The effect of verapamil on myocardial ultrastructure during and following release of coronary artery occlusion

Kloner, Robert A.; DeBoer, Laurence W.V.; Carlson, Nancy; Braunwald, Eugene

doi:10.1016/0014-4800(82)90057-0

Cited by 18 publications

(7 citation statements)

References 19 publications

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“…Each micrograph was scored for visible damage by two independent observers without knowledge of the treatment group from which the muscle had been derived. A score of 0, 1, 2 or 3 was awarded by each observer for the degree of mitochondrial injury in the manner described by Kloner et al (1978Kloner et al ( , 1982, and as illustrated in Figure 1.…”

Section: Structural Changesmentioning

confidence: 99%

Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia

Northover

1988

British J Pharmacology

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Section: Structural Changesmentioning

confidence: 99%

Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia

Northover

1988

British J Pharmacology

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“…1 Reperfusion of irreversibly injured myocardium results in cellular swelling and further increase in the number of granular densities present in the mitochondria. 2 The dense bodies that accumulate during the reperfusion interval are believed to result from increased Ca 2+ influx into the cell and subsequent Ca 2+ sequestration by the mitochondria. 34 This interpretation is given further support by the protective action of calcium channel blocking agents, e.g., verapamil, in reduction of ultrastructural damage to the cell as well as in preservation of mitochondrial structure 2 and function.…”

mentioning

confidence: 99%

Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium.

Kajiyama¹,

Pauly²,

Hughes³

et al. 1987

Circulation Research

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Pretreatment of the ischemic myocardium with verapamil protects against mitochondrial respiratory depression observed during ischemic arrest as well as during reperfusion. Since ischemic mitochondrial function appears not to be altered further by reperfusion, the purpose of this study is to identify a biochemical event affecting mitochondria that is specifically associated with reperfusion injury. It has been proposed that increased cellular Ca2+ influx and oxygen toxicity may result from reintroduction of coronary flow. Increased cytosolic Ca2+ is transmitted to the mitochondria with subsequent activation of Ca2+-dependent events, including phospholipase A2. Net production of lysophospholipids (and loss of total diacylphospholipids from the mitochondria) will proceed when reacylation mechanisms are inhibited. Since acyl-CoA:lysophospholipid acyltransferase is a sulfhydryl-sensitive enzyme and since increased activity of glutathione peroxidase shifts the levels of the mitochondrial sulfhydryl buffer, glutathione, towards oxidation, levels of glutathione and its oxidation state were measured during reperfusion in the absence or presence of verapamil pretreatment. Ischemia lowers total glutathione and reduces the redox ratio (reduced glutathione: oxidized glutathione) by 85%. Reperfusion partially returns the redox ratio to control by causing oxidized glutathione to disappear from the matrix. Verapamil maintains both the concentration and the redox potential of glutathione at control levels. Concomitant with alterations in reduced glutathione:oxidized glutathione is a decrease in ischemic mitochondrial phospholipid content. During reperfusion, phosphatidylethanolamine and its major constituent fatty acids (C 18:0 and C 20:4) are specifically lost from the mitochondrial membrane. Accompanying the significant loss of arachidonic acid during reperfusion is the decreased content of 11-OH, 12-OH, and 15-OH arachidonate. These lipid peroxidation products are not increased in ischemia. It is proposed that oxidation of matrix glutathione to glutathione disulfide during ischemia results in formation of glutathione-protein mixed disulfides and inhibition of sulfhydryl-sensitive proteins, including acyl-CoA lysophosphatide acyltransferase. Thus, metabolic events occurring within the ischemic period set the stage for prolonged dysfunction during reperfusion.

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“…In previous studies in our laboratory carried out in open-chest dogs subjected to 1 hr of ischemia, it was observed that verapamil caused a marked reduction in ultrastructural damage with striking preservation of the mitrochondrial ultrastructure. 38 …”

Section: Resultsmentioning

confidence: 99%

Preservation of high-energy phosphates by verapamil in reperfused myocardium.

Lange¹,

Ingwall²,

Hale³

et al. 1984

Circulation

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To determine whether verapamil prevents depletion of adenine nucleotides during and after severe myocardial ischemia, dogs were subjected to 15 min occlusions of the left anterior descending coronary artery followed by 240 min of reperfusion. One hour before occlusion, dogs were randomly assigned to a treatment group (n = 10) to which an infusion of intravenous verapamil was given until the onset of reperfusion or to an untreated saline group (n = 9). Verapamil reduced mean aortic pressure and heart rate. After 15 min of ischemia, endocardial adenosine triphosphate (ATP) level, determined by needle biopsy, decreased in the untreated group from 34.7 + 2.0 to 24.4 + 2.7 nmol-mg protein-' (p < .005 vs preocclusion) and in the verapamil group from 32.8 + 1.5 to 30.3 + 1.5 nmol.mg protein-' (NS vs preocclusion). Dogs receiving verapamil had significantly higher ATP levels than untreated animals after 90 and 240 min of reperfusion. In untreated animals the sum of inosine and hypoxanthine levels increased during occlusion from very low levels to 4.6 + 1. 1 nmol mg protein-' in the epicardium and to 6.8 1.5 nmol.mg protein-' in the endocardium (p < .05 compared with preocclusion values). In verapamil-treated dogs inosine and hypoxanthine levels increased to only 1.2 ± 0.3 (epicardium) and 1.9 + 0.6 nmol.mg protein-' (endocardium) (both NS compared with preocclusion values). After 90 min of reperfusion the sum of ATP, adenosine diphosphate, adenosine monophosphate, inosine, and hypoxanthine levels was decreased in the endocardium by 10.2 nmolPmg protein-' in the untreated group, but no change was observed in verapamil-treated animals. We conclude that breakdown of ATP to inosine and hypoxanthine during severe ischemia is reduced by verapamil, resulting in higher ATP concentrations during occlusion and reperfusion and decreased washout of the diffusible purines inosine and hypoxanthine during reperfusion. Circulation 70, No. 4, 734-741, 1984. REPERFUSION after a brief period of coronary arterial occlusion (not long enough to cause myocardial infarction) does not result in an immediate recovery of cardiac function or metabolism, and this phenomenon has been referred to as "stunning of the myocardium. '1 1-0 In an effort to accelerate postischemic recovery from myocardial infarction, attention has been focused on restoration of adenosine triphosphate (ATP) content. Although the relationship between postischemic recovery and rate of ATP synthesis and degradation remains to be fully defined, restoration of myocar-

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The effect of verapamil on myocardial ultrastructure during and following release of coronary artery occlusion

Cited by 18 publications

References 19 publications

Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia

Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia

Protection by verapamil of mitochondrial glutathione equilibrium and phospholipid changes during reperfusion of ischemic canine myocardium.

Preservation of high-energy phosphates by verapamil in reperfused myocardium.

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