Biomedical subjects

R S Sheldon

Publications and source records attributed to R S Sheldon.

71 records · Page 4Linked to original sources

PubMed1988

Stereospecific interaction of tocainide with the cardiac sodium channel.

The antiarrhythmic action of type I antiarrhythmic drugs may be mediated via binding of the drugs to a receptor associated with the cardiac sodium channel. This suggested that the effects of type I drugs might be stereospecific. We measured the effect of the tocainide stereoisomers (which have stereospecific antiarrhythmic effects) on conduction time and on radioligand binding to the cardiac sodium channel. The concentration-dependent effects of the individual enantiomers of tocainide on interventricular conduction time measured during constant rate ventricular pacing at 350 msec were assessed in 47 isolated perfused rabbit heart preparations. Significant increases (p less than 0.05) in conduction time occurred for both R-(-)-tocainide (75 microM, 10 +/- 5 msec) and S-(+)-tocainide (150 microM, 4 +/- 1 msec). R-(-)-Tocainide was more potent than the S-(+)-tocainide in prolonging conduction time (p less than 0.05). This stereospecific prolongation of conduction time suggested a stereospecific interaction with the sodium channel. The affinities of the enantiomers for the channel were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate and freshly isolated cardiac myocytes. Both enantiomers inhibited [3H]batrachotoxin benzoate binding, but the IC50 (+/- SD) values were different: R-(-)-tocainide 184 +/- 8 microM; S-(+)-tocainide, 546 +/- 37 microM (p less than 0.003). Tocainide isomers are stereospecific in terms of prolonging conduction time and in binding to the sodium channel. The stereospecific electrophysiologic effects of tocainide may result from binding to a receptor associated with the cardiac sodium channel.

Animals↗

PubMed1988

Determinants of stereospecific binding of type I antiarrhythmic drugs to cardiac sodium channels.

The determinants of stereospecific binding of type I antiarrhythmic drugs to specific sites associated with the sodium channel were assessed using rat cardiac myocytes. The asymmetric carbon atoms of stereoisomers may be located at two sites within type I drugs. The structure of these drugs can be schematically illustrated as Aromatic-C1-link-C2-Amine, where C1 and C2 represent potentially asymmetric carbon atoms. We used enantiomeric pairs with either C1 or C2 asymmetric carbon atoms to assess the importance of conformation at these sites to drug binding. The affinities of enantiomers of seven sodium channel blockers were measured with a radioligand binding assay using [3H]batrachotoxinin benzoate [( 3H]BTXB) and freshly isolated cardiac myocytes. The enantiomers inhibited [3H]BTXB binding in a dose-dependent manner, with a mean Hill number of 1.0 +/- 0.1. The ratios of affinities [IC50 of (+)-isomer/IC50 of (-)-isomer] were, for the C1 pairs: quinidine, 0.29; cinchonidine, 0.55; disopyramide, 1.11; RAC 109, 5.33; and for C2 pairs: flecainide, 1.03; mexiletine, 2.15; tocainide, 3.01. The stereospecific differences in drug binding suggest that the orientations of both the aromatic and the amine groups to the rest of the drug molecule are important determinants of drug binding to the cardiac sodium channel. This also suggests the presence of at least two stereospecific domains within the binding sites for type I antiarrhythmic drugs.

Animals↗

PubMed1987

A receptor for type I antiarrhythmic drugs associated with rat cardiac sodium channels.

We assessed the effects of type I antiarrhythmic drugs on the binding of ligands to receptors on voltage-sensitive sodium channels of rat cardiac myocytes. The radioligand was [3H]batrachotoxinin A 20 alpha-benzoate ([3H]BTXB), a toxin that binds to the sodium channel. The 8 drugs tested inhibited [3H]BTXB binding in a dose-dependent fashion with IC50 values from 1.34 microM for O-demethylencainide to 811 microM for procainamide. A log-log plot of IC50 versus mean therapeutic serum concentration yielded a regression line with slope of 1.17 and r of 0.95. Scatchard analysis of [3H]BTXB binding showed that lidocaine reduced the maximal binding without altering the KD for [3H]BTXB binding, indicating allosteric inhibition. The inhibition by lidocaine of [3H]BTXB binding was reversible within 30 minutes when the samples were diluted from 390 to 39 microM lidocaine. In other studies, the stereoisomers of tocainide were shown to have a threefold to fourfold difference in IC50 for inhibition of [3H]BTXB binding. The binding of antiarrhythmic drugs to this site is saturable, reversible, and stereospecific and occurs at pharmacologically relevant concentrations with similar rank order of potency in vivo and in vitro. This suggests that binding at this site relates to pharmacologic activity.

Animals↗

PubMed1987

Intraventricular masses detected by radionuclide angiocardiography.

Two patients are described in whom intraventricular tumors were incidentally detected by radionuclide angiocardiography. This finding led, in one patient, to surgical cure.

Adult↗

PubMed1987

Hypoparathyroidism and pseudotumor cerebri: an infrequent clinical association.

We report a patient with chronic, untreated idiopathic hypoparathyroidism who presented with papilledema and progressive deterioration of visual function. The papilledema resolved with treatment of the hypocalcemia. Visual acuity progressively improved as the serum calcium rose during treatment with vitamin D and calcium supplements. Lumbar puncture may also have contributed to the normalization of cerebrospinal fluid pressure and recovery of vision in this patient. The association of hypoparathyroidism and pseudotumor cerebri is rare, and a retrospective review of 41 patients with hypoparathyroidism admitted to two local general hospitals revealed no other cases.

Adult↗

PubMed1986

Binding of [3H]batrachotoxinin A benzoate to specific sites on rat cardiac sodium channels.

Radiolabeled neurotoxins have been used to study the structure and function of sodium channels. We studied the binding of [3H] batrachotoxinin A 20 alpha-benzoate [( 3H]BTX-B) to specific sites on sodium channels on rat cardiac myocytes. Calcium-tolerant myocytes were prepared by collagenase dispersion of adult rat hearts and were 75-83% viable. As with the nerve channel, specific binding of [3H]BTX-B to its receptor site was seen only in the presence of sea anemone toxin (ATX). The affinity of ATX for its binding sites may be estimated from its concentration-dependent stimulatory effect on [3H]BTX-B binding. These results suggest that, in the presence of 5.4 mM KCl, the myocytes have two affinities for ATX with estimated dissociation constants of 0.52 microM and 12.9 microM. Depolarization of the myocytes with either 65 mM KCl or 0.1 mM BaCl2 results in the loss of the 0.52 microM component, suggesting that it is voltage sensitive. The 0.52 microM and 12.9 microM components have maximal binding capacities corresponding to 4 and 11 sites/micron 2 of myocyte surface area, respectively. Scatchard analysis of [3H]BTX-B binding in the presence of ATX demonstrates a single class of sites with a KD of 25-35 nM. These results demonstrate that [3H]BTX-B can be used as a radioligand probe of the adult rat sodium channel and will facilitate a biochemical approach to the study of the interaction between antiarrhythmic drugs and the sodium channel.

Animals↗

PubMed1977

A spring-loaded needle for amniocentesis.

The spring-loaded needle for amniocentesis that is described has theoretic advantages over a spinal needle. These include increased safety for the fetus and better recognition of when the needle enters the uterine cavity.

Amniocentesis↗

PubMed1974