CP-060S, a Novel Cardioprotective Drug, Limits Myocardial Infarct Size in Anesthetized Dogs

1998 ◽  
Vol 31 (3) ◽  
pp. 400-407 ◽  
Author(s):  
Yoshiyuki Suzuki ◽  
Kazuhiko Tamura ◽  
Michitaka Akima ◽  
Yuichiro Adachi ◽  
Masanori Fukazawa ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Anesthetized Dogs ◽  
Cardioprotective Drug

scholarly journals CP-060S, a novel cardioprotective drug, limits myocardial infarct size in anesthetized dogs

1997 ◽  
Vol 73 ◽  
pp. 233
Author(s):  
Yoshiyuki Suzuki ◽  
Kazuhiko Tamura ◽  
Michitaka Akima ◽  
Takaki Koga ◽  
Yuichiro Adachi ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Anesthetized Dogs ◽  
Cardioprotective Drug

Isoflurane Mimics Ischemic Preconditioning via Activation of KATPChannels 

1997 ◽  
Vol 87 (2) ◽  
pp. 361-370 ◽  
Author(s):  
Judy R. Kersten ◽  
Todd J. Schmeling ◽  
Paul S. Pagel ◽  
Garrett J. Gross ◽  
David C. Warltier
Keyword(s):  
Infarct Size ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Protective Effects ◽  
Hemodynamic Effects ◽  
Area At Risk ◽  
Triphenyltetrazolium Chloride ◽  
Anesthetized Dogs

Background The authors tested the hypothesis that isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels and that the protection afforded by isoflurane is associated with an acute memory phase similar to that of ischemic preconditioning. Methods Barbiturate-anesthetized dogs (n = 71) were instrumented for measurement of systemic hemodynamics. Myocardial infarct size was assessed by triphenyltetrazolium chloride staining. All dogs were subjected to a single prolonged (60 min) left anterior descending coronary artery (LAD) occlusion followed by 3 h of reperfusion. Ischemic preconditioning was produced by four 5-min LAD occlusions interspersed with 5-min periods of reperfusion before the prolonged LAD occlusion and reperfusion. The actions of isoflurane to decrease infarct size were examined in dogs receiving 1 minimum alveolar concentration (MAC) isoflurane that was discontinued 5 min before prolonged LAD occlusion. The interaction between isoflurane and ischemic preconditioning on infarct size was evaluated in dogs receiving isoflurane before and during preconditioning LAD occlusions and reperfusions. To test whether the cardioprotection produced by isoflurane can mimic the acute memory of ischemic preconditioning, isoflurane was discontinued 30 min before prolonged LAD occlusion and reperfusion. The mechanism of isoflurane-induced cardioprotection was evaluated in two final groups of dogs pretreated with glyburide in the presence or absence of isoflurane. Results Myocardial infarct size was 25.3 +/- 2.9% of the area at risk during control conditions. Isoflurane and ischemic preconditioning produced significant (P < 0.05) and equivalent reductions in infarct size (ischemic preconditioning alone, 9.6 +/- 2.0; isoflurane alone, 11.8 +/- 2.7; isoflurane and ischemic preconditioning, 5.1 +/- 1.9%). Isoflurane-induced reduction of infarct size also persisted 30 min after discontinuation of the anesthetic (13.9 +/- 1.5%), independent of hemodynamic effects during LAD occlusion. Glyburide alone had no effect on infarct size (28.3 +/- 3.9%), but it abolished the protective effects of isoflurane (27.1 +/- 4.6%). Conclusions Isoflurane directly preconditions myocardium against infarction via activation of K(ATP) channels in the absence of hemodynamic effects and exhibits acute memory of preconditioning in vivo.

Reduction of Myocardial Infarct Size by Trapidil in Anesthetized Dogs

1983 ◽  
Vol 5 (3) ◽  
pp. 499-505 ◽  
Author(s):  
K. Yamaguchi ◽  
K. Suzuki ◽  
T. Niho ◽  
M. Sato ◽  
C. Ito ◽  
...  
Keyword(s):  
Infarct Size ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Anesthetized Dogs

Activation of ATP-sensitive potassium channels lowers threshold for ischemic preconditioning in dogs

