Effect of dantrolene in an in vivo and in vitro model of myocardial reperfusion injury

Background: In skeletal muscle, dantrolene reduces free cytosolic calcium b y inhibiting calcium release from the sarcoplasmic reticulum. A similar eff ect in ischemic-reperfused heart cells would protect myocardial tissue agai nst reperfusion injury We tested the hypothesis that dantrolene infusion du ring reperfusion protects the heart against reperfusion injury. Methods: Isovolumetric beating rat hearts were subjected to 30 min of ische mia followed by 60 min of reperfusion. Left ventricular (LV) developed pres sure (LVDP) and creatine kinase release (CKR) were determined as indices of myocardial performance and cellular injury, respectively. Zn the treatment groups, dantrolene (25 (DAN25) or 100 (DAN100) mu mol l(-1))was infused du ring the first 15 min of reperfusion; control hearts received the respectiv e concentration of the vehicle (mannitol (CON25, CON100), each group n=7). To investigate the effects of dantrolene on reperfusion injury in vivo, 18 chloralose-anesthetized rabbits were subjected to 30 min occlusion and 180 min reperfusion of a major coronary artery. LV pressure (LVP), cardiac outp ut (CO), and infarct size were determined. During the last 5 min of ischemi a, nine rabbits received 10 mg kg(-1) dantrolene intravenously (DAN). Anoth er nine rabbits received the vehicle (dimethylsulfoxide) and served as cont rols (CON). Results: In isolated rat hearts, there was no recovery of LVDP in any group . Total CKR during 1 h of reperfusion was 845+/-76 (CON100) and 550+/-81 U g(-1) dry mass (DAN100, P<0.05). In rabbits ill vine, hemodynamic baseline values were similar between groups (CON vs. DAN: LVP, 99+/-6 (mean+/-SEM) v s. 91+/-6 mm Hg, P=0.29; CO, 252+/-26 vs. 275+/-23 ml min(-1), P=0.53). Dur ing coronary artery occlusion, LVP and CO were reduced in both groups (CON: LVP, 89+/-3%; CO, 90+/-5% of baseline values) and LVP did nut recover to b aseline values during reperfusion (51+/-5% (CON) vs. 65+/-7% (DAN) of basel ine, P=0.10). Infarct size was 41+/-4% of the area at risk in controls and 37+/-6% in dantrolene treated hearts (P=0.59). Conclusions: Dantrolene reduced CKR, indicating an attenuation of lethal ce llular reperfusion injury in isolated rat hearts. However, in the rabbit il l vivo, there was no effect on the extent of reperfusion injury after regio nal myocardial ischemia.