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J K Aronson

Publications and source records attributed to J K Aronson.

At least 91 records · Page 5Linked to original sources
PubMed1991

Evidence for altered Na+/H+ antiport activity in cultured skeletal muscle cells and vascular smooth muscle cells from the spontaneously hypertensive rat.

1. Intracellular pH and Na+/H+ antiport activity were determined by a fluorimetric method in cultured skeletal muscle cells (myoblasts) and aortic vascular smooth muscle cells from spontaneously hypertensive and normotensive Wistar-Kyoto rats. 2. The intracellular pH was significantly more alkaline at three different extracellular pH values in both myoblasts and vascular smooth muscle cells from the spontaneously hypertensive rats than in those from the normotensive control rats. 3. A kinetic analysis of the Na+/H+ antiport activity in these cells showed that the raised activity in the spontaneously hypertensive rats was due to an increased maximal transport capacity in vascular smooth muscle cells and to an increase in the affinity of the antiport for internal H+ in the myoblasts. 4. When the extracellular pH was reduced in the skeletal muscle cells of both types of rat, the intracellular pH fell. However, in vascular smooth muscle cells, a reduction in the extracellular pH was not associated with a fall in the intracellular pH. This resistance of the intracellular pH to changes in the extracellular pH differentiates vascular smooth muscle cells from other cells that have been studied in this way.

Animals↗
PubMed1991

Na+/H+ and HCO3-/Cl- exchange in the control of intracellular pH in vivo in the spontaneously hypertensive rat.

1. We have previously shown that the cytosolic acid concentration changes in skeletal muscle during contraction in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats in vivo. We have now found that this change was unaffected by 20% inhaled CO2 or by 4,4'-di-isothiocyanostilbene-2,2'-disulphonate. This is evidence that HCO3- exchange in vivo is not important in the control of cytosolic acid concentration during skeletal muscle contraction in either spontaneously hypertensive or Wistar-Kyoto rats. 2. We have also previously shown that the difference in cytosolic acid response during contraction between spontaneously hypertensive and Wistar-Kyoto rats is due to increased Na+/H+ antiporter activity in the spontaneously hypertensive rats. Our current findings suggest that this increase in Na+/H+ antiporter activity is more likely to be due to a change in the Km of the antiporter than to a change in the Vmax. We estimate that the Km of the antiporter changes in hypertension from pH 7.16 to 7.33. 3. We did not find any differences between adult spontaneously hypertensive and Wistar-Kyoto rats with regard to resting intracellular and extracellular pH and resting intracellular and extracellular HCO3- concentrations. In addition, we did not find any evidence of a difference in skeletal muscle HCO3-/Cl- exchange between adult spontaneously hypertensive and Wistar-Kyoto rats. 4. At rest, skeletal muscles of the spontaneously hypertensive and Wistar-Kyoto rats have the same lactate production, HCO3-/Cl- exchange and arterial partial pressure of CO2. In addition, we can also calculate that at a resting intracellular pH of 7.05 in the spontaneously hypertensive rats, the antiporter is 66% saturated.(ABSTRACT TRUNCATED AT 250 WORDS)

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

The effect of nifedipine on the disposition of strontium gluconate used as a kinetic marker for calcium in healthy volunteers.

1. We have studied the disposition of stable strontium after the intravenous administration of strontium gluconate to eight healthy male volunteers both in control conditions and while they were taking the calcium antagonist nifedipine 10 mg three times daily. 2. Nifedipine, presumably by its action in blocking voltage-operated calcium channels, altered the in vivo disposition of strontium, causing large reductions in the half-life and the apparent volume of distribution of strontium. Total and renal clearances of strontium were unaltered by nifedipine. 3. These results support our previous suggestion that the delineation of strontium disposition can be used as a means of studying calcium disposition in vivo in man, and of studying the effects of drugs and diseases on that disposition.

Adult↗
PubMed1991

Intravenous strontium gluconate as a kinetic marker for calcium in healthy volunteers.

