Bay K 8644, modifier of calcium transport and energy metabolism in rat heart mitochondria: a new intracellular site of action.
1. The dihydropyridine Ca2+ channel agonist Bay K 8644 (10-200 microM) produced a concentration-dependent increase in State 4 respiration in the rat heart mitochondria with the highest concentration (200 microM) increasing the rate from 33.1 +/- 0.7 to 187.0 +/- 13.3 ng atoms O2 consumed min-1 mg-1 protein. 2. Bay K 8644 (200 microM) reduced State 3 respiration from 247.2 +/- 11.7 to 174.4 +/- 0.06 ng atoms O2 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 microM), the rate increasing from 22.6 +/- 1.0 to 33.1 +/- 1.8 ng atoms O2 consumed min-1 mg-1 protein in the presence of 200 microM nitrendipine. 4. Bay K 8644 (10-60 microM) increased the total Ca2+ uptake into rat heart mitochondria, the total increasing from 248.8 +/- 8.4 to 406.9 +/- 17.6 ng Ca2+ mg-1 protein at 60 microM Bay K 8644 (EC50 = 18.9 +/- 1.4 microM). 5. Bay K 8644 (10-60 microM) produced a concentration-dependent reduction in the Ca2+ influx rate (IC50 = 52.5 +/- 2.8 microM). Similar effects were seen with (+)-Bay K 8644 and (-)-Bay K 8644. 6. Nitrendipine (40-120 microM) stimulated Ca2+ efflux from mitochondria preloaded with the ion; the efflux rate increasing from 2.9 +/- 0.05 to 114.2 +/- 6.2 nmol Ca2+ min-1 mg-1 protein (EC50 = 57.3 +/- 1.3 microM). 7. These data indicate dihydropyridine-induced changes in the activity of the mitochondrial Na+/Ca2 . antiporter pathway; nitrendipine causing stimulation and Bay K 8644 causing inhibition.
Baydoun
A R
AR
School of Pharmacology, Faculty of Science, Sunderland Polytechnic.
Markham
A
A
Morgan
R M
RM
Sweetman
A J
AJ
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001693:Biological Transport, Active / Q000187:drug effects; D002118:Calcium / Q000378:metabolism*; D004110:Diltiazem / Q000494:pharmacology; D004734:Energy Metabolism / Q000187:drug effects; D005260:Female; D005971:Glutamates / Q000378:metabolism; D066298:In Vitro Techniques; D008293:Malates / Q000378:metabolism; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009243:NAD / Q000378:metabolism; D009568:Nitrendipine / Q000494:pharmacology; D010084:Oxidation-Reduction; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D012430:Ruthenium Red / Q000494:pharmacology; D014700:Verapamil / Q000494:pharmacology
D005971:Glutamates; D008293:Malates; D009243:NAD; D012430:Ruthenium Red; D000244:Adenosine Diphosphate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D009568:Nitrendipine; D014700:Verapamil; D004110:Diltiazem; D002118:Calcium