Nucleoside transport inhibition and fMLP-stimulated whole blood luminescence.

Abstract Adenosine (ADO) 1 has a pharmacological profile which makes it an interesting ‘drug’ to handle many of the problems arising with ischemia and reperfusion [for references see 4 ]. In human blood, however, it is rapidly taken up by the red blood cells and metabolized to inactive inosine and hypoxanthine. This transporter-mediated uptake can be specifically inhibited in vitro by a few drugs, known as nucleoside transport inhibitors. It has been reported that ADO can inhibit platelet aggregation in whole blood in the presence of dipyridamole [ 2 ], and it is well-known that ADO can inhibit the respiratory burst of purified neutrophils induced by certain stimuli [ 1 ]. We investigated the effect of some of these drugs on the ADO-mediated inhibition of the fMLP-induced respiratory burst in neutrophils (as measured by lucigenin-enhanced luminescence [ 3 ]), in undiluted whole blood. The combination of R 75 231 (a newly developed analog of mioflazine, with unique pharmacokinetic properties, for details see [ 5 ]) with ADO (0.1 μ m ) inhibited the luminescence by 40 ± 4% ( n = 10), while either R 75 231 or ADO alone did not affect the response to fMLP. In the presence of ADO (1 μ m ), R 75 231 (EC 50 = 1.9 ± 0.3 × 10 −7 m ) ( n = 3) was almost as potent as dilazep (EC 50 = 1.1 ± 0.2 × 10 −7 m ) ( n = 3), but far more potent than dipyridamole (EC 50 = 1.2 ± 0.2 × 10 −6 m ) ( n = 3). The present data show that ADO can inhibit PMN-activation in whole blood in the presence of R 75 231 or of other nucleoside transport inhibitors. This suggests that ADO, whenever produced locally, as during cardiac ischemia [ 6 ], may exert its biological effects in the presence of effective nucleoside transport inhibition.