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

2000 ◽  
Vol 279 (5) ◽  
pp. H2350-H2359 ◽  
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.

Reduction of infarct size with d-myo-inositol trisphosphate: role of PI3-kinase and mitochondrial KATP channels

2006 ◽  
Vol 290 (2) ◽  
pp. H830-H836 ◽  
Author(s):  
Karin Przyklenk ◽  
Michelle Maynard ◽  
Peter Whittaker
Keyword(s):  
Infarct Size ◽  
Katp Channels ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Additional Treatment ◽  
Pi3 Kinase ◽  
Mitochondrial Katp Channels ◽  
Tetrazolium Staining ◽  
Sparing Effect

Prophylactic treatment with d- myo-inositol 1,4,5-trisphosphate hexasodium [d- myo-Ins(1,4,5)P3], the sodium salt of the endogenous second messenger Ins(1,4,5)P3, triggers a reduction of infarct size comparable in magnitude to that seen with ischemic preconditioning (PC). However, the mechanisms underlying d- myo-Ins(1,4,5)P3-induced protection are unknown. Accordingly, our aim was to investigate the role of four archetypal mediators implicated in PC and other cardioprotective strategies (i.e., PKC, PI3-kinase/Akt, and mitochondrial and/or sarcolemmal KATP channels) in the infarct-sparing effect of d- myo-Ins(1,4,5)P3. Fifteen groups of isolated buffer-perfused rabbit hearts [5 treated with d- myo-Ins(1,4,5)P3, 5 treated with PC, and 5 control cohorts] underwent 30 min of coronary artery occlusion and 2 h of reflow. One set of control, d- myo-Ins(1,4,5)P3, and PC groups received no additional treatment, whereas the remaining sets were infused with chelerythrine, LY-294002, 5-hydroxydecanoate (5-HD), or HMR-1098 [inhibitors of PKC, PI3-kinase, and mitochondrial and sarcolemmal ATP-sensitive K+ (KATP) channels, respectively]. Infarct size (delineated by tetrazolium staining) was, as expected, significantly reduced in both d- myo-Ins(1,4,5)P3- and PC-treated hearts versus controls. d- myo-Ins(1,4,5)P3-induced cardioprotection was blocked by 5-HD but not HMR-1098, thereby implicating the involvement of mitochondrial, but not sarcolemmal, KATP channels. Moreover, the benefits of d- myo-Ins(1,4,5)P3 were abrogated by LY-294002, whereas, in contrast, chelerythrine had no effect. These latter pharmacological data were corroborated by immunoblotting: d- myo-Ins(1,4,5)P3 evoked a significant increase in expression of phospho-Akt but had no effect on the activation/translocation of the cardioprotective ε-isoform of PKC. Thus PI3-kinase/Akt signaling and mitochondrial KATP channels participate in the reduction of infarct size afforded by prophylactic administration of d- myo-Ins(1,4,5)P3.

Cyclooxygenase-2 does not mediate late preconditioning induced by activation of adenosine A1 or A3receptors

2001 ◽  
Vol 281 (2) ◽  
pp. H959-H968 ◽  
Author(s):  
Eitaro Kodani ◽  
Ken Shinmura ◽  
Yu-Ting Xuan ◽  
Hitoshi Takano ◽  
John A. Auchampach ◽  
...  
Keyword(s):  
Infarct Size ◽  
Receptor Agonist ◽  
Coronary Occlusion ◽  
Late Phase ◽  
Cyclooxygenase 2 ◽  
Late Preconditioning ◽  
Cardioprotective Effects ◽  
Cox 2 ◽  
Delayed Phase