1. We have studied the pharmacokinetics of stable strontium in 10 healthy male volunteers. We gave each volunteer 5 mmol strontium gluconate by intravenous infusion over 1 h and measured strontium concentrations in plasma and urine samples for 20 days. The plasma strontium concentration vs time data for each volunteer were fitted by a triexponential function using NONLIN. Compartmental model-dependent and model-independent pharmacokinetic variables were then calculated. 2. The mean half-life we report (5.4 days) is longer than that previously reported (about 2 days), since we continued sampling for 20 days. However, the rates of clearance (CL 9.4 ml min-1. CLR 5.4 ml min-1, and CLNR 4.0 ml min-1) are similar to those previously reported, and the apparent volume of distribution at steady state (64 l) is similar to the values previously reported for the size of the exchangeable pool of both strontium and calcium. 3. The similarities in the pharmacokinetic behavior of strontium and calcium suggest that the in vivo disposition of strontium may be used as a marker of calcium disposition and for studying the effects of drugs such as the calcium antagonists.

Adult↗
PubMed1990

The effects of a low extracellular concentration of potassium on the activity and numbers of Na+/K+ pumps in an EB-virus transformed human lymphocyte cell line.

The BM1A EB-virus transformed human lymphocyte cell line contains approximately 950,000 Na+/K(+)-ATPase sites per cell. The turnover number of each site is approx. 2240 molecules of rubidium per min. When cells are exposed to a low extracellular concentration of potassium the intracellular concentration of sodium rises, and the cells respond in the short term by increasing the Vmax of 86Rb+ uptake. In the longer term the cells respond by increasing both the Vmax of 86Rb+ uptake and the Bmax of [3H]ouabain binding. The suggestion that increases in the intracellular concentration of sodium is responsible for these changes is supported by the finding that monensin, which increases intracellular sodium without affecting intracellular potassium, is capable of inducing both the short- and long-term changes associated with a low external concentration of potassium.

5'-Nucleotidase↗
PubMed1990

A non-invasive method of measuring concentrations of rubidium in rat skeletal muscle in vivo by 87Rb nuclear magnetic resonance spectroscopy: implications for the measurement of cation transport activity in vivo.

1. We have used n.m.r. spectroscopy to measure rubidium concentrations in the skeletal muscle of live intact rats. Using a 1.9 T superconducting magnet and an ear-phone coil tuned to both protons (1H) and rubidium (87Rb), it was possible to make measurements of both tissue rubidium content and water content, and from these measurements to obtain the rubidium concentration. 2. The n.m.r. estimate of rubidium concentration in muscle in vivo was found to be a constant 31% (SEM 4%) of that estimated by flame atomic absorption spectroscopy in an extract of excised muscle. This is close to the predicted theoretical n.m.r. visibility of 33%. The visibility was constant for muscle rubidium concentrations ranging between 10 and 34 mmol/l. 3. Rubidium concentration measurement by this method is unaffected by variations in sample geometry, sample volume, tissue conductivity, coil tuning and amplifier gain. 4. By using this method to measure changes in tissue rubidium concentration with time in the same animal, it should now be possible to assess the activity of ion transport systems, such as sodium- and potassium-activated adenosine triphosphatase in vivo, by measuring the rates of change of tissue rubidium concentrations during the administration of rubidium salts. 5. This method could also be used to measure the absolute concentration of any n.m.r.-visible nucleus and could be applied to man.

Animals↗
PubMed1990

Evidence for increased in vivo Na(+)-H+ antiporter activity and an altered skeletal muscle contractile response in the spontaneously hypertensive rat.

We have assessed the in vivo activity of the Na(+)-H+ antiporter skeletal muscle in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls using phosphorus (31P) nuclear magnetic resonance spectroscopy to measure changes in cytosolic acid concentrations during isometric contraction. During contraction there was a small rate of rise in skeletal muscle cytosolic acid concentration to a smaller maximum concentration in SHR. This difference in acid response was removed by amiloride and was not attributable to differences in cell buffering or the rate of production of lactic acid, suggesting that the difference in acid response in SHR skeletal muscle is due to increased in vivo Na(+)-H+ antiporter activity. Amiloride reduced resting muscle glycogen concentration and increased muscle lactate concentration in the SHR. This could be related to altered in vivo calcium metabolism. The maximum tension produced by skeletal muscle during contraction in SHR was less than in WKY rats, and relaxation between twitches was significantly greater, consistent with the finding of increased vascular smooth muscle relaxation in essential hypertension. Since increased Na(+)-H+ antiporter activity occurs in association with increased relaxation of both skeletal and vascular smooth muscle, these data are not consistent with a relationship between increased Na(+)-H+ antiporter activity and increased maximal muscle tension development. However, they show that increase Na(+)-H+ antiporter activity is associated with increased muscle relaxation.

