Cardioprotective effects of carvedilol, a novel beta adrenoceptor antagonist with vasodilating properties, in anaesthetised minipigs: comparison with propranolol.
OBJECTIVE
The aim was to evaluate in a minipig model of acute myocardial infarction the cardioprotection provided by the beta adrenoceptor blocking and vasodilating activities present in carvedilol; comparison was made to the pure beta adrenoceptor antagonist, propranolol.


METHODS
Experiments were performed in 25 Yucatan minipigs (9-12 kg), randomly assigned to receive vehicle (n = 7), carvedilol 0.3 mg.kg-1 (n = 6), carvedilol 1 mg.kg-1 (n = 6), or propranolol 1 mg.kg-1 (n = 6). Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 45 min followed by 4 h of reperfusion. Vehicle, carvedilol (0.3 and 1 mg.kg-1) or propranolol (1 mg.kg-1) were given intravenously 15 min before the coronary artery occlusion. At the end of the reperfusion period, infarct size was determined using Evans blue dye and triphenyltetrazolium chloride staining. Infarct volumes were visualised using computer assisted three dimensional image analysis of the stained myocardial tissue sections. Myeloperoxidase activity was measured in tissue samples removed from normal, infarcted, and at risk areas.


RESULTS
Carvedilol (1 mg.kg-1) reduced infarct size by over 90% without producing pronounced changes in systemic haemodynamic variables. The ability of carvedilol to reduce infarct size was clearly dose dependent. Thus infarct size, which represented 27.5(SEM 2.3)% of the area at risk in the vehicle treated group, was only 13.1(4.0)% (p < 0.05) and 2.4(1.5)% (p < 0.01) in pigs treated with carvedilol at 0.3 and 1 mg.kg-1, respectively. In animals treated with propranolol (1 mg.kg-1), infarct size represented 10.9(2.4)% of the area at risk (p < 0.05). The 60% and 91% reductions in infarct size produced by propranolol (1 mg.kg-1) and carvedilol (1 mg.kg-1), respectively, were clearly evident upon three dimensional image analysis. The reduction in infarct size was significantly greater for carvedilol (1 mg.kg-1) compared to propranolol (1 mg.kg-1) at equivalent beta adrenoceptor blocking doses. Pretreatment with propranolol did not reduce the increases in myeloperoxidase activity observed in the area at risk or in the infarcted area. In contrast, carvedilol produced a dose dependent reduction in myeloperoxidase activity in these areas.


CONCLUSIONS
Carvedilol limits myocardial necrosis resulting from coronary artery occlusion and reperfusion in a more pronounced manner than the pure beta adrenoceptor antagonist, propranolol. The cardioprotective effect of carvedilol, which reduced infarct size by 91%, may result from the combined effects of beta adrenoceptor blockade and vasodilatation, and possibly also from inhibition of intracellular calcium overload in cardiac cells resulting from antagonism of myocardial alpha 1 adrenoceptors and/or calcium channel blockade. The cardioprotection provided by carvedilol may ultimately be of benefit in hypertensive patients who are at risk for acute myocardial infarction.
SmithKline Beecham Pharmaceuticals plc, Department of Pharmacology, King of Prussia, PA 19406.
A
A
Bril
M
M
Slivjak
M J
MJ
DiMartino
G Z
GZ
Feuerstein
P
P
Linee
R H
RH
Poyser
R R
RR
Ruffolo
E F
EF
Smith
D000319:Adrenergic beta-Antagonists / Q000627:therapeutic use*; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001794:Blood Pressure / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use*; D000077261:Carvedilol; D004195:Disease Models, Animal; D006339:Heart Rate / Q000187:drug effects; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011412:Propanolamines / Q000627:therapeutic use*; D011433:Propranolol / Q000627:therapeutic use; D013552:Swine; D013556:Swine, Miniature; D014665:Vasodilator Agents / Q000627:therapeutic use*
D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D002227:Carbazoles; D011412:Propanolamines; D014665:Vasodilator Agents; D000077261:Carvedilol; D011433:Propranolol; D009195:Peroxidase