MODULATING THE OXYGEN-AFFINITY OF HUMAN FETAL HEMOGLOBIN WITH SYNTHETIC ALLOSTERIC MODULATORS

Improving the delivery of oxygen to the tissues by decreasing the oxyg en affinity of haemoglobin has been a major aim of several laboratorie s over recent years because this may reduce the consequences of anaemi a and/or improve tissue oxygenation in cases of decreased blood perfus ion. Within the same context, lowering the oxygen affinity may prove v aluable in the application of native or recombinant haemoglobin soluti ons as a blood substitute. The shift of the oxygen equilibrium curve t o the right is obtained by various modulators. Among them, the bezafib rate derivatives are considered as a most interesting group. These pri nciples are of the utmost importance in thalassaemia and other haemogl obinopathies where the beneficial effects of the compensatory synthesi s of fetal haemoglobin are diminished by the increased oxygen affinity of this pigment. In this paper we present the results of a study init iated to determine whether a potent oxygen affinity modifier, RSR-4, c ould satisfactorily decrease the oxygen affinity of fetal haemoglobin, thus improving tissue oxygenation. The experiments were carried out o n whole blood and on purified haemoglobin solutions and showed that th e effector markedly decreased the oxygen affinity of HbF (from 18.7 to 37.3 mmHg in whole blood). At the same time the cooperativity index ( n(50)) and the oxygen saturation levels remained within normal limits under the conditions of the main experiment. These observations have i mportant implications for the potential application of oxygen affinity modifiers in vivo.