No Involvement of Endogenous Nitric Oxide In Classical Ischemic Preconditioning in Swine

Post, Heiner; Schulz, Rainer; Behrends, Matthias; Gres, Petra; Umschlag, Christian; Heusch, Gerd

doi:10.1006/jmcc.2000.1117

Cited by 68 publications

(35 citation statements)

References 36 publications

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“…AG had no effect on CBF, anterior wall thickening and LVPP in shamoperated animals. This contrasts well with the effects of L-NNA, a NOS inhibitor also directed against eNOS 29 , in the same animal model in an earlier study 30 , which showed pronounced effects on endothelial and regional myocardial function (Online Figure I A). In line with an iNOS-mediated dysfunction, we demonstrated increased iNOS activity during sustained ischemia, and found that tissue nitrite concentrations as a surrogate of NO production correlated inversely with in vivo regional function ( Fig.…”

Section: Discussioncontrasting

confidence: 86%

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

Heinzel

Gres

Boengler

et al. 2008

Circulation Research

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Abstract-In acute myocardial ischemia, regional blood flow and function are proportionally reduced. With prolongation of ischemia, function further declines at unchanged blood flow. We studied the involvement of an inflammatory signal cascade in such progressive dysfunction and whether dysfunction is intrinsic to cardiomyocytes. In 10 pigs, ischemia was induced by adjusting inflow into the cannulated left anterior coronary artery to reduce coronary arterial pressure to 45 mm Hg (ISCH); 4 pigs received the inducible nitric oxide synthase (iNOS) inhibitors aminoguanidine or L-N 6 -(1-iminoethyl)-lysine during ISCH (ISCHϩiNOS-Inhib); 6 pigs served as controls (SHAM). Anterior (AW) and posterior (PW) systolic wall thickening (sonomicrometry) were measured. After 6 hours, nitric oxide (NO) synthase (NOS) protein expression, NOS activity, and NO metabolites (nitrite/nitrate/nitroso species) were quantified in biopsies isolated from AW and PW. Cardiomyocyte shortening and intracellular calcium (Indo-1 acetoxymethyl ester) were measured without and with the NOS substrate L-arginine (100 mol/L). In ISCH, AW wall thickening decreased from 42Ϯ4% (baseline) to 16Ϯ3% (6 hours). Wall thickening remained unchanged in ISCH-PW and SHAM-AW/PW. NOS2 (iNOS) protein expression and activity, but not NOS3 (endothelial NO synthase), were increased in ISCH-AW and ISCH-PW. iNOS expression correlated with increased nitrite contents. Cardiomyocyte shortening was reduced in ISCH-AW versus SHAM-AW (4.4Ϯ0.3% versus 5.6Ϯ0.3%). L-Arginine reduced cardiomyocyte shortening further in ISCH-AW (to 2.8Ϯ0.2%) and ISCH-PW (3.4Ϯ0.4% versus 5.4Ϯ0.4%) but not in SHAM or in ISCHϩiNOS-Inhib; intracellular [Ca 2ϩ ] remained unchanged. With L-arginine, in vitro AW cardiomyocyte shortening correlated with in vivo AW wall thickening (rϭ0.72). In conclusion, sustained regional ischemia induces myocardial iNOS expression in pigs, which contributes to contractile dysfunction at the cardiomyocyte level.

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Section: Discussioncontrasting

confidence: 86%

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

Heinzel

Gres

Boengler

et al. 2008

Circulation Research

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“…The role of NO in early preconditioning is controversial. In some studies, NOS inhibitors failed to abolish preconditioning-induced protection in rats (24,46), rabbits (27,47), and pigs (33). In the rat heart, Weselcouch et al (46) found that protection was not blocked by L-NAME at 30 M, yet Lochner et al (19) were able to block protection with 50 M. Nakano et al (27) found that NO donors induced preconditioning in the rabbit heart but were unable to abolish protection with L-NAME at 100 M. We found that L-NAME inhibited protection at 200 M, but preliminary studies failed to show any effect at 50 or 100 M. Thus dose-dependent effects of NOS inhibitors may explain, at least in part, the negative results observed in some previous reports.…”

Section: Discussionmentioning

confidence: 99%

ROS and NO trigger early preconditioning: relationship to mitochondrial K_ATP channel

