Ronald Korthuis

The major purpose of this book is to review the evidence supporting the concept that intrinsic cell survival programs can be activated by a variety of mildly noxious stimuli or pharmacologic agents to confer protection against the deleterious effects of ischemia/reperfusion (I/R). We begin with a discussion of the concept of hormesis (a term used most extensively in the toxicologic literature which refers to biphasic cellular responses that depend on concentration or intensity of a stimulus), review the seminal studies that led to the discovery of the cardioprotective effects of ischemic preconditioning, and outline its therapeutic potential (Chapter 1). This is followed by a summary of our current understanding of the mechanisms of I/R injury (Chapter 2), as this provides several points of intervention in limiting postischemic tissue injury that may be targeted by the adaptive programs invoked by conditioning stimuli. Chapters 3 and 4 focus on the mechanisms underlying ischemic pre-, post-, and remote conditioning, which establishes the mechanistic rationale for development of pharmacologic conditioning strategies that may mimic the remarkably powerful effects of ischemic conditioning (and are covered in Chapter 5). Lifestyle interventions, including exercise, caloric restriction, and consumption of alcoholic beverages and/or phytochemicals, that may induce hormetic responses will also be reviewed in this chapter. While the promise for conditioning as a therapeutic approach is enormous, there are obstacles to its practical application in patients, which are covered in Chapter 6. The final chapter (Chapter 7) examines the extension of our mechanistic understanding of the signaling pathways invoked by conditioning stimuli into the realm of gene therapy and to the preservation of stem cell viability in the harsh ischemic environment as natural translational outgrowths of preconditioning into therapeutics.Table of Contents: Introduction / Hormesis and Preconditioning Defined / Mechanisms of Ischemia/Reperfusion Injury / Ischemic Preconditioning and Cardioprotection / Clinically Useful Applications of Ischemic Conditioning: Distant Site Ischemic Preconditioning and Ischemic Postconditioning / Cardioprotection Induced by Pharmacologic Conditioning and Lifestyle Interventions that Mimic Preconditioning / Cardiovascular Risk Factors, Tachyphylaxis, and the Efficacy of Pre- and Postconditioning / Logical Extensions of Preconditioning: Gene and Stem Cell Therapy for I/R / Acknowledgments / References

The aim of this treatise is to summarize the current understanding of the mechanisms for blood flow control to skeletal muscle under resting conditions, how perfusion is elevated (exercise hyperemia) to meet the increased demand for oxygen and other substrates during exercise, mechanisms underlying the beneficial effects of regular physical activity on cardiovascular health, the regulation of transcapillary fluid filtration and protein flux across the microvascular exchange vessels, and the role of changes in the skeletal muscle circulation in pathologic states. Skeletal muscle is unique among organs in that its blood flow can change over a remarkably large range. Compared to blood flow at rest, muscle blood flow can increase by more than 20-fold on average during intense exercise, while perfusion of certain individual white muscles or portions of those muscles can increase by as much as 80-fold. This is compared to maximal increases of 4- to 6-fold in the coronary circulation during exercise. These increases in muscle perfusion are required to meet the enormous demands for oxygen and nutrients by the active muscles. Because of its large mass and the fact that skeletal muscles receive 25% of the cardiac output at rest, sympathetically mediated vasoconstriction in vessels supplying this tissue allows central hemodynamic variables (e.g., blood pressure) to be spared during stresses such as hypovolemic shock. Sympathetic vasoconstriction in skeletal muscle in such pathologic conditions also effectively shunts blood flow away from muscles to tissues that are more sensitive to reductions in their blood supply that might otherwise occur. Again, because of its large mass and percentage of cardiac output directed to skeletal muscle, alterations in blood vessel structure and function with chronic disease (e.g., hypertension) contribute significantly to the pathology of such disorders. Alterations in skeletal muscle vascular resistance and/or in the exchange properties of this vascular bed also modify transcapillary fluid filtration and solute movement across the microvascular barrier to influence muscle function and contribute to disease pathology. Finally, it is clear that exercise training induces an adaptive transformation to a protected phenotype in the vasculature supplying skeletal muscle and other tissues to promote overall cardiovascular health.

The partition of fluid between the vascular and interstitial compartments is regulated by forces (hydrostatic and oncotic) operating across the microvascular walls and the surface areas of permeable structures comprising the endothelial barrier to fluid and solute exchange, as well as within the extracellular matrix and lymphatics. In addition to its role in the regulation of vascular volume, transcapillary fluid filtration also allows for continuous turnover of water bathing tissue cells, providing the medium for diffusional flux of oxygen and nutrients required for cellular metabolism and removal of metabolic byproducts. Transendothelial volume flow has also been shown to influence vascular smooth muscle tone in arterioles, hydraulic conductivity in capillaries, and neutrophil transmigration across postcapillary venules, while the flow of this filtrate through the interstitial spaces functions to modify the activities of parenchymal, resident tissue, and metastasizing tumor cells. Likewise, the flow of lymph, which is driven by capillary filtration, is important for the transport of immune and tumor cells, antigen delivery to lymph nodes, and for return of filtered fluid and extravasated proteins to the blood. Given this background, the aims of this treatise are to summarize our current understanding of the factors involved in the regulation of transcapillary fluid movement, how fluid movements across the endothelial barrier and through the interstitium and lymphatic vessels influence cell function and behavior, and the pathophysiology of edema formation.