THE MECHANISM OF PROTECTIVE EFFECT OF DILTIAZEM ON REPERFUSION-INDUCED ARRHYTHMIAS IN ISOLATED RAT HEART : 51st Annual Meeting of the Japanese Circulation Society

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This investigation was undertaken to define the mechanism by which diltiazem protects against life-thereatening, reperfusion-induced arrhythmias. Using an isolated retrogressively perfused rat heart preparation with transient coronary artery occlusion, we compared the effects of diltiazem in its active form (d-cis) to its stereo-isomer (1-cis). Pre-ischemic administration of d-diltiazem (5 × 10^<-8> , 5 × 10^<-7> , 5 × 10^<-6> M) caused a dose-dependent reduction in ventricular arrhythmias upon reperfusion following 10 min of regional ischemia. The incidence of reperfusion-induced ventricular fibrillation (RVF) was 50%, 0% (P<0.05) and 0% (P<0.05) with 5 × 10^<-8>, 5 × 10^<-7>, 5 × 10^<-6> M diltiazem, respectively, compared with 60% in the control group. Pre-ischemic administration of the 1-isomer caused different dose-dependent reduction in RVF. With 5 × 10^<-6>M, the l-isomer also reduced the incidence of RVF to 0% (P<0.05). However below this concentration it was ineffective (67%). D-diltiazem (5 × 10^<-7> and 5 × 10^<-6>M) increased coronary flow from 11.5 ± 1.9 ml/min to 15.3 ± 1.6 ml/min (p<0.05) and 15.2 ± 1.0 ml/min (p<0.05) respectively, prior to ischemia. In contrast. the same dose of the 1-isomer did not alter coronary flow. The highest dose (5 × 10^<-6>M) of d-diltiazem decreased heart rate by approximately 30% during the reperfusion phase, but all other concentrations had no significant effects. The high-energy phosphate content of the ischemic myocardium was significantly elevated after treatment with diltiazem. ATP content was increased from 11.1 ± 3.7 μmol/g dry weight to 18.0 ± 1.8 μmol/g dry weight (p<0.05), 17.2 ± 2.9 μmol/g dry weight (p<0.05) and 17.9 ± 3.4 μmol/g dry weight (p<0.05) with 5 × 10^<-8>, 5 × 10^<-7> and 5 × 10^<-6>M diltiazem. The 1-isomer, at 5 × 10^<-7>M, preserved ischemic myocardial creatine phosphate content (16.9 ± 5.6 μmol/g dry weight: p<0.05 compared to 6.2 ± 1.8 μmol/g dry , wt in the control group) however the ATP content was not significantly higher. Thus, effects of the drugs on coronary flow, heart rate and high-energy phosphate content failed to explain the anti-arrhythmic properties of diltiazem. We conclude that the protective effect of diltiazem against reperfusion-induced arrhythmias is mediated mainly by its specific effect on the slow calcium channel, although a sodium channel blocking effect may also play an additional role.
社団法人日本循環器学会の論文
1990-01-20

THE MECHANISM OF PROTECTIVE EFFECT OF DILTIAZEM ON REPERFUSION-INDUCED ARRHYTHMIAS IN ISOLATED RAT HEART : 51st Annual Meeting of the Japanese Circulation Society

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