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J K Aronson

Publications and source records attributed to J K Aronson.

At least 55 records · Page 3Linked to original sources
PubMed2000

Voltage-dependent blockade of normal and mutant muscle sodium channels by benzylalcohol.

1. We studied the effects of benzylalcohol on heterologously expressed wild type (WT), paramyotonia congenita (R1448H) and hyperkalaemic periodic paralysis (M1360V) mutant alpha-subunits of human skeletal muscle sodium channels. 2. Benzylalcohol blocked rested channels at -150 mV membrane potential, with an ECR(50) of 5.3 mM in wild type, 5.1 mM in R1448H, and 6.2 mM in M1360V. When blockade was assessed at -100 mV, the ECR(50) was reduced in R1448H (2 mM) compared with both wild type (4.3 mM; P<0.01) and M1360V (4.3 mM). 3. Membrane depolarization before the test depolarization significantly promoted benzylalcohol-induced sodium channel blockade. The values of K(D) for the fast-inactivated state derived from benzylalcohol-induced shifts in steady-state availability curves were 0.66 mM in wild type and 0.58 mM in R1448H. In the presence of slow inactivation induced by 2.5 s depolarizing prepulses, the ECI(50) for benzylalcohol-induced current inhibition was 0.59 mM in wild type and 0.53 mM in R1448H. 4. Recovery from fast inactivation was prolonged in the presence of drug in all clones. 5. Benzylalcohol induced significant frequency-dependent block at stimulating frequencies of 10, 50, and 100 Hz in all clones. 6. Our results clearly show that benzylalcohol is an effective blocker of muscle sodium channels in conditions that are associated with membrane depolarization. Mutants that enter voltage-dependent inactivation at more hyperpolarized membrane potentials compared with wild type are more sensitive to inhibitory effects at the normal resting potential.

Amino Acid Substitution↗
PubMed1999

Identification of system y+L as the high-affinity transporter for L-arginine in human platelets: up-regulation of L-arginine influx in uraemia.

Kinetic studies of L-arginine transport in human platelets have identified a high-affinity, low-capacity transport system [Michaelis-Menten constant (K(m)) about 10 microM] for cationic amino acids that also transports neutral amino acids with high affinity in the presence of Na+ but not K+. These characteristics, together with our kinetic cis-inhibition studies, indicate that saturable L-arginine transport in human platelets is mediated via the system y+L and not the classic cationic transporter system y+. We present here the first evidence that L-arginine transport via system y+L is increased twofold in platelets from patients with chronic renal failure. System y+L has been described in human erythrocytes, peripheral blood mononuclear cells and placenta, and up-regulation of system y+L activity in human platelets could explain the paradox of increased nitric oxide (NO) production by uraemic platelets under conditions of decreased plasma L-arginine and elevated NG-monomethyl-L-arginine (L-NMMA) concentrations.

Amino Acid Transport Systems, Basic↗
PubMed1998

Abnormal function of potassium channels in platelets of patients with Alzheimer's disease.

BACKGROUND: Reports of abnormalities of potassium-channel function in various cultured cells of Alzheimer's disease patients led us to attempt to characterise the pharmacological characteristics of the abnormal channel. METHODS: We studied platelets from 14 patients with Alzheimer-type dementia and 14 non-demented controls matched for age and sex. The effects of specific inhibitors of K+ channels on the efflux of rubidium-86 ions, a radioactive analogue of K+, from the platelets were measured. FINDINGS: Normal platelets contain three types of K+ channel, sensitive to the inhibitory actions of apamin (small-conductance calcium-dependent potassium channels), charybdotoxin (of less specificity, but probably intermediate-conductance calcium-dependent K+ channels), and alpha-dendrotoxin (voltage-sensitive K+ channels). However, 8Rb+ efflux from the platelets of patients with Alzheimer-type dementia was not inhibited by either apamin or charybdotoxin. By contrast, inhibition by alpha-dendrotoxin did occur. INTERPRETATION: Our results suggest that calcium-dependent K+ channels in platelets are selectively impaired in Alzheimer's disease. A similar abnormality in neurons could contribute to the pathophysiology of the disorder.

Aged↗
PubMed1998

Digoxin revisited.

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Cardiotonic Agents↗
PubMed1997

Evidence for an R(+)-[(dihydroindenyl)oxy]alkanoic acid-sensitive K+/Cl- co-transporter in human platelets and its interaction with the Na+/K+/2Cl- co-transporter.