Recent studies have demonstrated that the adenosine A1 receptor agonist 2-chloro- N 6-cyclopentyladenosine (CCPA) and the adenosine A3 receptor agonist N 6-(3-iodobenzyl)adenosine-5′- N-methyluronamide (IB-MECA) produce a delayed phase of protection against infarction similar to the late phase of ischemic preconditioning (PC). However, the mechanism for adenosine A1 or A3receptor-induced late PC remains unknown. The goal of this study was to determine whether the delayed cardioprotective effects of adenosine A1 or A3 receptors are mediated by cyclooxygenase-2 (COX-2), which is an obligatory mediator of ischemic PC. We found that COX-2 protein expression (Western blotting) did not increase 24 h after the administration of either CCPA (100 μg/kg iv) or IB-MECA (300 μg/kg iv) compared with controls. To probe the role of constitutive COX-2 expression, conscious rabbits were subjected to 30-min coronary occlusion followed by 72-h reperfusion. Twenty-four hours before the occlusion, the rabbits were pretreated with CCPA (100 μg/kg iv) or IB-MECA (300 μg/kg iv). Both CCPA and IB-MECA resulted in a marked (∼47%) reduction in infarct size vs. controls [36.2 ± 4.0% of the risk region ( n = 9), 31.2 ± 4.7% ( n = 9), and 59.5 ± 3.8% ( n = 9), respectively; P < 0.05], similar to that induced by the late phase of ischemic PC [31.8 ± 3.2% ( n = 9)]. The selective COX-2 inhibitor N-(2-[cyclohexyloxy]4-nitrophenyl)methanesulfonamide (NS-398, 5 mg/kg), which abolished the protective effect of ischemic late PC, failed to block the protection of either CCPA or IB-MECA, indicating that COX-2 does not mediate the delayed protection of either CCPA or IB-MECA [CCPA + NS-398, 29.1 ± 3.4% ( n = 7); IB-MECA + NS-398, 34.9 ± 2.9% ( n = 8)]. NS-398 in itself did not affect infarct size [54.9 ± 3.7% ( n = 9)]. Taken together, these results demonstrate that, in contrast to ischemia-induced late PC, the mechanisms of adenosine A1 or A3 receptor-induced late PC is independent of COX-2.

Reduction in postsystolic wall thickening during late preconditioning

2007 ◽  
Vol 292 (1) ◽  
pp. H158-H164 ◽  
Author(s):  
Xavier Monnet ◽  
Laurence Lucats ◽  
Patrice Colin ◽  
Geneviève Derumeaux ◽  
Jean-Luc Dubois-Rande ◽  
...  
Keyword(s):  
Myocardial Stunning ◽  
Time Course ◽  
Coronary Artery Occlusion ◽  
Artery Occlusion ◽  
Wall Thickening ◽  
Circumflex Artery ◽  
Late Preconditioning ◽  
Rapid Ventricular Pacing ◽  
Systolic Wall Thickening ◽  
Similar Decrease

Brief coronary artery occlusion (CAO) and reperfusion induce myocardial stunning and late preconditioning. Postsystolic wall thickening (PSWT) also develops with CAO and reperfusion. However, the time course of PSWT during stunning and the regional function pattern of the preconditioned myocardium remain unknown. The goal of this study was to investigate the evolution of PSWT during myocardial stunning and its modifications during late preconditioning. Dogs were chronically instrumented to measure (sonomicrometry) systolic wall thickening (SWT), PSWT, total wall thickening (TWT = SWT + PSWT), and maximal rate of thickening (dWT/d tmax). Two 10-min CAO (circumflex artery) were performed 24 h apart ( day 0 and day 1, n = 7). At day 0, CAO decreased SWT and increased PSWT. During the first hours of the subsequent stunning, evolution of PSWT was symmetrical to that of SWT. At day 1, baseline SWT was similar to day 0, but PSWT was reduced (−66%), while dWT/d tmax and SWT/TWT ratio increased (+48 and +14%, respectively). After CAO at day 1, stunning was reduced, indicating late preconditioning. Simultaneously vs. day 0, PSWT was significantly reduced, and dWT/d tmax as well as SWT/TWT ratio were increased, i.e., a greater part of TWT was devoted to ejection. Similar decrease in PSWT was observed with a nonischemic preconditioning stimulus (rapid ventricular pacing, n = 4). In conclusion, a major contractile adaptation occurs during late preconditioning, i.e., the rate of wall thickening is enhanced and PWST is almost abolished. These phenotype adaptations represent potential approaches for characterizing stunning and late preconditioning with repetitive ischemia in humans.