Amiloride↗
PubMed1990

Evidence for increased in vivo sodium-potassium pump activity and potassium efflux in skeletal muscle of spontaneously hypertensive rats.

We have used 87Rb nuclear magnetic resonance spectroscopy (NMR) to study in vivo rubidium kinetics in spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls, using rubidium as a marker for potassium. We gave 15 male, 13-week-old SHR, mean +/- s.d. blood pressure 180 +/- 10 mmHg, and 15 age-matched normotensive controls, mean blood pressure 120 +/- 9 mmHg, a daily dose of RbCl (2 mmol/kg intraperitoneally). We made repeated NMR measurements of skeletal muscle rubidium concentrations until steady state was reached. We then withdrew rubidium and made further measurements of rubidium concentrations, at intervals, for up to 1 week after the last injection. We also measured plasma and erythrocyte rubidium concentrations by flame atomic absorption spectroscopy at similar intervals after the withdrawal of rubidium. Rubidium concentrations rose at a faster rate in SHR skeletal muscle, but the steady-state muscle rubidium concentration was the same (45 mmol/l) in both SHR and WKY rats. There was also a threefold increase in the rate of rubidium efflux from both muscle and erythrocytes in SHR. These results are consistent with a marked increase in Na+,K(+)-ATPase activity and an increase in the rate of rubidium efflux in vivo in SHR. The increased rate of rubidium efflux in SHR could represent increased K+ efflux via calcium-activated K+ channels and/or result as part of cell volume regulation secondary to increased Na(+)-H+ antiporter activity.

Animals↗
PubMed1990

The effect of oral salbutamol on cation transport measured in vivo in healthy volunteers.

1. We have measured the effect of oral salbutamol on cation transport in vivo by studying the disposition of an oral load of rubidium chloride in healthy treated volunteers and in untreated matched controls. 2. During the administration of salbutamol there was a significantly lower plasma rubidium concentration 5 h after the administration of the oral load of rubidium chloride, reflecting an increase in the net clearance of rubidium from the plasma into at least some tissues in vivo. 3. There was no difference in either intraerythrocytic rubidium concentrations or the pseudo-rate constant for erythrocyte rubidium uptake in vivo after salbutamol. 4. Ex vivo incubation of whole blood preloaded in vivo with rubidium showed that the clearance of rubidium from the plasma was inhibited by 95% in the presence of the Na+,K(+)-ATPase inhibitor digoxin. 5. These data suggest that salbutamol stimulates cation transport via Na+,K(+)-ATPase in vivo into some tissues but not into the erythrocyte. 6. This pattern of change in rubidium disposition after salbutamol is completely different from the patterns of change we have seen in patients with essential hypertension or acute manic illness. We therefore suggest that the changes in erythrocyte rubidium uptake which we have previously described in vivo in patients with essential hypertension or acute manic illness do not result from beta 2-adrenoceptor-mediated catecholamine stimulation of Na+,K(+)-ATPase.

Administration, Oral↗
PubMed1989

Measurement of cation transport in vivo in healthy volunteers after the oral administration of lithium carbonate.

1. We have measured cation transport in vivo in seven healthy volunteers under control conditions and after they had taken lithium carbonate for 21 days in doses which maintained the serum lithium concentration in the range 0.6-0.8 mmol/l. 2. We have measured cation transport in vivo after the administration of an oral load of rubidium chloride, and have found that, although intra-erythrocytic concentrations of rubidium were significantly lower 1 h after the administration of rubidium when the subjects were taking lithium, there was a significant increase in the rate of uptake of rubidium into the erythrocytes over the subsequent period of the test, suggesting a direct stimulation of sodium, potassium-activated adenosine triphosphatase by lithium. 3. Lithium administration did not affect the plasma concentration versus time profile of rubidium after the rubidium load, implying that the lithium-stimulated uptake of rubidium which occurs in erythrocytes does not necessarily occur in other cell types. 4. These results suggest that previous studies of cation transport using peripheral cells and assay systems in vitro do not necessarily reflect changes in cation transport in vivo in excitable tissues.

Administration, Oral↗
PubMed1989

A study of the transport of lithium across the erythrocyte membrane in vivo and of the effects of the ion transport inhibitors digoxin and dipyridamole.

