Clinical studies on cardioprotection by preinfarct angina are ambiguous, which may involve development of tolerance to repeated episodes of ischemia. Not all preconditioning stimuli use identical signaling pathways, and because patients likely experience varying numbers of episodes of preinfarct angina of different degrees and durations, it is important to know whether myocardium tolerant to a particular preconditioning stimulus can still be protected by stimuli employing alternative signaling pathways. We tested the hypothesis that development of tolerance to a particular stimulus does not affect cardioprotection by stimuli that employ different signaling pathways. Anesthetized rats underwent classical, remote or pharmacological preconditioning. Infarct size (IS), produced by a 60-min coronary artery occlusion (CAO), was determined after 120 min of reperfusion. Preconditioning by two 15-min periods of CAO (2CAO15, an adenosine-dependent stimulus) limited IS from 69 +/- 2% to 37 +/- 6%, but when 2CAO15 was preceded by 4CAO15, protection by 2CAO15 was absent (IS = 68 +/- 1%). This development of tolerance coincided with a loss of cardiac interstitial adenosine release, whereas two 15-min infusions of adenosine (200 microg/min i.v.) still elicited cardioprotection (IS = 40 +/- 4%). Furthermore, cardioprotection was produced when 4CAO15 was followed by the adenosine-independent stimulus 3CAO3 (IS = 50 +/- 8%) or the remote preconditioning stimulus of two 15-min periods of mesenteric artery occlusion (IS = 49 +/- 6%). In conclusion, development of tolerance to cardioprotection by an adenosine-dependent preconditioning stimulus still allows protection by pharmacological or ischemic stimuli intervention employing different signaling pathways.
"For example it has been suggested that the contact between the remote preconditioned organ/tissue and the heart could include humoral   , neural factors  , and systemic changes. It is suggested that protection by RIPC is triggered by release of metabolites (e.g., adenosine, bradykinin, and opioids) from the remotely preconditioned organ     . In fact recent work has shown that adenosine A1 receptors are directly involved in RIPC . "
[Show abstract][Hide abstract] ABSTRACT: Remote ischemic preconditioning (RIPC) induced by brief ischemia/reperfusion cycles of remote organ (e.g., limb) is cardioprotective. The myocardial cellular changes during RIPC responsible for this phenomenon are not currently known. The aim of this work was to identify the activation by phosphorylation of cardiac proteins following RIPC. To achieve our aim we used isobaric tandem mass tagging (TMT) and reverse phase nanoliquid chromatography tandem spectrometry using a Linear Trap Quadropole (LTQ) Orbitrap Velos mass spectrometer.
Male C57/Bl6 mice were anesthetized by an intraperitoneal injection of Tribromoethanol. A cuff was placed around the hind limb and inflated at 200 mmHg to prevent blood flow as confirmed by Laser Doppler Flowmetry. RIPC was induced by 4 cycles of 5 min of limb ischemia followed by 5 min of reperfusion. Hearts were extracted for phosphoproteomics. We identified approximately 30 phosphoproteins that were differentially expressed in response to RIPC protocol. The levels of several phosphoproteins in the Z-disk of the sarcomere including phospho-myozenin-2 were significantly higher than control. This study describes and validates a novel approach to monitor the changes in the cardiac phosphoproteome following the cardioprotective intervention of RIPC and prior to index ischemia. The increased level of phosphorylated sarcomeric proteins suggests they may have a role in cardiac signaling during RIPC.
