Nucleoside transport inhibition and fMLP-stimulated whole blood luminescence

Adenosine (ADO) has a pharmacological profile which makes it an interesting 'drug' to handle many of the problems arising with ischemia and reperfusion. 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, and it is well-known that ADO can inhibit the respiratory burst of purified neutrophils induced by certain stimuli. 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), in undiluted whole blood. The combination of R 75,231 (a newly developed analog of mioflazine, with unique pharmacokinetic properties, for details see with ADO (0.1 microM) 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 microM), R 75,231 (EC50 = 1.9 +/- 0.3 x 10(-7) M) (n = 3) was almost as potent as dilazep (EC50 = 1.1 +/- 0.2 x 10(-7) M) (n = 3), but far more potent than dipyridamole (EC50 = 1.2 +/- 0.2 x 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.(ABSTRACT TRUNCATED AT 250 WORDS)