Effects of allopurinol, propranolol and methylprednisolone on infarct size in experimental myocardial infarction

doi:10.1016/0002-9149(76)90398-2

The American Journal of Cardiology

Volume 37, Issue 4, 31 March 1976, Pages 572-580

https://doi.org/10.1016/0002-9149(76)90398-2 Get rights and content

Abstract

With use of a canine model of occlusion of the left anterior descending coronary artery and an intracellular lactic dehydrogenase stain to measure infarct size directly, the effects of allopurinol, methylprednisolone sodium succinate and propranolol were studied. Allopurinol did not influence the extent of myocardial necrosis, whereas both methylprednisolone and propranolol significantly reduced myocardial infarct size. Possible mechanisms of action and clinical applicability of these agents are discussed.

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Cited by (78)

Depressed function in remote myocardium after myocardial infarction: Influence of orotic acid
1996, Annals of Thoracic Surgery
Background. We have previously shown that infarction impairs recovery of global function after subsequent cardioplegic arrest and that therapy with orotic acid improves recovery. The aim of this study was to measure the effect of infarction on regional and global left ventricular function and to determine whether orotic acid exerts a beneficial effect exclusive of the effects of cardioplegia.
Methods. Acute myocardial infarction was produced in dogs. They then received either orotic acid or placebo (control) orally (n = 12 per group). Fractional radial shortening and systolic wall thickening were measured by two-dimensional echocardiography before and 1 and 3 days after infarction with and without β-adrenergic blockade, and in 6 dogs up to 9 days after infarction. Global function was measured under anesthesia 4 days after infarction.
Results. In control animals, fractional radial shortening in the infarct decreased from 20.6% ± 5.1% before infarction to 3.0% ± 2.2% at day 1 and to 1.9% ± 1.9% at day 3 (p < 0.01). In the border zone radial shortening declined from 21.9% ± 3.7% to 11.0% ± 2.3% at day 1 and 9.3% ± 2.8% at day 3 (p < 0.05). In the noninfarcted myocardium radial shortening also declined from 27.1% ± 1.9% before infarction to 18.3% ± 2.3% on day 1 (p < 0.05) and to 16.0% ± 2.8% on day 3 after infarction (p < 0.05) with recovery to preinfarct levels by 9 days after infarction. These findings were confirmed by measurements of systolic thickening. Before infarction β-receptor blockade decreased fractional shortening in all regions of the left ventricle, but this effect was absent on day 3 after infarction, implying that the myocardium had become less responsive to β-adrenergic stimulation. Measurements of global function 4 days after infarction showed marked depression of stroke work. There was no effect of orotic acid treatment on regional or global function.
Conclusions. Myocardial infarction causes reversible depression of resting function and β-adrenergic responsiveness in the remote and border zone areas, which is not prevented by metabolic therapy with orotic acid. This finding may explain the adverse response of the infarcted heart to cardioplegic arrest.
(Ann Thorac Surg 1996;62:1765–72)
Failure of intravenous metoprolol to limit acute myocardial infarct size in a nonreperfused porcine model
1995, American Heart Journal
The usefulness of intravenous β-adrenergic receptor blockade in limiting infarct size when neither reperfusion nor collateral flow occurs is unknown. The effect of intravenous metoprolol on limiting myocardial infarct size was therefore examined in a nonreperfused porcine model. Closed-chest techniques were used to occlude the left anterior descending coronary artery, after which animals were randomized at 20 minutes to receive intravenous metoprolol, 0.75 mg/kg, or placebo. Infarct size examined at 5 hours with Evans blue and triphenyltetrazolium ataining techniques was expressed as a percentage of total ventricular myocardium at ischemic risk. This percentage was not significantly different between the groups (84% ± 5% with metoprolol vs 90% ± 4% with placebo; p = 0.4). Myocardial infarct size was not significantly decreased at 5 hours by early administration of intravenous metoprolol when the infarct artery remained occluded and collateral flow was minimal.
A method for monitoring the effectiveness of allopurinol pretreatment in the prevention of ischemic/reperfusion injury
1989, Journal of Pharmacological Methods
The protective actions of allopurinol in ischemic/reperfusion injury seem critically determined by the drug pretreatment regimen and may involve generalized alterations in tissue antioxidant status. In the present study, 12 male swine to be used as donors and recipients in a heart-lung transplantation study were treated with allopurinol given orally at a dose of 50 $mg kg$ for 4 days prior to surgery. Red cells from allopurinol-treated animals showed a progressive decrease in susceptibility to in vitro peroxidative challenge. Although the degree and time-course of protection showed some degree of interanimal variation, maximal effects were obtained in most animals after 2–3 days. The extent of red cell protection in both donor and recipient animals correlated significantly with the functional viability of the transplanted lung, as assessed by tissue water content. It is suggested that the susceptibility of red cells to in vitro oxidative damage may provide a useful functional assessment of generalized alterations in antioxidant status produced by pharmacological interventions.
Coronary reperfusion by thrombolysis and early beta-adrenergic blockade in acute experimental myocardial infarction
1989, Journal of the American College of Cardiology
The effects of beta-adrenergic blockade, thrombolysis and their combination on infarct size and left ventricular function were investigated in a canine model of thrombotic occlusion of the left anterior descending coronary artery. Metoprolol was administered intravenously (0.5 mg/kg) over 10 min, starting 15 min after occlusion. Recombinant human tissue-type plasminogen activator (rt-PA) was given intravenously 1 h after occlusion for clot lysis. Anatomic infarct size was measured as a percent of perfusion area and ventricular mass. Left ventricular function was assessed by ejection fraction and the centerline method.
Groups 1, 3, 5 and 7 were evaluated after 24 h and received, respectively, metoprolol plus rt-PA, rt-PA, metoprolol and no treatment; groups 2, 4, 6 and 8 were studied after 1 week and treated, respectively, as groups 1, 3, 5 and 7. Metoprolol did not influence infarct size and global or regional ventricular function after 24 h and 1 week. Thrombolysis reduced infarct size from 69.5 ± 3.4% (24 h) and 76.6 ± 1.8% (1 week) in the control group to, respectively, 44.1 ± 11.6% and 39.5 ± 10.5% (p > 0.05), did not influence left ventricular function after 24 h and was accompanied after I week by a definite recovery of global and regional left ventricular function when compared with findings in control dogs. Metoprolol plus rt-PA further reduced infarct size (percent perfusion area) to 20.4 ± 3.7% and 19.9 ± 8.1% after 24 h and 1 week, respectively (p = NS versus rt-PA). After 24 h, a significant early recovery of global and regional left ventricular function was present; this better recovery persisted after 1 week.
It is concluded that early administration of metoprolol plus rt-PA enhances the effects of thrombolysis on infarct size and left ventricular function after 24 h and 1 week.
Free radical and granulocyte-mediated injury during myocardial ischemia and reperfusion
1989, The American Journal of Cardiology
The success of thrombolytic/reperfusion therapy in limiting the extent of myocardial infarction may be limited by reperfusion injury. Damage from acute ischemia is not due solely to the interruption of blood flow; rather, ischemia initiates a cascade of reactions involving partially reduced oxygen, inflammatory mediators, mechanical capillary obstruction by granulocytes and other events that lead to irreversible injury. A surprising consequence is that reperfusion by delivering oxygen and granulocytes may counteract some of the benefits of restoring flow. Mechanisms of neutrophil and free radical injury include superoxide radical formation and lipid peroxidation, progressive leukocyte capillary plugging and capillary no-reflow, and edema. The interaction of various specific mechanisms of injury in the heart (i.e., xanthine oxidase, mitochondrial superoxide leak, neutrophil superoxide, degranulation and capillary plugging, and neutrophil-derived vasoconstrictors) deserves further study.
Propranolol as xanthine oxidase inhibitor: Implications for antioxidant activity
1989, Life Sciences
Propranolol is the β-blocker most widely used in the management of cardiovascular disorders. It has been proposed that propranolol may act as a “chain-breaking” antioxidant. We have directly examined the ability of propranolol to inhibit superoxide-dependent, iron-promoted cardiac membrane phospholipid peroxidation, with xanthine oxidase (XOD) as a physiologically-recognized, enzymatic superoxide generator. Our results demonstrate that propranolol not only protects cardiac-membrane lipid from peroxidative damage, but also acts as a simple, reversible XOD inhibitor, noncompetitive with xanthine substrate. Propranolol, at effective antiperoxidant and XOD-inhibitory concentrations, cannot scavenge superoxide radical. The antiperoxidative profile of propranolol resembles that of the known XOD inhibitor allopurinol, although allopurinol, a tight-binding substrate-analog competitive with xanthine, inhibits XOD in a manner mechanistically very different from that of propranolol. Furthermore, the antiperoxidative profiles of both propranolol and allopurinol do not resemble those of chain-breaking antioxidants such as α-tocopherol. These data, along with the tendency of propranolol to concentrate in myocardial membranes and cytosol, suggest that the observed antioxidant action of propranolol, as a consequence of XOD inhibition, could play a pharmacologic role in propranolol's cardioprotective effects.