1. The K+/Cl- co-transport system is activated by a number of interventions, such as cell swelling and stimulation with N-ethylmaleimide. It is specifically inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid and requires the presence of K+ and Cl- on the same side of the cell membrane. This co-transporter has been studied extensively, mainly in erythrocytes of many species, in which it plays a key role in cell volume regulation. Here we present evidence that human platelets contain K+/Cl- co-transporters. 2. We have studied the efflux of 86Rb+ (a marker for K+) from 86Rb(+)-loaded human platelets, and have defined their response to stimulation by N-ethylmaleimide. 3. N-Ethylmaleimide (0.5 and 1 mmol/l) stimulated an increase in cumulative 86Rb+ efflux in a concentration-dependent manner. This efflux was inhibited by R(+)-[(dihydroindenyl)oxy]alkanoic acid (10 mumol/l) but was insensitive to bumetanide. It also required the presence of external Cl-. 4. These observations suggest that 86Rb+ efflux from the platelets stimulated by N-ethylmaleimide occurs via K+/Cl- co-transport. 5. When the K+/Cl- co-transporter was stimulated by N-ethylmaleimide we were unable to stimulate the Na+/K+/2Cl- co-transporter with a high external concentration of KCl or inhibit 86Rb+ efflux with bumetanide. Together with other evidence, this suggests that when the K+/Cl- co-transporter is stimulated with N-ethylmaleimide, the Na+/K+/2Cl- co-transporter is inhibited.

Blood Platelets↗
PubMed1997

Pharmacological evidence of calcium-activated and voltage-gated potassium channels in human platelets.

1. Previous electrophysiological studies have suggested the presence of KCa and Kv channels in human platelets. However, the pharmacology of these channels has not been defined. 2. We have studied potassium channels in human platelets by measuring the efflux of 86Rb+ (a marker for K+) from 86Rb(+)-loaded cells, and have defined their responses to stimulation by the platelet agonist thrombin and the calcium ionophore ionomycin. 3. Thrombin (0.1-0.6 i.u./ml) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l), charybdotoxin (300 nmol/l) and alpha-dendrotoxin (100-200 nmol/l), blockers of SKCa channels, KCh channels and Kv channels respectively. Iberiotoxin (300 nmol/l), a specific inhibitor of BKCa channels, had no effect on the thrombin-stimulated 86Rb+ efflux. Although glibenclamide, an inhibitor of KATP channels, inhibited the thrombin-stimulated efflux, it did so only in a high concentration (20 mumol/l). 4. Ionomycin (1-5 mumol/l) stimulated an increase in 86Rb+ efflux from the platelets in a concentration-dependent manner. This efflux was significantly inhibited by apamin (100 nmol/l) and charybdotoxin (300 nmol/l). However, iberiotoxin (300 nmol/l) had no effect on the ionomycin-stimulated 86Rb+ efflux. 5. These findings suggest that 86Rb+ efflux from platelets stimulated by thrombin and ionomycin occurs via two types of KCa channel: SKCa and KCh channels. Thrombin also stimulated efflux via Kv channels.

Apamin↗
PubMed1996

Adverse drug reactions in a hospital general medical unit meriting notification to the Committee on Safety of Medicines.

1. We have retrospectively analysed data collected by a local adverse drug reactions reporting scheme in an acute hospital medical setting and have determined the numbers and types of reactions that would have merited notification as yellow card reports according to the guidelines of the Committee on Safety of Medicines. 2. The data related to 20,695 consecutive acute general medical admissions on seven general medical wards (140 beds) and were collected over 3 years, from April 1990 to March 1993. 3. Over 3 years there were 1420 reports of suspected adverse drug reactions, a rate of 68.7 per 1000 admissions. 4. If the guidelines for reporting issued by the Committee on Safety of Medicines had been strictly followed, 477 yellow cards would have been sent (23.1 per 1000 admissions). In 357 of these reports (74.8%), the reaction had caused admission to hospital. Only 31 of the 477 potential cards (6.5%) involved black triangle drugs and 10 of these were for minor reactions. 5. Only 30 of the 477 potential yellow cards (6.3%) were known to have been sent. The majority of those reactions not reported were for drug-related admissions, most of which were for well-known reactions to established drugs. 6. We have confirmed and quantified the extent of under-reporting of serious suspected adverse drug reactions to the Committee on Safety of Medicines from our hospital medical unit.

