Effects of Adenine Nucleotide Analogues on Myocardial Dysfunction During Reperfusion After Ischemia in Dogs

Nakaï, T.; Kano, Seiichiro; Satoh, Kumi; Hoshi, Katsuji; Ichihara, Kazuo

doi:10.1097/00005344-199608000-00013

Cited by 15 publications

(6 citation statements)

References 23 publications

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“…Inhibition of NF‐κB activation is already thought to have a major role in the anti‐inflammatory actions of glucocorticoids and salicylates. Inhibition of NF‐κB would also offer an additional reason for the success of AICAR in preventing or reducing ischaemic tissue damage 29 , 30 as it is well known that NF‐κB is activated by hypoxia 31…”

Section: Discussionmentioning

confidence: 99%

5‐aminoimidazole‐4‐carboxamide ribonucleoside and AMP‐activated protein kinase inhibit signalling through NF‐κB

et al. 2010

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Activation of nuclear factor‐kappa B (NF‐κB) is one of the most important pro‐inflammatory mechanisms in disease. In this study, we show that 5‐aminoimidazole‐4‐carboxamide ribonucleoside (AICAR), an intermediate in nucleoside metabolism, inhibits signalling by NF‐κB in three cell types, including bovine aortic endothelial cells (BAEC). The block in the NF‐κB signalling pathway occurred beyond degradation of IκB‐α and movement of p65 into the nucleus of BAEC. There was, however, reduced binding of NF‐κB from AICAR‐treated cells to a κB‐consensus oligonucleotide, suggesting that part of the mechanism was a reduction in NF‐κB DNA‐binding activity. Although AICAR is metabolized to ZMP and then adenosine, adenosine had no effect on activation of an NF‐κB reporter. ZMP, however, activates the metabolic stress‐sensing AMP‐activated protein kinase (AMPK). Transfection of active AMPK into BAEC reduced NF‐κB reporter activity compared with a kinase‐dead mutant, suggesting that part of the ability of AICAR to inhibit NF‐κB signalling is due to activation of AMPK. Inhibition of NF‐κB signalling may be important in the anti‐inflammatory action of drugs such as sulfasalazine and methotrexate, which led to the accumulation of AICAR within target cells.

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Section: Discussionmentioning

confidence: 99%

5‐aminoimidazole‐4‐carboxamide ribonucleoside and AMP‐activated protein kinase inhibit signalling through NF‐κB

et al. 2010

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“…Preconditioning ϩ 8-bromo-AMP (PCϩIϩbAMP) (n ϭ 6): Same as group 7, but with previous administration of 5 mmol/L 8-bromo-AMP, 0.1 mL/kg/min intravenously during 30 minutes before preconditioning. 26,27 10. Preconditioning ϩ araA (PCϩIϩaraA) (n ϭ 6): Same as group 7, but with previous administration of araA at 100 g/kg/min during 10 minutes before preconditioning.…”

Section: Experimental Designmentioning

confidence: 99%

Adenosine monophosphate[ndash ]activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat

