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Biomedical subjects

H C Gonick

Publications and source records attributed to H C Gonick.

At least 37 records · Page 2Linked to original sources
PubMed1993

Predominance of high molecular weight plasma Na(+)-K(+)-ATPase inhibitor in essential hypertension.

Circulating inhibitors of the transport enzyme, sodium-potassium-activated adenosine triphosphatase (Na(+)-K(+)-ATPase), have been shown to be of possible pathogenetic importance in the mechanism of essential hypertension. Although previous studies have demonstrated the presence of both high molecular weight (HMW) and low molecular weight (LMW) natriuretic plasma Na(+)-K(+)-ATPase inhibitors, no previous attempts have been made to ascertain whether HMW or LMW forms predominate in hypertension. In this study, plasma samples obtained from 26 patients with essential hypertension, 12 normotensive controls, and six normotensives with a family history of hypertension, were separated into HMW and LMW moieties by passage through a 1 kDa Amicon membrane. The LMW moiety was separated on C18 Sep-Pak cartridges, applying a 10% step-wise acetonitrile trifluoroacetic acid gradient. The HMW moiety was further separated on Sephadex G-75. Sodium dodecyl sulfate polyacrylamide gel electrophoresis revealed that the fraction with inhibitory activity contained a distinct 12 kDa protein band, with staining intensity depending on the presence or absence of hypertension. Na(+)-K(+)-ATPase inhibitory activity was found in several LMW fractions, but differences between hypertensives and normotensives were observed in only one fraction (0.29 +/- 0.12 SD v 0.11 +/- .12 mumol/L ouabain equivalents, P < .01). Na(+)-K(+)-ATPase inhibitory activity in the HMW fraction was 38 x the inhibitory activity in the LMW fraction and was significantly increased in hypertensives as compared to normotensive controls (10.9 +/- 8.9 v 1.3 +/- 0.8 mumol/L ouabain equivalents, P < .01). Inhibitory activity in both HMW and LMW fractions correlated positively with mean blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Chromatography, Ion Exchange↗
PubMed1993

Lead-induced hypertension: possible role of endothelial factors.

The results of this study confirm that low lead (0.01%) but not high lead (0.5%) administration results in increased blood pressure in rats treated for up to 12 months. This effect appeared to be related to an imbalance of endothelially-derived vasoconstrictor and vasodilator compounds in low lead-treated animals but not in high lead-treated animals. In low lead-treated rats, measurement of plasma endothelins 1 and 3 (ET-1 and ET-3) revealed that ET-3 concentration increased significantly after both 3 months (Experimental, 92.1 +/- 9.7 v Control, 46.7 +/- 12.0 pmol/mL; P < .001) and 12 months (Experimental, 105.0 +/- 9.3 v Control, 94.1 +/- 5.0 pmol/mL; P < .01) while ET-1 was unaffected. Plasma and urinary cGMP concentrations (as a reflection of endothelium-derived relaxing factor (EDRF)) decreased significantly at 3 months (plasma, Experimental, 1.8 +/- 0.9 v Control, 4.2 +/- 1.6 pmol/mL; P < .001) and 12 months (plasma, Experimental, 2.2 +/- 0.7 v Control, 4.2 +/- 0.9 pmol/mL; P < .001). Thus, the path to development of hypertension in low lead rats may be through an increase in the concentration of the vasoconstrictor hormone, ET-3, and a decrease in the vasodilator hormone, EDRF. High levels of lead exposure did not result in hypertension, perhaps because plasma concentrations of ET-1, ET-3 and cGMP were unaltered at 3 months, while ET-1, ET-3 and cGMP concentrations were coordinately and significantly decreased at 12 months.

Animals↗
PubMed1993

Comparison of low-molecular-weight plasma and urine Na-K-ATPase inhibitors/hypertensive factors.

