The Late Phase of Preconditioning Against Myocardial Stunning

Although protein tyrosine kinases (PTKs) signaling has been implicated in the late phase of ischemic preconditioning (PC), it is unknown whether PTK signaling is necessary for the development of nitric oxide (NO) donor-induced late PC. Thus conscious rabbits underwent a sequence of six 4-min coronary occlusion (O)/4-min reperfusion (R) cycles followed by a 5-h recovery period of reperfusion for 3 consecutive days ( days 1, 2, and 3). On day 0 (24 h before the 6 O/R cycles on day 1), rabbits received no treatment (control), the NO donor diethylenetriamine (DETA)/NO (DETA/NO), the PTK inhibitor 4-amino-5-(4-chlorophenyl)-7-( t-butyl)pyrazolo[3,4- d]pyrimidine (PP2), or DETA/NO plus PP2 (DETA/NO + PP2). In control rabbits ( n = 6), the six O/R cycles on day 1resulted in delayed functional recovery, indicating severe myocardial stunning. In rabbits pretreated with DETA/NO ( n = 5) on day 1, myocardial stunning caused by the six O/R cycles on day 1 was markedly attenuated, with a significant reduction (∼60%) in the total deficit of wall thickening (WTh) compared with controls, indicating that DETA/NO induced a late PC effect against stunning. However, in rabbits pretreated with DETA/NO + PP2 ( n = 5), the total deficit of WTh was significantly greater than that in rabbits treated with DETA/NO alone and was similar to that in controls, indicating that PP2 prevented the development of DETA/NO-induced late PC. In rabbits pretreated with PP2 on day 0 ( n = 4), the total deficit of WTh was similar to that in controls, indicating that PP2 does not affect myocardial stunning in itself. We conclude that a PTK-dependent signaling mechanism is necessary for the development of NO donor-induced late PC against myocardial stunning in conscious rabbits.

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Increased protein synthesis is necessary for the development of late preconditioning against myocardial stunning

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.3.h874 ◽

1999 ◽

Vol 277 (3) ◽

pp. H874-H884 ◽

Cited By ~ 11

Author(s):

Ali Rizvi ◽

Xian-Liang Tang ◽

Yumin Qiu ◽

Yu-Ting Xuan ◽

Hitoshi Takano ◽

...

Keyword(s):

Protein Synthesis ◽

Myocardial Stunning ◽

Late Phase ◽

Group Vi ◽

Group V ◽

Group Iii ◽

Late Preconditioning ◽

Protein Pool ◽

Group I ◽

Delayed Toxicity

In phase I of this study, the rate of protein synthesis was measured by the incorporation of [3H]leucine into the protein pool in the heart of conscious rabbits. At 2 h after ischemic preconditioning (PC) with six 4-min occlusion/4-min reperfusion (O/R) cycles ( group II), the [3H]leucine content in the ischemic-reperfused region was increased by 82% compared with that in controls ( group I), indicating increased protein synthesis. This increase was completely abrogated by pretreatment with cycloheximide (CH; group III). In phase II, rabbits underwent six O/R cycles for three consecutive days ( days 1–3). Controls ( group IV) exhibited late PC against myocardial stunning on days 2 and 3. In group V, which received CH 30 min before the 1st O/R cycle on day 1 (same dose as group III), late PC against stunning on day 2 was completely abrogated. In group VI, pretreatment with CH 24 h before the 1st sequence of O/R cycles had no effect on myocardial stunning on day 1, indicating that the absence of late PC on day 2 in group V cannot be ascribed to delayed toxicity of CH. Taken together, these results demonstrate that, in the conscious rabbit, ischemic PC causes a rapid increase in myocardial protein synthesis and that this increased protein synthesis (or at least a fraction of it) is necessary for the development of the protection against myocardial stunning 24 h later. The late phase of ischemic PC is therefore dependent on the formation of new proteins in intact animals.

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Differential role of KATP channels in late preconditioning against myocardial stunning and infarction in rabbits

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.2000.279.5.h2350 ◽

2000 ◽

Vol 279 (5) ◽

pp. H2350-H2359 ◽

Cited By ~ 36

Author(s):

Hitoshi Takano ◽

Xian-Liang Tang ◽

Roberto Bolli

Keyword(s):

Infarct Size ◽

Myocardial Stunning ◽

Late Phase ◽

Katp Channels ◽

Wall Thickening ◽

Late Preconditioning ◽

End Effectors ◽

Sparing Effect ◽

Systolic Wall Thickening

The role of ATP-sensitive potassium (KATP) channels in the late phase of ischemic preconditioning (PC) remains unclear. Furthermore, it is unknown whether KATP channels serve as end effectors both for late PC against infarction and against stunning. Thus, in phase I of this study, conscious rabbits underwent a 30-min coronary occlusion (O) followed by 72 h of reperfusion (R) with or without ischemic PC (6 4-min O/4-min R cycles) 24 h earlier. Late PC reduced infarct size ∼46% versus controls. The KATPchannel blocker 5-hydroxydecanoic acid (5-HD), given 5 min before the 30-min O, abrogated the infarct-sparing effect of late PC but did not alter infarct size in non-PC rabbits. In phase II, rabbits underwent six 4-min O/4-min R cycles for 3 consecutive days ( days 1, 2, and 3). In controls, the total deficit of systolic wall thickening (WTh) after the sixth reperfusion was reduced by 46% on day 2 and 54% on day 3compared with day 1, indicating a late PC effect against myocardial stunning. Neither 5-HD nor glibenclamide, given on day 2, abrogated late PC. The KATP channel opener diazoxide, given on day 1, attenuated stunning, and this effect was completely blocked by 5-HD. Thus the same dose of 5-HD that blocked the antistunning effect of diazoxide failed to block the antistunning effects of late PC. Furthermore, when diazoxide was administered in PC rabbits on day 2, myocardial stunning was further attenuated, indicating that diazoxide and late PC have additive anti-stunning effects. We conclude that KATP channels play an essential role in late PC against infarction but not in late PC against stunning, revealing an important pathogenetic difference between these two forms of cardioprotection.

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The early and late phases of preconditioning against myocardial stunning and the essential role of oxyradicals in the late phase: an overview

New Paradigms of Coronary Artery Disease ◽

10.1007/978-3-642-53793-6_52 ◽

1996 ◽

pp. 175-181 ◽

Cited By ~ 1

Author(s):

R. Bolli

Keyword(s):

Myocardial Stunning ◽

Essential Role ◽

Late Phase

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Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1999.277.6.h2488 ◽

1999 ◽

Vol 277 (6) ◽

pp. H2488-H2494 ◽

Cited By ~ 18

Author(s):

Supratim Banerjee ◽

Xian-Liang Tang ◽

Yumin Qiu ◽

Hitoshi Takano ◽

Srinivas Manchikalapudi ◽

...

Keyword(s):

Myocardial Stunning ◽

Late Phase ◽

Group Iv ◽

Control Group ◽

Wall Thickening ◽

Signaling Mechanism ◽

No Donors ◽

Group Iii ◽

Late Preconditioning ◽

Group I

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−1iv over 1 h) on day 0 ( group II, 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.

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