The structural and functional consequences of the interaction of various antiarrhythmics with human erythrocyte membranes, guinea pig brain synap-tosomes and myocardial sarcolemmal membranes were studied at drug concentrations affecting the stability of intact erythrocytes to hypotonic lysis. It was assumed that such stabilization might bear some molecular resemblance to the electrical stabilizing properties of these drugs in excitable tissues. Membrane perturbational actions of these drugs were measured in terms of the specific incorporation of the chromophoric probes, 5,51-dithio-bis-(2-nitrobenzoic acid) (DTNB) and trinitrobenzenesulfonic acid (TNBS) into membrane sulfhydryl and amino groups respectively. Most drugs tested, including lidocaine, quinidine, the verapamil analogue D-600 and the quaternary analogues QX 572 and pranolium, exhibited a concentration-dependent stimulation of DTNB and TNBS incorporation. At drug concentrations producing erythrocyte stabilization, the protein perturbational properties of quinidine, lidocaine, D-600 and QX 572 as viewed in terms of DTNB labelling were equivalent while differences were apparent with quinidine, D-600 and lidocaine at high concentrations in the destabilizing range. Most agents, with the exception of pranolium, showed a similar pattern of DTNB incorporation in brain synaptic membranes as in erythrocytes. Studies of the incorporation of TNBS into erythrocyte membranes indicated that antiarrhythmics induce greater structural alterations in membrane phospholipids as compared with membrane proteins. Bretylium and practolol, two substances with minimal direct cardiodepressant properties, did not enhance DTNB or TNBS incorporations into erythrocyte membranes, although both agents, especially practolol, possessed marked antihemolytic properties. It appeared, therefore, that the membrane perturbational actions of antiarrhythmics as analyzed here by means of group-specific chemical probes are a better index of their direct myocardial membrane actions than erythrocyte stabilization.
The functional consequences of drug-membrane interaction as reflected in the inhibition of membrane-associated enzymes by antiarrhythmics were shown to be critically dependent on the drug and membrane in question. The activity of erythrocyte membrane ouabain-sensitive K+-stimulated p-nitrophenyl-phosphatase (K+-NPPase) was more readily inhibited than that of Mg++-independent and Mg++-stimulated NPPase by most drugs examined. In myocardial sarcolemmal membranes, lidocaine was stimulatory to the K+-NPPase whereas all other agents exhibited stimulatory actions only at the lowest drug concentrations. The Ca++-ATPase system in the erythrocyte membrane was also inhibited by antiarrhythmics with propranolol, pranolium and lidocaine showing a relatively higher degree of inhibition of the high Ca++ affinity component while quinidine and D-600 exerted equal inhibitory actions on both high and low Ca++ affinity components of the enzyme. A comparison of the perturbational actions of antiarrhythmics in isolated erythrocyte membranes, in the membranes of the intact erythrocyte and in brain synaptic membranes was made by analyzing the effects of drugs on the activity of the membrane acetylcholinesterase present in these preparations. Inhibitory actions of all drugs tested were comparable in both intact and isolated erythrocyte membranes but differed in the excitable tissue membrane. The nature of the inhibition exerted by the antiarrhythmics on acetylcholinesterase of intact erythrocytes was of a mixed type for most drugs except practolol which inhibited non-competitively. The transmembrane chloride gradient had no influence on the inhibition by bretylium, lidocaine and D-600 of the acetylcholinesterase activity of the intact cells but the inhibition produced by quinidine and propranolol was enhanced when erythrocytes were suspended in a low chloride medium.
The foregoing results, therefore, indicate that the membrane perturbational actions of antiarrhythmics vary with the agent in question and with the particular membrane system. It is suggested that the molecular mechanisms by which these drugs alter cardiac automaticity may not be identical and may differ in various regions of the myocardium. This in turn may underlie the differing spectra of clinical effectiveness exhibited by these pharmacological agents. / Medicine, Faculty of / Anesthesiology, Pharmacology and Therapeutics, Department of / Graduate
| Identifer | oai:union.ndltd.org:UBC/oai:circle.library.ubc.ca:2429/20859 |
| Date | January 1978 |
| Creators | Au, Tony Long Sang |
| Source Sets | University of British Columbia |
| Language | English |
| Detected Language | English |
| Type | Text, Thesis/Dissertation |
| Rights | For non-commercial purposes only, such as research, private study and education. Additional conditions apply, see Terms of Use https://open.library.ubc.ca/terms_of_use. |
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