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Effects of allopurinol, propranolol and methylprednisolone on infarct size in experimental myocardial infarction

Abstract

Am J Cardiol

Am J Cardiol

Am Heart J

Am J Cardiol

J Biol Chem

Am J Cardiol

Am Heart J

Am J Cardiol

Am Heart J

Am J Cardiol

The cardiac care unit in 1973

Hosp Prac: February

Treatment of acute myocardial infarction with particular reference to shock

JAMA

Protection of the ischemic myocardium

Hosp Prac: May

Myocardial-infarct extension detected by precordial S-T segment mapping

N Engl J Med

Estimation of infarct size in man and its relation to prognosis

Circulation

Effects of intra-aortic balloon counterpulsation on the severity of myocardial ischemic injury following acute coronary occlusion: counterpulsation and myocardial injury

Circulation

Effect of glucose-insulin-potassium infusion on myocardial infarction following experimental coronary artery occlusion

Circulation

Reduction of experimental myocardial infarction size by corticosteroid administration

J Clin Invest

Modification of myocardial infarct volume

Arch Surg

The Colorimetric Determination of Creatine Phosphokinase in Serum or Other Fluids

Sigma Technical Bulletin 661

Factors influencing infarct size following experimental coronary artery occlusion

Circulation

Effects of practolol on the extent of myocardial ischemic injury after experimental coronary occlusion and its effects on ventricular function in the normal and ischemic heart

Cardiovasc Res

Pharmacological therapy of angina pectoris

Mod Concepts Cardiovasc Dis

Myocardial oxygen consumption in acute experimental cardiac depression

Circ Res

Effect of glucose-insulin-potassium on cardiac ultrastructure following acute experimental coronary occlusion

Am J Pathol