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: 3.42). 11/2003; 97(4):1025-32, table of contents. DOI: 10.1213/01.ANE.0000077072.67502.CC
Source: PubMed

ABSTRACT 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).

  • 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
  • Journal of cardiothoracic and vascular anesthesia 11/2014; DOI:10.1053/j.jvca.2014.11.012 · 1.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Diabetes alters mitochondrial bioenergetics and consequently disrupts cardioprotective signaling. The authors investigated whether mitochondrial DNA (mtDNA) modulates anesthetic preconditioning (APC) and cardiac susceptibility to ischemia-reperfusion injury by using two strains of rats, both sharing nuclear genome of type 2 diabetes mellitus (T2DN) rats and having distinct mitochondrial genomes of Wistar and fawn-hooded hypertensive (FHH) rat strains (T2DN and T2DN, respectively). Myocardial infarct size was measured in Wistar, T2DN, and T2DN rats with or without APC (1.4% isoflurane) in the presence or absence of antioxidant N-acetylcysteine. Flavoprotein fluorescence intensity, a marker of mitochondrial redox state, 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity, a marker of reactive oxygen species generation, and mitochondrial permeability transition pore opening were assessed in isolated rat ventricular cardiomyocytes with or without isoflurane (0.5 mmol/l). Myocardial infarct size was decreased by APC in Wistar and T2DN rats (to 42 ± 6%, n = 8; and 44 ± 7%, n = 8; of risk area, respectively) compared with their respective controls (60 ± 3%, n = 6; and 59 ± 9%, n = 7), but not in T2DN rats (60 ± 2%, n = 8). N-acetylcysteine applied during isoflurane treatment restored APC in T2DN (39 ± 6%, n = 7; and 38 ± 5%, n = 7; 150 and 75 mg/kg N-acetylcysteine, respectively), but abolished protection in control rats (54 ± 8%, n = 6). Similar to the data on infarct size, APC delayed mitochondrial permeability transition pore opening in T2DN but not in T2DN cardiomyocytes. Isoflurane increased flavoprotein and 5-(and-6)-chloromethyl-2',7'-dichlorofluorescein fluorescence intensity in all rat strains, with the greatest effect in T2DN cardiomyocytes. Differences in the mitochondrial genome modulate isoflurane-induced generation of reactive oxygen species which translates into differential susceptibility to APC and ischemia-reperfusion injury in diabetic rats.
    Anesthesiology 12/2013; DOI:10.1097/ALN.0000000000000107 · 6.17 Impact Factor

Full-text (2 Sources)

Available from
Jun 1, 2014