Effects of oral pretreatment with metoprolol on left ventricular wall motion, infarct size, hemodynamics, and regional myocardial blood flow in anesthetized dogs during thrombotic coronary artery occlusion and reperfusion.
OBJECTIVE
To study the effects of oral pretreatment with metoprolol over 3 days on hemodynamics, left ventricular function, regional myocardial blood flow, and infarct size in an anesthetized dog model of thrombotic occlusion of the anterior descending coronary artery treated with thrombolysis.


METHODS
Ten dogs received 200 mg metoprolol (Selozok) orally and 8 dogs received placebo for 3 days twice daily and 1 hour before the experiment. Under general anesthesia, thrombotic occlusion was provoked by the copper-coil technique. Intracardiac pressures and their derivatives, cardiac output (thermodilution method), regional coronary blood flow (microspheres), global and regional left ventricular function (ventriculography), and infarct size (triphenyltetrazolium staining) were measured. Measurements were performed during control, after 60 minutes of occlusion, and after 30 and 90 minutes of reperfusion. Thrombolysis was performed in all dogs 60 minutes after occlusion by intravenous infusion of 10 micrograms/kg/min of rt-PA for 30 minutes.


RESULTS
During control cardiac output was lower, total peripheral resistance higher, and Tau and the left ventricular isovolumic relaxation time greater in the metoprolol group. During occlusion and after reperfusion, there were no significant hemodynamic differences between both groups. Blood flow to the area at risk and circumflex territory during occlusion were, respectively, 12.8 +/- 5.80 ml/100 g/min versus 9.65 +/- 8.35 ml/100 g/min (p > 0.05) and 42.58 +/- 7.86 ml/100 g/min versus 61.52 +/- 20.43 ml/100 g/min (p = 0.01) in the metoprolol- and placebo-treated dogs. The ratios of flow area at risk/circumflex territories in the epicardial, midmyocardial, and endocardial layers were, respectively, 0.44 +/- 0.20, 0.19 +/- 0.09, and 0.20 +/- 0.13 in the metoprolol- versus 0.24 +/- 0.16, 0.08 +/- 0.06, and 0.06 +/- 0.07 (p > or = 0.04) in the placebo-treated dogs. The ratio of flow endocardium/epicardium was higher (p > or = 0.02) in the active treatment group during the control period, both in the area at risk and circumflex territory; this was also the case in the circumflex territory at the end of the experiment (p = 0.003). Thirty minutes after occlusion, blood flow to the three layers of the area at risk rose to 2-3 times control values in both groups; a significant increase above control values also occurred in the circumflex territory. After 90 minutes reperfusion, blood flow to both territories was similar in both groups but was comparable to the control; however, in necrotic tissue of the subendocardial layer of both groups, flow fell below control values (p < 0.05). End-systolic volume rose from 21.2 +/- 7.4 ml to 36.1 +/- 11.5 ml (p < 0.05), end-diastolic volume remained constant (46.0 +/- 13.8 vs. 47.9 +/- 12.1 ml; p > 0.05), and ejection fraction fell from 53.9 +/- 8.3% to 25.8 +/- 10.2% (p < 0.05) at the end of the experiment in the metoprolol group. Respective figures for the placebo group were 19.4 +/- 7.9 versus 27.9 +/- 10.9 (p < 0.05), 38.5 +/- 13.0 versus 42.1 +/- 11.0 (p > 0.05), and 50.6 +/- 5.7 versus 35.5 +/- 11.7 (p < 0.05). Fractional shortening of the chords analyzed was similar in both groups during the control period; it fell significantly at the end of the experiment in three chords of the metoprolol group and in five chords of the placebo group. The apical chord in the placebo, but not in the metoprolol, dogs was dyskinetic: fractional shortening was -0.86 +/- 9.7 versus 7.5 +/- 13.5% (p > 0.05). The area at risk was 41.6 +/- 10.6 cm2 in metoprolol- and 40.5 +/- 7.2 cm2 in placebo-treated dogs (p > 0.05); the infarct size, expressed as a percentage of the area at risk, was 29.0 +/- 22.5% and 45.3 +/- 23.6% (p = 0.02), respectively.


CONCLUSIONS
Oral pretreatment with metoprolol limited infarct size and improved regional left ventricular function, probably due to its negative chronotropic and inotropic effects, and also due to an enhancement of collateral flow fr
Zmudka
K
K
Department of Cardiology, University Hospital Gasthuisberg, Leuven, Belgium.
Dubiel
J
J
Vanhaecke
J
J
Flameng
W
W
De Geest
H
H
D000284:Administration, Oral; D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects*; D003328:Coronary Thrombosis / Q000150:complications; D003331:Coronary Vessels / Q000502:physiology; D004195:Disease Models, Animal; D004285:Dogs; D006439:Hemodynamics / Q000187:drug effects*; D008790:Metoprolol / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000209:etiology; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology; D011897:Random Allocation; D016277:Ventricular Function, Left / Q000187:drug effects*
D008790:Metoprolol