Lebuffe

Schumacker

Shao

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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NO trigger early preconditioning: relationship to mitochondrial K ATP channel. Am J Physiol Heart Circ Physiol 284: H299-H308, 2003. First published September 26, 2002 10.1152/ajpheart.00706.2002Reactive oxygen species (ROS) and nitric oxide (NO) are implicated in induction of ischemic preconditioning. However, the relationship between these oxidant signals and opening of the mitochondrial ATP-dependent potassium (K ATP) channel during early preconditioning is not fully understood. We observed preconditioning protection by hypoxia, exogenous H 2O2, or PKC activator PMA in cardiomyocytes subjected to 1-h ischemia and 3-h reperfusion. Protection was abolished by K ATP channel blocker 5-hydroxydecanoate (5-HD) in each case, indicating that these triggers must act upstream from the K ATP channel. Inhibitors of NO synthase abolished protection in preconditioned cells, suggesting that NO is also required for protection. DAF-2 fluorescence (NO sensitive) increased during hypoxic triggering. This was amplified by pinacidil and inhibited by 5-HD, indicating that NO is generated subsequent to K ATP channel activation. Exogenous NO during the triggering phase conferred protection blocked by 5-HD. Exogenous NO also restored protection abolished by 5-HD or N -nitro-L-arginine methyl ester in preconditioned cells. Antioxidants given during pinacidil or NO triggering abolished protection, confirming that ROS are generated by K ATP channel activation. Coadministration of H 2O2 and NO restored PMA-induced protection in 5-HD-treated cells, indicating that ROS and NO are required downstream from the K ATP channel. We conclude that ROS can trigger preconditioning by causing activation of the K ATP channel, which then induces generation of ROS and NO that are both required for preconditioning protection. hydrogen peroxide; nitric oxide; ischemia; cardiomyocytes PRECONDITIONING CONFERS PROTECTION against ischemiareperfusion injury in the heart. After a brief triggering stimulus is applied, the "early window" of protection begins within minutes and lasts for several hours. The persistence of protection after removal of the trigger indicates that a signal transduction pathway has been activated. Numerous triggers of preconditioning have been identified, including brief hypoxia/ischemia, opioids, ACh, bradykinin, activators of PKC, and pharmacological agents that activate the mitochondrial ATPdependent potassium (mitoK ATP ) channel (10,13,15,16,26,39,50). However, the signal transduction sequence activated by these triggers is not fully understood.Reactive oxygen species (ROS) have been implicated as participants in the signaling pathway involved in preconditioning triggering (1,2,4,23,41). We previously reported (42, 50) that exogenous H 2 O 2 induces preconditioning in cardiomyocytes and that mitochondrial ROS are involved in the triggering by hypoxia or by ACh administration. However, an interesting controversy has developed regarding the relationship between the mitoK ATP channel activation and the ROS signal during triggering. On...

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“…*P Ͻ 0.05 vs. group 1. (15,16). The mechanism of cardioprotection by TNF-␣ is not fully understood but might be related to mitochondrial ATP-sensitive potassium channel activation (10).…”

Section: Discussionmentioning

confidence: 99%

TNF-α antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits

Belosjorow

Bolle

Duschin

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Pretreatment with tumor necrosis factor-α (TNF-α) antibodies abolishes myocardial infarct size reduction by late ischemic preconditioning (IP). Whether or not TNF-α is also important for myocardial infarct size reduction by classic IP is unknown. Anesthetized rabbits were untreated ( group 1, n = 7), classically preconditioned by 5 min left coronary artery occlusion/10 min reperfusion ( group 2, n = 6), or pretreated with TNF-α antibodies without ( group 3, n = 6) or with IP ( group 4, n = 6) before undergoing 30 min of occlusion and 180 min of reperfusion. Infarct size in group 1 was 44 ± 11 (means ± SD)% of the area at risk. With a comparable area at risk, infarct size was reduced to 13 ± 7%, 23 ± 8%, and 19 ± 12% (all P < 0.05) in groups 2, 3, and 4, respectively. The circulating TNF-α concentration was increased during ischemia in group 1 from 752 ± 403 to 1,542 ± 482 U/ml ( P < 0.05) but remained unchanged in all other groups. Circulating TNF-α concentration during ischemia and infarct size correlated in all groups ( r = 0.76). IP, TNF-α antibodies, and the combined approach reduced infarct size to a comparable extent. Therefore, the question of whether or not TNF-α is causally involved in the infarct size reduction by IP in rabbits could not be answered.

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No Involvement of Endogenous Nitric Oxide In Classical Ischemic Preconditioning in Swine

Cited by 68 publications

References 36 publications

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

ROS and NO trigger early preconditioning: relationship to mitochondrial K_ATP channel

TNF-α antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits

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No Involvement of Endogenous Nitric Oxide In Classical Ischemic Preconditioning in Swine

Cited by 68 publications

References 36 publications

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

Inducible Nitric Oxide Synthase Expression and Cardiomyocyte Dysfunction During Sustained Moderate Ischemia in Pigs

ROS and NO trigger early preconditioning: relationship to mitochondrial KATP channel

TNF-α antibodies are as effective as ischemic preconditioning in reducing infarct size in rabbits

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Product

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ROS and NO trigger early preconditioning: relationship to mitochondrial K_ATP channel