Pravastatin Reduces Myocardial Infarct Size Via Increasing Protein Kinase C-Dependent Nitric Oxide, Decreasing Oxyradicals and Opening the Mitochondrial Adenosine Triphosphate-Sensitive Potassium Channels in Rabbits

Protein kinase C (PKC) has been implicated in the cardioprotective effects of ischemic preconditioning in rabbits, but whether it plays a role in rats is unknown. We tested this preconditioning PKC theory by assessing whether the inhibition of PKC with calphostin C, a potent and specific inhibitor of PKC, can block the preconditioning effects in this model. Four groups of rats were studied: 1) control + vehicle, 2) control + calphostin C, 3) preconditioning + vehicle, and 4) preconditioning + calphostin C. All rats underwent 90 min of coronary occlusion followed by 4 h of reperfusion; in addition, preconditioned rats underwent three 3-min episodes of ischemia and 5 min of reperfusion before the 90 min of ischemia. Two injections of vehicle or calphostin C (0.1 mg/kg) were administered in intravenous boluses 29 min and 3 min before the 90-min coronary occlusion, i.e., one dose was given 5 min before preconditioning, and another dose was given between preconditioning and the sustained 90 min of ischemia in preconditioned rats. After 4 h of reperfusion, the area at risk (AR) was delineated by dye injection and area of necrosis was assessed by triphenyltetrazolium chloride staining. The electrocardiogram was recorded for the incidence of ventricular tachycardia (VT) and ventricular fibrillation. AR was similar in all four groups. In the nonpreconditioned control rats receiving vehicle, myocardial infarct size expressed as a percentage of the AR averaged 45.7 +/- 1.7%. Pretreatment with calphostin C had no effect on infarct size (48.9 +/- 3.4%) in nonpreconditioned control rats.(ABSTRACT TRUNCATED AT 250 WORDS)

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Limitation of myocardial infarct size by adenosine A1 receptor activation is abolished by protein kinase C inhibitors in the rabbit

Cardiovascular Research ◽

10.1016/0008-6363(96)88641-x ◽

1995 ◽

Vol 29 (5) ◽

pp. 682-688 ◽

Cited By ~ 20

Author(s):

J Sakamoto

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Infarct Size ◽

Myocardial Infarct ◽

Receptor Activation ◽

Myocardial Infarct Size ◽

Protein Kinase C Inhibitors ◽

Kinase C ◽

Adenosine A1 ◽

A1 Receptor

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Treatment with Sheng-Mai-San Reduces Myocardial Infarct Size Through Activation of Protein Kinase C and Opening of Mitochondrial KATP Channel

The American Journal of Chinese Medicine ◽

10.1142/s0192415x01000381 ◽

2001 ◽

Vol 29 (02) ◽

pp. 367-375 ◽

Cited By ~ 5

Author(s):

Ningyuan Wang ◽

Shinya Minatoguchi ◽

Yoshihiro Uno ◽

Masazumi Arai ◽

Kazuaki Hashimoto ◽

...

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Infarct Size ◽

Myocardial Infarct ◽

Katp Channels ◽

Myocardial Infarct Size ◽

Mitochondrial Katp Channel ◽

Kinase C ◽

Radix Ginseng ◽

Mitochondrial Katp Channels

Sheng-Mei-San (SMS), a traditional Chinese formulation comprising Radix Ginseng, Radix Ophiopogonis and Fructus Schisandrae, has long been used for more than 700 years for patients with coronary heart disease. We attempted to clarify 1) whether SMS reduces myocardial infarct size, and 2) whether the infarct size-reducing effect of SMS is related to activation of protein kinase C and the opening of the mitochondrial KATP channels in Japanese white rabbits without collateral circulation. The results indicate that three days treatment but not acute treatment with SMS reduces myocardial infarct size through activation of protein kinase C and opening of the mitochondrial KATP channels.

