Role of activation of ectosolic 5'-nucleotidase in the cardioprotection mediated by opening of K+c channels

Abstract

We tested the hypothesis that the opening of ATP-sensitive K+ channels contributes to activation of ectosolic 5'-nucleotidase and the infarct size-limiting effect of ischemic preconditioning. In open-chest dogs, the left anterior descending coronary artery was occluded four times for 5 min each, separated by a 5-min period of reperfusion (ischemic preconditioning, n = 8). After this procedure, the coronary artery was occluded for 90 min, followed by 6 h of reperfusion. Infarct size was smaller in this group than in the group (control, n = 8) with a 45 min interval instead of the ischemic preconditioning procedure (40.1 +/- 3.9 vs. 6.4 +/- 1.9%). Glibenclamide blunted the infarct size-limiting effect of ischemic preconditioning (infarct size, 37.3 +/- 5.8%; n = 7), and transient exposures to cromakalim and nicorandil mimicked it [infarct size, 10.1 +/- 3.1 (n = 7) and 11.1 +/- 2.7% (n = 8), respectively]. Ectosolic and cytosolic 5'-nucleotidase activity increased in the ischemic preconditioning group compared with that in the control group; this preconditioning-induced increase in 5'-nucleotidase activity was blunted by glibenclamide (n = 5) and mimicked by cromakalim (n = 5) and nicorandil (n = 5). The infarct size-limiting effect due to cromakalim and nicorandil was blunted by alpha,beta-methyleneadenosine 5'-diphosphate, an inhibitor of ectosolic 5'-nucleotidase [infarct size, 37.7 +/- 5.6 (n = 9) and 36.8 +/- 4.8% (n = 7), respectively] and 8-sulfophenyltheophylline (infarct size with cromakalim, 44.7 +/- 4.6%; n = 7). We conclude that activation of ectosolic 5'-nucleotidase due to the openers of ATP-sensitive K+ channels contributes to the infarct size- limiting effect of ischemic preconditioning.

Evidence for Preconditioning by Isoflurane in Coronary Artery Bypass Graft Surgery

“…27 This opening could then account for the increase in ecto-5Ј-ectosolic activity that has been reported after pharmacological activation of the potassium channels. 28 Alternatively, the primary target of isoflurane could be PKC itself. The subsequent increased activity of ecto-5Ј-nucleotidase would then cause a release of adenosine and, downstream, the adenosineinduced opening of potassium channels.…”

“…The subsequent increased activity of ecto-5Ј-nucleotidase would then cause a release of adenosine and, downstream, the adenosineinduced opening of potassium channels. 28 Regardless of the precise sequence of events, the fact that simultaneous administration of ischemic preconditioning and isoflurane does not confer additional protection over that yet provided by each intervention alone 8 suggests that the drug exerts its cardioprotective effects via the same pathway as classic ischemic preconditioning. Additional support for this hypothesis comes from the observation that in the present study, isoflurane increased ecto-5Ј-nucleotidase levels despite a 10-minute washout period, which suggests a "memory" phase consistent with a preconditioning pattern.…”

Biochemical and Ultrastructural Evaluations of the Effect of Ischemic Preconditioning on Ischemic Myocardial Injury

“…Thus, we confirmed that our present study could estimate the role of the ATPsensitive potassium channel in IP, similar to other studies using Gl as a specific inhibitor of this channel. [26][27][28] In the present study, preadministration of Ni enhanced the IP effects on myocardial contractility; histological observation and biochemical analyses of the SR and Mt; pretreatments of Gl abolished Ni and IP effects. From these results, we speculated that in the dog model the ATP-sensitive potassium channel is one of the initiators of protection for ischemic cellular injury.…”

“…From these results, we speculated that in the dog model the ATP-sensitive potassium channel is one of the initiators of protection for ischemic cellular injury. In the reports concerning the role of the potassium channel in IP [26][27][28] Mizumura et al used an open-chest anesthetized dog model with 60 min ischemia followed by 3 h ischemia, and reported that brimakalim, an ATP-sensitive potassium channel opener, mimicked the effects of IP by reducing infarct size, adenosine release, and neutrophil function. 26 Kitakaze et al found that four 5-min intracoronary infusions of 3 kinds of ATP-sensitive potassium channel openers (ie, brimakalim, nicorandil or cromakalim) with intermittent 5-min drug-free periods mimicked the effect of four 5-min periods of ischemia with intermittent 5-min reperfusion periods, thereby reducing the infarct size in anesthetized dogs.…”

Inactivation of Membrane Surface Ecto-5′-nucleotidase by Sodium Nitroprusside in C6 Glioma Cells

“…Previously, we demonstrated that NT5E-mediated adenosine production is coupled functionally to adenosine receptor stimulation (10,11). In addition, NT5E is implicated in pathophysiological conditions through its control of the extracellular adenosine level, which has a protective action against ischemia-reperfusion injury in the cardiovascular (5,6,12) and central nervous systems (13). Furthermore, recent studies demonstrated that NT5E plays an important role in breast cancer growth, and NT5E is suggested to be a promising target for anti-cancer therapy (9,14,15).…”