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Pharmacological preconditioning: Potential new treatment modalities for the ischemic myocardium
Vascular Pharmacology 42 (2005) 199 www.elsevier.com/locate/vph
Prologue
Pharmacological preconditioning: Potential new treatment modalities for the ischemic myocardium
Ischemic preconditioning (IPC) was first identified and defined by the classical paper of Murry et al. in 1986 in which these investigators demonstrated that four 5 min periods of ischemia prior to a prolonged 40 min of occlusion and 72 h of reperfusion resulted in a marked decrease in infarct size in the canine heart as compared to control hearts which did not receive the preconditioning stimulus. Subsequently, two windows of cardioprotection were identified, an early period in which the protective effect only lasted 1–3 h and a later or delayed phase in which the protection was shown to last from 24 to 72 h (Yellon and Downey, 2003). This phenomenon was shown to occur in all species tested including man and the reduction in infarct size was remarkably similar across species. In addition, a number of endogenous pharmacological agents have been shown to mimic the cardioprotective effects of IPC including adenosine, bradykinin, opioids, acetylcholine, erythropoeitin (EPO) and nitric oxide. In addition, exogenously administered drugs including several direct KATP channel openers such as diazoxide and nicorandil, HMG-CoA reductase inhibitors such as simvistatin and fluvastatin, phosphodiesterase 5 inhibitors such as sildenafil, an extract found in grapes and red wine, resveretrol, and certain volatile anesthetics including desflurane and isoflurane, have all been shown to reduce infarct size to an extent similar to that observed following IPC. In the current issue of Vascular Pharmacology, a series of review articles and research papers written by experts in the preconditioning field will discuss in detail an update on various pharmacological preconditioning mimetics which
1537-1891/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2005.02.002
may have potential clinical uses and the cellular and subcellular mechanisms as to how these agents might produce their cardioprotective effects in several animal, isolated organ and cellular models of ischemia/reperfusion or hypoxia/reoxygenation injury. Several of the drug classes are already FDA approved and are currently used for other therapeutic purposes than cardioprotection and these include adenosine (antiarrhythmic), opioids (pain), statins (choesterol lowering), volatile anesthetics (general anesthesia), EPO (anemia) and sildenafil (erectile dysfunction), so their potential use as cardioprotective agents would not take nearly the time period required to produce a new drug before their potential use in the clinic for cardioprotection may become reality. Several well-designed clinical trials are needed to bring this possibility to fruition in the near future.
References Murry, C.E., Jennings, R.B., Reimer, K.A., 1986. Preconditioning with ischemia: a delay of lethal injury in ischemic myocardium. Circulation 74, 1124 – 1136. Yellon, D.M., Downey, J.M., 2003. Preconditioning the myocardium: From cellular physiology to clinical cardiology. Physiol. Rev. 83, 1113 – 1151.
Garrett J. Gross Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226-3548, United States E-mail address: [email protected].
Prologue
Pharmacological preconditioning: Potential new treatment modalities for the ischemic myocardium
Ischemic preconditioning (IPC) was first identified and defined by the classical paper of Murry et al. in 1986 in which these investigators demonstrated that four 5 min periods of ischemia prior to a prolonged 40 min of occlusion and 72 h of reperfusion resulted in a marked decrease in infarct size in the canine heart as compared to control hearts which did not receive the preconditioning stimulus. Subsequently, two windows of cardioprotection were identified, an early period in which the protective effect only lasted 1–3 h and a later or delayed phase in which the protection was shown to last from 24 to 72 h (Yellon and Downey, 2003). This phenomenon was shown to occur in all species tested including man and the reduction in infarct size was remarkably similar across species. In addition, a number of endogenous pharmacological agents have been shown to mimic the cardioprotective effects of IPC including adenosine, bradykinin, opioids, acetylcholine, erythropoeitin (EPO) and nitric oxide. In addition, exogenously administered drugs including several direct KATP channel openers such as diazoxide and nicorandil, HMG-CoA reductase inhibitors such as simvistatin and fluvastatin, phosphodiesterase 5 inhibitors such as sildenafil, an extract found in grapes and red wine, resveretrol, and certain volatile anesthetics including desflurane and isoflurane, have all been shown to reduce infarct size to an extent similar to that observed following IPC. In the current issue of Vascular Pharmacology, a series of review articles and research papers written by experts in the preconditioning field will discuss in detail an update on various pharmacological preconditioning mimetics which
1537-1891/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.vph.2005.02.002
may have potential clinical uses and the cellular and subcellular mechanisms as to how these agents might produce their cardioprotective effects in several animal, isolated organ and cellular models of ischemia/reperfusion or hypoxia/reoxygenation injury. Several of the drug classes are already FDA approved and are currently used for other therapeutic purposes than cardioprotection and these include adenosine (antiarrhythmic), opioids (pain), statins (choesterol lowering), volatile anesthetics (general anesthesia), EPO (anemia) and sildenafil (erectile dysfunction), so their potential use as cardioprotective agents would not take nearly the time period required to produce a new drug before their potential use in the clinic for cardioprotection may become reality. Several well-designed clinical trials are needed to bring this possibility to fruition in the near future.
References Murry, C.E., Jennings, R.B., Reimer, K.A., 1986. Preconditioning with ischemia: a delay of lethal injury in ischemic myocardium. Circulation 74, 1124 – 1136. Yellon, D.M., Downey, J.M., 2003. Preconditioning the myocardium: From cellular physiology to clinical cardiology. Physiol. Rev. 83, 1113 – 1151.
Garrett J. Gross Department of Pharmacology and Toxicology, 8701 Watertown Plank Road, Medical College of Wisconsin, Milwaukee, WI 53226-3548, United States E-mail address: [email protected].