1994 ◽  
Vol 267 (5) ◽  
pp. H1888-H1894 ◽  
Author(s):  
Z. Yao ◽  
G. J. Gross
Keyword(s):  
Action Potential ◽  
Infarct Size ◽  
Potassium Channel ◽  
Ischemic Preconditioning ◽  
Myocardial Infarct ◽  
Myocardial Infarct Size ◽  
Potassium Channel Opener ◽  
Intracoronary Infusion ◽  
Anesthetized Dogs ◽  
Action Potential Shortening

The purpose of the present study was to determine whether enhanced activation of myocardial ATP-dependent potassium channels (KATP) with a potassium channel opener, bimakalim, can reduce the time necessary to produce the protective effect of ischemic preconditioning and to determine whether this effect is mediated via accelerating the rate of action potential shortening during preconditioning. Barbital-anesthetized dogs were subjected to 60 min of left anterior descending coronary artery (LAD) occlusion followed by 4 h of reperfusion. Ten minutes of preconditioning was found to markedly reduce myocardial infarct size from 30.6 +/- 4.7 to 7.1 +/- 2.6%. Subsequently, it was observed that either 3 min of LAD occlusion or a 3-min intracoronary infusion with 0.3 micrograms/min of bimakalim did not reduce myocardial infarct size. However, intracoronary infusion with bimakalim during the 3-min preconditioning period markedly reduced myocardial infarct size to a similar extent as that of ischemic preconditioning (12.2 +/- 1.9%). In addition, it was observed that bimakalim markedly accelerated the ischemia-induced shortening of the action potential during preconditioning. These results are the first to demonstrate that activation of KATP channels with a potassium channel opener reduces the threshold of time necessary to produce preconditioning in anesthetized dogs. These data also suggest that KATP channel activation may produce this effect by enhancing the rate of ischemic myocardial action potential shortening during preconditioning.

scholarly journals Hydralazine protects the heart against acute ischaemia/reperfusion injury by inhibiting Drp1-mediated mitochondrial fission

2021 ◽  
Author(s):  
Siavash Beikoghli Kalkhoran ◽  
Janos Kriston-Vizi ◽  
Sauri Hernandez-Resendiz ◽  
Gustavo E Crespo-Avilan ◽  
Ayeshah A Rosdah ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Infarct Size ◽  
Myocardial Infarct ◽  
Mitochondrial Fission ◽  
Vehicle Control ◽  
Myocardial Infarct Size ◽  
Ischaemia Reperfusion Injury ◽  
Ischaemia Reperfusion ◽  
Pre Treatment ◽  
Apoptotic Effects

Abstract Aims Genetic and pharmacological inhibition of mitochondrial fission induced by acute myocardial ischaemia/reperfusion injury (IRI) has been shown to reduce myocardial infarct size. The clinically used anti-hypertensive and heart failure medication, hydralazine, is known to have anti-oxidant and anti-apoptotic effects. Here, we investigated whether hydralazine confers acute cardioprotection by inhibiting Drp1-mediated mitochondrial fission. Methods and results Pre-treatment with hydralazine was shown to inhibit both mitochondrial fission and mitochondrial membrane depolarisation induced by oxidative stress in HeLa cells. In mouse embryonic fibroblasts (MEFs), pre-treatment with hydralazine attenuated mitochondrial fission and cell death induced by oxidative stress, but this effect was absent in MEFs deficient in the mitochondrial fission protein, Drp1. Molecular docking and surface plasmon resonance studies demonstrated binding of hydralazine to the GTPase domain of the mitochondrial fission protein, Drp1 (KD 8.6±1.0 µM), and inhibition of Drp1 GTPase activity in a dose-dependent manner. In isolated adult murine cardiomyocytes subjected to simulated IRI, hydralazine inhibited mitochondrial fission, preserved mitochondrial fusion events, and reduced cardiomyocyte death (hydralazine 24.7±2.5% vs. control 34.1±1.5%, P=0.0012). In ex vivo perfused murine hearts subjected to acute IRI, pre-treatment with hydralazine reduced myocardial infarct size (as % left ventricle: hydralazine 29.6±6.5% vs. vehicle control 54.1±4.9%, P=0.0083), and in the murine heart subjected to in vivo IRI, the administration of hydralazine at reperfusion, decreased myocardial infarct size (as % area-at-risk: hydralazine 28.9±3.0% vs. vehicle control 58.2±3.8%, P<0.001). Conclusion We show that, in addition to its antioxidant and anti-apoptotic effects, hydralazine, confers acute cardioprotection by inhibiting IRI-induced mitochondrial fission, raising the possibility of repurposing hydralazine as a novel cardioprotective therapy for improving post-infarction outcomes.

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