Adverse Drug Reaction Reporting Systems↗
PubMed1996

Effects of high external concentrations of K+ on 86Rb+ efflux in human platelets: evidence for Na+/K+/2Cl- co-transport.

1. Na+/K+/2Cl- co-transport mediates a bidirectional symport of Na+, K+ and Cl-. The important properties of the co-transport system are its requirement for Na+, K+ and Cl- and its inhibition by loop diuretics such as bumetanide. This co-transporter has been described in a number of animal and human tissues. However, its presence in human platelets, although inferred, has not been demonstrated directly. 2. We have studied the efflux of 86Rb+ (a marker for K+) from Rb(+)-loaded platelets, and have defined their response to stimulation by high concentrations of external K+. 3. KCl (30-120 mmol/l) stimulated a concentration-dependent increase in 86Rb+ efflux from the platelets. This efflux was completely inhibited by bumetanide (10 mumol/l) but was insensitive to ouabain and R(+)-[(dihydroindenyl)oxy]alkanoic acid. It also required Cl- in the external medium, but did not depend on the presence of extracellular Na+. 4. These observations suggest that 86Rb+ efflux from platelets stimulated by external K+ occurs via Na+/K+/2Cl- co-transport acting in a K+/K+ (K+/Rb+) exchange mode. 5. Non-stimulated efflux of 86Rb+ from the platelets (i.e. in the presence of 5 mmol/l K+) had the characteristics of Na+/K+/2Cl- co-transport acting in normal mode.

Adult↗
PubMed1995

The upregulation of Na+,K(+)-ATPase pump numbers in lymphocytes from the first-degree unaffected relatives of patients with manic depressive psychosis in response to in vitro lithium and sodium ethacrynate.

Patients with manic depressive disorder (DSM-III-R bipolar disorder) have an abnormality of the Na+,K(+)-ATPase pumps in their lymphocytes: the pump numbers do not upregulate to stimulation with lithium and ethacrynate. We have now investigated the in vitro adaptive responses of lymphocyte Na+,K(+)-ATPase pumps in the first-degree unaffected relatives of patients with a clear history of manic depressive disorder. The lymphocytes of the healthy relatives upregulated their Na+,K(+)-ATPase pumps normally, suggesting that the abnormal response that we have previously observed in patients with the disorder reflects a complex relation between the biochemical phenotype and the development of clinical symptoms.

Bipolar Disorder↗
PubMed1995

Prolonged half-life of verapamil in a case of overdose: implications for therapy.

After an overdose of verapamil (2.4 g) in a 59-year-old man the apparent half-life of verapamil was prolonged (15 h). The most likely mechanism is rate-limiting absorption, although changes in clearance and volume of distribution may contribute. As the elimination half-life of verapamil is increased in overdose, therapy may have to be continued for longer than expected. Moreover since the half-life of absorption of verapamil in overdose may be prolonged, activated charcoal should be given in repeated doses, even if an ordinary-release formulation has been taken.

Drug Overdose↗
PubMed1995

Confusion over similar drug names. Problems and solutions.

Confusion over similar drug names is one of the reasons for errors in the prescribing or administration of drugs. The risks of such errors could be reduced by some simple measures. National and international agencies: Licensing authorities should exercise more control over the naming of new proprietary formulations; Nonproprietary names should be internationalised; New proprietary names should be internationalised; Common prefixes in names should be avoided if possible. Pharmaceutical manufacturers: Manufacturers should play their part in ensuring that new names are carefully chosen and internationalised; Over-the-counter formulations should be given unique names; Generic formulations should be marketed under their nonproprietary names, not new proprietary names. Doctors: Should inform patients about the nature and risks of their therapy; Should issue printed prescriptions if possible, or use clearly-penned block capitals in handwritten prescriptions. In most cases they should use nonproprietary names when prescribing. Abbreviations of drug names should never be used. Pharmacists: Should discuss the nature and risks of patients' therapy with them and check that they recognise the medicines they are taking; Should ask patients to hand in their old medicines containers when they fill a new prescription; In hospital, clinical pharmacists can help to check doctors' prescriptions and to liaise between doctors and nurses, advising on correct therapy. Special cases: Special care should be taken with sulphonylureas: manufacturers should produce distinctive formulations and pharmacists should keep them in a separate section in the dispensary.

