Experimental evidence suggests that ATP-sensitive potassium channels are involved in myocardial ischemic preconditioning. Because some pharmacologic effects of isoflurane are mediated by K(ATP) channels, the authors tested the hypothesis: Isoflurane administration, before myocardial ischemia, can induce or mimic myocardial preconditioning.
Myocardial infarct size was measured in three groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed in their pretreatment: Group 1 (control, N = 13) no pretreatment, Group 2 (ischemic preconditioning, N = 8), 5 min of coronary occlusion and 15 min of reperfusion; Group 3 (isoflurane pretreatment; N = 15), 15 min of isoflurane (1.1% end-tidal) and 15 min of washout. Hemodynamics were monitored serially. Myocardial infarct size and the area at risk were defined using triphenyltetrazolium chloride staining and fluorescent microspheres, respectively, and both were measured using computerized planimetry.
Infarct size expressed as a percentage of area at risk was 23.4 +/- 8.5% (mean +/- SD) in the isoflurane group compared with 33.1 +/- 13.3% in controls, and 8.7 +/- 6.2% in the ischemia-preconditioned group. Analysis for coincidental regressions, followed by tests for equality of slope and elevation, showed that the linear relationship between infarct size and area at risk was significantly (P < 0.05) different in all three groups because of differences in line elevation. Minor differences in hemodynamic variables were found between groups, which were unlikely to account for the significant differences in infarct size.
Preadministration of isoflurane, before myocardial ischemia, reduces myocardial infarct size, and mimics myocardial preconditioning.
"Recent studies using animal models of regional ischemia have shown that isoflurane can duplicate the infarct-limiting effects of ischemic preconditioning. On the other hand, this drug causes potassium channel activation, as suggested by the abolishment of its infarct-limiting effects with potassium channel blockers.14-16 It has also been confirmed that isoflurane increases the probability of potassium channel opening for any given concentration of ATP.17 "
[Show abstract][Hide abstract] ABSTRACT: Some pharmacological preconditioning approaches are utilized as an effective adjunct to myocardial protection, particularly following cardiac procedures. The current study addressed the potential clinical implications and protective effects of isoflurane as an anesthetic most applicable on postoperative myocardial function measured by cardiac biomarkers.
46 patients were included in the study. In 23 of them, preconditioning was elicited after the onset of cardiopulmonary bypass via a 5-minute exposure to isoflurane (2.5 minimum alveolar concentration), followed by a 10-minute washout before aortic cross clamping and cardioplegic arrest. 23 case-matched control patients underwent an equivalent period (15 minutes) of pre-arrest isoflurane-free bypass. Outcome measurements included creatine phosphokinase (CPK) and creatine kinase-MB (CK-MB) levels until 24 hours after the surgery.
None of the differences in enzyme levels at baseline and 24 hours after surgery between the two groups reached the threshold of statistical significance. The level of CPK was significantly reduced 24 hours after surgery compared with the baseline in the two groups. However, the postoperative release of CPK was consistently smaller in the isoflurane-preconditioned group than in the control group. The release of CK-MB displayed a statistically similar pattern. Multivariate linear regression analysis showed the effect of isoflurane regimen on reducing CPK level within the 24 hours after surgery compared with placebo.
Our study supports the cardio protective effect of isoflurane and the role of pharmacological preconditioning of the human heart by this volatile anesthetic during elective coronary artery bypass surgery.
"This phenomenon is achieved by several pharmacological agents, including volatile anesthetics. Volatile anesthetics such as isoflurane have cardioprotective effects when administered before a period of myocardial ischemia and reperfusion, and this phenomenon is referred to as anesthetic preconditioning (APC) , . APC is a cardioprotective strategy that increases resistance to ischemia and reperfusion (I/R) by eliciting innate protective mechanisms, and was described in various animal models –, as well as in humans , . "
[Show abstract][Hide abstract] ABSTRACT: The volatile anesthetic, isoflurane, protects the heart from ischemia/reperfusion (I/R) injury. Aldehyde dehydrogenase 2 (ALDH2) is thought to be an endogenous mechanism against ischemia-reperfusion injury possibly through detoxification of toxic aldehydes. We investigated whether cardioprotection by isoflurane depends on activation of ALDH2.Anesthetized rats underwent 40 min of coronary artery occlusion followed by 120 min of reperfusion and were randomly assigned to the following groups: untreated controls, isoflurane preconditioning with and without an ALDH2 inhibitor, the direct activator of ALDH2 or a protein kinase C (PKCε) inhibitor. Pretreatment with isoflurane prior to ischemia reduced LDH and CK-MB levels and infarct size, while it increased phosphorylation of ALDH2, which could be blocked by the ALDH2 inhibitor, cyanamide. Isolated neonatal cardiomyocytes were treated with hypoxia followed by reoxygenation. Hypoxia/reoxygenation (H/R) increased cardiomyocyte apoptosis and injury which were attenuated by isoflurane and forced the activation of ALDH2. In contrast, the effect of isoflurane-induced protection was almost abolished by knockdown of ALDH2. Activation of ALDH2 and cardioprotection by isoflurane were substantially blocked by the PKCε inhibitor. Activation of ALDH2 by mitochondrial PKCε plays an important role in the cardioprotection of isoflurane in myocardium I/R injury.
PLoS ONE 02/2013; 8(2):e52469. DOI:10.1371/journal.pone.0052469 · 3.23 Impact Factor
"Historically, the first preconditioning stimulus described in 1986 by Murry et al. (1986) was a short period of sub-lethal ischemia which they termed ischemic preconditioning (IPC). Subsequently both opioids (Schultz et al., 1997) and volatile anesthetic agents (Cason et al., 1997; Kersten et al., 1997), as well as other pharmacologic agents that activate GPCRs, were shown to confer a similar protective advantage. Preconditioning occurs in a biphasic pattern: an early phase, which occurs within minutes of the conditioning stimulus via post-translational modification of pre-existing proteins, and lasts 1–2 h, and a delayed phase occurring 12–24 h afterwards mediated by de novo synthesis of pro-survival signaling components (Tonkovic-Capin et al., 2002). "
[Show abstract][Hide abstract] ABSTRACT: The present review discusses intracellular signaling moieties specific to membrane lipid rafts (MLRs) and the scaffolding proteins caveolin and introduces current data promoting their potential role in the treatment of pathologies of the heart and brain. MLRs are discreet microdomains of the plasma membrane enriched in gylcosphingolipids and cholesterol that concentrate and localize signaling molecules. Caveolin proteins are necessary for the formation of MLRs, and are responsible for coordinating signaling events by scaffolding and enriching numerous signaling moieties in close proximity. Specifically in the heart and brain, caveolins are necessary for the cytoprotective phenomenon termed ischemic and anesthetic preconditioning. Targeted overexpression of caveolin in the heart and brain leads to induction of multiple pro-survival and pro-growth signaling pathways; thus, caveolins represent a potential novel therapeutic target for cardiac and neurological pathologies.
Frontiers in Physiology 10/2012; 3:393. DOI:10.3389/fphys.2012.00393 · 3.53 Impact Factor
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