As reported, o-vanillin was found to increase O2 affinity and inhibit sickling, but their effects on these permeability pathways do not depend on this action. Thus, for KCC and Gardos channel, inhibition also occurred when RBCs were treated with either the sulphydryl reacting reagent NEM or the Ca2+ ionophore
A23187, manipulations which bypass any anti-sickling action of o-vanillin. The Na+/K+ pump was also inhibited by o-vanillin. Although this raises the possibility that it acts non-specifically, as suggested for the phenylalanine benzyl esters [12], perhaps by partitioning into the membrane and destabilising the transporters, the much reduced effect of its
isoform, para-vanillin (or usually simply vanillin) argues against this. 5HMF, currently in clinical trials in SCD patients, was different in effect, at least in the transport assays carried out in this work. Nevertheless, present findings indicate that it is possible to design aromatic aldehydes which combine a direct inhibitory effect on HbS polymerisation together with favourable effects on reduction of RBC permeability to thereby increase RBC hydration. These dual effects may potentiate their ability to ameliorate the complications of SCD.