BRADYCARDIAC AGENT UL-FS-49 ATTENUATES ISCHEMIC REGIONAL MYOCARDIAL DYSFUNCTION AND REDUCES INFARCT SIZE IN SWINE - COMPARISON WITH THE BETA-BLOCKER ATENOLOL

Heart rate (HR) is a major factor determining the severity of myocardi al ischemia, and HR reduction is an effective therapy for myocardial i schemia. We tested the effects of HR reduction induced by either UL-FS 49 or atenolol on regional myocardial blood flow, function, and infar ct size CIS) in a porcine model of 90-min low-flow ischemia and 2-h re perfusion. In 24 Gottinger miniswine, the left anterior descending cor onary artery (LAD) was cannulated and hypoperfused at constant inflow to reduce anterior systolic wall thickening (AWT, sonomicrometry) by s imilar to 85%. Eight swine served as a placebo group, and 8 other swin e received UL-FS 49 (0.60 mg/kg intravenously, i.v.) after 10-min isch emia. In the remaining 8 swine, atenolol was infused after 10-min isch emia at a dosage [mean 1.75 +/- 1.20 (SD) mg/kg i.v.] to mimic the HR reduction observed with UL-FS 49. Systemic hemodynamics, subendocardia l blood flow (ENDO, microspheres) and AWT were measured under control conditions, at 10 and 90 min of ischemia. In the swine receiving UL-FS 49 or atenolol, additional measurements were made 5 min after adminis tration of the respective drug. After 2-h reperfusion, IS (percentage of area at risk) was determined with TTC-staining. Five minutes after administration of UL-FS 49, HR was decreased from 113 +/- 9 to 83 +/- 13 beats/min (p < 0.05) and remained unchanged when ischemia was prolo nged to 90 min. In the swine receiving atenolol, HR was reduced from 1 17 +/- 14 to 93 +/- 7 beats/min (p < 0.05) 5 min after drug administra tion and decreased further to 87 +/- 10 beats/min when ischemia was pr olonged to 90 min. At 10 min of ischemia, AWT in the placebo, UL-FS 49 , and atenolol group was decreased to 7.0 +/- 5.5, 6.4 +/- 3.5, and 6. 2 +/- 3.3% (all p < 0.05 vs. control), respectively. The reduction in ENDO was also comparable among the three groups. In the placebo group, AWT remained unchanged when ischemia was prolonged to 90 min (4.4 +/- 2.6%). In swine receiving atenolol, AWT tended to increase (13.6 +/- 10.5%), whereas in swine receiving UL-FS 49, AWT was significantly inc reased to 21.4 +/- 7.1% (p < 0.05 vs. 10-min ischemia and vs. the plac ebo and atenolol groups). IS was significantly reduced in swine receiv ing atenolol (3.9 +/- 3.5%) or UL-FS 49 (5.8 +/- 4.6%) as compared wit h the placebo-group (10.4 +/- 8.9%). For a given ENDO, IS also was sig nificantly reduced in the UL-FS 49 and atenolol groups as compared wit h the placebo group. HR reduction by UL-FS 49 or atenolol decreases my ocardial IS to a comparable extent. The improvement in regional contra ctile function during ischemia, however, is more pronounced with UL-FS 49 than with atenolol.