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

1999 ◽  
Vol 277 (6) ◽  
pp. H2488-H2494 ◽  
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.

scholarly journals The cardioprotection of the late phase of ischemic preconditioning is enhanced by postconditioning via a COX-2-mediated mechanism in conscious rats

2007 ◽  
Vol 293 (4) ◽  
pp. H2557-H2564 ◽  
Author(s):  
Hiroshi Sato ◽  
Roberto Bolli ◽  
Gregg D. Rokosh ◽  
Qiuli Bi ◽  
Shujing Dai ◽  
...  
Keyword(s):  
Protein Expression ◽  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Coronary Occlusion ◽  
Late Phase ◽  
Conscious Rats ◽  
Late Preconditioning ◽  
Cox 2 ◽  
Sparing Effect ◽  
Combined Interventions

The present study sought to determine whether the combination of late preconditioning (PC) with postconditioning enhances the reduction in infarct size. Chronically instrumented rats were assigned to a 45-min ( subset 1) or 60-min ( subset 2) coronary occlusion followed by 24 h of reperfusion. In each subset, rats received no further intervention (control) or were preconditioned 24 h before occlusion (PC), postconditioned at the onset of reperfusion following occlusion, or preconditioned and postconditioned without (PC + postconditioning) or with the COX-2 inhibitor celecoxib (3 mg/kg ip; PC + postconditioning + celecoxib) 10 min before postconditioning. Myocardial cyclooxygenase-2 (COX-2) protein expression and COX-2 activity (assessed as myocardial levels of PGE2) were measured 6 min after reperfusion in an additional five groups (control, PC, postconditioning, PC + postconditioning, and PC + postconditioning + celecoxib) subjected to a 45-min occlusion. PC alone reduced infarct size after a 45-min occlusion but not after a 60-min occlusion. Postconditioning alone did not reduce infarct size in either setting. However, the combination of late PC and postconditioning resulted in a robust infarct-sparing effect in both settings, suggesting additive cardioprotection. Celecoxib completely abrogated the infarct-sparing effect of the combined interventions in both settings. Late PC increased COX-2 protein expression and PGE2 content. PGE2 content (but not COX-2 protein) was further increased by the combination of both interventions, suggesting that postconditioning increases the activity of COX-2 induced by late PC. In conclusion, the combination of late PC and postconditioning produces additive protection, likely due to a postconditioning-induced enhancement of COX-2 activity.

Protein tyrosine kinase signaling is necessary for NO donor-induced late preconditioning against myocardial stunning

2003 ◽  
Vol 284 (4) ◽  
pp. H1441-H1448 ◽  
Author(s):  
Xian-Liang Tang ◽  
Eitaro Kodani ◽  
Hitoshi Takano ◽  
Michael Hill ◽  
Ken Shinmura ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Myocardial Stunning ◽  
Protein Tyrosine Kinase ◽  
Late Phase ◽  
Recovery Period ◽  
Wall Thickening ◽  
No Donor ◽  
Signaling Mechanism ◽  
Protein Tyrosine ◽  
Conscious Rabbits

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.

Differential role of sarcolemmal and mitochondrial KATP channels in adenosine-enhanced ischemic preconditioning

2000 ◽  
Vol 279 (6) ◽  
pp. H2694-H2703 ◽  
Author(s):  
Yoshiya Toyoda ◽  
Ingeborg Friehs ◽  
Robert A. Parker ◽  
Sidney Levitsky ◽  
James D. McCully
Keyword(s):  
Infarct Size ◽  
Functional Recovery ◽  
Ischemic Preconditioning ◽  
Channel Blocker ◽  
Katp Channels ◽  
Size Reduction ◽  
Ischemia And Reperfusion ◽  
Infarct Size Reduction ◽  
Mitochondrial Katp Channels

