Low concentrations of an nitric oxide-donor combined with a liposoluble antioxidant compound enhance protection against reperfusion injury in isolated rat hearts.
Nitric oxide (NO) and reactive oxygen species (ROS) are double-edged swords in reperfused hearts. The effects of a NO-donor and an antioxidant compound against ischemia/reperfusion were studied. The compounds were tested separately, as a mixture and as a new hybrid molecule containing both leads. Isolated rat hearts underwent 30 min global ischemia and 2 hrs reperfusion. Compounds were infused either at 1 or 10 microM concentrations during the first 20 min of reperfusion. Hybrid was also tested in the presence of mitochondrial K(+) ATP-sensitive (mKATP) channel blockade by 5-HD (100 microM). Reduction of infarct size and recovery of left ventricular developed pressure during reperfusion were evaluated. When given at 1 microM concentration, hybrid significantly improved all indices of protection; its beneficial effects were abolished by mKATP channel blockade. At the same concentration, mixture and NO-donor alone improved recovery of left ventricular developed pressure but did not reduce infarct size; antioxidant was ineffective. When given at 10 microM concentration, antioxidant and mixture improved all parameters of protection; NO-donor and hybrid were ineffective. Our data suggest that different signaling cascades could be elicited by low and high concentrations of antioxidant compound and/or NO-donor. It is likely that a different NO-induced release of reactive oxygen species via mKATP channel activation may play a pivotal role in affecting infarct size and post-ischemic contractile recovery.
University of Turin, Department of Clinical and Biological Sciences, Turin, Italy. raffaella.rastaldo@unito.it
R
R
Rastaldo
S
S
Cappello
A
A
Folino
A
A
Di Stilo
K
K
Chegaev
I
I
Tritto
P
P
Pagliaro
G
G
Losano
D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage / Q000378:metabolism*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000378:metabolism*; D004347:Drug Interactions / Q000502:physiology; D004359:Drug Therapy, Combination; D008055:Lipids; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D020030:Nitric Oxide Donors / Q000008:administration & dosage / Q000378:metabolism*; D009924:Organ Culture Techniques; D051381:Rats; D017208:Rats, Wistar; D012995:Solubility
D000975:Antioxidants; D002316:Cardiotonic Agents; D008055:Lipids; D020030:Nitric Oxide Donors