TY - JOUR
T1 - Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway
AU - Banerjee, Supratim
AU - Tang, Xian Liang
AU - Qiu, Yumin
AU - Takano, Hitoshi
AU - Manchikalapudi, Srinivas
AU - Dawn, Buddhadeb
AU - Shirk, Gregg
AU - Bolli, Roberto
PY - 1999/12
Y1 - 1999/12
N2 - 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 this 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 severity 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 and 3 vs. day 1, respectively, indicating late PC against stunning. Pretreatment with NTG (2 μg · kg-1 · min-1 iv over 1 h) on day 0 (group H, n = 6) was as effective as ischemic PC in mitigating myocardial stunning 24 h later (day 1); on days 2 and 3, no further reduction of stunning was seen. Coadministration 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 IV, n = 5) did not alter stunning. These results demonstrate that a relatively brief infusion of NTG induces a robust protective effect against stunning 24 h later via a protein kinase C (PKC)-dependent signaling mechanism. The magnitude of NTG- induced protection is equivalent to that observed during the late phase of ischemic PC. Late PC induced by brief treatment with NTG could be a useful therapeutic strategy for myocardial protection in patients with ischemic heart disease.
AB - 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 this 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 severity 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 and 3 vs. day 1, respectively, indicating late PC against stunning. Pretreatment with NTG (2 μg · kg-1 · min-1 iv over 1 h) on day 0 (group H, n = 6) was as effective as ischemic PC in mitigating myocardial stunning 24 h later (day 1); on days 2 and 3, no further reduction of stunning was seen. Coadministration 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 IV, n = 5) did not alter stunning. These results demonstrate that a relatively brief infusion of NTG induces a robust protective effect against stunning 24 h later via a protein kinase C (PKC)-dependent signaling mechanism. The magnitude of NTG- induced protection is equivalent to that observed during the late phase of ischemic PC. Late PC induced by brief treatment with NTG could be a useful therapeutic strategy for myocardial protection in patients with ischemic heart disease.
KW - Myocardial ischemia-reperfusion
KW - Nitrates
KW - Nitric oxide
KW - Protein kinase C
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U2 - 10.1152/ajpheart.1999.277.6.h2488
DO - 10.1152/ajpheart.1999.277.6.h2488
M3 - Article
C2 - 10600873
AN - SCOPUS:0033373160
SN - 0363-6135
VL - 277
SP - H2488-H2494
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 6 46-6
ER -