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Intracellular Ph Regulation and the Acid Delusion

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Intracellular Ph Regulation and the Acid Delusion Canadian Journal of Physiology and Pharmacology Intracellular pH Regulation and the Acid Delusion Journal: Canadian Journal of Physiology and Pharmacology Manuscript ID cjpp-2020-0631 Manuscript Type: Review Date Submitted by the 29-Oct-2020 Author: Complete List of Authors: Magder, Sheldon; Mcgill University Health Centre Magder, Alexandr; Royal College of Surgeons in Ireland Samoukovic, Gordan; McGill University Faculty of Medicine, critical care Is the invited manuscript for consideration in a Special Not applicable (regular submission) Issue: Draft Keyword: strong ion, acid base, stewart, buffer, sodium hydrogen exchanger © The Author(s) or their Institution(s) Page 1 of 67 Canadian Journal of Physiology and Pharmacology 1 1 2 3 4 Intracellular pH Regulation and the Acid Delusion 5 Sheldon Magder, Alexandr Magder, Gordan Samoukovic 6 McGill University Health Centre 7 Department of Critical Care 8 687 Pine Av W 9 Montreal, Quebec 10 H3A 1A1 11 12 13 14 15 Address correspondence to: 16 Draft 17 S Magder 18 Royal Victoria Hospital 19 687 Pine Av W 20 Montreal, Quebec 21 H3A 1A1 22 [email protected] 23 24 25 26 27 Dec 14 edits © The Author(s) or their Institution(s) Canadian Journal of Physiology and Pharmacology Page 2 of 67 2 29 Abstract 30 The concentration H+ ([H+]) in intracellular fluid (ICF) must be maintained in a narrow range in 31 all species for normal protein functions. Thus, mechanisms regulating ICF are of fundamental 32 biological importance. Studies on the regulation of ICF [H+] have been hampered by use of pH 33 notation, failure to consider the roles played by differences in the concentration of strong ions ( + - 34 SID), the conservation of mass, the principle of electrical neutrality and that [H ] and [HCO3 ] 35 are dependent variables. This argument is based on the late Peter Stewart’s physical- chemical 36 analysis of [H+] regulation reported in this journal nearly forty years ago. We start by outlining 37 the principles of Stewart’s analysis and then provide a general understanding of its significance 38 for regulation of ICF [H+]. The system mayDraft initially appear complex, but it becomes evident that 39 changes in SID dominanate regulation of [H+]. The primary strong ions are Na+, K+ and Cl-, and 40 a few organic strong anions. The second independent variable, PCO2, can easily be assessed. The 41 third independent variable, the activity of intracellular weak acids ([Atot]), is much more complex 42 but largely plays a modifying role. Attention to these principles potentially will provide new 43 insights into ICF pH regulation. 44 45 Key Words: strong ion, acid-base, Stewart, buffer, sodium-hydrogen exchanger 46 47 48 49 Dec 14 edits © The Author(s) or their Institution(s) Page 3 of 67 Canadian Journal of Physiology and Pharmacology 3 51 Introduction 52 Close to 40 years ago in this journal the late Peter Stewart laid out the principles of a 53 quantitative physical-chemical approach to the understanding of the determinants of hydrogen 54 ion concentration ([H+], pH, and acid-base in the water-based biological solutions (Stewart 55 1983). His work created a lot of controversy at the time, but over the past decades his approach 56 has become increasing accepted in clinical medicine for analysis of acid-base disturbances in 57 serum (Berend et al. 2014; Gilfix et al. 1993; Jones 1990a, b; Kellum et al. 1995; Magder and 58 Emami 2015). Stewart’s detailed monograph on the subject (Stewart 1981) also has been 59 republished in a new edition (Kellum and Elbers 2009). However, there still is a striking lack of 60 consideration of the principles he laid outDraft for analysis of intracellular fluid (ICF) [H+] regulation, 61 even though ICF volume is twice as large as extracellular volume and it is where changes in [H+] 62 ultimately have their greatest biological implications. As will be seen, the reason why we believe 63 that this is of importance is that when physical-chemical principles are not taken into account, 64 [H+] is considered as an independent variable when it actually is a dependent variable, and the 65 factors that really determine the regulation of ICF [H+] such as the role of strong ions, the 66 importance of electrical neutrality and the behavior of weaker electrolytes are not considered. 67 As a result, many experimental errors occur in experimental reasoning and important 68 mechanisms are missed. 