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Flumazenil is a benzodiazepine receptor antagonist. Chemically, flumazenil is ethyl-8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazol(1,5-a)-(1,4) benzodiazepine-3-carboxylate (Fig. 1). It is used clinically to reverse theeffects of benzodiazepines in conscious sedation, general anesthesia, and management of suspected benzo-diazepine overdose. Kochs and colleagues reported that flumazenil might be beneficial in protecting against cerebral ischemia. Rapid administration of flumazenil produced minimal coronary and left ventricular hemodynamic responses. Thus this agent may be a potential candidate for clinical application in patients with ischemic heart diseases if it can mimic preconditioning to protect the heart. The study by Zhang and Yao indicates that flumazenil mimics preconditioning in cardiomyocytes via the generation of H2O2 as the reactive oxygen species (ROS). H2O2 opens mitochondrial KATP channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes inducing ischemic preconditioning. This signal transduction and preconditioning protects ischemic cardiomyocytes. Zhang et al. indicate that the potential beneficial effects of Allitridum appear to mimic the same effects as flumazenil, to precondition cardiacmycytes, via the stimulation of PKC. Allitridum is an extract of garlic taken as a medicine in China for over 3000 years. |
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Kosi Gramatikoff |
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H. Liu, B. C. McPherson, X. Zhu, M. L. A. Da Costa, V. Jeevanandam, and Z. Yao Role of nitric oxide and protein kinase C in ACh-induced cardioprotection Am J Physiol Heart Circ Physiol, July 1, 2001; 281(1): H191 - 197.
Kochs E, Roewer N, Peter A, and Schulte am Esch J. Effect of flumazenil on global cerebral blood flow and on intracranial pressure in reperfusion phase following incomplete global cere-bralischemia. Anasth Intensivther Notfallmed 23: 159162, 1998.
Lorente P, Lacampagne A, Pouzeratte Y, Richards S, Malitschek B, Kuhn R, Bettler B, Vassort G. gamma-aminobutyric acid type B receptors are expressed and functional in mammalian cardiomyocytes. Proc Natl Acad Sci U S A. 2000 Jul 18;97(15):8664-9.
Ohnuma Y, Miura T, Miki T, Tanno M, Kuno A, Tsuchida A, Shimamoto K. Opening of mitochondrial K(ATP) channel occurs downstream of PKC-epsilon activation in the mechanism of preconditioning. Am J Physiol Heart Circ Physiol. 2002 Jul;283(1):H440-7
Yao Z, McPherson BC, Liu H, Shao Z, Li C, Qin Y, Vanden Hoek TL, Becker LB, Schumacker PT. Signal transduction of flumazenil-induced preconditioning in myocytes. Am J Physiol Heart Circ Physiol. 2001 Mar;280(3):H1249-55.
Zhang HY, McPherson BC, Liu H, Baman TS, Rock P, Yao Z. H(2)O(2) opens mitochondrial K(ATP) channels and inhibits GABA receptors via protein kinase C-epsilon in cardiomyocytes. Am J Physiol Heart Circ Physiol. 2002 Apr;282(4):H1395-403.
Zhang Q, Yao Z. Flumazenil preconditions cardiomyocytes via oxygen radicals and K(ATP) channels. Am J Physiol Heart Circ Physiol. 2000 Oct;279(4):H1858-63.
Zhang WJ, Shi ZX, Wang BB, Cui YJ, Guo JZ, Li B. Allitridum mimics effect of ischemic preconditioning by activation of protein kinase C. Acta Pharmacol Sin. 2001 Feb;22(2):132-6.
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