Nitroglycerin induces late preconditioning against myocardial stunning viaa PKC-dependent pathway

Previous studies have shown that administration of nitric oxide (NO) donors induces a delayed cardioprotective effect indistinguishable from the late phase of ischemic preconditioning (PC). However, the ability of clinically relevant NO donors to elicit this phenomenon has not been evaluated. In thi s study we tested whether an NO-releasing agent that is nitroglycerin (NTG) , which is widely used clinically, can mimic the late phase of ischemic PC. Four groups of conscious rabbits underwent six cycles of 4-min occlusion ( O)/4-min reperfusion (R) for 3 consecutive days (days 1, 2, and 3). The sev erity of myocardial stunning was assessed as the total deficit of systolic wall thickening (WTh) after the last O/R cycle. In the control group (group I, n = 6), the total deficit of WTh was reduced by 50% and 51% on days 2 a nd 3 vs. day 1, respectively, indicating late PC against stunning. Pretreat ment with NTG (2 mu g.kg(-1) min(-1) iv over 1 h) on day 0 (group II, n = 6 ) was as effective as ischemic PC in mitigating myocardial stunning 24 h la ter (day 1); on days 2 and 3, no further reduction of stunning was seen. Co administration of the PKC inhibitor chelerythrine (5 mg/kg) with NTG (group III, n = 6) completely abrogated the NTG-induced protection. Pretreatment with chelerythrine alone (group N, n = 5) did not alter stunning. These res ults demonstrate that a relatively brief infusion of NTG induces a robust p rotective effect against stunning 24 h later via a protein kinase C (PKC)-d ependent signaling mechanism. The magnitude of NTG-induced protection is eq uivalent to that observed during the late phase of ischemic PC. Late PC ind uced by brief treatment with NTG could be a useful therapeutic strategy for myocardial protection in patients with ischemic heart disease.