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Mechanisms of Isoflurane-induced Myocardial Preconditioning in Rabbits

Anesthesiology ◽

10.1097/00000542-199903000-00024 ◽

1999 ◽

Vol 90 (3) ◽

pp. 812-821 ◽

Cited By ~ 50

Author(s):

Mohamed S. Ismaeil ◽

Igor Tkachenko ◽

Kurt A. Gamperl ◽

Robert F. Hickey ◽

Brian A. Cason

Keyword(s):

At Risk ◽

Potassium Channels ◽

Infarct Size ◽

Adenosine Triphosphate ◽

Ischemic Preconditioning ◽

Adenosine Receptors ◽

Coronary Occlusion ◽

Myocardial Infarct ◽

Myocardial Infarct Size ◽

Area At Risk

Background Isoflurane has cardioprotective effects that mimic the ischemic preconditioning phenomenon. Because adenosine triphosphate-sensitive potassium channels and adenosine receptors are implicated in ischemic preconditioning, the authors wanted to determine whether the preconditioning effect of isoflurane is mediated through these pathways. Methods Myocardial infarct size was measured in seven groups of propofol-anesthetized rabbits, each subjected to 30 min of anterolateral coronary occlusion followed by 3 h of reperfusion. Groups differed only in the pretreatments given, and controls received no pretreatment. An ischemia-preconditioned group was pretreated with 5 min of coronary occlusion and 15 min of reperfusion. An isoflurane-preconditioned group was pretreated with 15 min end-tidal isoflurane, 1.1%, and then 15 min of washout. An isoflurane-plus-glyburide group was administered 0.33 mg/kg glyburide intravenously before isoflurane pretreatment. An isoflurane plus 8-(p-sulfophenyl)-theophylline (SPT) group received 7.5 mg/kg SPT intravenously before isoflurane. Additional groups were administered identical doses of glyburide or SPT, but they were not pretreated with isoflurane. Infarct size and area at risk were defined by staining. Data were analyzed by analysis of variance or covariance. Results Infarct size, expressed as a percentage of the area at risk (IS:AR) was 30.2+/-11% (SD) in controls. Ischemic preconditioning and isoflurane preexposure reduced myocardial infarct size significantly, to 8.3+/-5% and 13.4+/-8.2% (P<0.05), respectively. Both glyburide and SPT pretreatment eliminated the preconditioning-like effect of isoflurane (IS:AR = 30.0+/-9.1% and 29.2+/-12.6%, respectively; P = not significant). Neither glyburide nor SPF alone increased infarct size (IS:AR = 33.9+/-7.6% and 31.8+/-12.7%, respectively; P = not significant). Conclusions Glyburide and SPT abolished the preconditioning-like effects of isoflurane but did not increase infarct size when administered in the absence of isoflurane. Isoflurane-induced preconditioning and ischemia-induced preconditioning share similar mechanisms, which include activation of adenosine triphosphate-sensitive potassium channels and adenosine receptors.

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Regulation of adenosine triphosphate-sensitive potassium channels from rabbit ventricular myocytes by protein kinase C and type 2A protein phosphatase

Biochemistry ◽

10.1021/bi00021a041 ◽

1995 ◽

Vol 34 (21) ◽

pp. 7252-7257 ◽

Cited By ~ 39

Author(s):

Peter E. Light ◽

Bruce G. Allen ◽

Michael P. Walsh ◽

Robert J. French

Keyword(s):

Protein Kinase C ◽

Protein Kinase ◽

Potassium Channels ◽

Adenosine Triphosphate ◽

Protein Phosphatase ◽

Ventricular Myocytes ◽

Kinase C ◽

Rabbit Ventricular Myocytes

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Morphine Enhances Pharmacological Preconditioning by Isoflurane

Anesthesiology ◽

10.1097/00000542-200303000-00019 ◽

2003 ◽

Vol 98 (3) ◽

pp. 705-711 ◽

Cited By ~ 80

Author(s):

Lynda M. Ludwig ◽

Hemal H. Patel ◽

Garrett J. Gross ◽

Judy R. Kersten ◽

Paul S. Pagel ◽

...

Keyword(s):

