Age- and gender-related differences in ischemia/reperfusion injury and cardioprotection: effects of diazoxide.
BACKGROUND
Recent studies have demonstrated that aging is associated with reduced tolerance to ischemia and that the aged (not senescent) female heart has greater susceptibility to ischemia as compared with the aged male heart. Previously, we have shown that ischemia can be modulated with cardioplegia in the male heart; however, efficacy in the female heart was unknown.


METHODS
In this study, male and female mature (15 to 20 weeks) aged (>32 months) rabbit hearts (n = 134) were subjected to Langendorff perfusion. Control hearts were perfused for 180 minutes. Global ischemia hearts received 30 minutes of equilibrium, 30 minutes of global ischemia, and 120 minutes of reperfusion. Cardioplegia +/- diazoxide was infused separately, 5 minutes before global ischemia.


RESULTS
Global ischemia significantly decreased postischemic functional recovery and significantly increased infarct size in the mature and aged male and female heart (p < 0.05 versus control). The effects of global ischemia were significantly exacerbated (p < 0.05) in the aged heart as compared with the mature heart. Cardioplegia +/- diazoxide significantly increased postischemic functional recovery and significantly decreased infarct size in mature male and female hearts, but these effects were significantly decreased in the aged heart (p < 0.05) and in the aged female as compared with the aged male heart.


CONCLUSIONS
Postischemic functional recovery and infarct size are affected by age but not by gender. The cardioprotection afforded by cardioplegia is affected by age and gender with a strong age-by-gender interaction for end-diastolic pressure and infarct size. Our results indicate that currently optimized cardioplegia protocols effective in the male heart are not as efficacious in the aged female heart.
McCully
James D
JD
Division of Cardiothoracic Surgery, Beth Israel Deaconess Medical Center, Harvard Institutes of Medicine, Boston, Massachusetts 02115, USA. james_mccully@hms.harvard.edu
Toyoda
Yoshiya
Y
Wakiyama
Hidetaka
H
Rousou
Anthony J
AJ
Parker
Robert A
RA
Levitsky
Sidney
S
D000375:Aging / Q000502:physiology*; D000818:Animals; D002314:Cardioplegic Solutions / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D003981:Diazoxide / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D004198:Disease Susceptibility; D004353:Drug Evaluation, Preclinical; D005260:Female; D066298:In Vitro Techniques; D007552:Isotonic Solutions / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D017202:Myocardial Ischemia / Q000150:complications*; D015428:Myocardial Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D010477:Perfusion; D015221:Potassium Channels / Q000187:drug effects; D011817:Rabbits; D012727:Sex Characteristics; D016277:Ventricular Function, Left / Q000187:drug effects
D002314:Cardioplegic Solutions; D002316:Cardiotonic Agents; D007552:Isotonic Solutions; C051865:Krebs-Ringer solution; D015221:Potassium Channels; C117780:mitochondrial K(ATP) channel; D003981:Diazoxide