SPECIAL TOPIC
Prologue: ischemic preconditioning in cardiac vascular muscle

Department of Physiology and Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226

	INTRODUCTION

TOP INTRODUCTION EDITOR'S NOTE REFERENCES

Ischemic preconditioning is the most potent means of salvaging tissue from necrosis resulting from ischemia-reperfusion injury. The documentation of this response was first noted nearly a decade ago, and during the intervening time, much research has focused on identifying causal mechanisms. The elucidation of mechanisms of ischemic preconditioning has great potential benefit, because such a therapy could spare the myocardium from severe injury following stunning or an acute myocardial infarction. The current knowledge about mechanisms of ischemic preconditioning and how some of the articles in this Special Topic section relate and expand this knowledge are shown in Fig. 1. Dickson and colleagues (6) reported that a factor (or factors) in coronary effluent of preconditioned hearts can precondition a recepient heart. This observation gives plausibility to the notion that in the future, administration of the causal factor(s) may protect the myocardium or other tissues from ischemic insults. Davis et al. (5) reported that ischemic preconditioning in the small intestine decreased P-selectin expression. Administration of an adenosine A₁ antagonist unfettered the P-selectin expression and abolished the protective effects of preconditioning. Butler et al. (3) found that the beneficial effects of preconditioning were augmented following administration of the angiotensin I antagonist losartan. This implies that endogenously released angiotensin during ischemia impairs preconditioning. Interestingly, this beneficial effect of losartan occurred in both normal and hypertrophied myocardium. A role for enkephalins in preconditioning is reported by Takasaki et al. (10). In a isolated myocyte model of ischemic preconditioning (hypoxia/reoxygenation) Met⁵- or Leu⁵-enkephalin or Met⁵-enkephalin-Arg-Phe, but not -endorphin, provided protection. This observation extends previous reports that endogenous opioids are cardioprotective by establishing the particular family of opioids involved in the response. In another report by Yao et al. (12), who used isolated cardiac myocytes, the mechanism of the cardioprotective effect of acetylcholine was delineated. These investigators found that acetylcholine activates mitochondrial ATP-regulated potassium (K_ATP) channels by stimulating the production of reactive oxygen species in the mitochondria. The protective effect could be blocked by an inhibitor of electron transport. Nitric oxide (NO) was reported to confer protective effects against stunning [Shinmura et al. (9)] and decrease infarct size [Ockaili et al. (8)]. These investigators found that NO donors, in doses that did not produce hemodynamic effects, decreased stunning and that blockade of endogenous NO synthase increased injury by opening mitochondrial K_ATP channels. A role for NO in delayed preconditioning is reported by Xi and colleagues (11). In their study, RC-552 induced inducible NO synthase (iNOS) and reduced infarct size after 1 day of treatment. In a group of iNOS knockout mice, RC-552 was not protective. Furthermore, Banerjee et al. (1) reported that NO donors also induce late preconditioning against stunning in a protein kinase C (PKC)-dependent pathway. A parallel to this previous finding was made by Belosjorow et al. (2), who reported that exposure to endotoxin reduces infarct size. These investigators related the cardioprotection to reductions in tumor necrosis factor- (TNF-) and induction of TNF--inhibitory activity in serum. A central role for calcium was reported by Gysembergh et al. (7), who found that successive adminstration of an inositol 1,4,5-trisphospate agonist and an antagonist mimicked the protective effects of preconditioning. The effects of the drugs on calcium levels were confirmed by measurements of calcium in fura-loaded myocytes. Finally, Birincioglu et al. (4) reported that preconditioning cannot be predicted from S-T segment changes during coronary occlusion. These investigators observed dissociation between myocardial protection and S-T segment changes. In the aggregate, the papers published in this special section not only fill gaps in our knowledge concerning mechanisms of ischemic preconditioning, but they also raise new questions.

View larger version (48K): [in this window] [in a new window]   Fig. 1.   Schematic diagram of major factors thought to be involved in ischemic preconditioning. Emphasis is on those factors that have been addressed in this special section by the original papers published. IP3, inositol 1,4,5-trisphosphate; PKC, protein kinase C; TNF-, tumor necrosis factor-; GTN, glyceryl trinitrate (nitroglycerin); NO, nitric oxide; iNOS, inducible NO synthase; KATP, ATP-regulated potassium channels; Raf, MEKK, TAK1, MEK1/2 SEK, MEK3/6, ERK, JNK, p38 (mitogen-activated protein kinase family).