Two highly purified low-molecular-weight (< 500 Da) Na-K-ATPase inhibitors, one originating from human plasma and the second from human urine, which both eluted in the identical locus from a C18 reversed-phase high-pressure liquid chromatography (HPLC) column, were compared with respect to (a) K effect on Na-K-ATPase inhibition; (b) displacement of [3H]ouabain from binding sites on purified hog brain Na-K-ATPase; (c) cross-reactivity with digoxin antibodies; and (d) vasoconstrictor effects in isolated rabbit femoral arteries. Inhibition of Na-K-ATPase by the plasma factor correlated inversely with K concentration, whereas inhibition by the urine factor correlated directly with K concentration. In the absence of K, the plasma factor displaced [3H]ouabain from both high- and low-affinity binding sites, whereas the urine factor displaced [3H]ouabain only from the low-affinity binding site. Neither factor possessed digoxin-like immunoreactivity. Both factors acted as direct vasoconstrictors, and potentiated the vasoconstrictor action of norepinephrine. The degree of vasoconstriction caused by the plasma factor diminished progressively with added K, indicating that the vasoconstrictor effect of this factor was mediated by the Na-K-ATPase pump. Thus, although both the plasma and urine Na-K-ATPase inhibitors are vasoconstrictors, their mechanisms of action are different.

Animals↗
PubMed1992

Experimental model of lead nephropathy. II. Effect of removal from lead exposure and chelation treatment with dimercaptosuccinic acid (DMSA).

Male Sprague-Dawley rats were exposed to high-dose (0.5%) lead acetate for periods ranging from 1 to 9 months; then lead exposure was discontinued, and animals were sacrificed after 12 months. Controls were pair-fed. Two additional groups of low-dose (0.01%) and high-dose (0.5%) rats were exposed to lead for 6 months, then lead was discontinued and the rats were treated with three 5-day courses of 0.5% DMSA (dimercaptosuccinic acid) over the next 6 months. Controls were rats exposed to lead for 6 months, then removed from exposure for 6 months without receiving DMSA. Low-dose lead-treated rats showed no significant pathological changes with or without DMSA treatment, but exhibited a significant increase in GFR after DMSA. High-dose lead-treated animals showed no functional or pathological changes when lead exposure was discontinued after 1 month. However, when duration of exposure was 6 or 9 months, GFR was decreased and serum creatinine and urea nitrogen were increased as compared to controls. Tubulointerstitial disease was severe. Administration of DMSA resulted in an improvement in GFR and a decrease in albuminuria, together with a reduction in size and number of nuclear inclusion bodies in proximal tubules. However, tubulointerstitial scarring was only minimally reduced. It may be concluded that, except for brief initial exposure, discontinuation of high-dose lead exposure fails to reverse lead-induced renal damage. Treatment with the chelator, DMSA, improves renal function but has less effect on pathological alterations. As GFR improved after DMSA treatment in both low-dose and high-dose lead-treated rats, irrespective of the degree of pathological alterations, it may be concluded that the DMSA effect is most likely mediated by hemodynamic changes.

Acetylglucosaminidase↗
PubMed1992

Experimental model of lead nephropathy. I. Continuous high-dose lead administration.

This study followed the progression of lead nephropathy in male Sprague-Dawley rats (E) administered lead acetate (0.5%) continuously in drinking water for periods ranging from 1 to 12 months. Control animals (C) were pair-fed. Observations included renal pathology by light and electron microscopy, wet and dry kidney weights, and glomerular filtration rate (GFR) to assess renal function. Urinary excretion of lead, the enzymes N-acetyl-beta-D-glucosaminidase (NAG) and glutathione-S-transferase (GST), and brush border antigens (BB50, CG9, and HF5) were utilized to explore possible markers of kidney injury. GFR was increased significantly after three months of lead exposure, but was decreased significantly after 12 months. Kidney wet weights were significantly greater in E than C from three months on. Kidney dry weight/wet weight ratio was constant up to three months, but decreased in E at 12 months. Glomerular diameters were normal at all time periods; the nephromegaly was related primarily to hypertrophy of proximal tubules. Lead inclusion bodies were found in nuclei of proximal convoluted tubules and pars recta at all times. Tubular atrophy and interstitial fibrosis first appeared at six months, and increased in severity thereafter. Brush borders of proximal tubules were disrupted at one and three months, but recovered thereafter. Focal and segmental glomerulosclerosis was observed in 2 of 10 rats at 12 months. Arteries and arterioles remained normal at all time periods. Urinary NAG was elevated in E above C after three months of lead exposure. However, urinary NAG in C also increased with age, obscuring changes in the 12 month E rats. GST was elevated after three months of lead administration in E, not without an attendant age-related increase in C rats. In three-month E rats, urinary brush border antigens were increased above C, but were decreased at six and 12 months, correlating with the morphologic changes in brush border. We conclude that a high dose of lead in rats may initially stimulate both renal cortical hypertrophy and an increase in GFR. Later, the adverse effects of lead on the tubulointerstitium predominate, and GFR falls. The urinary marker, NAG, was abnormal in the early stages of the disease, but age-related changes obscured its utility at later stages; urinary GST appeared to be a more consistent marker of injury.

