INJURY TO THE CA2-RETICULUM IN ANESTHETIZED DOGS CONTRIBUTES TO MYOCARDIAL REPERFUSION INJURY( ATPASE OF THE SARCOPLASMIC)

Objective: Sarcoplasmic reticulum dysfunction may contribute to calciu m (Ca2+) overload during myocardial reperfusion. The aim of this study was to investigate its role in reperfusion injury. Methods: Open ches t dogs undergoing 15 min of left anterior descending coronary artery o cclusion and 3 h of reperfusion were randomized to intracoronary infus ions of 0.9% saline, vehicle, or the Ca2+ channel antagonist, nifedipi ne (50 mu g/min from 2 minutes before to 5 minutes after reperfusion). After each experiment, transmural myocardial biopsies were removed fr om ischemic/reperfused and nonischemic myocardium in the beating state and analyzed for (i) sarcoplasmic reticulum protein content (Ca2+ ATP ase, phospholamban, and calsequestrin) by immunoblotting and (ii) Ca2 uptake by sarcoplasmic reticulum vesicles with and without 300 microm olar ryanodine or the Ca2+ ATPase activator, antiphospholamban (2D12) antibody. Results: Contractile function did not recover in controls an d vehicle-treated dogs after ischemia and reperfusion (mean systolic s hortening, -2 +/- 2%), but completely recovered in nifedipine-treated dogs (17 +/- 2%, p = NS vs. baseline, p < 0.01 vs. control). Ventricul ar fibrillation occurred in 50% of controls and vehicle dogs and 0% of nifedipine-treated dogs (p < 0.01). Ca2+ uptake by the sarcoplasmic r eticulum vesicles was severely reduced in ischemic/reperfused myocardi um of controls and vehicle dogs (p < 0.01 vs. nonischemic). Ryanodine and the 2D12 antibody improved, but did not reverse the low Ca2+ uptak e. Protein content was similar in ischemic/reperfused and nonischemic myocardium. In contrast, Ca2+ uptake and the responses to ryanodine an d 2D12 antibody were normal in ischemic/reperfused myocardium from nif edipine-treated dogs. Conclusion: Dysfunction of the sarcoplasmic reti culum Ca2+ ATPase pump correlates with reperfusion injury. Reactivatio n of Ca2+ channels at reperfusion contributed to Ca2+ pump dysfunction . Ca2+ pump injury may be a critical event in myocardial reperfusion i njury. (C) 1997 Elsevier Science B.V.