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Kinetic modulation of guinea‐pig cardiac L‐type calcium channels by fendiline and reversal of the effects of Bay K 8644
Author(s) -
Schreibmayer Wolfgang,
Tripathi Onkar,
Tritthart Helmut A.
Publication year - 1992
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1992.tb14308.x
Subject(s) - chemistry , nifedipine , dihydropyridine , agonist , calcium channel , verapamil , endocrinology , l type calcium channel , bay k8644 , medicine , calcium , voltage dependent calcium channel , receptor , biochemistry
1 The modulation of L‐type calcium channel current ( I Ca ) 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 I Ca is accompanied by modulation of the channel kinetics in a complex manner. The time course of I Ca inactivation is significantly faster and the channel availability (f∞) 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 μ m fendiline a further reduction of I Ca instead of the expected stimulatory effect was observed. 4 A similar ‘paradoxical’ inhibition of I Ca 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 IC 50 for fendiline was reduced to 3.0 ± 0.1 μ m (control value: 17.0 ± 2.4 μ m ) and the Hill slope in its presence was increased to 1.90 ± 0.1 (control value: 1.39 ±0.23) by 1 μ m (4R, 4S)‐Bay K 8644. 6 (4R,4S)‐Bay K 8644 caused the expected stimulation of I Ca 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.