Acetylglucosaminidase↗
PubMed1990

Effects of lead and a low-molecular-weight endogenous plasma inhibitor on the kinetics of sodium-potassium-activated adenosine triphosphatase and potassium-activated p-nitrophenylphosphatase.

1. Lead, ouabain and an endogenous plasma inhibitor were all found to be potent inhibitors of purified hog cerebral cortex sodium-potassium-activated adenosine triphosphatase and potassium-stimulated p-nitrophenyl-phosphatase. 2. The kinetic characteristics of inhibition of both enzymes by lead and the endogenous plasma inhibitor differed in several respects. For sodium-potassium-activated adenosine triphosphatase, lead and the endogenous plasma inhibitor were non-competitive inhibitors with respect to potassium; lead was competitive with respect to sodium, whereas the endogenous plasma inhibitor had no effect; lead was competitive with respect to magnesium adenosine triphosphate, whereas the endogenous plasma inhibitor was uncompetitive. For potassium-activated p-nitrophenylphosphatase, both lead and the endogenous plasma inhibitor were competitive with respect to potassium; lead showed a mixed type of inhibition with respect to p-nitrophenylphosphate, whereas the endogenous plasma inhibitor was non-competitive. 3. Lead and the endogenous plasma inhibitor exhibited synergistic inhibitory activity on sodium-potassium-activated adenosine triphosphatase. 4. These results suggest that lead could play a contributory role in the pathogenesis of essential hypertension via an additive inhibition of vascular smooth muscle sodium-potassium-activated adenosine triphosphatase.

4-Nitrophenylphosphatase↗
PubMed1989

Effects of a human-derived sodium transport inhibitor on in vitro vascular reactivity.

Concentrations of sodium-transport inhibitors (STI) which block the sodium-potassium-ATPase pump are increased in the plasma and urine of volume-expanded and low-renin hypertensive humans and animals. To evaluate the physiologic relevance of STI to blood-pressure-raising mechanisms, we have examined the in vitro properties of STI extracted from the urine of human subjects. STI produced a significant (by ANOVA: P less than .01) dose-contraction response in the isolated rabbit femoral artery. Moreover, small noncontractile doses of STI in this in vitro preparation produced a fivefold leftward shift in the contraction dose-response curve of norepinephrine (P less than .01) and a threefold shift for angiotensin II (P less than .01); at lower, physiologic, concentrations of these vasoconstrictor hormones the amplifications in contraction caused by STI ranged from 100% to 500%. In studies in calcium-free tissue bath solutions, the direct contractile action of STI was abolished; however, its amplification of responses to norepinephrine remained, suggesting that this latter effect of STI is not entirely dependent upon calcium influx into vascular smooth muscle cells. The glycoside ouabain produced effects identical to those of STI in arteries, but its actions on a rabbit atrium preparation were different: ouabain stimulated powerful inotropic effects, whereas human STI failed to cause myocardial contractions even though the amounts of STI administered had the same sodium-transport inhibitory capacity as the ouabain. Thus, the actions of human STI are primarily in the peripheral circulation, where they directly produce arterial contractions and also enhance contractile responses to other pressor hormones, suggesting that they may have a role in regulating systemic blood pressure.

Angiotensin II↗
PubMed1989

Aluminum-binding protein in dialysis dementia. I. Characterization in plasma by gel chromatography and electrophoresis.