Adenosine-enhanced ischemic preconditioning (APC) extends the protection afforded by ischemic preconditioning (IPC) by both significantly decreasing infarct size and significantly enhancing postischemic functional recovery. The purpose of this study was to determine whether APC is modulated by ATP-sensitive potassium (KATP) channels and to determine whether this modulation occurs before ischemia or during reperfusion. The role of KATP channels before ischemia (I), during reperfusion (R), or during ischemia and reperfusion (IR) was investigated using the nonspecific KATP blocker glibenclamide (Glb), the mitochondrial (mito) KATP channel blocker 5-hydroxydecanoate (5-HD), and the sarcolemmal (sarc) KATPchannel blocker HMR-1883 (HMR). Infarct size was significantly increased ( P < 0.05) in APC hearts with Glb-I, Glb-R, and 5-HD-I treatment and partially with 5-HD-R. Glb-I and Glb-R treatment significantly decreased APC functional recovery ( P < 0.05 vs. APC), whereas 5-HD-I and 5-HD-R had no effect on APC functional recovery. HMR-IR significantly decreased postischemic functional recovery ( P < 0.05 vs. APC) but had no effect on infarct size. These data indicate that APC infarct size reduction is modulated by mitoKATP channels primarily during ischemia and suggest that functional recovery is modulated by sarcKATP channels during ischemia and reperfusion.

Oxidant species trigger late preconditioning against myocardial stunning in conscious rabbits

2002 ◽  
Vol 282 (1) ◽  
pp. H281-H291 ◽  
Author(s):  
Xian-Liang Tang ◽  
Hitoshi Takano ◽  
Ali Rizvi ◽  
Julio F. Turrens ◽  
Yumin Qiu ◽  
...  
Keyword(s):  
Myocardial Stunning ◽  
Cumene Hydroperoxide ◽  
High Plasma ◽  
Vehicle Group ◽  
Wall Thickening ◽  
Oxygen Species ◽  
Group Vi ◽  
Late Preconditioning ◽  
Group I ◽  
Conscious Rabbits

Conscious rabbits underwent six 4-min occlusion and 4-min reperfusion cycles for 3 consecutive days ( day 1, 2, and 3); on day 1, rabbits received intravenous vehicle [preconditioning (PC)] ( group I, n = 6), superoxide dismutase (SOD; group II, n = 5), catalase ( group III, n = 6), or the hydroxyl radical (· OH) and peroxynitrite (ONOO−) scavenger N-2-mercaptopropionyl glycine (MPG [group IV], n = 6). In the PC group, the recovery of systolic wall thickening (WTh) after the sixth reperfusion was markedly improved on days 2 and 3 compared with day 1 and the total deficit of WTh was correspondingly reduced, indicating a late PC effect against myocardial stunning. Neither SOD nor catalase had any significant effect on the severity of stunning on day 1 or on the development of late PC on days 2 and 3, despite high plasma levels. In contrast, MPG markedly attenuated the severity of stunning on day 1 and prevented the development of late PC on day 2. Two additional groups of rabbits received an intracoronary infusion of vehicle ( group V, n = 4) or the reactive oxygen species (ROS) generating solution [cumene hydroperoxide (CuOOH, group VI, n = 7)] on day 0, and were then subjected to the six occlusion/reperfusion cycles on days 1, 2, and 3. In group VI, infusion of CuOOH elicited a late PC effect 24 h later (on day 1). Taken together, these results demonstrate that oxidant species play an essential role in triggering the development of late PC against stunning in conscious rabbits. The fact that late PC was blocked by MPG and mimicked by CuOOH implicate ONOO− and/or ·OH as the oxygen species responsible for the initiation of this phenomenon. In addition, the finding that exogenous ROS (CuOOH) reproduced the phenotype of late PC indicates that ROS are not only necessary but also sufficient to trigger this defensive adaptation of the heart to stress.

