Biomedical subjects
Publications and source records attributed to B Bohn.
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Functional properties of tetrameric HbA are schematically described in this short review. After considering the various structures of the protein and its binding with heme, an attempt is made to explain the influence of this structure on the affinity of Hb for oxygen, cooperative binding of oxygen, and the alkaline Bohr effect. Fixation of erythrocytic anions (chlorine and 2,3 diphosphoglycerate) modulate certain intrinsic properties, allowing the Hb molecule to provide for efficacious transport of oxygen between the environment and the metabolically active tissues.
Chloride anions, when bound to human hemoglobin, lower the affinity for oxygen and increase the alkaline Bohr effect. These oxygen-linked characteristics are attributed to the preferential binding of Cl- to both alpha- and beta-chains in their deoxy configuration. It is demonstrated that the release of Cl- upon oxygenation is mainly due to tertiary changes, as shown by the effect of the anion on K1, the affinity constant of hemoglobin for oxygen at a very low saturation level (y less than or equal to 1.5%) where the cooperativity is unity. Investigation of the chloride effect on adult hemoglobin specifically carbamylated at the N-terminal valine of the alpha-chains, indicated a large inhibition of the effect of Cl-. The alpha-chain-binding sites appear to be the sites of the greatest affinity for the anion.
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The affinity for oxygen of normal human haemoglobin (Hb) solutions was measured in the presence of increasing concentrations of halothane. We observed a maximum increase in P50 of 25% with halothane 40 kPa compared with control (oxygen-argon gas mixtures) indicating the oxygen-linked character of the binding of halothane to the Hb molecule. The effect of halothane on P50 was independent of pH between 7.0 and 8.0 and of chloride concentration between 10 and 100 mmol litre-1. This suggests that halothane-Hb interactions may occur through hydrophobic linkage as occurs with short chain aliphatic hydrocarbons. The oxygen-linked binding of halothane appears of minor importance in altering oxygen binding to Hb in vivo compared with other factors such as chloride ion or 2, 3-DPG.
The binding of various alkanes by proteins was recognized years ago. We have studied the effect of butene (C4H8), a short-chain aliphatic hydrocarbon, on the functional properties of human adult hemoglobin. Under 1 atm pressure (100 kPa) butene decreased the affinity of hemoglobin (Hb) for oxygen (p50) by 45% without altering the cooperativity of ligand binding. This effect was independent of pH (from 7.0 to 8.0) and of ionic strength. The changes in the affinity of hemoglobin for oxygen were dependent upon the partial pressure of butene and evoked a saturating mechanism of the binding site(s). Mathematical simulation of the curve relating p50 to the concentration of dissolved butene allowed us to calculate the apparent association constants for one single binding site KHb = 10.4 mmol-1 and KHbO2 = 1.53 mmol-1 to Hb and HbO2 respectively. The larger binding of butene by Hb was confirmed by a 25% decrease in K1, the first association constant of oxygen to the tetrameric hemoglobin. It is concluded that butene is an allosteric effector of human Hb which acts most likely through hydrophobic interactions. It is postulated that the oxygen-linked binding site may be located at the alpha 1 beta 2 interface.
The effects of sodium lactate (Lact) on the oxygen affinity and the Bohr effect of purified human adult hemoglobin solutions have been compared to the effects of sodium chloride (Cl). Changes in the affinity for oxygen have been estimated from the variations of log(O2)50 with pH and at various salt concentration from 0.005 up to 2.0 mol.l-1. (O2)50 was calculated as alpha.P0.5 where alpha is the solubility coefficient of oxygen in the solutions at various salt concentrations. Variations of log(O2)50 with pH at constant salt concentration and variations of log(O2)50 with anion concentration at constant pH have been studied according to the linked-functions theory (Wyman, 1968). Bohr curves and salt binding curves were calculated from standard iterative curve fitting procedures and various parameters relevant to the effects of salts on hemoglobin function were estimated. It is shown that Lact and Cl increase (O2)50 and the alkaline Bohr effect in a comparable way at low salt concentration. At high concentration the effect of Lact predominated over that of Cl. The amount of oxygen linked Lact was larger than that of Cl. Binding constants for both anions to deoxy and oxy Hb were estimated. Lact and Cl have comparable binding constants to deoxy hemoglobin. By contrast Lact binds to oxy hemoglobin to a lesser extent than Cl. This may account for the differences observed in the effects of Lact and Cl on the function of hemoglobin. The reason for the low affinity of oxy hemoglobin for Lact may be related to steric differences between the two anions.
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1. Adaptive mechanisms of oxygen transport by blood have been studied in severely anaemic young patients on maintenance haemodialysis, in conditions of hyperphosphataemia (Pi greater than or equal to 2.2 mmol/l) or normophosphataemia. 2. In hyperphosphataemia whole-blood affinity for oxygen was slightly decreased, as measured by an increase in P50 (the partial pressure of oxygen necessary to half saturate haemoglobin). 2,3-Diphosphoglycerate was increased by 10% (P less than 0.10) whereas Pi, total erythrocyte phosphate and ATP were increased by 100%, 47% and 36% respectively, compared with control values. 3. After correction of hyperphosphataemia a small but significant decrease in P50 and 2,3-diphosphoglycerate, to normal values, was observed whereas the other variables, although significantly lowered, remained above control values. 4. In these severely anaemic and hyperphosphataemic patients P50 and 2,3-diphosphoglycerate are only slightly increased. ATP synthesis appears to be favoured over that of 2,3-diphosphoglycerate. This is possibly due to alterations in the erythrocyte membrane elicited by bi-weekly extracorporeal circulation. Adequate oxygen transport can be achieved only through a drastic increase in blood flow. Correction of hyperphosphataemia adds further to the abnormality. It is concluded that this condition could induce a long-term myocardial fatigue, which might be prevented with occasional small blood transfusions.
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The effects of hypoxic hypoxia on renal hemodynamics and metabolism have been studied in anaesthetized mechanically ventilated rabbits. Acute hypoxa (FIO2 = 0.10, PaO2 = 35 torr) induces at constant mean arterial pressure a 45% decrease in RBF, GFR, TNa and RVO2 whereas free water clearance increases. These alterations were still apparent 50 min after resuming normal arterial oxygenation. In order to assess the role of the stimulation of catecholamine release in these observations, two other sets of experiments were performed: 1) the animals were ventilated with the same hypoxic gas mixture but after alpha adrenergic blockade (phentolamine: 0.2 mg - kg - min-1 i.v.), 2) hypoxia was induced by ventilating the animals with CO (FICO = 0.002) at constnat PaO2. Increase in renal vascular resistance and reduction of renal O2 uptake were still observed. This indicates that adrenergic stimulation cannot fully explain the renal vasoconstriction encountered in hypoxia. The role of a local vasoactive factor, especially that of the renin angiotensin system is discussed. The apparent O2 cost of Na reabsorption was not greatly modified by any type of hypoxia and the Na: O2 ratio remained close to the value observed in normoxic animals. This indicates that the kidney may adapt to hypoxia by reducing its O2 demand keeping unaltered its tubular function and basal O2 needs.
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