Cyclooxygenase inhibition aggravates ischemia-reperfusion injury in the perfused guinea pig heart: involvement of isoprostanes.
OBJECTIVE
Postischemic contractile dysfunction in the heart may be due, in part, to isoprostanes, thought to accumulate during myocardial reperfusion. This study tested whether cyclooxygenase (COX) inhibitors increase the amount of isoprostanes and, consequently, lead to deterioration of postischemic heart function.


BACKGROUND
Isoprostanes are bioactive prostaglandin-like compounds that are formed in vivo directly by free radical-catalyzed peroxidation of arachidonic acid. In particular, 8-isoprostaglandin (PG) F2alpha is a potent vasoconstrictor.


METHODS
Isolated working guinea pig hearts underwent 30-min low flow ischemia followed by reperfusion, 15 min in a nonworking mode and 20 min performing pressure-volume work. Hearts were perfused with or without 100 micromol/liter acetylsalicylic acid (ASA), 3 or 10 micromol/liter indomethacin or 1 micromol/liter SQ 29548, a thromboxane-A2 (TxA2) receptor antagonist able to abolish the vasoconstrictive actions of 8-iso-PGF2alpha. External heart work (EHW) and coronary resistance were compared before and after ischemia. Coronary release and tissue content of 8-iso-PGF2alpha were also determined.


RESULTS
During reperfusion, 8-iso-PGF2alpha release increased tenfold compared with the preischemic value in all groups. However, in ASA- and indomethacin-treated hearts, 8-iso-PGF2alpha levels were approximately 15-fold higher than in control hearts (5.4 vs. 0.35 pg/ml, respectively). Postischemic tissue levels of 8-iso-PGF2alpha were also markedly higher: 215 (indomethacin) and 301 (ASA) pg/ml g dry weight versus 43 pg/mg dry weight for control hearts (p < 0.05). Treatment of hearts with COX inhibitor led to a reduction in recovery of EHW (40% vs. 71%, p < 0.05) and seemed to be due to impaired myocardial oxygenation: Coronary venous oxygen was lower (67% of control values), whereas anaerobic metabolism (lactate release vs. pyruvate consumption) was enhanced. Coronary resistance was correspondingly elevated (164% of control values). SQ 29548 caused all variables to revert to control values.


CONCLUSIONS
These data demonstrate that in the guinea pig heart, COX-inhibiting drugs exacerbate loss of cardiac function after ischemia. The enhanced production of isoprostanes favors coronary vasoconstriction and leads to myocardial oxygen deprivation.
Möbert
J
J
Institute of Physiology, University of Munich, Germany. moebert@lrz.uni-muenchen.de
Becker
B F
BF
D000818:Animals; D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D015237:Dinoprost / Q000494:pharmacology*; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D006439:Hemodynamics; D006834:Hydrazines / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D015428:Myocardial Reperfusion Injury / Q000503:physiopathology*; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D014655:Vascular Resistance / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D016861:Cyclooxygenase Inhibitors; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; D017482:Receptors, Thromboxane; C045749:SQ 29548; D015237:Dinoprost