Depletion of membrane phospholipid and mitochondrial dysfunction associated with coronary reperfusion.
The role of phospholipase (PLase) in the development of heart mitochondrial dysfunction following reperfusion was studied together with the effects of dilazep on the action of PLases and reperfusion injury. In vivo experiment: Seventy six adult mongrel dogs were divided into 3 groups; the control group (n = 36), the dilazep 0.5 mg group (n = 17) and the dilazep 1 mg group (n = 23). Fifteen min after premedication with physiological saline or dilazep (0.5 mg/kg or 1 mg/kg), the left anterior descending coronary artery was occluded for 15 min and then reperfused for 5 min. Each group was further divided into two subgroups depending on the presence or absence of reperfusion arrhythmia. Immediately after 5 min of reperfusion, myocardial mitochondria were prepared from the normal and the reperfused areas. Pretreatment with dilazep induced a dose-dependent decrease in the incidence of reperfusion arrhythmia from 31% of the control to 24% (0.5 mg/kg) and 9% (1 mg/kg). In the arrhythmia cases in each group, functional deterioration of mitochondria from the reperfused area was observed with the increase in free fatty acids and the decrease in phospholipids in the reperfused mitochondria. In vitro experiment: Using L-alpha-dimyristoyl phosphatidylcholine as a substrate, myristic acid released by PLase A2 or by PLase C with or without pretreatment by dilazep was quantitatively determined. Dilazep inhibited the release of myristic acid by PLase A2 or by PLase C in a concentration-dependent manner. These results suggest that decomposition of mitochondrial membrane phospholipids caused by PLase activation following reperfusion was primarily responsible for the development of mitochondrial dysfunction, and that dilazep showed beneficial effects against reperfusion injury by inhibiting the action of PLases.
D000818:Animals; D003326:Coronary Circulation / Q000187:drug effects; D003327:Coronary Disease / Q000503:physiopathology*; D004109:Dilazep / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D008297:Male; D008563:Membrane Lipids / Q000378:metabolism*; D008929:Mitochondria, Heart / Q000502:physiology*; D009206:Myocardium / Q000201:enzymology; D010101:Oxygen Consumption / Q000187:drug effects; D010740:Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology*; D010741:Phospholipases A / Q000502:physiology; D010743:Phospholipids / Q000378:metabolism*; D010738:Type C Phospholipases / Q000502:physiology
D005230:Fatty Acids, Nonesterified; D008563:Membrane Lipids; D010743:Phospholipids; D010740:Phospholipases; D010741:Phospholipases A; D010738:Type C Phospholipases; D004109:Dilazep