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Hypokalaemia was induced by infusing polystyrene sulphonate into the colon of mongrel dogs. Sixty minutes after infusion adrenaline 10 micrograms.kg-1 was injected intravenously, which had no effect on serum creatine kinase activity or myocardial histology in the control dogs. However, in dogs with hypokalaemia creatine kinase activity was increased, and pronounced histological changes were seen 60 min after injection. A clear reciprocal relation was found between serum potassium concentration and creatine kinase activity. Premedication with an alpha 1 blocking agent prevented the changes associated with hypokalaemia. Heart mitochondria were prepared from other dogs with hypokalaemia 5 min after adrenaline injection and their calcium content measured. Heart mitochondrial calcium content was increased in parallel with the decrease in serum potassium concentration. Alpha 1 blockade also prevented the increase in mitochondrial calcium content. These results indicate that the intracellular calcium concentration is considerably increased by alpha 1 receptor stimulus under hypokalaemic conditions and that this increase in calcium concentration plays a crucial role in the genesis of myocardial damage. Since adrenaline increases coronary blood flow small doses of adrenaline in subjects with hypokalaemia may lead to the development of myocardial injury not associated with ischaemia.

This study was designed to evaluate whether or not increase in coronary blood flow after reperfusion accelerates the recovery of ischemia-induced mitochondrial damage. Using anesthetized dogs, the left anterior descending coronary artery was occluded for 30 min, followed by 20 min of reperfusion. Five minutes after reperfusion, either physiological saline (n = 9), 0.5 mg/kg of dilazep (n = 7), 0.2 mg/kg of diltiazem (n = 7), or 0.5 mg/kg of nicorandil (n = 8) were administered intravenously. Arterial blood pressure, heart rate, and coronary blood flow were measured throughout the experiment. Twenty minutes after reperfusion, heart mitochondria from normal and reperfused areas were prepared, and mitochondrial function was measured. Significant increase in coronary flow was observed during reperfusion in all drug-treated groups; however, no significant increase was observed in the control group 10 min after reperfusion. Significant hemodynamic changes were not observed in all groups. Mitochondrial function from reperfused areas was recovered significantly in all drug-treated groups, though in the control group mitochondrial dysfunction persisted. Coronary dilative mechanisms of drugs used here differ; however, a similar effect was demonstrated, i.e., administration of a coronary dilator accelerates the recovery of mitochondria after reperfusion. Therefore, it is concluded that coronary flow after reperfusion might be a primary factor in the recovery of ischemia-induced mitochondrial damage.

Summary To clarify the mechanism of reperfusion arrhythmia, the following experiments were performed. In vivo study : Using anesthetized mongrel dogs, the left anterior descending coronary artery was occluded for 15 min and the ligation was released. The dogs were divided into two groups depending on whether the pretreatment was with saline or coenzyme Q 10 (CoQ 10 ), 15 mg/kg, before the ligation, i.e., the control and the CoQ 10 groups. Each group was further divided into two subgroups depending on the presence or the absence of reperfusion arrhythmia. Reperfusion arrhythmia was observed in 12 out of 38 dogs in the control, whereas in the CoQ 10 group none developed arrhythmia. Nine species of free fatty acids (FFA) were detected in the plasma membrane in each group. In the dogs in the control group with arrhythmia, all species of detected FFA increased, and phospholipid content in plasma membrane decreased. These changes were not observed in the dogs without arrhythmia in both the control and the CoQ 10 groups. In vitro study : Incubation of myocardial plasma membrane with phospholipase (PLase) A 2 increased only unsaturated FFA, while PLase C increased all detected FFA. Premedication with CoQ 10 prevented the increase in FFA caused by PLases. Perfusion with PLase A 2 or C altered membrane action potential. Premedication with CoQ 10 also prevented changes in membrane action potential. PLase liberates fatty acids from phospholipids, and CoQ 10 is known to protect the membrane phospholipids from the attack of PLase. These facts and results suggest that activation of PLase associated with coronary reperfusion is closely related to the development of reperfusion arrhythmia.

An epoxy derivative of linoleate, 9, 10-epoxy-12-octadecenoate, was demonstrated to be biosynthesized by leukocytes, thus nominated as leukotoxin. Its chemical structure was determined by gas-chromatography/mass spectrometry and nuclear magnetic resonance measurements. When it was injected intravenously, 15 mg/kg, canine heart showed signs of a typical cardiac failure; viz. Aortic flow started to drop immediately after the injection, and fell to 22% of the original at 40 min after the injection. At that point, systolic aortic pressure dropped to 35%, diastolic aortic pressure to 23%, and electronically differentiated maximal rate of left ventricular pressure rise (LV dp/dt) to 29%. All of experimental dogs died 40 to 50 min after the injection. On the contrary, administration of linoleic acid (15 mg/kg) did not affect these hemodynamical parameters. Therefore, leukotoxin seems to be an important factor to the genesis of heart failure.

Leukotoxin (9,10-epoxy-12-octadecenoate) biosynthesised from linoleate by neutrophils is highly toxic to cellular function. Its cardiovascular effects were studied in dogs together with the effects of various fatty acids. Aortic flow, left ventricular peak dP·dt−1, and aortic pressure were measured in 60 anaesthetised dogs, which were divided into 10 groups of six animals each — namely, control group (10 ml of physiological saline), three leukotoxin groups (5, 10, and 50 mg·kg−1), two linoleic acid groups (10 and 50 mg·kg−1), two oleic acid groups (10 and 50 mg·kg−1), and two stearic acid groups (10 and 50 mg·kg−1). Leukotoxin injected intravenously depressed cardiac function in a dose dependent manner. Administration of leukotoxin 5 mg·kg−1 showed no significant cardiotoxic effect. However, 10 mg·kg−1 of leukotoxin significantly decreased aortic flow from 0.74(0.04) to 0.40(0.07) litre·min−1 (mean(SEM)), left ventricular peak dP·dr1 from 2040(205) to 1140(217) mmHg·s−1, and aortic pressure from 106(7. l)/67(6.3) to 75(9.2)/48(6.5) mmHg 5 min after injection. Dogs given leukotoxin 50 mg·kg−1 showed more pronounced cardiodepressive effects; aortic flow was decreased to 0.19(0.06), left ventricular dP·dt−1 to 560(134), and aortic pressure to 72(15.l)/41(10.6) 5 min after injection. All dogs in this group were dead within 45 min. Administration of 10 mg·kg−1 of linoleic acid, oleic acid, or stearic acid caused no significant haemodynamic changes. Administration of linoleic acid 50 mg·kg−1 had cardiotoxic effects, but the effect was less than that of leukotoxin. Since leukotoxin appears to be a potent cardiodepressive agent it may be an important factor in the development of heart failure observed in patients with severe burns.