that comprise the heterogeneous mammalian nephron. This study attempts to circumvent this problem by monitoring Na-K ATPase activity in the rabbit renal cortical collecting tubule (CCT), a proposed target epithelium for mineralocorticoids. Using an ultramicro assay, Na-K ATPase activity was measured in CCT from normal, adrenalectomized (adx), and adx rabbits subjected to one of several corticosteroid treatment protocols. The results indicate that Na-K ATPase activity in the CCT decreased by 86% subsequent to adrenalectomy. Injection of physiological doses of aldosterone (10 micrograms/kg) but not dexamethasone (100 micrograms/kg) restored CCT Na-K ATPase activity in adx rabbits to normal levels within 3 h after injection. An insignificant rise in activity was observed 1.5h after aldosterone treatment. In addition, spirolactone SC 26304, a specific mineralocorticoid antagonist, blocked the action of aldosterone on Na-K ATPase.. Therefore an acute increase in Na-K ATPase activity participates in the action of aldosterone on Na transport in this segment. To differentiate between primary vs. secondary activation of this enzyme, adx animals were treated with amiloride before the injection of aldosterone with the intent of blocking luminal membrane Na entry into CCT. In these animals, pretreatment with amiloride blocked the increase in CCT Na-K ATPase act activity seen with aldosterone alone at 3 h. Thus the increase in activity with aldosterone appears to be a secondary adaptation that is dependent on an aldosterone-enhanced increase in the passive entry of Na across the luminal membrane. The subcellular mechanism by which Na modulates Na-K ATPase activity remains obscure.

Adrenalectomy↗