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Bay K 8644, modifier of calcium transport and energy metabolism in rat heart mitochondria: a new intracellular site of action
Author(s) -
Baydoun Anwar R.,
Markham Anthony,
Morgan Rae M.,
Sweetman Alan J.
Publication year - 1990
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.1476-5381.1990.tb12081.x
Subject(s) - nitrendipine , dihydropyridine , calcium , chemistry , respiration , endocrinology , medicine , biochemistry , biology , anatomy
1 The dihydropyridine Ca 2+ channel agonist Bay K 8644 (10–200 μ m ) produced a concentration‐dependent increase in State 4 respiration in the rat heart mitochondria with the highest concentration (200 μ m ) increasing the rate from 33.1 ± 0.7 to 187.0 ± 13.3 ng atoms O 2 consumed min −1 mg −1 protein. 2 Bay K 8644 (200 μ m ) reduced State 3 respiration from 247.2 ± 11.7 to 174.4 ± 0.06 ng atoms O 2 min −1 mg −1 protein, reduced the respiratory control index (RCI) from 5.3 ± 0.45 to 1.1 ± 0.03 and reduced the ADP:O ratio from 2.75 ± 0.03 to 1.3 ± 0.15. 3 A similar, but smaller, stimulation of State 4 respiration was seen with nitrendipine (25–200 μ m ), the rate increasing from 22.6 ± 1.0 to 33.1 ± 1.8 ng atoms O 2 consumed min −1 mg −1 protein in the presence of 200 μ m nitrendipine. 4 Bay K 8644 (10–60 μ m ) increased the total Ca 2+ uptake into rat heart mitochondria, the total increasing from 248.8 ± 8.4 to 406.9 ± 17.6 ng Ca 2+ mg −1 protein at 60 μ m Bay K 8644 (EC 50 = 18.9 ± 1.4 μ m ). 5 Bay K 8644 (10–60 μ m ) produced a concentration‐dependent reduction in the Ca 2+ influx rate (IC 50 = 52.5 ± 2.8 μ m ). Similar effects were seen with (+)‐Bay K 8644 and (−)‐Bay K 8644. 6 Nitrendipine (40–120 μ m ) stimulated Ca 2+ efflux from mitochondria preloaded with the ion; the efflux rate increasing from 2.9 ± 0.05 to 114.2 ± 6.2 nmol Ca 2+ min −1 mg −1 protein (EC 50 = 57.3 ± 1.3 μ m ). 7 These data indicate dihydropyridine‐induced changes in the activity of the mitochondrial Na + /Ca 2+ . antiporter pathway; nitrendipine causing stimulation and Bay K 8644 causing inhibition.