Subcellular myocardial changes following amsacrine in rats

21 SUBCELLULAR MYOCARDIAL CHANGES FOLLOWING AMSACRINE IN RATS. S. N. Kim, E. A. de la Iglesia, J. E. Fitzgerald. Department of Pathology and Experimental Toxicology Warner-Lambert/Parke-Davis Pharmaceutical Research, Ann Arbor, Michigan 48105 In a previous study the potential cardiotoxicity of amsacrine was suggested by elevation of serum enzyme levels in rats [J Molec Cell Cardiol 14 (Suppl i):44, 1982] This electron microscopic study evaluated the effects of the drug on rat myocardium. Groups of male rats were given weekly intraperitoneal injections of amsacrine for 13 weeks at 3, 6 and 12 mg/m 2. Samples of myocardium from 3 rats per group were evaluated at 13 and 17 weeks. At 13 weeks, the principal ultrastructural changes with 12 mg/m 2 involved mitochondria and consisted of enlargement with irregular stacking of cristae, clear matrix, aggregation, extrusion and other degenerative changes. Other cardiomyoeyte changes of less frequency were dilated T-tubules, disarray of Z bands and intercalated discs, rarefaction of sareoplasm and contraction bands and a moderate increase in interstitial collagen fibrils. At the 3 and 6 mg/m 2 levels, occasional mitochondrial myelin figures were present. At 17 weeks, mitochondrial changes were less prominent and contraction bands persisted at 12 mg/m 2 but not at 3 and 6 mg/m 2. Morphometric analysis showed increased mitochondrial volume fraction with subsequently reduced mitochondria/sarcoplasmic ratios in rats given 12 mg/m 2 at 13 weeks and were largely reversible at 17 weeks. These results indicate that amsacrine can elicit primarily moderate mitochondrial injury in cardiomyocytes at maximally tolerated dose level.

LIPOLYSIS AND NEUTRAL TRIACYLGLYCEROL LIPASE ACTIVITY IN TRIACYLGLYCEROL ENRICHED CARDIAC MYOCYTES. K.A. Kenno, I. Ramirez and D.L. Severson. Department of Pharmacology, University of Calgary, Calgary, Alberta, Canada, T2N IN4. Calcium-tolerant myocytes (0.75 mM) were isolated from control and acute (3 day) streptozotocin-induced diabetic (I00 mg/kg) rat hearts. In diabetic cells triacylglycerol content (71.6 • 12 nmol/106 cells, TG) and subsequent rates of lipolysis (glycerol output) during incubation (51.9 • 4.3 nmol/30 min/lO 6 cells, n=7) were elevated in comparison to control myoeyte TG levels (19.5 • 1.9 nmol/lO 6 cells) and their glycerol output (10.6 • 1.0 nmol/30 min/lO 6 cells, n=ll). Addition of isoproterenol (i0 ~m, ISO) or methylisobutylxanthine (i00 ~m, MIX) increased glycerol output by 1.9-fold in control cells but only 1.2-fold in diabetic myocytes. A similar pattern of results, high basal rates of lipolysis (43.2 • 5.8 nmol/30 min/ 106 cells, n=6) and little stimulation by ISO or MIX was also observed in control myocytes where TG levels were elevated by pre-incubation with 0.5 mM palmitate. TG lipase activity, in homogenates from control and diabetic myocytes, at pH 7.5 was 54.6 • 6.7 (n=9) and 47.4 • 3.6 (n=6) nmoles oleic acid/hr/106 cells, respectively. The addition of serum (3%) in the presence of 50 mM MgCI2 resulted in an 8.8 • 0.7 fold stimulation of lipase activity in the control myocytes but only a 5.3 • 0.7 fold stimulation in diabetic myocytes suggesting diabetic myocytes have a decreased lipoprotein lipase activity. Supported by AHFMR, CIRIT (Catalunya, Spain) and MRC of Canada. CONSIDERATION FOR YOUNG INVESTIGATOR COMPETITION

- K.A. Kenno

THE MECHANISM OF THE ANTI-FIBRILLATORY EFFECTS OF CLASS III DRUGS. EXPERIENCE WITH BRETYLIDM AND CLOFILIUM. P. Kowey, T. Friehling, K. O'Connor, L. Wetstein, G~ Kelliher

Cardiovascular Research Laboratory, Medical College of Pennsylvania, Philadelphia, PA. This study was undertaken to define the mechanism by which Class III drugs prevent ventricular fibrillation (VF). Right VF thresholds (VFT) and effective refractory periods (ERP) at 6 left ventricular (LV) sites were measured before and after left anterior coronary occlusion in chloralose anesthetized cats. In 8 untreated animals there was a decrease in VFT of 73% (p<0.Ol) 20 minutes after occlusion and dispersion of refractoriness (DR) (difference in ERP between normal and ischemic LV sites) increased from 18+5 to 46+7 msec (p<0.Ol). Pretreatment with Bretylium (B) (10-20 mg/kg) increased ~esting ERP (+20 msec, p