"Tanaka et al., 1994; Baines et al., 1997; Das et al., 1999), others have failed to demonstrate such a significant effect (Iwamoto et al., 1991; Richard et al., 1993; Hajnal et al., 2005). These differences may be related to the model used; that is, as to whether the experiments are performed under in vitro or in vivo conditions, the dose and route of administration of the antioxidant applied, as well as the intensity of the preconditioning stimulus (that is, the duration and number of the preconditioning occlusions), which may substantially determine the signalling pathways that lead to cardioprotection (Liem et al., 2005). Furthermore , the situation regarding the possible trigger or mediator role of ROS and their relation to the mitoK ATP channel, is also not fully understood (Gross and Peart, 2003; Kevin et al., 2003; Lebuffe et al., 2003). "
[Show abstract][Hide abstract] ABSTRACT: Exogenous peroxynitrite from nanomolar to micromolar concentrations exerts cardioprotection. Here, we have assessed its effects on ischaemia- and reperfusion-induced ventricular arrhythmias in vivo and a possible role for mitochondrial K(ATP) channels in these effects, using the channel inhibitor 5-hydroxydecanoate (5-HD).
Chloralose-urethane-anaesthetized dogs were treated twice for 5 min with peroxynitrite (100 nM, by intracoronary infusions) in both the absence and presence of 5-HD (150 microg kg(-1) min(-1)), and then subjected to 25 min occlusion of the left anterior descending coronary artery. The severity of ischaemia and of arrhythmias, as well as the levels of nitrotyrosine were assessed and compared with a group of control dogs, subjected only to a 25 min occlusion and reperfusion insult.
Compared with controls, infusion of peroxynitrite markedly suppressed the number of ventricular premature beats (388+/-88 vs 133+/-44), the incidence of ventricular fibrillation both during occlusion (50% vs 10%) and reperfusion (100% vs 44%), and increased survival (0% vs 50%; all P<0.05). The severity of ischaemia (epicardial ST-segment changes, inhomogeneity of electrical activation) during occlusion and nitrotyrosine levels on reperfusion were significantly less in the peroxynitrite-treated dogs than in the controls. 5-HD did not modify the cardioprotective effects of peroxynitrite.
Exogenous peroxynitrite provided antiarrhythmic protection in vivo, which might have been on account of a reduction in endogenous peroxynitrite formation. This protection seemed not to be mediated through mitoK(ATP) channels.
British Journal of Pharmacology 09/2008; 155(7):1015-24. DOI:10.1038/bjp.2008.344 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The possible involvement of reactive oxygen species (ROS) in the protective effects of ischaemic preconditioning (PC) against arrhythmias was examined in anaesthetised dogs using the ROS scavenger N-2-mercaptopropionylglycine (MPG).
PC was induced in 20 chloralose-urethane anaesthetised dogs by two 5 min occlusions of the left anterior descending (LAD) coronary artery 20 min prior to the prolonged (25 min) ischaemia/reperfusion (I/R) insult. In 10 of these dogs MPG was infused locally into a small side branch of the LAD in a dose of 0.15 mg kg(-1) min(-1), starting 10 min prior to and continuing throughout the entire PC procedure. In another four dogs subjected to preconditioning in the absence and then 2h later in the presence of MPG free radical formation was evaluated by the chemiluminescence method. Eleven dogs, infused with saline and subjected to a 25 min I/R insult, served as controls. A further 9 dogs, which were not preconditioned, were given MPG over a period of 60 min prior to occlusion.
Preconditioning markedly reduced the number of ventricular premature beats (VPBs; 86 +/- 34 v. 377 +/- 78; P < 0.05), the episodes of ventricular tachycardia (VT; 2.0 +/- 0.7 v. 13.6 +/- 4.5; P < 0.05) and the incidences of both VT (60% v. 91%) and ventricular fibrillation (0% v. 82%; P < 0.05) during the prolonged occlusion. Survival (from the combined ischaemia and reperfusion insult) was significantly increased (40% v. 0%; P < 0.05) by PC. MPG did not modify the protective effects of PC, although free radical (mostly superoxide) formation that occurred following PC was abrogated in the presence of MPG. Thus, the number of VPBs (111 +/- 39), VT episodes (1.2 +/- 0.9) and the incidences of VT (20%) and VF (0%) during occlusion were similar to the PC dogs. MPG itself did not significantly modify arrhythmia severity in non-PC dogs.
We conclude that in our canine model of ischaemia/reperfusion the generation of ROS does not play a trigger role in the early PC-induced antiarrhythmic protection.
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