et al. 2001

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Hepatic ischemia-reperfusion (I/R) injury associated with liver transplantation and hepatic resections are an unresolved problem in the clinical practice. Preconditioning is known to preserve energy metabolism in liver during sustained ischemia, but the molecular mechanisms underlying this effect are still unclear. Different metabolic signals, including adenosine monophosphate (AMP) and nitric oxide (NO), have been implicated in preconditioning. AMP-activated protein kinase (AMPK) protects cells by acting as a low-fuel warning system, becoming switched on by adenosine triphosphate (ATP) depletion. NO synthesis is induced by AMPK in the heart during ischemia. The aim of this study was to investigate: 1) whether preconditioning induces AMPK activation; and 2) if AMPK activation leads to ATP preservation and reduced lactate accumulation during prolonged ischemia and its relationship with NO. Preconditioning activated AMPK and concomitantly reduced ATP degradation, lactate accumulation, and hepatic injury. The administration of an AMPK activator, AICAR, before ischemia simulated the benefits of preconditioning on energy metabolism and hepatic injury. The inhibition of AMPK abolished the protective effects of preconditioning. The effect of AMPK on energy metabolism was independent of NO because the inhibition of NO synthesis in the preconditioned group and the administration of the NO donor before ischemia, or to the preconditioned group with previous inhibition of AMPK, had no effect on energy metabolism. Hepatic ischemia-reperfusion (I/R) injury associated with liver transplantation and hepatic resections is still an unresolved problem in clinical practice. [1][2][3] In 1986, Murry et al. discovered that a short period of ischemia and reperfusion led to an unexpected resistance of the myocardium to a subsequent prolonged ischemia. 4 This phenomenon, called preconditioning, has been subsequently documented in several organs, including the liver. 4-7 Recently, Clavien et al. reported the first clinical evidence suggesting a beneficial effect of ischemic preconditioning during major hepatic surgery in patients subjected to 30 minutes of ischemia. 8 The hope that this phenomenon may find new surgical and/or pharmacologic therapeutic applications in complex hepatic resections-in which long periods of ischemia are necessary-in livers with underlying disease or steatosis-which tolerate injury poorly-as well as in liver transplantation, provides a strong impetus to identify the underlying mechanisms.Previous studies from our group indicated that ischemic preconditioning during sustained ischemia is able to reduce adenosine triphosphate (ATP) degradation and glycolysis, thus lowering the net formation of lactate. 9 ATP preservation probably results from a decreased ATP use, suggesting that preconditioning could promote energy-saving mechanisms. Furthermore, the changes induced by preconditioning on energy metabolism occurred a few minutes after the onset of prolonged ischemia. This would suggest that preconditioning might i...

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“…We [10] have demonstrated that enalapril and telmisartan improve contractile dysfunction of the stunned myocardium, and that the former action is due to inhibition of bradykinin breakdown, whereas the latter is due to a direct block of myocardial AT 1 receptors. Ischemia depletes the ATP store in the myocardium, and reperfusion can restore it with ATP, but incompletely [15,16] . Both telmisartan and olmesartan enhance the restitution of ATP after ischemia.…”

Section: Discussionmentioning

confidence: 99%

Improvement of Stunned Myocardium in Dogs with Olmesartan, an Angiotensin II Type 1 Receptor Antagonist, Is Independent of Type 2 Receptors

Kano¹,

Satoh²,

Kaneta³

et al. 2008

Pharmacology

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Olmesartan is a selective angiotensin II type 1 receptor (AT₁) antagonist. In pentobarbital-anesthetized open-chest dogs, ischemia/reperfusion was induced by ligating the left anterior descending coronary artery for 20 min and releasing it for 60 min, respectively. The myocardial contraction in the ischemic area decreased and returned towards its pre-ischemic level during reperfusion but incompletely. Olmesartan improved the recovery of myocardial contraction during reperfusion associated with restoration of myocardial ATP. Angiotensin II repelled by AT₁ receptors occupied by olmesartan can reach and stimulate the angiotensin II type 2 (AT₂) receptors, resulting in some beneficial effects on the ischemic myocardium. In fact, AT₂ receptor mRNA was found in the adult dog myocardium. In addition, the plasma level of angiotensin II was significantly increased by olmesartan. PD123319, a selective AT₂ receptor antagonist, however, did not modify the effect of olmesartan on the cardiac contraction. The hypertensive response to exogenous angiotensin II was completely inhibited by olmesartan, whereas PD123319 did not abolish the effect of olmesartan. In conclusion, olmesartan protects the ischemic/reperfused heart against ischemic injury through inhibition of AT₁ receptors but not indirect activation of AT₂ receptors.

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Effects of Adenine Nucleotide Analogues on Myocardial Dysfunction During Reperfusion After Ischemia in Dogs

Cited by 15 publications

References 23 publications

5‐aminoimidazole‐4‐carboxamide ribonucleoside and AMP‐activated protein kinase inhibit signalling through NF‐κB

5‐aminoimidazole‐4‐carboxamide ribonucleoside and AMP‐activated protein kinase inhibit signalling through NF‐κB

Adenosine monophosphate[ndash ]activated protein kinase mediates the protective effects of ischemic preconditioning on hepatic ischemia-reperfusion injury in the rat

Improvement of Stunned Myocardium in Dogs with Olmesartan, an Angiotensin II Type 1 Receptor Antagonist, Is Independent of Type 2 Receptors

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