A low molecular weight (approx. 8,000 daltons) protein has been found to be the major aluminum-binding protein in plasma of patients with dialysis dementia. Following treatment with desferrioxamine, the concentration of the low molecular weight protein and its aluminum content rise in parallel. The results suggest that aluminum exposure in dialysis dementia may result in the de novo synthesis of an aluminum-binding protein and that desferrioxamine may release aluminum in conjunction with its binding protein from tissue stores.

Aluminum↗
PubMed1989

Aluminum-binding protein in dialysis dementia. II. Characterization in plasma by ultrafiltration.

Ultrafiltration experiments, using Amicon membranes with molecular weight exclusions of 1,000, 10,000 and 30,000 daltons, have revealed that Desferal, both in vitro and in vivo, markedly increases aluminum ultrafilterability in plasma from patients with dialysis dementia. Ultrafilterability was greater with the 10,000-dalton membrane (60%) as compared with the 1,000-dalton membrane (40%); the difference could be related to the presence of an 8,000-dalton aluminum-binding protein in the 10,000-dalton filtrate. These observations are pertinent to in vivo dialysis studies which have demonstrated enhanced aluminum clearance with high-permeability polyacrylonitrile dialysis membranes.

Aluminum↗
PubMed1989

Renal lesions and clinical findings in thalassemia major and other chronic anemias with hemosiderosis.

Renal lesions found in 21 autopsied patients with hemosiderosis, 18 with beta-thalassemia, two with Blackfan-Diamond anemia, and one with aplastic anemia included: cellular glomeruli with increased mesangial matrix; hemosiderin deposit in visceral and parietal glomerular epithelial cells; greater hemosiderin deposit in terminal straight portions of proximal convoluted tubules and distal convoluted tubules than in connecting segments, or collecting tubules, connective tissue ferrugination; lipofuscin in tubular epithelium and vascular smooth muscle; infrequently, intimal or medial arterial thickening, and, in one patient with thalassemia, an infarct resulting from arterial thrombus. The progression of these lesions over the course of disease, and possible effects on the various lesions of high transfusion regimen, oral pancreatin, vitamin E supplementation, or treatment with intramuscular, subcutaneous, or intravenous desferrioxamine were evaluated. The results of urine and renal function studies of 4 of the autopsied patients (3 thalassemia, 1 Blackfan-Diamond anemia), and 14 patients with thalassemia and 4 with Blackfan-Diamond anemia who were not autopsied, are presented. Rarely significant until preterminal stages, the renal functional changes reflect distal more than proximal tubule dysfunction.

Adolescent↗
PubMed1989

Mineral balance (iron, aluminum, copper, zinc) after high-dose intravenous Desferal in a child with hemoglobin Hammersmith and Turner's syndrome.

A 12-day balance study with measurements of urine and stool excretion was undertaken to determine the effects of intravenous (i.v.) Desferal (293 mg/kg/24 h x 2) on iron, aluminum, copper, and zinc in a child with Hemoglobin Hammersmith and Turner's syndrome treated as a thalassemia major patient because of symptoms of anemia and ineffective erythropoiesis. Iron balance was positive, 34 mg/3 days baseline. The Desferal infusion induced iron excretion of 117 mg over 48 h, almost equally in stool and urine. This child receives approximately 20 transfusion/i.v. Desferal treatments yearly. If iron excretion is roughly the same with each treatment, it would equal 2,340 mg or 47% of her annual iron intake from transfusion. The i.v. infusions are an important part of this patient's therapy and may also be useful for other chronic transfusion patients for whom subcutaneous Desferal is inadequate for preventing continued iron accumulation. Some patients have successfully received their i.v. Desferal therapy at home, thereby decreasing hospitalization time and cost. Desferal induced moderate aluminum excretion in urine but had no effect on copper or zinc excretion.

Child↗
PubMed1987

Pattern of Na-K-ATPase inhibitors in plasma and urine of hypertensive patients: a preliminary report.

The pattern of endogenous Na-K-ATPase inhibitors in plasma and urine from patients with essential hypertension and normal controls was established by sequential Amicon ultrafiltration through membranes with molecular weight cut-offs of 50 K daltons, 30 K daltons and 1 K daltons, followed by C18 Sep-Pak cartridge separation of the 1 K filtrate. Significantly increased Na-K-ATPase inhibitory activity in the hypertensive population was found in a high molecular weight (30-50 K daltons) urine fraction, one low molecular weight (less than 1 K daltons) urine fraction and two low molecular weight plasma fractions. Preliminary evidence is presented to suggest that large molecular weight plasma fractions may contain a "masked" Na-K-ATPase inhibitor, in either carrier or precursor form.