Myocardial Infarction ◽

Potassium Channels ◽

Infarct Size ◽

Adenosine Triphosphate ◽

Opioid Receptors ◽

Myocardial Infarct ◽

Coronary Artery Occlusion ◽

Myocardial Infarct Size ◽

Area At Risk

Background Adenosine triphosphate-regulated potassium channels mediate protection against myocardial infarction produced by volatile anesthetics and opioids. We tested the hypothesis that morphine enhances the protective effect of isoflurane by activating mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors. Methods Barbiturate-anesthetized rats (n = 131) were instrumented for measurement of hemodynamics and subjected to a 30 min coronary artery occlusion followed by 2 h of reperfusion. Myocardial infarct size was determined using triphenyltetrazolium staining. Rats were randomly assigned to receive 0.9% saline, isoflurane (0.5 and 1.0 minimum alveolar concentration [MAC]), morphine (0.1 and 0.3 mg/kg), or morphine (0.3 mg/kg) plus isoflurane (1.0 MAC). Isoflurane was administered for 30 min and discontinued 15 min before coronary occlusion. In eight additional groups of experiments, rats received 5-hydroxydecanoic acid (5-HD; 10 mg/kg) or naloxone (6 mg/kg) in the presence or absence of isoflurane, morphine, and morphine plus isoflurane. Results Isoflurane (1.0 MAC) and morphine (0.3 mg/kg) reduced infarct size (41 +/- 3%; n = 13 and 38 +/- 2% of the area at risk; n = 10, respectively) as compared to control experiments (59 +/- 2%; n = 10). Morphine plus isoflurane further decreased infarct size to 26 +/- 3% (n = 11). 5-HD and naloxone alone did not affect infarct size, but abolished cardioprotection produced by isoflurane, morphine, and morphine plus isoflurane. Conclusions Combined administration of isoflurane and morphine enhances the protection against myocardial infarction to a greater extent than either drug alone. This beneficial effect is mediated by mitochondrial adenosine triphosphate-regulated potassium channels and opioid receptors in vivo.

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Protein Kinase C Translocation and Src Protein Tyrosine Kinase Activation Mediate Isoflurane-induced Preconditioning In Vivo

Anesthesiology ◽

10.1097/00000542-200403000-00011 ◽

2004 ◽

Vol 100 (3) ◽

pp. 532-539 ◽

Cited By ~ 68

Author(s):

Lynda M. Ludwig ◽

Dorothee Weihrauch ◽

Judy R. Kersten ◽

Paul S. Pagel ◽

David C. Warltier

Keyword(s):

Reactive Oxygen Species ◽

Protein Kinase C ◽

Protein Kinase ◽

Tyrosine Kinase ◽

Infarct Size ◽

Adenosine Triphosphate ◽

Protein Tyrosine Kinase ◽

Oxygen Species ◽

Kinase C

Background The authors tested the hypotheses that protein kinase C (PKC)-specific isoform translocation and Src protein tyrosine kinase (PTK) activation play important roles in isoflurane-induced preconditioning in vivo. Methods Rats (n = 125) instrumented for measurement of hemodynamics underwent 30 min of coronary artery occlusion followed by 2 h of reperfusion and received 0.9% saline (control); PKC inhibitors chelerythrine (5 mg/kg), rottlerin (0.3 mg/kg), or PKC-epsilonV1-2 peptide (1 mg/kg); PTK inhibitors lavendustin A (1 mg/kg) or 4-amino-5-(4-methylphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP1; 1 mg/kg); mitochondrial adenosine triphosphate-sensitive potassium channel antagonist 5-hydroxydecanote (10 mg/kg); or reactive oxygen species scavenger N-acetylcysteine (150 mg/kg) in the absence and presence of a 30-min exposure to isoflurane (1.0 minimum alveolar concentration) in separate groups. Isoflurane was discontinued 15 min before coronary occlusion (memory period). Infarct size was determined using triphenyltetrazolium staining. Immunohistochemistry and confocal microscopic imaging were performed to examine PKC translocation in separate groups of rats. Results Isoflurane significantly (P < 0.05) reduced infarct size (40 +/- 3% [n = 13]) as compared with control experiments (58 +/- 2% [n = 12]). Chelerythrine, rottlerin, PKC-epsilonV1-2 peptide, lavendustin A, PP1, 5-hydroxydecanote, and N-acetylcysteine abolished the anti-ischemic actions of isoflurane (58 +/- 2% [n = 8], 50 +/- 3% [n = 9], 53 +/- 2% [n = 9], 59 +/- 3% [n = 6], 57 +/- 3% [n = 7], 60 +/- 3% [n = 7], and 53 +/- 3% [n = 6], respectively). Isoflurane stimulated translocation of the delta and epsilon isoforms of PKC to sarcolemmal and mitochondrial membranes, respectively. Conclusions Protein kinase C-delta, PKC-epsilon, and Src PTK mediate isoflurane-induced preconditioning in the intact rat heart. Opening of mitochondrial adenosine triphosphate-sensitive potassium channels and generation of reactive oxygen species are upstream events of PKC activation in this signal transduction process.

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