Biomedical subjects
Publications and source records attributed to A Malan.
When blood temperature is varied in closed ('anaerobic') conditions, the difference between plasma pH and red cell pH stays remarkably constant. Model studies show that this constancy results from diffusive CO2 equilibration and Donnan equilibrium of HCO3- and Cl- ions, more than from a strictly defined buffer composition.
Information available in the literature on the acid-base properties of oxygenated mammalian blood at a constant or variable temperature was put together into a synthetic model; this also aimed at reconciling the single compartment descriptions of acid-base vs temperature relationships in closed ('anaerobic') conditions with the standard dual compartment analysis of isothermal titrations. Experimental values for the concentrations of blood constituents, buffer dissociation constants, etc. were introduced into the set of physicochemical equations governing the steady-state distribution of CO2, electrolytes and water between plasma and red cells. Design of the model was such as to permit monitoring of all variables (e.g. concentrations) throughout any simulated acid-base transformation. A fairly good fit was obtained between model predictions and experimentally-determined relationships or quantities not introduced into the model from the start. Applications to variable temperature titration and to the effects of changes in blood composition or osmolality are presented. The latter underline the implicit assumptions made by neglecting such variables in current presentations of blood acid-base state.
Mammalian hibernation is characterized by the alternation of prolonged periods of hypothermia and spontaneous arousals with a temporary return to euthermia. Of special interest to the physiology of effectors of thermogenesis are the following points: a) In the second part of the arousal process, the metabolic rate reaches 6 to 8 times BMR, with a body temperature about 10 degrees C lower. Enzymatic adaptations provide for the maintenance of normal reaction rates and regulatory potentials at low temperatures, but how very high thermogenetic rates can be achieved still remains largely unexplained. b) Entrance into hibernation involves a resetting of the hypothalamic thermostat to a lower level, but this is probably not the only intervening regulation. Evidence is presented in favor of a control of thermogenesis at the effector level, in terms both of baseline levels and of loop gains. One likely control factor is acid-base state, which can be changed rapidly and reversibly by ventilation and is characterized by a strong acidosis in hibernation.
When temperature changes are superimposed on changes in the control variables of acid-base state (PCO2, strong ion difference), the understanding of acid-base changes becomes difficult. A solution has recently been proposed for blood (Malan, 1977); it was based on the assumption that closed system conditions correspond to a minimal change in the overall acid-base state when temperature varies. The feasibility of extending these concepts to muscle intracellular acid-base vs temperature relationships is evaluated on the basis of a model study; the errors made by replacing closed conditions (which require knowledge of chemical composition) by more convenient approximations are estimated. A representation of both extracellular and intracellular acid-base data on a temperature-corrected bicarbonate-pH diagram is derived. It allows the interpretation of variable-temperature intracellular acid-base changes in terms of changes in control variables, 'respiratory (PCO2) or 'metabolic' (strong ion difference).
When blood temperature is changed in closed system ('anaerobic') conditions, plasma pH and PCO2 vary but no titration by external CO2, acid or alkaline equivalents takes place. It is therefore assumed that the overall acid-base state undergoes no fundamental change. This is further justified by the constancy of osmotic relationships between plasma and red cells, and to a lesser extent of relative alkalinity and protein alpha imidazole (Reeves, 1972, 1976a, b). These considerations serve as a basis for a correction procedure of pH and PCO2 of blood in open systems in vivo to a standard temperature T* (25 degrees C, eventually 37 degrees C). The temperature-corrected values pH* and P*CO2, and the derived [HCO3]* can be represented on a temperature-independent bicarbonate-pH diagram. This permits an easier interpretation of blood acid-base changes occurring together with body temperature variations, such as in ectotherms, hibernators or in artificial hypothermia. Extension to intracellular pH is considered.
Intracellular pH (pHi) was measured in vivo in tissue of frogs (Rana catesbeiana) and turtles (Pseudemys scripta) using the DMO technique. Animals were permitted 3-8 days to come to a new steady-state body temperature (Tb) which ranged 5-32 degrees C. Least squares regression equation for pHi data are: frog blood, 8.184-0.0206 Tb; frog striated muscle, 7.275-0.0152 Tb; turtle blood, 8.092-0.0207Tb; turtle muscle, 7.421-0.0186 Tb; turtle heart, 7.452-0.0122 Tb; turtle liver, 7.753-0.0233 Tb; turtle esophageal smooth muscle, 7.513-0.0141 Tb. Only turtle cardiac muscle deltapHi/deltaT was significantly different from deltapH/deltaT of blood. Results have been interpreted in terms of protein charge state alterations; in the physiological pH range, histidine residues of proteins are the principal dissociable groups (HPr+ = H+ + Pr) affected by pHi and Tb changes. Constancy of protein charge state can be assessed by monitoring alpha imidazole, alphaIM = Pr/(HPr+ + Pr). A uniform pKIM of 6.85 (20degreesC) and a deltaHO of 7 kcal/mol are assumed in calculating alphaIM. Intracellular alphaIM is preserved in the tissues studied as body temperature changes. These results indicate that ectotherm acid-base balance, alphastat control, regulates not only extracellular blood proteins, but also intracellular compartment proteins in such a way as to preserve functions dependent upon protein net charge states.
Measurements of intracellular pH (pHi) in air-breathing ectotherms have only been made in the steady state; these pHi indicate that protein charge state, measured as alpha imidazole (alphaIM), the fractional dissociation of protein histidine imidazole groups, is preserved when ectotherm tissues change temperature in vivo, with related changes in pHi and PCO2. In partial answer to the question of how such tissues are able to avoid disrupting transients to functions sensitive to protein charge states, model studies were carried out to assess the passive intracellular buffer system response to a combined change in body temperature and CO2 partial pressure as occurs in vivo in these species. The cell compartment was modeled as a closed volume of ternary buffer solution, containing protein imidazole (50 mM/1); phosphate (15 mM/1) and CO2-bicarbonate buffer components, permeable only to CO2 and permitted no change in buffer base. Excursions from a steady-state non-equilibrium pHi were computed to a step-change in temperature/PCO2. Computations for frog (Rana catesbeiana) striated muscle show that the calculated pHi response on the basis of estimated composition and concentration of cell buffer components, moves along the curve describing the steady-state temperature relationship. No transient away from steady-state alphaIM and carbon dioxide content need be postulated. Applications to turtle (Pseudemys scripta) striated muscle are also explored. These calculations show that ectotherm cells may be capable of responding without appreciable time for adaptation to intracellular acid-base state changes incurred by sudden alteration of body temperature in vivo, given the observed adjustments of blood PCO2 with temperature.
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