Ischemia of the heart : a study of sarcomere dynamics and cellular metabolism

Abstract

Since 1628, when Harvey was the first to recognize that interruption of coronary flow results in an immediate decrease of force development, researchers were intrigued by the possible explanations of this phenomenon (Harvey, 1628). In the previous chapter I reviewed the possible hypotheses to explain the rapid decay of force development that results from hypoxia On the basis of the available xperimental and clinical evidence the most likely explanations include: a) impairment of the excitation-contraction coupling process, at least partially explained by abbreviation of the duration of the action potential by ischemia activated ATP-sensitive potassium channels (Weiss and Lamp, 1989), b) impairment of force development as a result of accumulation of metabolites from high-energy phosphates, notably protons and inorganic phosphate (Kentish, 1986), c) decreased free energy change of ATP hydrolysis at normal or slightly decreased high-energy phosphate content (Kammermeier et al., 1982; Fiolet, 1984 but see Hoerter et al, 1988), and d) interaction between myocytes and the coronary vasculature (Koretsune, 1991). The primary goal of the studies that are included in this thesis was to improve our insights in sarcomere mechanics. For this purpose not only norm.oxic but also hypoxic preparations were studied, both intact and following skinning. In addition we attempted to define the relationship between sarcomere mechanics and biochemistry, notably tb.e content of energy-rich phosphate compounds.The following hypotheses were tested: 1. The properties of the cardiac myoflorils, including the length dependence of calcium sensitivity, largely account for the shape of the ascending limb of the force - sarcomere length relation, both in intact and skinned cardiac muscle (Chapter 4). 2. Acidosis causes a shift of the force - pCa2+ curve to the right at all sarcomere lengths as a result of competition between H+ and Ca2+ ions for binding to the myofilaments (Chapter 5). 3. Strontium is able to induce maximal force development by direct activation of the contractile apparatus and stimulation of calcium release by the sarcoplasmic reticulum (Chapter 6). 4. During hypoxic perfusion followed by flow standstil, rat cardiac muscle develops rigor in spite of the fact that concentrations of high-energy phosphates are only slightly diminished (Chapte' 7). 5. The increased diastolic force that is observed during hypoxia of rat heart can nearly completely be explained on the basis of formation of rigor bonds (Chapter 8). 6. Impaired relaxation during repeated hypoxia is accounted for by calcium overload without evidence for rigor bound formation or a shift of the diastolic force - SL relation (Chapte' 9). These hypotheses will be addressed in more detail in the chapters that are mentioned in parentheses