Cardioprotective effects of the MR contrast agent MnDPDP and its metabolite MnPLED upon reperfusion of the ischemic porcine myocardium.
OBJECTIVE
To evaluate whether manganese dipyridoxyl diphosphate (MnDPDP) or its metabolite manganese dipyridoxyl ethyldiamine (MnPLED) reduces post-ischemic myocardial injury.


METHODS
Left anterior descending artery (LAD) in anesthetized pigs was occluded (30 min) followed by reperfusion (120 min) during hemodynamic monitoring and infarct assessment. Three micromol/kg MnDPDP, 1 micromol/kg MnPLED (or a mixture of both) or saline was injected i.v. 10 min before reperfusion followed by infusion of either 3 micromol/kg/h MnDPDP, 1 micromol/kg/h MnPLED (or a mixture of both) or saline. The plasma concentrations of MnDPDP, MnPLED and other metabolites (e.g., ZnDPDP and ZnPLED) were analyzed.


RESULTS
Femoral blood flow was reduced by 60% during early reperfusion in controls, whereas only 23 and 31% reductions were seen in animals treated with MnDPDP and MnPLED. During that time, +LV/dP and -LV/dP (maximum rate of left ventricular isovolumic contraction and relaxation, respectively), systolic pressure and diastolic pressure fell significantly less in animals treated with MnDPDP or MnPLED. Three out of 5 control animals experienced ventricular fibrillation (VF) during reperfusion, whereas VF was not seen in any of the pigs treated with MnPLED or/and MnDPDP. The infarct sizes in saline- and MnPLED-treated animals were 39+/-6 and 16+/-5%, respectively, of the occluded areas. MnDPDP did not reduce the infarct size. A mixture of MnDPDP and MnPLED significantly reduced infarct size (10+/-4%). When reperfusion started and throughout reperfusion, almost all injected MnDPDP was present as Zn-metabolites.


CONCLUSIONS
MnPLED seems to reduce reperfusion-induced cardiac dysfunction and infarct size in pigs. MnDPDP does not reduce infarct size in the pig, probably because of the rapid exchange of Mn2+ for Zn2+ taking place in the pig.
Karlsson
J O
JO
Department of Pharmacology, Linköping University, Linköping, Sweden.
Brurok
H
H
Eriksen
M
M
Towart
R
R
Toft
K G
KG
Moen
O
O
Engebretsen
B
B
Jynge
P
P
Refsum
H
H
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002316:Cardiotonic Agents / Q000627:therapeutic use*; D003287:Contrast Media / Q000627:therapeutic use*; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004492:Edetic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D005260:Female; D008279:Magnetic Resonance Imaging; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000188:drug therapy* / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology / Q000503:physiopathology / Q000517:prevention & control*; D009206:Myocardium / Q000473:pathology; D011732:Pyridoxal Phosphate / Q000031:analogs & derivatives* / Q000627:therapeutic use*; D013552:Swine
D002316:Cardiotonic Agents; D003287:Contrast Media; D011732:Pyridoxal Phosphate; D004492:Edetic Acid; C060076:N,N'-bis(pyridoxal-5-phosphate)ethylenediamine-N,N'-diacetic acid