© 2002 by European Society of Cardiology
Copyright © 2002, European Society of Cardiology
Male and female mice overexpressing the β2-adrenergic receptor exhibit differences in ischemia/reperfusion injury: role of nitric oxide
aDepartment of Pathology, Box 3712, Duke University Medical Center, Durham, NC 27710, USA
bDepartment of Surgery, Duke University Medical Center, Durham, NC 27710, USA
cNIEHS, Research Triangle Park, Durham, NC 27709, USA
cross017{at}mc.duke.edu
* Corresponding author. Tel.: +1-919-541-5411; fax: +1-919-541-3385
Objective: Cardiac overexpression of β2-adrenergic receptors (β2ARs) in male mice (MTG4) results in increased contractility and increased ischemic injury. Considering recent clinical data indicating that premenopausal women are protected from cardiovascular injury, we assessed the consequences of β2AR overexpression in females (FTG4). Since protection in females is mediated via estrogen, which activates endothelial and inducible nitric oxide synthases (eNOS and iNOS) we also examined the role of NOS in ischemia/reperfusion injury in male and female TG4 and wild-type (WT) mice. Methods: Hearts from MTG4, FTG4, MWT and FWT mice were isolated and perfused in the Langendorff mode. Hearts were pretreated with either 1 µmol/l of the nonspecific NOS inhibitor, L-NAME, or 100 nmol/l of the specific iNOS inhibitor, 1400W. Control hearts received no treatment. All hearts were subjected to 20 min ischemia and 40 min reperfusion while 31P-NMR spectra were acquired. Results: During ischemia, ATP and pH fell lower in MTG4 hearts than in FTG4 or WT hearts. Hearts from MTG4 mice exhibited increased ischemia/reperfusion injury as indicated by lower recoveries of postischemic contractile function, ATP and PCr than WT. Despite contractility being elevated in FTG4 hearts to the same level as MTG4 hearts, ischemia/reperfusion injury was not increased, as indicated by similar postischemic recoveries of contractile function, ATP and PCr in FTG4 hearts compared to WT. ATP and pH fell lower during ischemia in L-NAME-treated FTG4 hearts than in untreated FTG4 hearts, falling as low as untreated MTG4s. Recoveries of contractile function, ATP and PCr were as low in L-NAME-treated FTG4 hearts as in untreated MTG4 hearts and lower than untreated FTG4 hearts. In contrast, 1400W had no effect on FTG4 hearts. MTG4 hearts were unaffected by L-NAME or 1400W. Conclusions: β2AR overexpression increased ischemia/reperfusion injury in males but not females, thus females were protected from the detrimental effects of β2AR overexpression. Protection was abolished by treatment with L-NAME, but not 1400W, implying that protection was mediated by eNOS not iNOS.
KEYWORDS Energy metabolism; Gender; Ischemia; Nitric oxide; NMR
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