Summary
Dihydropyridine compounds are an important group that serve as powerful tools for probing the structure and function of calcium channels in a variety of tissues as well as being important therapeutic agents. The 1,4-dihydropyridine calcium channel antagonists such as nisoldipine and nitrendipine are among the most patent inhibitors of Ca influx in cardiac and smooth muscle cells. The actions of these drugs have been shown to depend very strongly on the membrane potential of the cell. The drugs inhibit current more potently at depolarized membrane potentials. This activity has been suggested to be due to an interaction with the inactivated state of these channels, which is favored at depolarized membrane voltages. Another series of structurally related dihydropyridines (calcium channel agonists) has been shown to enhance currents through calcium channels primarily by prolonging the mean open time of the channels [5]. However, even the activity of this group of drugs depends on membrane potential, and at positive voltages the agonists can promote antagonist-like effects [18]. We are presently investigating the mechanisms behind these voltage-dependent actions. Our experiments are designed to determine whether antagonists such as nisoldipine do, in fact, interact with the inactivated state of the calcium channel and to test the possibility that antagonism and agonism are mediated by distinct receptors, access to which depends on the state of the channel and, in turn, membrane potential.
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Armstrong CM (1969) Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J Gen Physiol 54: 553–575
Bennett P, KcKinney L, Begenisich T, Kass RS (1986) Adrenergic modulation of the delayed rectifier potassium channel in calf cardiac Purkinje fibers. Biophys J 49: 839–848
Ferry DR, Glassman H (1982) Evidence for multiple receptor sites within the putative calcium channel. Naunyn Schmiedebergs Arch Pharrnacol 321: 80–83
Green F, Farmer BB, Wiseman GL, Jose MJL, Watanabe A (1985) Effect of membrane depolarization on binding of [3H]-nitrendipine to rat cardiac myocytes. Circ 56: 576–585
Hess (1984) Nature 311: 538–543
Hille B (1977) Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol 69: 497–515
Hondeghem LM, Katzung BG (1977) Time- and voltage-dependent interactions of antiarrhythmic drugs with cardiac sodium channels. Biochim Biophys Acta 472: 373–398
Janis RA, Triggle DJ (1983) New developments in Ca channel antagonists. J Med Chern 26: 775–785
Kass RS (1982) Nisoldipine: a new, more selective calcium current blocker in cardiac Purkinje fibers. J Pharmacal Exp Ther 223: 446–456
Kass RS (1984) Delayed rectification in the cardiac Purkunje fiber is not activated by intracellular calcium. Biophys J 45: 837–839
Kass RS, Krafte DS (1987) Negative surface charge density near heart calcium channels: relevance to single channel studies and block by dihydropyridines. J Gen Physiol 837–839
Kass RS, Tsien RW (1975) Multiple effects of Ca antagonists on plateau currents in cardiac Purkinje fibers. J Gen Physiol 66: 169–192
Kass RS, Siegelbaum SA, Tsien RW (1979) Three-micro-electrode voltage clamp experiments in calf cardiac Purkinje fibres: is slow inward current adequately measured? J Physiol (Paris) 290: 201–225
Kokubun S, Prod’hom B, Becker C, Porzig H, Reuter H (1986) Studies on Ca channels in intact cardiac cells: voltage-dependent effects and cooperative interactions of dihydropyridine enantiomers. Mol Pharmacal 30: 571–584
Marty A, Neher E (1983) Tight-seal whole-cell recording. In: Neher E, Sakmann B. (eds.) Single channel recording. Plenum, New York, pp 107–121
Rios E, Brum G (1987) Involvement of dihydropyridine receptors in excitation-contraction coupling in skeletal muscle. Nature 325: 717–720
Rodenkirchen R, Bayer R, Mannhold R (1982) Specific and non-specific Ca antagonists. A structure-activity analysis of cardiodepressive drugs. Pro Pharmacol 5: 9–23
Sanguinetti MC, Kass RS (1984) Voltage-dependent block of calcium channel current in the calf cardiac Purkinje fiber by dihydropyridine calcium channel antagonists. Circ Res 55: 336–348
Takahashi M, Catterall WA (1987) Identification ofan alpha subunit of dihydropyridine-sensitive brain calcium channels. Science 236: 88–91
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© 1987 Springer-Verlag Berlin Heidelberg
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Kass, R.S., Arena, J.P., Wiener, R.S. (1987). Membrane Potential and Nisoldipine Block of Calcium Channels in the Heart: Interactions with Channel Gating. In: Hugenholtz, P.G., Meyer, J. (eds) Nisoldipine 1987. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-642-73010-8_2
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DOI: https://doi.org/10.1007/978-3-642-73010-8_2
Publisher Name: Springer, Berlin, Heidelberg
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