Mepacrine protects the isolated rat heart during hypoxia and reoxygenation--but not by inhibition of phospholipase A2.
Mepacrine (quinacrine) has in a number of studies been shown to protect the heart from ischemic injury, a protection commonly claimed to be due to inhibition of phospholipase A2. The aim of the present study was to investigate the effect of mepacrine 1 microM on isolated, buffer perfused rat hearts subjected to 60 min hypoxia and 30 min reoxygenation. We also wanted to clarify whether any cardioprotective effect was due to inhibition of phospholipase A2 or to other effects of the drug. Mepacrine led to a substantial fall in left ventricular developed pressure (LVDP) and coronary flow (CF) during normoxic perfusion. Treated hearts showed less increase in LVEDP and less fall in LVDP during the hypoxic period, and significantly fewer hearts stopped beating compared to untreated controls. Release of CK during hypoxia and reoxygenation was reduced in treated hearts compared to controls (19.9 +/- 3.8 vs. 73.1 +/- 13.3 IU, p < 0.05). Lipid analyses of the myocardium showed a significant increase in the total amount of non esterified fatty acids (NEFA) in both untreated and mepacrine treated hypoxic hearts compared to normoxic controls, but to a significantly lower level in the mepacrine treated hearts. However, contribution of polyunsaturated NEFAs to total NEFAs did not differ between the groups. Also, neither total amount of fatty acids nor amount of polyunsaturated fatty acids obtained from the 2-position of the phospholipid fraction differed between the treated and untreated groups. In an enzyme assay, mepacrine 1 microM did not inhibit phospholipase A2 activity. We conclude that in our model mepacrine protects the heart from hypoxic injury, but probably by another mechanism than inhibition of phospholipase A2 induced membrane damage.
Bugge
E
E
Department of Medical Physiology, University of Tromso, Norway.
Gamst
T M
TM
Hegstad
A C
AC
Andreasen
T
T
Ytrehus
K
K
D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005230:Fatty Acids, Nonesterified / Q000032:analysis / Q000378:metabolism; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006439:Hemodynamics / Q000187:drug effects; D000860:Hypoxia / Q000188:drug therapy*; D066298:In Vitro Techniques; D008297:Male; D009206:Myocardium / Q000737:chemistry; D010477:Perfusion; D010741:Phospholipases A / Q000037:antagonists & inhibitors / Q000187:drug effects* / Q000378:metabolism; D054467:Phospholipases A2; D011796:Quinacrine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D005230:Fatty Acids, Nonesterified; D010741:Phospholipases A; D054467:Phospholipases A2; D011796:Quinacrine