Inhibition of iNOS protects the aging heart against beta-adrenergic receptor stimulation-induced cardiac dysfunction and myocardial ischemic injury.

BACKGROUND

beta-adrenergic receptor (AR) and aging are two major contributors to pathogenesis of perioperative myocardial ischemia and infarction. This study compared the response to beta-AR stimulation in the young and aging heart and examined the role of inducible nitric oxide synthase (iNOS) in aging related myocardial ischemic injury and its relation to beta-AR stimulation.

MATERIAL AND

METHODS

Isolated perfused hearts from young (3-5 months) and aging (24-25 months) rats were subjected to 60 min of 50% coronary flow reduction and 30 min of isoproterenol (Iso) stimulation starting at 30 min of ischemia. The rats were randomized to receive vehicle or 1400W (a selective iNOS inhibitor) at 24 h (2 mg/kg, i.p.) and 1 h (1 mg/kg, i.p.) pre-ischemia.

RESULTS

The 30 min of myocardial ischemia resulted in cardiac dysfunction as indicated by a 13 to 45% of reduction in left ventricular developed pressure (LVDP) and +/- dp/dtmax in either young or aging rats. Infusion of Iso for 30 min caused a partial recovery of cardiac function in hearts from young animals receiving either vehicle or 1400W as evidenced by improvements in LVDP and +/- dp/dtmax. In striking contrast, Iso infusion to hearts from aging animals receiving vehicle not only failed to improve ischemia-induced cardiac depression but worsened cardiac function as indicated by a 43 to 60% further reduction in LVDP and +/- dp/dtmax at the end of 30-min Iso infusion, which was also associated with a significant increase in myocardial NO production, ONOO- formation, caspase-3 activation and creatine kinase (CK) release. However, the treatment with a selective iNOS inhibitor-1400W blocked NO production and ONOO- formation, attenuated caspase-3 activation and CK release, and improved LV function in the aging heart, demonstrating a critical link between iNOS generated NO production and aging myocardial ischemic injury. A significant increase of iNOS protein expression, activity and immunoreactivity was found in the baseline aging LV tissues versus their young counterparts.

CONCLUSIONS

Aging induces phenotypic up-regulation of iNOS in the heart, in which beta-AR stimulation interacts with ischemia and triggers a markedly increased NO production, which creates a nitrative stress, generates toxic peroxynitrite, activates apoptosis, and eventually causes cardiac dysfunction and myocardial injury. An iNOS inhibitor-1400W can markedly attenuate these adverse effects in the aging heart.