ISCHEMIC CHANGES IN CANINE HEART AS AFFECTED BY DIMETHYL QUATERNARY ANALOG OF PROPRANOLOL, UM-272 (SC-27761)

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  • 1 January 1976
    • journal article
    • research article
    • Vol. 199  (2) , 310-328
Abstract
The effects of the dimethyl quaternary analog of propranolol, UM-272 [pranolium chloride], were studied on myocardial infarct volume in the canine heart. Myocardial infarction was produced by occlusion of the left circumflex coronary artery for 60 min followed by reperfusion and quantitation of infarct volume 24 h later. Groups of dogs were either untreated or pretreated with UM-272 with an initial loading dose of 5.0 mg/kg (group A) or 2.5 mg/kg (group B) 30 min before occlusion of the left circumflex coronary artery. Both group A and group B animals received additional doses of 2.5 mg/kg of UM-272 every 90 min for 6 h so that the total respective doses were 15 and 12.5 mg/kg. Control animals received comparable volumes of 0.9% NaCl solution. All animals were followed throughout the 6 h procedure with continuous ECG recordings which were used to assess the effects of acute myocardial ischemia upon disturbances in cardiac rhythm and the effects of drug treatment. Dogs which survived the procedure were given tetracycline i.v. the next day and sacrificed 1 h later by an overdose of sodium pentobarbital. The hearts were removed and the left ventricle was sliced and examined first under UV light to localize the ischemic zone by noting the tetracycline fluorescence. The ventricular slices were next incubated in nitro blue tetrazolium which stains normal myocardial tissue, thus allowing one to quantitate the volume of infarcted myocardium by excising and weighing the nonstained and stained muscle separately. The untreated control group had an infarct volume of 23.8 .+-. 3.2 g/100 g of left ventricle. The treated animals in groups A and B had repsective infarct volumes of 2.3 .+-. 0.8 g/100 g (P < .001) and 7.0 .+-. 3.3 g/100 g (P < .025) of left ventricle. During the acute phase of ischemia and reperfusion, arrhythmias and alterations in the ST-segment. R-wave amplituted and development of pathologic Q-waves were more prominent in the untreated animals and almost totally absent in the treated animals. UM-272 produced a dose-dependent decrease in heart rate as well as a decrease in developed isometric tension. Pretreatment with UM-272 did not prevent the derangement of function in the ischemic zone nor did it permit a return of function upon reperfusion, even though it reduced the degree of cellular damage resulting from 60 min of regional ischemia. A possible mechanism for the protective effect of UM-272 may be through its ability to reduce myocardial contractility and heart rate, both of which would reduce myocardial O2 consumption and thus produce a more favorable balance between myocardial O2 supply and myocardial O2 demand.