Intracellular Mechanism of Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channel Activation with Isoflurane

Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin, United States
Anesthesia & Analgesia (Impact Factor: 3.47). 11/2003; 97(4):1025-32, table of contents. DOI: 10.1213/01.ANE.0000077072.67502.CC
Source: PubMed


The precise mechanism of isoflurane and mitochondrial adenosine triphosphate-sensitive potassium channel (mitoK(ATp)) interaction is still unclear, although the mitoK(ATP) is involved in isoflurane-induced preconditioning. We examined the role of various intracellular signaling systems in mitoK(ATP) activation with isoflurane. Mitochondrial flavoprotein fluorescence (MFF) was measured to quantify mitoK(ATP) activity in guinea pig cardiomyocytes. To confirm isoflurane-induced MFF, cells were exposed to Tyrode's solution containing either isoflurane (1.0 +/- 0.1 mM) or diazoxide and then both drugs together (n = 10 each). In other studies, the following drugs were each added during isoflurane administration: adenosine or the idenosine receptor antagonist 8-(p-sulfophenyl)theophylline (SPT); the protein kinase C (PKC) activators phorbol-12-myristate-13-acetate (PMA) and phorbol-12,13-dibutyrate (PDBu); the PKC inhibitors polymyxin B and staurosporine; the tyrosine kinase inhibitor lavendustin A; or the mitogen-activated protein kinase inhibitor SB203580 (n = 10 each). Isoflurane potentiated MFF induced by diazoxide (100 muM), and diazoxide also increased isoflurane-induced MFF. PMA (0.2 muM), PDBu (1 muM), and adenosine (100 muM) induced MFF. However, SPT (100 muM), polymyxin B (50 muM), staurosporine (200 nM), lavendustin A (0.5 muM), and SB203580 (10 muM) all failed to inhibit the effect of isoflurane. Our results show that isoflurane, adenosine, and PKC activate mitoK(ATP). However, our data do not support an action of isoflurane through pathways involving adenosine, PKC, tyrosine kinase, or mitogen-activated protein kinase. These results suggest that isoflurane may directly activate mitoK(ATP).

Download full-text


Available from: Zeljko Bosnjak,
  • Source
    • "Early and late preconditioning probably involves different signalling pathways that have yet to be fully elucidated. Early preconditioning is thought to involve opening mitochondrial ATP dependent potassium channels [4,5,6,7,8,9], increasing mitochondrial reactive oxygen species [4,10,11], decreasing cytosolic and mitochon-drial calcium loading [12], protection of endothelial coronary cells by mediating nitric oxide release [13] and by suppressing neutrophil activation and the neutrophil-endothelium interactions that cause myocardial dysfunction [14,15]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Ischaemic preconditioning is a powerful innate adaptive phenomenon whereby brief periods of sublethal ischaemia result in marked tolerance to subsequent lethal ischaemia. Halogenated anaesthetics have been shown to mimic ischaemic preconditioning, modifying and attenuating ischaemia reperfusion injury. This review aims to present the current animal and human data, discuss the possible mechanisms of action and review the clinical evidence for volatile anaesthetic-induced myocardial protection. There is class Ia evidence for the myocardial protective properties of sevoflurane and desflurane in low risk patients undergoing coronary artery bypass grafting surgery. These volatile anaesthetics have been shown to improve clinical outcomes and health economics following cardiac surgery, reducing intensive care and hospital stay. The evidence for the benefit of volatile anaesthetics in non-cardiac surgery is less robust and further large randomized controlled trials are required to elucidate this question.
    04/2010; 2(2):105-9.
  • Source
    • "However, the mechanism of Iso-induced preconditioning seems to have multiple complex signal transduction pathways and to share some of the mechanisms of IPC [4]. In particular, mitochondrial K ATP channels play a pivotal role in volatile anesthetic-induced preconditioning and in classic IPC [4] [9]. Diazoxide, a potent and specific mitochondrial K ATP channel opener, reduced neurologic injury in a rabbit model of SCI and decreased myocardial infarct size after coronary artery occlusion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: We examined in a rabbit model of transient spinal cord ischemia (SCI) whether isoflurane (Iso) preconditioning induces ischemic tolerance to SCI in a dose-response manner, and whether this effect is dependent on mitochondrial adenosine triphosphate-dependent potassium (K(ATP)) channel. Eighty-six rabbits were randomly assigned to 10 groups: Control group (n=8) received no pretreatment. Ischemic preconditioning (IPC) group (n=8) received 5 min of IPC 30 min before SCI. The Iso 1, Iso 2 and Iso 3 groups (n=10, 9, 8) underwent 30 min of 1.05, 2.1 and 3.15% Iso inhalation commencing 45 min before SCI. The Iso 1HD, Iso 2HD and Iso 3HD groups (n=9, 9, 8) each received a specific mitochondrial K(ATP) channel blocker, 5-hydroxydecanoic acid (5HD, 20mg/kg), 5 min before each respective Iso inhalation. The 5HD group (n=8) received 5HD without Iso inhalation. The sham group (n=9) had no SCI. SCI was produced by infra-renal aortic occlusion via the inflated balloon of a Swan-Ganz catheter for 20 min. The Iso 1, Iso 2 and Iso 3 groups showed a better neurologic outcome and more viable motor nerve cells (VMNCs) in the anterior spinal cord 72 h after reperfusion than the control group (p<0.05). Iso 3 group showed a better neurologic outcome and more VMNCs than Iso 1 group (p<0.05). And, the Iso 1, Iso 2 and Iso 3 groups showed a better neurologic outcome and higher VMNC numbers than the corresponding Iso 1HD, Iso 2HD and Iso 3HD groups (p<0.05). This study demonstrates that Iso preconditioning protects the spinal cord against neuronal damage due to SCI in a dose-response manner via the activation of mitochondrial K(ATP) channels.
    Neuroscience Letters 11/2005; 387(2):90-4. DOI:10.1016/j.neulet.2005.06.072 · 2.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cardiovascular disease is a major healthcare problem in the US. The presence of this disease significantly affects the outcome of both cardiac and non-cardiac surgery, and peri-operative cardiac morbidity is one of the leading causes of death following anesthesia and surgery. The considerable incidence of myocardial infarction, congestive heart failure, myocardial ischemia, or serious dysrhythmias during the intra- operative or post-operative periods has led many studies to examine medical factors and interventions for decreasing cardiac risk in patients with cardiovascular disease. An extensive amount of work has focused on whether any one anesthetic agent or technique is particularly beneficial for patients with coronary artery disease (CAD). Experimental studies conducted in the laboratory have clearly demonstrated that volatile anesthetics exert profound cardioprotection against myocardial ischemia and reperfusion injury. The purpose of this overview is to summarize the interaction of volatile anesthetics with ischemic myocardium and briefly discuss the underlying mechanisms of cardioprotection against ischemia and reperfusion injury. Discussion
Show more