P. Ferrandon
2009
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Journal
Fundamental & Clinical Pharmacology
Abstract
In a recent paper in this journal, Ferrandon et a1 (1994) suggest that soluflazine “and related molecules” mainly act on adenosine deaminase instead of on the nucleoside transporter. In addition, they claim that inhibition of the uptake process would be negative for the recovery of cardiac function following ischaemia. To start, 1 will comment on some technical aspects of this study. Firstly the finding of hypoxanthine as by far the major endproduct recovered when adenosine is incubated in a suspension of red blood cells may indicate an incubation time far too extended to assess the effect of moderate nucleoside transport inhibition. The transport process in this condition becomes rate-limiting only when nearly completely inhibited, hence, a lack of effect at lower doses of soluflazine. Secondly, the high recovery of products in the cells raises the suspicion of contaminates of these cells with incubation medium. The cells are centrifuged at low speed (900 g for 10 min) and are not “washed”. With a total cell volume of around 70 pl (8.5 x 108 cells; cell volume = 85 p3) elimination of any supernatant or fluid trapped in the cell pellet without disturbing this pellet may be extremely tricky. Illustrative in this respect is the “recovery” inside the cells of hypoxanthine (which is the major product (70%) in control conditions). Indeed 20 to 25% (fig 3, Ferrandon et al, 1994) of this hypoxanthine is found in a cell volume which constitutes around 3.5% of the total incubation volume. Such an “enrichment” is not compatible with the well-known free diffusion of hypoxanthine between the erythrocytes (inside) and the incubation medium (outside). Thirdly, the similarity of effect on adenosine metabolism between erythro-9-(2-hydroxy-3-nonyl adenosine) (EHNA) and soluflazine is not an argument to suggest that the latter mainly acts on adenosine deaminase. Adding these drugs to red cell lysates and following adenosine’s disappearance would have shown the difference: EHNA will block catabolism but soluflazine would not have any effect. As to the negative effect of transport inhibition on post-ischaemic cardiac recovery, there is insufficient evidence now that adenosine does not serve as a precursor to replenish the nucleotide pool upon reperfusion. Adenosine’s benefit indeed entirely stems from its triggering many receptors. The fate of adenosine, once produced in ischaemic myocardium, is determined by catabolism inside endothelial cells and erythrocytes (adenosine deaminase is an intracellular, cytosolic enzyme) and inhibition of the transport process which mediates uptake (= catabolism) will lead to prolonged accumulation (Van Belle, 1993).