Blood Proteins↗
PubMed1986

In vitro inhibition of Na-K-ATPase by trace metals: relation to renal and cardiovascular damage.

The potential role of trace metals in the pathogenesis of various disease states, especially of renal and cardiovascular disease, has been recognized increasingly. Moreover, altered membrane transport was recently incriminated to play a role in renal tubular syndromes, such as the Fanconi syndrome, as well as in the pathogenesis of volume dependent hypertension. We therefore investigated the possible in vitro effects of various trace metals on Na-K-ATPase, the biochemical correlate of active cellular transmembrane sodium and sodium-dependent transport. To more closely mimic the in vivo situation, we deliberately chose as enzyme source renal tissue homogenate, which may contain protective agents. Under these experimental conditions, the metals studied inhibited the enzyme quantitatively in the following order: Hg greater than Pb greater than Cd greater than Ur greater than Cu greater than Zn greater than Mn greater than Ba greater than Ni greater than Sr. Enzyme kinetic studies showed that Hg, Pb, and Cd competitively, and Cu noncompetitively, inhibited the enzyme. In general, Mg-ATPase was significantly less sensitive to the trace metals. Accumulation of these metals may present serious health hazards by producing a general defect in cell membrane transport. From the other metals studied, i.e., Mn, Ba, Ni and Sr, some may have toxic effects via other mechanisms, whereas some may exert a protective role against toxicity of other agents including metal ions.

Animals↗
PubMed1985

Observations on the "cascade" of Na-K-ATPase inhibitory and digoxin-like immunoreactive material in human urine: possible relevance to essential hypertension.

Previous investigations have demonstrated an increased amount of a sodium pump inhibitor (N.H.) in plasma from humans with essential hypertension and from animals with various forms of experimental hypertension. The present study has employed Sephadex column and C18 reverse phase separation of urines from patients with essential hypertension and normal controls to distinguish "high", "intermediate" and "low" molecular weight forms of N.H., measured through properties of Na-K-ATPase inhibition and digoxin-like immunoreactivity. The major difference between hypertensive and normotensive urines was a highly significant increase in the "intermediate" molecular weight form of N.H., as measured by Na-K-ATPase inhibition. In contrast, digoxin-like immunoreactivity was significantly decreased in urine from hypertensive patients. The results are compatible with an hypothesis that the defect in some forms of essential hypertension may be partial inhibition of enzymatic conversion of intermediate to final form of N.H., with the increased sodium pump inhibition primarily related to the precursor.

Chromatography, Gel↗
PubMed1982

Pathophysiology of human proximal tubular transport defects.

The generalized proximal tubular transport abnormalities comprising the Fanconi syndrome (glycosuria, generalized aminoaciduria, the proximal form of renal tubular acidosis, and increased renal clearance of phosphate, urate, calcium, magnesium, and potassium) may be ascribed to interference with "sodiumlinked" active transport. Evidence is presented that the majority of conditions known to cause Fanconi syndrome in man or experimental animals are associated with inhibitors of the renal Na-K-ATPase-ATP transport system.

Adenosine Triphosphate↗
PubMed1982

Subclinical effects of chronic increased lead absorption--a prospective study. Part IV. Evaluation of heme synthesis effects.

The effects of lead exposure on heme synthesis in workers with subclinical responses and in controls were evaluated. delta-Aminolevulinic acid dehydratase (ALA-d) correlated significantly with blood lead levels in the control group but not with those in the exposed group. Free erythrocyte protoporphyrin correlated significantly with blood lead levels in the exposed group but not with those in the controls and was found to be a good indicator of blood lead history among exposed persons. Hemoglobin values determined at initial employment were not statistically different from those determined during the baseline test for a group of 12 workers with a maximum blood lead level of 86 micrograms/100 ml during their exposure history. The effect such heme inhibition may have on other body functions is uncertain.

Environmental Exposure↗