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Schreibmayer, W; Tripathi, O; Tritthart, HA.
Kinetic modulation of guinea-pig cardiac L-type calcium channels by fendiline and reversal of the effects of Bay K 8644.
Br J Pharmacol. 1992; 106(1):151-156 Doi: 10.1111/j.1476-5381.1992.tb14308.x [OPEN ACCESS]
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Leading authors Med Uni Graz: Schreibmayer Wolfgang
Co-authors Med Uni Graz: Tritthart Helmut
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Abstract:: 1. The modulation of L-type calcium channel current (ICa) by fendiline, a diphenylalkylamine type of calcium channel blocker was investigated on guinea-pig ventricular myocytes by use of the whole-cell patch-clamp technique. 2. Fendiline-induced block of ICa is accompanied by modulation of the channel kinetics in a complex manner. The time course of ICa inactivation is significantly faster and the channel availability (f infinity) curve is shifted considerably to more negative potentials by fendiline. These findings can be interpreted qualitatively in terms of a modulated receptor. 3. When the 1,4-dihydropyridine agonist (4R, 4S)-Bay K 8644 was added in presence of 30 microM fendiline a further reduction of ICa instead of the expected stimulatory effect was observed. 4. A similar 'paradoxical' inhibition of ICa was produced by the pure agonist enantiomer (4S)-Bay K 8644. Thus this novel effect of Bay K 8644 cannot be attributed to changes in affinity of the 1,4-dihydropyridine receptor site for (4R)-Bay K 8644 during fendiline action. 5. The IC50 for fendiline was reduced to 3.0 +/- 0.1 microM (control value: 17.0 +/- 2.4 microM) and the Hill slope in its presence was increased to 1.90 +/- 0.1 (control value: 1.39 +/- 0.23) by 1 microM (4R, 4S)-Bay K 8644. 6. (4R,4S)-Bay K 8644 caused the expected stimulation of ICa in the presence of verapamil, diltiazem and nifedipine, overcoming the inhibitory effect of these calcium channel blockers. 7. The 'paradoxical' inhibitory effect of the agonist Bay K 8644 can be explained in terms of an allosteric interaction between fendiline and the dihydropyridine agonist.
Find related publications in this database (using NLM MeSH Indexing): 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester - pharmacology; Animals - pharmacology; Calcium Channel Blockers - pharmacology; Calcium Channels - drug effects; Cells, Cultured - drug effects; Drug Interactions - drug effects; Fendiline - pharmacology; Guinea Pigs - pharmacology; Heart - drug effects; Myocardium - cytology
Find related publications in this database (Keywords): L-Type Calcium Channel; Fendiline; Bay K 8644; Guinea-Pig Ventricular Mycetes