K. S. Lee

Bio: K. S. Lee is an academic researcher from Yale University. The author has contributed to research in topics: Voltage-dependent calcium channel & Diltiazem. The author has an hindex of 1, co-authored 1 publications receiving 833 citations. Previous affiliations of K. S. Lee include University of Oxford.

Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells

Abstract: Organic inhibitors of calcium influx prevent outward as well as inward current through cardiac calcium channels but do not slow current activation. Although block is antagonized by raising external calcium or barium concentrations, the competitive effect of permeant cations does not occur at the same cation binding site at which inorganic blockers act. Organic drugs show varying degrees of use-dependent block, due in part to blockade of open channels. Nitrendipine blockade of calcium currents requires doses >100-fold higher than expected from radioligand binding to isolated membranes.

Different modes of Ca channel gating behaviour favoured by dihydropyridine Ca agonists and antagonists

Abstract: Single cardiac transmembranous Ca channels have three modes of gating behaviour in the absence of drugs, expressed as current records with brief openings (mode 1), with no openings because of channel unavailability (mode 0 or null mode) and with long-lasting openings and very brief closings that appear only rarely (mode 2). The dihydropyridine Ca agonist Bay K 8644 enhances Ca channel current by promoting mode 2, while the Ca antagonists nitrendipine and nimodipine inhibit the current by favouring mode 0.

Dominant role of N-type Ca2+ channels in evoked release of norepinephrine from sympathetic neurons.

Abstract: Multiple types of calcium channels have been found in neurons, but uncertainty remains about which ones are involved in stimulus-secretion coupling Two types of calcium channels in rat sympathetic neurons were described, and their relative importance in controlling norepinephrine release was analyzed N-type and L-type calcium channels differed in voltage dependence, unitary barium conductance, and pharmacology Nitrendipine inhibited activity of L-type channels but not N-type channels Potassium-evoked norepinephrine release was markedly reduced by cadmium and the conesnail peptide toxin omega-Conus geographus toxin VIA, agents that block both N- and L-type channels, but was little affected by nitrendipine at concentrations that strongly reduce calcium influx, as measured by fura-2 Thus N-type calcium channels play a dominant role in the depolarization-evoked release of norepinephrine

Non-selective conductance in calcium channels of frog muscle: calcium selectivity in a single-file pore.

Abstract: Voltage-clamp studies were carried out to compare currents through Ca2+ channels (ICa) with Na+ currents (Ins) through a non-selective cation conductance blocked by micromolar concentrations of external Ca2+. The gating of both currents was found to have similar time and voltage dependence. The amplitudes of ICa and Ins varied widely, but Ins was always large in fibres with large ICa, and small in fibres with small ICa. Both ICa and Ins were blocked by the specific Ca2+ channel blocker nifedipine, with half-blockage concentrations that were virtually identical (KD = 0.9 microM for ICa and 0.7 microM for Ins). ICa and Ins were also equally sensitive to block by diltiazem (KD = 80 microM). These parallels between Ins and ICa are most easily explained if Ins flows through Ca2+ channels. Apparently, Ca2+ channels bear high-affinity Ca2+-binding sites, and are highly permeable to monovalent cations when Ca2+ is absent. Ba2+ currents (IBa) and ICa were measured in external solutions containing mixtures of Ba2+ and Ca2+. IBa is blocked by Ca2+, as is Ins. Adding Ba2+ to Ca2+ produces only small or no increases in current, as if Ba2+ is only sparingly permeant when Ca2+ is present. Membrane currents in Ba2+/Ca2+ mixtures show anomalous mole-fraction behaviour, suggesting that Ca2+ channels are single-file, multi-ion pores. Complex current transients are observed under maintained depolarizations in Na+/Ca2+ and Ba2+/Ca2+ mixtures. They suggest that in ion mixtures, Ca2+ channels transport Ca2+ in preference to Na+ and Ba2+. Hence Ca2+ channels are selective for Ca2+, even though current amplitudes suggest that the Na+ or Ba2+ permeabilities in the absence of Ca2+ are as high as, or higher than, the Ca2+ permeability. We conclude that the selective permeability of Ca2+ channels depends on the presence of Ca2+. In model calculations, our observations are explained as a consequence of Ca2+ channels being single-file pores. It is proposed that Ca2+ channels derive much of their ion selectivity from high-affinity Ca2+ binding sites located in an otherwise unselective aqueous pore.

Antiarrhythmic Agents: The Modulated Receptor Mechanism of Action of Sodium and Calcium Channel-Blocking Drugs

Abstract: At the time of the last review of antiarrhythmic drugs in this series in 1 975 (1) , the important developments in the field centered around the "classical" agents: lidocaine, procainamide, quinidine, diphenylhydantoin (now phenytoin), and propranolol. That review properly emphasized the importance of new informa­ tion regarding the effects of these agents on diseased tissue (e.g. obtained from infarcted hearts) or on normal tissue stressed in the muscle chamber (e.g. by depolarization with potassium). However, data and concepts available at that time were not sufficient to explain the important differences among the effects of these drugs on different types of cardiac tissue, or the difference in sensitiv­ ity of diseased and depolarized tissue as compared to normal tissue. Since 1 975, a modest revolution in antiarrhythmic drug development, re­ search, and clinical application has occurred. The number of agents in active clinical use or investigation in the U.S. is now more than 18 (2, 3). In addition, a major new class of agents, the calcium channel blockers, has come into general use (4, 5) . Furthermore, an attempt has been made to extend our understanding of the mechanism of action at the molecular level: the modulated receptor hypothesis (6, 7). This review concentrates on the antiarrhythmic drug literature pertinent to an evaluation of the modulated receptor hypothesis. A number of general reviews

Sodium current-induced release of calcium from cardiac sarcoplasmic reticulum

Abstract: The role of sodium-calcium exchange at the sarcolemma in the release of calcium from cardiac sarcoplasmic reticulum was investigated in voltage-clamped, isolated cardiac myocytes. In the absence of calcium entry through voltage-dependent calcium channels, membrane depolarization elicited release of calcium from ryanodine-sensitive internal stores. This process was dependent on sodium entry through tetrodotoxin-sensitive sodium channels. Calcium release under these conditions was also dependent on extracellular calcium concentration, suggesting a calcium-induced trigger release mechanism that involves calcium entry into the cell by sodium-calcium exchange. This sodium current-induced calcium release mechanism may explain, in part, the positive inotropic effects of cardiac glycosides and the negative inotropic effects of a variety of antiarrhythmic drugs that interact with cardiac sodium channels. In response to a transient rise of intracellular sodium, sodium-calcium exchange may promote calcium entry into cardiac cells and trigger sarcoplasmic calcium release during physiologic action potentials.