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Diltiazem Inhibition of Sodium-Induced Calcium Release

1991; Oxford University Press; Volume: 4; Issue: 7_Pt_2 Linguagem: Inglês

10.1093/ajh/4.7.435s

1941-7225

Mohammed A. Matlib, Kevin L. McFarland,

Molecular Sensors and Ion Detection

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 //mol/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 μmol/L. The IC50 of the d-cis isomer of diltiazem was 350 μmol/L, indicating that the inhibitory effect is stereospecific. Of the calcium antagonists, rf-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 sodiuminduced Ca2+ release. Am J Hypertens 1991;4:435S-441S