Bradycardic 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 myocardial ischemia, and HR reduction is an effective therapy for myocardial ischemia. We tested the effects of HR reduction induced by either UL-FS 49 or atenolol on regional myocardial blood flow, function, and infarct size (IS) in a porcine model of 90-min low-flow ischemia and 2-h reperfusion. In 24 Göttinger miniswine, the left anterior descending coronary artery (LAD) was cannulated and hypoperfused at constant inflow to reduce anterior systolic wall thickening (AWT, sonomicrometry) by approximately 85%. Eight swine served as a placebo group, and 8 other swine received UL-FS 49 (0.60 mg/kg intravenously, i.v.) after 10-min ischemia. In the remaining 8 swine, atenolol was infused after 10-min ischemia 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, subendocardial 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 administration 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 prolonged to 90 min. In the swine receiving atenolol, HR was reduced from 117 +/- 14 to 93 +/- 7 beats/min (p < 0.05) 5 min after drug administration and decreased further to 87 +/- 10 beats/min when ischemia was prolonged to 90 min. After 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 increased to 21.4 +/- 7.1% (p < 0.05 vs. 10-min ischemia and vs. the placebo and atenolol groups). IS was significantly reduced in swine receiving atenolol (3.9 +/- 3.5%) or UL-FS 49 (5.8 +/- 4.6%) as compared with the placebo-group (10.4 +/- 8.9%).(ABSTRACT TRUNCATED AT 400 WORDS)
Schulz
R
R
Abteilung für Pathophysiologie, Universitätsklinikum Essen, German.
Rose
J
J
Skyschally
A
A
Heusch
G
G
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001262:Atenolol / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D001919:Bradycardia / Q000188:drug therapy; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006321:Heart / Q000187:drug effects; D006339:Heart Rate / Q000187:drug effects; D007275:Injections, Intravenous; D007773:Lactates / Q000378:metabolism; D008297:Male; D009203:Myocardial Infarction / Q000188:drug therapy*; D017202:Myocardial Ischemia / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D010101:Oxygen Consumption / Q000187:drug effects; D010725:Phosphocreatine / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy; D013552:Swine; D013556:Swine, Miniature
D001552:Benzazepines; D002317:Cardiovascular Agents; D007773:Lactates; D010725:Phosphocreatine; D001262:Atenolol; D000255:Adenosine Triphosphate; C043636:zatebradine