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Regulation of intracellular pH in the myocardium; relevance to pathology
1National Heart and Lung Institute, London, UK.
Insights
Acidosis, or lower pH, impairs heart contractility by affecting calcium sensitivity. While it causes early contractile failure in ischemia, its role in cell death remains unclear.
Area of Science:
- Cardiology
- Physiology
- Biochemistry
Background:
- Intracellular pH is crucial for cardiac function, influencing contractility, metabolism, and ion balance.
- Extracellular acidosis is known to decrease cardiac contractility, primarily by altering intracellular pH.
- Previous studies suggested intracellular pH changes mediate the negative effects of acidosis on heart muscle.
Purpose of the Study:
- To investigate the precise mechanisms by which intracellular pH affects cardiac contractility.
- To determine the primary site of action for hydrogen ions in cardiac muscle during acidosis.
- To understand the role of acidosis in myocardial ischemia and reperfusion.
Main Methods:
- Measurement of cytosolic intracellular pH using microelectrodes.
- Analysis of calcium currents and sarcoplasmic reticulum calcium release.
- Assessment of calcium sensitivity of contractile proteins.
Main Results:
- Acidosis reduces slow calcium currents and calcium release from the sarcoplasmic reticulum.
- Cytosolic calcium levels do not significantly decrease, indicating altered calcium sensitivity of contractile proteins.
- Acidosis is detected rapidly in human myocardial ischemia and contributes to contractile loss.
- Mild respiratory acidosis during hypoxia improved recovery, while severe acidosis was detrimental.
Conclusions:
- The primary effect of acidosis on cardiac contractility appears to be a reduction in the calcium sensitivity of contractile proteins.
- Acidosis is a significant factor in early contractile failure during myocardial ischemia.
- The potential benefits of acidosis in ischemia (cardioplegia, altered calcium flux) and its role in cell necrosis require further investigation.
Abstract:
Intracellular pH affects the contractile function of the heart, metabolic reactions, ion exchange and calcium homoeostasis. Numerous studies have concluded that a fall of extracellular pH, by whatever mechanism, causes a fall of contractility by alteration of intracellular pH. Measurement of cytosolic intracellular pH using microelectrodes has confirmed that earlier deduction. Acidosis reduces the slow calcium current and the release of calcium from the sarcoplasmic reticumul but, because the cytosolic calcium does not fall, the major site of action of hydrogen ions appears to be on the calcium sensitivity of the contractile proteins. In man acidosis can be detected 15 s after the occlusion of a coronary artery and is a major mechanism for the simultaneous loss of contractility in ischaemia. A transient alkalosis is not detected in man but has been reported in isolated heart preparations where ATP consumption is low. An imposed mild respiratory acidosis during hypoxia increases the subsequent recovery of mechanical function on reoxygenation whereas a severe acidosis can be harmful. Acidosis in ischaemic may be advantageous due to a cardioplegic effect, inhibition of transsarcolemmal calcium fluxes or a reduction of mitochondrial calcium overload. Calcium uptake on reperfusion or reoxygenation has been linked to an inward movement of sodium in exchange for hydrogen ions on reperfusion and subsequent sodium-calcium exchange. Such a mechanism in its simplest form cannot account for the similar uptake of calcium on reoxygenation and reperfusion. Acidosis is a cause of early contractile failure in ischaemia but the role of acidosis in causing cell necrosis is not established.