Diacylglycerol-induced protection against injury during ischemia and reperfusion in the rat heart: comparative studies with ischemic preconditioning.
The role of protein kinase C (PKC) activation in ischemic preconditioning remains controversial. Since diacylglycerol is the endogenous activator of PKC and as such might be expected cardioprotective, we have investigated whether: (i) the diacylglycerol analog 1,2-dioctanoyl-sn-glycerol (DOG) can protect against injury during ischemia and reperfusion; (ii) any effect is mediated via PKC activation; and (iii) the outcome is influenced by the time of administration. Isolated rat hearts were perfused with buffer at 37 degrees C and paced at 400 bpm. In Study 1, hearts (n=6/group) were subjected to one of the following: (1) 36 min aerobic perfusion (controls); (2) 20 min aerobic perfusion plus ischemic preconditioning (3 min ischemia/3 min reperfusion+5 min ischemia/5 min reperfusion); (3) aerobic perfusion with buffer containing DOG (10 microM) given as a substitute for ischemic preconditioning; (4) aerobic perfusion with DOG (10 microM) during the last 2 min of aerobic perfusion. All hearts then were subjected to 35 min of global ischemia and 40 min reperfusion. A further group (5) were perfused with DOG (10 microM) for the first 2 min of reperfusion. Ischemic preconditioning improved postischemic recovery of LVDP from 24+/-3% in controls to 71+/-2% (P < 0.05). Recovery of LVDP also was enhanced by DOG when given just before ischemia (54+/-4%), however, DOG had no effect on the recovery of LVDP when used as a substitute for ischemic preconditioning (22+/-5%) or when given during reperfusion (29+/-6%). In Study 2, the first four groups of study were repeated (n=4-5/group) without imposing the periods of ischemia and reperfusion, instead hearts were taken for the measurement of PKC activity (pmol/min/mg protein+/-SEM). PKC activity after 36 min in groups (1), (2), (3) and (4) was: 332+/-102, 299+/-63, 521+/-144, and 340+/-113 and the membrane:cytosolic PKC activity ratio was: 5.6+/-1.5, 5.3+/-1.8, 6.6+/-2.7, and 3.9+/-2.1 (P=NS in each instance). In conclusion, DOG is cardioprotective but under the conditions of the present study is less cardioprotective than ischemic preconditioning, furthermore the protection does not appear to necessitate PKC activation prior to ischemia.
Galiñanes
M
M
Cardiovascular Research, The Rayne Institute, St Thomas' Hospital, London, UK.
Goss
M W
MW
McGill
C J
CJ
Hearse
D J
DJ
Brooks
G
G
D000818:Animals; D004075:Diglycerides / Q000627:therapeutic use*; D066298:In Vitro Techniques; D019157:Ischemic Preconditioning, Myocardial / Q000379:methods*; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control*; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D016277:Ventricular Function, Left
D004075:Diglycerides; C044295:1,2-dioctanoylglycerol; D011493:Protein Kinase C