	EDITOR'S NOTE

TOP INTRODUCTION EDITOR'S NOTE REFERENCES

This is the first of a series of special topic manuscript calls that will be published twice per year. The purpose of these special calls is to provide broad input in specific and timely subject areas related to cardiovascular research. These calls take a fair amount of work by the topic editors, and I thank them for their time. Given that the topics discussed received input from a number of recognized scientists with varying points of view, the area will contain input in a manner that could not have been done by a single review. I hope the readership finds these special topics beneficial and again thank the topic editors for their efforts.

	FOOTNOTES

 
  This special topic section is a collection of papers accepted under a special call for manuscripts by the Editor. See Journal web site for information about the next call.

	REFERENCES

TOP INTRODUCTION EDITOR'S NOTE REFERENCES

1.   Banerjee, S., X.-L. Tang, Y. Qiu, H. Takano, S. Manchikalapudi, B. Dawn, G. Shirk, and R. Bolli. Nitroglycerin induces late preconditioning against myocardial stunning via a PKC-dependent pathway. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2488-H2494, 1999[Abstract/Free Full Text].

2.   Belosjorow, S., R. Schulz, H. Dörge, F. U. Schade, and G. Heusch. Endotoxin and ischemic preconditioning: TNF- concentration and myocardial infarct development in rabbits. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2470-H2475, 1999[Abstract/Free Full Text].

3.   Butler, K. L., A. H. Huang, and J. K. Gwathmey. AT₁-receptor blockade enhances ischemic preconditioning in hypertrophied rat myocardium. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2482-H2487, 1999[Abstract/Free Full Text].

4.   Birincioglu, M., X.-M. Yang, S. D. Critz, M. V. Cohen, and J. M. Downey. S-T segment voltage during sequential coronary occlusions is an unreliable marker of preconditioning. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2435-H2441, 1999[Abstract/Free Full Text].

5.   Davis, J., D. C. Gute, S. Jones, A. Krsmanovic, and R. J. Korthuis. Ischemic preconditioning prevents postischemic P-selectin expression in the rat small intestine. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2476-H2481, 1999[Abstract/Free Full Text].

6.   Dickson, E. W., M. Lorbar, W. A. Porcaro, R. Fenton, C. P. Reindhardt, A. Gysembergh, and K. Przyklenk. Rabbit heart can be "preconditioned" via transfer of coronary effluent. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2451-H2457, 1999[Abstract/Free Full Text].

7.   Gysembergh, A., S. Lemaire, C. Piot, C. Sportouch, S. Richard, R. A. Kloner, and K. Przyklenk. Pharmacological manipulation of Ins(1,4,5)P₃ signaling mimics preconditioning in rabbit heart. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2458-H2469, 1999[Abstract/Free Full Text].

8.   Ockaili, R., V. R. Emani, S. Okubo, M. Brown, K. Krottapalli, and R. C. Kukreja. Opening of mitochondrial K_ATP channel induces early and delayed cardioprotective effect: role of nitric oxide. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2425-H2434, 1999[Abstract/Free Full Text].

9.   Shinmura, K., X.-L. Tang, H. Takano, M. Hill, and R. Bolli. Nitric oxide donors attenuate myocardial stunning in conscious rabbits. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2495-H2503, 1999[Abstract/Free Full Text].

10.   Takasaki, Y., R. A. Wolff, G. L. Chien, and D. M. Van Winkle. Met⁵-enkephalin protects isolated adult rabbit cardiomyocytes via -opioid receptors. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2442-H2450, 1999[Abstract/Free Full Text].

11.   Xi, L., F. Salloum, D. Tekin, N. C. Jarrett, and R. C. Kukreja. Glycolipid RC-552 induces delayed preconditioning-like effect via iNOS-dependent pathway in mice. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2418-H2424, 1999[Abstract/Free Full Text].

12.   Yao, Z., J. Tong, X. Tan, C. Li, Z. Shao, W. C. Kim, T. L. Vanden Hoek, L. B. Becker, C. A. Head, and P. T. Schumacker. Role of reactive oxygen species in acetylcholine-induced preconditioning in cardiomyocytes. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H2504-H2509, 1999[Abstract/Free Full Text].