69 Of historical interest, in an early examination of temperature effects on pH in the blood of 70 in the non-endothermic alligator , Austen et al showed in 1927 that changes in the concentrations 71 of Na+, K+ and Cl- occur are part of the process regulating pH in whole blood presumably by 72 shifts between red cells and plasma(Austin et al. 1927). A more recent exception is the work of 73 Roberg (Robergs et al. 2004). He analyzed how the multiple metabolic biochemical changes that Dec 14 edits © The Author(s) or their Institution(s) Canadian Journal of Physiology and Pharmacology Page 4 of 67 4 74 occur inside muscle fibres during exercise alter intracellular [H+] and the limitation of the simple 75 terms lactic acid and lactic acidosis. However, even his work fails to consider the considerable 76 importance of strong elements in intracellular solutions and their potential to move into and out 77 of cells and into intracellular compartments (Demes et al. 2020). He also did not consider the 78 importance of the principle of electrical neutrality and thus the need for a quantitative analysis of 79 all positive and all negative charges. His work, though, does indicate that it is unlikely that 80 complexity of the rapid changes in electrolyte characteristics during a process such as exercise 81 will allow a precise prediction of changes in [H+] in cells. We will come back to his work later, 82 but our goal is less ambitions. In this review, we believe that what is important is to better 83 understanding the factors that can regulateDraft intracellular pH (pHi). Hopefully this will lead to an 84 appreciation of new processes that are critical for the regulation of intracellular [H+] and provide 85 some principles that should be considered in studies of intracellular [H+]. 86 The central thesis of this essay, which is based on the work of Peter Stewart(Stewart 87 1978, 1981, 1983), is that it is actual [H+] that we must care about in biological solutions. 88 Emphasis on “acids” and “bases” rather than maintenance of [H+] in a given range, the 89 definitions used for acids and bases, and the use of pH notation, obscure important mechanistic 90 insights into the regulation of [H+]. Key omissions are failure to account for the role of water 91 itself and ignoring the conservation of mass, the principle of electrical neutrality, and most 92 importantly, that all the components of solutions interact and together determine to [H+] and - 93 [HCO3 ] which are dependent and not independent variables. 94 There are over 1014 cells in the body, each with its own internal environment, and there 95 are even variations in sub-compartments within cells with pH values that vary from 8.0 in 96 mitochondria to 5.0 in lysosomes. Thus, this discussion is about a “generic” cell, and its Dec 14 edits © The Author(s) or their Institution(s) Page 5 of 67 Canadian Journal of Physiology and Pharmacology 5 97 “standard” intracellular cytoplasmic fluid (ICF), under quasi-steady state conditions, while 98 appreciating that there are large variations in cytoplasmic composition among cell types and in 99 sub-compartments of the cell (Bal et al. 2012; Demes et al. 2020; Kyne and Crowley 2016; 100 Luby-Phelps 2013). A key principle in a physical chemical analysis is that [H+] concentration is 101 unique for each fluid compartment. It thus is not meaningful to consider total body [H+] balance 102 or even [H+] in a whole cell. The factors that determine [H+] in each compartment can interact 103 with other compartments by moving from one compartment to another by moving down a 104 concentration gradients or by being actively moved (Demes et al. 2020), but the components 105 determining [H+] in each compartment are unique at any given instant. Hopefully, attention to 106 simple basic concepts will lead to more Draftdirected experimental approaches for analyzing [H+] 107 regulation in cells and their sub-compartments. Our objective is to provide a roadmap for use of 108 physical-chemical concepts in future studies on the regulation of ICF [H+]. 109 Importance of Hydrogen Ion 110 [H+] is maintained between 6 to 16 x 10-8 mol/L (pH 6.8-7.2) in almost all cells 111 throughout the animal kingdom, from the eggs of sea urchins to the cytoplasm of human cells 112 (Boron 2004; Burggren and Bautista 2019; Janis et al. 2020; Putnam 1998; Roos and Boron 113 1981). Even most bacteria regulate cytoplasmic pH in the 6.5 to 7.0 range (Booth 1985). [H+]1 is 114 extremely low compared to other major elements such as extracellular sodium (Na+) and 115 intracellular potassium (K+), which are in the range of 0.140-0.150 mol/L. To put this low [H+] 116 value into a more tangible context, there is one H+ per 500 million water molecules in a glass of 117 pure water at standard temperature and pH 7.0 (Ball 2001). Despite being very low, [H+] must be 118 maintained in a very tight range for normal cell function. This is because of the high charge 1 [ ] will be used to denote concentration Dec 14 edits © The Author(s) or their Institution(s) Canadian Journal of Physiology and Pharmacology Page 6 of 67 6 119 density of a proton (H+) relative to its mass.
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