Ultrastructural changes of mitochondria in ischemic and reperfused canine myocardium

ROLE FOR CALMODULIN IN HEART FAILURE. S.W. Schaffer, H.H. Oei H. Jones and K.P. Burton, Dept. Pharmacol., Univ. So. Ala., Mobile, AL. 36688. Several known calmodulin inhibitors were found to pro@ct the perfused rat heart against damage resulting from the2Fa paradox. In the absence of these inhibitors, 8 min of Ca free perfusion followT$ by 15 min of reperfusion with buffer containing 2.5mM Ca led to a 5-6 fold decrease in myocardial ATP and CP levels, a release of 1300 Units/gdw of CPK from the heart and major ultrastructural damage. Hearts treated with 1pM trifluoperazine (a potent calmodulin inhibitor) contained higher concentrations of ATP (8.2 vs 4.49 pmoles/gdw) and CP (11.5 vs 5.5 pmoles/gdw) than untreated hearts. Moreover, the amount of CPK lost from the treated hearts was nearly half of that found in the effluent of the untreated heart. Trifluoperazine was also observed to exert protection when included only during reperfusion syggesting that it partially inhibits the effects of excess Ca rather tha preventing changes in the 9+ glycocalyx which accompany the Ca free perfusion phase. Maximal protection was achieved with l-5nM trifluoperazine, which is similar to the concentration of the drug required to inhibit calmodulin mediated processes.. In agreement with their potency as calmodulin inhibitors, ~7 observed the order of effectiveness in protecting the Ca overloaded myocardium to be trifluoperazine > chlorpromazine > promethazine. We conclude that calmodulin is activated during the calcium paradox and contributes to cellular necrosis. Supported by grant HL27902.

ULTRASTRUCTURAL CHANGES OF MITOCHONDRIA IN ISCHEMIC AND REPEREdgar Pinkowski and FUSED CANINE MYOCARDIUM. Jutta Schaper, Max-Planck-Institute, Bad Nauheim, W.-Germany Renate Froede. Ischemia (isch) produces typical ultrastructural changes in cardiac mitochondria (mit) indicative of the degree of isch injury; mit also show the earliest signs of recovery upon repThese findings were completed by measurements erfusion (rep). of mit volume and surface densities (Vvmit resp S,,it) using morphometry. In 11 dog hearts global isch was produced for 30, 60 or 90 min followed by rep for 120 min. Tissue biopsies were taken at various time intervals (8-12/heart).Results see Table:

~1

control 23.4i4.3 % 0.39+0.06 cm-1 n=16 Summary: 1. As compared to control V,mit increased after isch depending on time. 2. Vvmit decreased during rep after 30 and 60 min of isch, it remained elevated after 90 min. 3. Svmit showed variable changes. Conclusion: Isch of 30 and 60 min produced heavy but reversible swelling of mitochondria, 90 min caused irreversible edema. Our earlier definition of the tolerance to ischemia based on qualitative ultrastructural results is confirmed by these quantitative data.