title: Effect of heart rate reduction by 4-(N-ethyl-N-phenyl-amino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride on infarct size in dog.
abstract: Heart rate (HR) reduction may reduce the severity of myocardial ischemia. ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium++ + chloride) is a novel bradycardic agent with a specific effect on the sinoatrial node without having any other direct effects on the heart. In the present study, the effect of ZD7288 on infarct size and regional myocardial function during regional myocardial ischemia and reperfusion was investigated. Seventeen anesthetized open chest dogs (control, n = 8, and ZD7288, n = 9) underwent 1 h of left anterior descendent artery (LAD) occlusion followed by 6 h of reperfusion. In one group, ZD7288 was given intravenously (0.7 mg/kg body weight) 45 min before LAD occlusion. Regional myocardial function was assessed by sonomicrometry as systolic wall thickening fraction (sWTF) in the anteroapical (interest region, IR) and the posterobasal wall (control region, CR). Ischemic regional myocardial blood flow (RMBF) was determined by colored microspheres and infarct size (IS) by triphenyltetrazolium staining. ZD7288 injection decreased HR from 104 +/- 5 to 74 +/- 3 bpm (mean +/- SEM, p < 0.001 vs control, vs baseline), but did not change sWTF. During reperfusion, sWTF of the IR was significantly greater in the ZD7288 group (26 +/- 12 vs -14 +/- 13%, 1 h reperfusion, p < 0.05), while sWTF of CR stayed equal (120 +/- 13 vs 111 +/- 16%, p = ns). IS was markedly reduced in the ZD7288 group (4.7 +/- 1.8 vs 18.0 +/- 5.2% of IR, p < 0.05). There was no difference in ischemic endocardial RMBF (ZD7288 11.0 +/- 4.3 vs control 12.3 +/- 6.5 ml/min/100 g, p = ns). ZD7288 reduces HR without having direct effects on regional myocardial function. This HR reduction leads to a smaller IS and to a better regional functional recovery.
authors.affiliation: Institut für Klinische Anaesthesiologie, Abteilung für Herz- und Kreislaufphysiologie, Heinrich-Heine Universität, Düsseldorf, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Schlack
authors.forename: D
authors.initials: D
authors.lastname: Ebel
authors.forename: S
authors.initials: S
authors.lastname: Grunert
authors.forename: S
authors.initials: S
authors.lastname: Halilović
authors.forename: O
authors.initials: O
authors.lastname: Meyer
authors.forename: V
authors.initials: V
authors.lastname: Thämer
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects / Q000502:physiology; D004285:Dogs; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D009336:Necrosis; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D002316:Cardiotonic Agents; D011743:Pyrimidines; C082246:ICI D2788