Kiminori Kajiyama

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

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.

Lipid peroxidation and radical formation in methyl linoleate following ultraviolet light exposure.

To gain information useful in understanding radical reactions of sunlight‐induced lipid peroxidation in the skin, methyl linoleate (ML) was used as a material for a study of electron spin resonance (ESR). The ESR spectrum of ML exposed to UV light was examined under aerobic and anaerobic conditions at low temperature. No ESR signal was detected from the unexposed ML, even at —150°C. However, exposure to UV resulted in the appearance of an ESR signal at —150°C. With the elevation of temperature from —150°C, the ESR signal became asymmetric in shape and the g value increased under aerobic conditions, but these alterations did not occur under anaerobic conditions. Lipid peroxidation through a radical reaction initiated by UV exposure was discussed.

Therapeutic management of dilated cardiomyopathy

SummaryThe therapeutic approach to dilated cardiomyopathy (DCM) still remains nonspecific and symptomatic, since no specific etiology is identified. Nevertheless, the recent introduction of angiotensin converting enzyme (ACE) inhibitors and beta-blockers greatly improved the treatment of DCM. The poor prognosis of patients with DCM encourages maximal aggressive attempts to prevent progression of ventricular dysfunction rather than to wait for treatable symptoms. To achieve this goal, vasodilators, particularly ACE inhibitors, now appear to be essential for the treatment of DCM. Digitalis is added unless contraindicated by adverse effects. Diuretics should be used only to relieve congestive symptoms. In the presence of sinus tachycardia or ventricular arrhythmias, beta-blockers are the next choice in our practice. When congestive symptoms or low output state are not controlled with vasodilators, diuretics, and digitalis, inotropic agents are indicated, with or without mechanical assist devices. For severely ill patients unresponsive to maximal medical management, heart transplantation is needed.

Increased Plasma Lipid Peroxide in Patients with Congestive Heart Failure

Oxygen free radicals such as superoxide radicals, hydrogen peroxide or hydroxyl radicals have been suggested to play an important role in ischemia-reperfusion injury, catecholamine injury or adriamycin cardiomyopathy1)- 3). However, the half life of these free radicals is a matter of microseconds, too short a period for their clinical significance to be determined. On the other hand, oxygen free radicals react with membrane phospholipid and produce lipid peroxide which can be reliably measured by thiobarbituric acid test4). Several invesitigators5) -7) have reported increases in plasma lipid peroxide in animal models of adriamycin cardiomyopathy, alcoholic cardiomyopathy or genetic cardiomyopathy. However, few reports have investigated the alteration of plasma lipid peroxide in patients with chronic heart failure, and the clinical significance of lipid peroxide is largely unknown. Therefore, we measured plasma lipid peroxide in patients with dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), ischemic heart disease (IHD) and mitral valve disease (MVD) to determine the clinical significance of lipid peroxide in the pathophysiology of congestive heart failure.