Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Bolli, Roberto; Zughaib, Marcel; Li, X Y; Tang, Xian Liang; Sun, Jun; Triana, J. F.; McCay, Paul B.

doi:10.1172/jci118093

Cited by 118 publications

(53 citation statements)

References 51 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In part, CK release may reflect damage sustained during the ischemic phase as well as injury sustained during the first minutes of reperfusion. Free radicals are generated in the first minute of reperfusion with a peak 4-7 min later, but ROS production continues at lower sustained levels for quite some time after that (32). The reduction in injury by ischemic postconditioning has been shown to be associated with diminished ROS production (33).…”

Section: Discussionmentioning

confidence: 99%

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Granville

Tashakkor²,

Takeuchi³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

157

113

View full text Add to dashboard Cite

Ischemia and reperfusion both contribute to tissue damage after myocardial infarction. Although many drugs have been shown to reduce infarct size when administered before ischemia, few have been shown to be effective when administered at reperfusion. Moreover, although it is generally accepted that a burst of reactive oxygen species (ROS) occurs at the onset of reperfusion and contributes to tissue damage, the source of ROS and the mechanism of injury is unclear. We now report the finding that chloramphenicol administered at reperfusion reduced infarct size by 60% in a Langendorff isolated perfused rat heart model, and that ROS production was also substantially reduced. Chloramphenicol is an inhibitor of mitochondrial protein synthesis and is also an inhibitor of a subset of cytochrome P450 monooxygenases (CYPs). We could not detect any effect on mitochondrial encoded proteins or mitochondrial respiration in chloramphenicol-perfused hearts, and hypothesized that the effect was caused by inhibition of CYPs. We tested additional CYP inhibitors and found that cimetidine and sulfaphenazole, two CYP inhibitors that have no effect on mitochondrial protein synthesis, were also able to reduce creatine kinase release and infarct size in the Langendorff model. We also showed that chloramphenicol reduced infarct size in an open chest rabbit model of regional ischemia. Taken together, these findings implicate CYPs in myocardial ischemia͞reperfusion injury.C urrent treatment of myocardial infarction is directed at the restoration of blood flow to the ischemic region and reduction of myocardial oxygen demand. However, during reperfusion, the heart undergoes further damage due, in large part, to the generation of reactive oxygen species (ROS) (1). It is clear that permanent ischemia results in necrotic cell death. However, it is unclear whether reperfusion itself induces apoptosis or merely permits the manifestation of cell death processes that were initiated and irreversibly committed to during ischemia. Moreover, the relative contributions to tissue injury by the ischemic phase and by reperfusion have been difficult to evaluate. Resolving this question carries important therapeutic implications, as efforts directed toward treating reperfusion injury would have limited value if most cell death were predestined during ischemia.Although we initially hypothesized that the protective effect of chloramphenicol was caused by inhibition of mitochondrial protein synthesis, we did not see down-regulation of mitochondrial-encoded proteins after chloramphenicol infusion. The energy-sparing effects of inhibition of cytosolic protein synthesis have been described (2), and our previously reported observation that mitochondrial elongation factor Tu is phosphorylated during ischemia suggests a similar process may take place in the mitochondria (3). However, because chloramphenicol also inhibits some cytochrome P450 monooxygenases (CYPs), it was important to determine whether that inhibitory effect was relevant to cardioprotection. In this re...

show abstract

Section: Discussionmentioning

confidence: 99%

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Granville

Tashakkor²,

Takeuchi³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

157

113

View full text Add to dashboard Cite

show abstract

“…2 Indeed, myocardial stunning might be regarded not as a single entity but instead as a phenomenon. At the experimental level, the available observations can be grouped into six categories 2 : (1) stunning after a single, completely reversible episode of regional ischemia in vivo (eg, a coronary occlusion Ͻ20 minutes in the dog), as originally described by Heyndrickx et al [3][4][5][6] ; (2) stunning after multiple, completely reversible episodes of regional ischemia in vivo (eg, repeated 5-or 10-minute coronary occlusions in the dog) [7][8][9][10][11] ; (3) stunning after a partly reversible (no necrosis) plus partly irreversible (some areas of necrosis) episode of regional ischemia in vivo (eg, a coronary occlusion Ͼ20 minutes but Ͻ3 hours in the dog) 12,13 (this category may be relevant to patients who receive thrombolysis or angioplasty for acute myocardial infarction and then demonstrate delayed recovery of function of the salvaged tissue); (4) stunning after global ischemia in vitro (isolated heart preparations) 14 -19 ; (5) stunning after global ischemia in vivo (cardioplegic arrest) 20 -23 ; and (6) stunning after exercise-induced ischemia (high-flow ischemia). 24 -26 Because of the heterogeneity of these settings, it is possible that findings developed in one setting may not be applicable to another.…”

