Diltiazem inhibition of sodium-induced calcium release. Effects on energy metabolism of heart mitochondria.
The effect of d-cis-diltiazem, a calcium antagonist, on calcium transport processes of rabbit heart mitochondria was studied in vitro. Up to a concentration of 350 mumol/L, the drug produced very little effect on calcium uptake; however, the rate of sodium-induced calcium release progressively decreased as diltiazem concentrations increased. The diltiazem concentration required to inhibit half the rate (IC50) of calcium release induced by 10 mmol/L of sodium chloride was 4.5 mumol/L. The IC50 of the 1-cis isomer of diltiazem was 350 mumol/L, indicating that the inhibitory effect is stereospecific. Of the calcium antagonists, d-cis-diltiazem most effectively inhibited sodium-induced calcium release from heart mitochondria. The consequences of that inhibitory effect were then investigated. When the calcium uptake process was not blocked, the progressive inhibition of sodium-induced calcium release by diltiazem resulted in a net gain of calcium by mitochondria in vitro, suggesting that a similar effect in vivo may increase intramitochondrial calcium. To determine whether sodium-induced calcium release affects respiration and whether diltiazem prevents this effect, we studied the effects of sodium ion and diltiazem on respiration and oxidative phosphorylation of isolated mitochondria. Sodium was found to decrease the rate of state 3 respiration, respiratory control index, and rate of oxidative phosphorylation; diltiazem prevented these effects on mitochondria. Diltiazem's effect was attributed to increased intramitochondrial calcium because of inhibited sodium-induced calcium release and activation of calcium-sensitive dehydrogenases in the matrix. The data indicate that diltiazem may increase the rate of ATP synthesis by mitochondria due to increased intramitochondrial calcium resulting from inhibition of sodium induced Ca2+ release.
Matlib
M A
MA
Department of Pharmacology and Cell Biophysics, University of Cincinnati College of Medicine, OH 45267-0575.
McFarland
K L
KL
D000818:Animals; D002118:Calcium / Q000037:antagonists & inhibitors*; D004110:Diltiazem / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D007656:Ketoglutaric Acids / Q000494:pharmacology; D008929:Mitochondria, Heart / Q000187:drug effects*; D009994:Osmolar Concentration; D010085:Oxidative Phosphorylation / Q000187:drug effects; D010101:Oxygen Consumption / Q000187:drug effects; D011817:Rabbits; D012964:Sodium / Q000494:pharmacology*
D007656:Ketoglutaric Acids; D012964:Sodium; D004110:Diltiazem; D002118:Calcium