Humans↗
PubMed1993

Modelling circadian variation in the pharmacokinetics of non-steroidal anti-inflammatory drugs.

A one-compartment model with first-order absorption has provided good fits to five sets of indomethacin data and four sets of ketoprofen data taken at different times of day. There was substantial variation in the model parameters with time of administration and most of the features of this variation applied equally to both drugs. From the data examined, the source of variation appears to be mainly in the absorption phase and this was confirmed using a chronokinetic analysis, in which simultaneous fits were obtained with time-variant rate parameters. However, there may also be circadian variation in protein binding. The danger of quoting parameter values for either of these two drugs based on administration at a single time of day has been illustrated, and this may well be true for other drugs.

Adult↗
PubMed1993

Effects of haemodialysis and continuous ambulatory peritoneal dialysis on abnormalities of ion transport in vivo in patients with chronic renal failure.

1. We have studied Na+/K+ pump activity in vivo in three groups of subjects: patients with chronic renal failure not receiving maintenance dialysis, patients being treated by either haemodialysis or continuous ambulatory peritoneal dialysis, and matched control subjects. 2. To do this we have measured the changes in plasma and intraerythrocytic rubidium concentrations after an oral load of rubidium chloride, having previously shown that changes in the disposition of rubidium measured in this way reflect changes in the activity of the Na+/K+ pump in vivo. 3. Erythrocyte rubidium uptake was significantly reduced both in ten patients with chronic renal failure not receiving maintenance dialysis and in 12 patients being treated by haemodialysis, when compared with 31 healthy control subjects. In contrast, erythrocyte rubidium uptake was not altered in 13 patients treated by continuous ambulatory peritoneal dialysis. There was also a significantly reduced rate constant for erythrocyte rubidium uptake in patients with undialysed chronic renal failure (0.66 h-1) and in those treated by haemodialysis (0.78 h-1), whereas in patients treated by continuous ambulatory peritoneal dialysis the rate constant for erythrocyte rubidium uptake was not significantly different from control values (1.36 h-1 and 1.41 h-1, respectively). 4. These findings are consistent with a reversal of the inhibition of erythrocyte Na+/K+ pump activity in vivo found in chronic renal failure by continuous ambulatory peritoneal dialysis, but not by haemodialysis. This difference may be due to the failure of haemodialysis to clear a circulating inhibitor of Na+, K(+)-ATPase or to the rapid re-accumulation of such an inhibitor after haemodialysis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1993

Evidence for an altered mode of action of the sodium-lithium countertransporter in vivo in patients with untreated essential hypertension.

OBJECTIVE: To study the activity of the sodium-lithium (Na(+)-Li+) countertransport system in vivo in the erythrocytes of patients with untreated essential hypertension. DESIGN: Lithium substitutes for sodium efflux in the sodium-sodium (Na(+)-Na+) countertransport system. In essential hypertension the efflux of lithium from cells in vitro has been used as a measure of the activity of the Na(+)-Na+ countertransporter and has been shown to be increased. We administered oral lithium and used its disposition in erythrocytes to measure Na(+)-Li+ countertransporter activity in vivo. PATIENTS: Ten men with essential hypertension who had never taken any antihypertensive treatment were matched with 10 male controls for age, weight, and plasma and erythrocyte sodium and potassium concentrations. METHODS: Repeated measurements were made of plasma and intra-erythrocytic lithium concentrations during the 48h after the oral administration of 16.2 mmol lithium carbonate. Data were analysed using standard pharmacokinetic techniques. RESULTS: The rate of lithium efflux from the erythrocytes was increased in all patients with hypertension and in none of the normotensive controls. Hill plots derived from in vivo activation curves for erythrocytic Na(+)-Li+ countertransport showed that the normotensive participants had a Hill slope of 1 (SD 0.1), whereas the hypertensives had a Hill slope of 3.2 (SD 1.0). CONCLUSIONS: The activity of the Na(+)-L+ countertransport system is increased in untreated essential hypertension in vivo; this confirms in vitro findings. A new finding is that there is a change in either the stoichiometry or the co-operativity of lithium efflux via the Na(+)-L+ countertransport system, suggesting that the rate of sodium efflux may be greater than that of influx in the cells of people with hypertension.

Antiporters↗