Section: Myocardial Stunning the Protean Nature Of Myocardial Stunningmentioning

confidence: 99%

“…It is now generally accepted that ROS play an important role in the pathogenesis of myocardial stunning in the following experimental settings (as reviewed in Reference 27): (1) after a single, completely reversible episode of regional ischemia in vivo 30 -32 ; (2) after multiple, completely reversible episodes of regional ischemia in vivo 9,33 ; (3) after global ischemia in vitro 18,19,34 -36 ; and (4) after global ischemia in vivo. 20 -23 For example, in the first setting (coronary occlusion Ͻ20 minutes), alleviation of stunning by antioxidant therapies has been reproducibly observed by several independent laboratories in a variety of animal models and species.…”

Section: Generation Of Ros (Oxyradical Hypothesis)mentioning

confidence: 99%

“…33,38,39 At the time of this writing, at least 22 full-length articles have been published that have examined the effect of antioxidants on myocardial stunning after a 15-minute coronary occlusion; all of these articles (except those that used superoxide dismutase alone [40][41][42] or catalase alone 40 ) have reported a protective effect of antioxidants against stunning. 37 Furthermore, generation of ROS in stunned myocardium has been demonstrated directly by both spin trapping 9,39,[43][44][45][46][47] and aromatic hydroxylation 48 techniques, and attenuation of ROS generation has repeatedly been shown to result in attenuation of contractile dysfunction. 9,39,43,45,46 A role of ROS in the genesis of myocardial stunning can now be regarded as a proven hypothesis.…”

Section: Generation Of Ros (Oxyradical Hypothesis)mentioning

confidence: 99%

See 1 more Smart Citation

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

et al. 1998

View full text Add to dashboard Cite

“…It occurs in patients with coronary artery diseases such as unstable angina, exercise-induced ischemia, percutaneous transluminal coronary angioplasty (PTCA), and open heart surgery [9]. In large mammals, dogs, and pigs, myocardial stunning can be induced by a single completely reversible episode of regional ischemia lasting less than 20 min, or multiple completely reversible episodes of ischemia [10][11][12].…”

Section: Introductionmentioning

confidence: 99%

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

Shibata

Use

Ureshino

et al. 2008

Cardiovasc Drugs Ther

View full text Add to dashboard Cite

We assessed the effect of administration time for fasudil treatment of the stunned myocardium in 40 anesthetized open chest swine. All swine were subjected to 12 min ischemia followed by reperfusion to generate stunned myocardium. Group A (n = 11) received saline in place of fasudil both before ischemia and after reperfusion. Group B (n = 10) received 30 min intravenous fasudil at a rate of 13 µg/kg/min starting 45 min before ischemia and received saline after reperfusion.Groups C (n = 10) and D (n = 9) received saline before ischemia, and received fasudil at a rate of 13 µg/kg/min starting just before reperfusion in group C and 30 min after reperfusion in group D. In both groups, treatment lasted 30 min. Myocardial contractility was assessed by percent segment shortening (%SS). Three swine in group A, 2 swine in each of groups B and C, and one swine in group D had ventricular fibrillation or tachycardia after reperfusion and were excluded from further analysis.The changes of %SS from baseline at 90 min after reperfusion in groups B and C were 68 ± 8% and 75 ± 8%, respectively, which were significantly higher than in group A or D (47 ± 10% or 43 ± 8%). We conclude that fasudil administered before ischemia or Shibata et al. 4 just after reperfusion, but not 30 min after reperfusion, protects the stunned myocardium. (228 words)

show abstract

Recurrent ischemia in the canine heart causes recurrent bursts of free radical production that have a cumulative effect on contractile function. A pathophysiological basis for chronic myocardial "stunning".

Cited by 118 publications

References 51 publications

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Reduction of ischemia and reperfusion-induced myocardial damage by cytochrome P450 inhibitors

Medical and Cellular Implications of Stunning, Hibernation, and Preconditioning

Administration of the Rho-Kinase Inhibitor Fasudil Before Ischemia or just After Reperfusion, but not 30 min After Reperfusion, Protects the Stunned Myocardium in Swine

Contact Info

Product

Resources

About