1. We have given an oral load of lithium carbonate to healthy volunteers in order to investigate the transport of lithium across the erythrocyte membrane in vivo and the effects of known inhibitors of that transport. 2. Using this technique we have shown that pretreatment with either digoxin, an inhibitor of the sodium/potassium pump, or dipyridamole, an inhibitor of the anion transporter, does not alter the plasma or erythrocyte lithium concentration profiles, nor any of the pharmacokinetic variables derived from these data, and we conclude that these two transport pathways do not contribute significantly to the in vivo handling of lithium by erythrocytes. 3. We have also shown that erythrocyte lithium concentrations measured directly differ significantly from the predicted concentrations calculated using the two-compartment pharmacokinetic model which has been used in some earlier comparisons of in vitro and in vivo lithium handling. 4. We suggest that the in vivo administration of lithium carbonate may permit a specific measure of the in vivo activity of the sodium/sodium countertransport pathway.

Adult↗
PubMed1989

Clinical, haemodynamic, and pharmacological effects of withdrawal and reintroduction of digoxin in patients with heart failure in sinus rhythm after long term treatment.

A randomised, double blind, placebo controlled, crossover study of digoxin withdrawal and reintroduction was carried out over two periods of eight weeks each after long term treatment. Forty four patients with stable heart failure in sinus rhythm and plasma digoxin concentrations over 0.8 ng/ml were studied. Their progress was assessed by clinical criteria, by haemodynamic measurements (systolic time intervals and echocardiography), and by pharmacological measurements of erythrocytic sodium pump numbers and activity. After withdrawal of digoxin clinical deterioration occurred in only 25% of the patients. Furthermore, in only 9% of cases was digoxin reintroduction thought to be necessary. There was deterioration in only 11% of the patients during digoxin treatment. Deterioration during digoxin withdrawal was accompanied by changes in systolic time intervals, but similar, albeit smaller changes in systolic time intervals also occurred in patients with no deterioration. Deterioration was accompanied by changes in the pharmacological effects of digoxin on the erythrocytes, consistent with a loss of effect, and these changes did not occur in those who did not deteriorate. The occurrence of deterioration could not be predicted by any clinical, haemodynamic, or pharmacological measurements made before withdrawal.

Adult↗
PubMed1989

The effect of lithium on cation transport measured in vivo in patients suffering from bipolar affective illness.

We have investigated cation transport in vivo in patients being treated with lithium for bipolar affective illness by studying the disposition of rubidium after an oral load of rubidium chloride. The rate of erythrocyte cation transport was increased in the patients when compared with matched healthy volunteers. However, the rate of in-vivo erythrocyte rubidium accumulation in the euthymic treated patients was significantly lower than in a matched group of unmedicated manic patients. The regulation of specific pathways for cation transport may be altered in individuals predisposed to affective illness.

Adult↗
PubMed1987

Enhancement of specific [3H]ouabain binding and ouabain sensitive 86rubidium influx in intact human lymphocytes by a dialysable factor in human and fetal calf serum.

We have measured specific [3H]ouabain binding and ouabain sensitive 86rubidium influx in intact human lymphocytes incubated for up to 7 days in media containing different concentrations of fetal calf serum and human serum. Incubation for periods of up to 7 days with fetal calf serum and human serum produced increases in both specific [3H]ouabain binding and ouabain sensitive 86rubidium influx that were dependent on concentration and time. Neither specific [3H]ouabain binding nor ouabain sensitive 86rubidium influx was altered when dialysed serum was used, suggesting that both fetal calf serum and human serum contain a dialysable factor or factors which stimulate specific [3H]ouabain binding and ouabain sensitive 86rubidium influx in intact human lymphocytes. To further elucidate the mechanisms underlying these changes we also measured the activity of two other enzymes of the lymphocyte plasma membrane, 5'-nucleotidase and gamma-glutamyltransferase, the uptake of [3H]thymidine by the intact cells, and the effects of cycloheximide, puromycin, and anisomycin, inhibitors of protein synthesis. The activity of 5'-nucleotidase was increased after incubation of the lymphocytes in fetal calf serum for 72 h, but the activity of gamma-glutamyltransferase was not changed, suggesting some selectivity of the stimulatory effect. Measurements of [3H]thymidine uptake by the lymphocytes showed that the major part of the observed changes in specific [3H]ouabain binding and ouabain sensitive 86rubidium influx was not attributable to transformation of the lymphocytes to lymphoblasts. All three inhibitors of protein synthesis prevented the increase in specific [3H]ouabain binding due to fetal calf serum.

5'-Nucleotidase↗