Late preconditioning enhances recovery of myocardial function after infarction in conscious rabbits

2000 ◽  
Vol 279 (5) ◽  
pp. H2372-H2381 ◽  
Author(s):  
Hitoshi Takano ◽  
Xian-Liang Tang ◽  
Eitaro Kodani ◽  
Roberto Bolli
Keyword(s):  
Myocardial Infarction ◽  
Infarct Size ◽  
Left Ventricular ◽  
Nitric Oxide Donor ◽  
Lv Function ◽  
Wall Thickening ◽  
Triphenyltetrazolium Chloride ◽  
Independent Evidence ◽  
Late Preconditioning ◽  
Conscious Rabbits

It is unknown whether late preconditioning (PC) enhances the recovery of left ventricular (LV) function after a myocardial infarction. Thus 25 conscious rabbits were subjected to a 30-min coronary occlusion followed by 28 days of reperfusion after PC 24 h earlier with either ischemia or nitric oxide donor administration [ S-nitroso- N-acetylpenicillamine (SNAP)]. The recovery of wall thickening (WTh) after reperfusion was significantly improved in the ischemic PC and SNAP PC groups compared with controls, both at rest and during dobutamine stress. Interestingly, neither ischemia- nor SNAP-induced late PC attenuated myocardial stunning from day 1 through day 14. Infarct size was smaller in the ischemic PC and SNAP PC groups compared with controls. In all groups, WTh at 28 days was positively and linearly related to the percentage of viable tissue in the region underlying the ultrasonic crystal ( r = 0.90), indicating that the improvement in LV function after both ischemia-induced and NO donor-induced late PC can be fully explained by the reduction in infarct size; a separate effect of late PC on LV remodeling or LV contractility need not be invoked. In conclusion, in conscious rabbits late PC, induced either by ischemia or pharmacologically, not only limits infarct size but also enhances the recovery of LV function after myocardial infarction. This finding has important clinical implications and provides triphenyltetrazolium chloride-independent evidence that late PC limits myocellular death after sustained ischemia.

Chemical preconditioning with 3-nitropropionic acid in hearts: role of mitochondrial KATP channel

2001 ◽  
Vol 280 (5) ◽  
pp. H2406-H2411 ◽  
Author(s):  
Ramzi A. Ockaili ◽  
Peeyush Bhargava ◽  
Rakesh C. Kukreja
Keyword(s):  
Infarct Size ◽  
Early Phase ◽  
Ischemia Reperfusion ◽  
Late Phase ◽  
Saline Group ◽  
Risk Area ◽  
Nitropropionic Acid ◽  
Delayed Phase ◽  
3 Nitropropionic Acid

We investigated the cardioprotective effect of 3-nitropropionic acid (3-NPA), an inhibitior of mitochondrial succinate dehydrogenase, and we wanted to show whether this protection is mediated by of opening mitochondrial ATP-sensitive potassium (KATP) channels. Adult rabbits were treated with either 3-NPA (3 mg/kg iv) or saline ( n = 6 rabbits/group). After 30 min (for early phase) or 24 h (for late phase) of the treatment, the animals were subjected to 30 min of ischemia and 3 h of reperfusion (ischemia-reperfusion). 5-Hydroxydecanoate (5-HD, 5 mg/kg iv),the mitochondrial KATP channel blocker, was administered 10 min before ischemia-reperfusion in the saline- and 3-NPA-treated rabbits. 3-NPA caused a decrease in the infarct size from 27.8 ± 4.2% in the saline group to 16.5 ± 1.0% in the 3-NPA-treated rabbits during early phase and from 30.4 ± 4.2% in the saline group to 17.6 ± 1.05 in the 3-NPA group during delayed phase ( P < 0.05, % of risk area). The anti-infarct effect of 3-NPA was blocked by 5-HD as shown by an increase in infarct size to 33 ± 2.7% (early phase) and 31 ± 2.4% (delayed phase) ( P < 0.05 vs. 3-NPA groups). 5-HD had no proischemic effect in control animals. Also, 3-NPA had no effect on systemic hemodynamics. We conclude that 3-NPA induces long-lasting anti-ischemic effects via opening of mitochondrial KATP channels.

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