Diadenosine pentaphosphate vasodilates the forearm vascular bed: Inhibition by theophylline and augmentation by dipyridamole

Background In rats, diadenosine pentaphosphate (AP 5 A) has been implicated in the pathogenesis of essential hypertension. This study describes for the first time the vasomotor action of AP 5 A in humans by means of the “perfused forearm technique.” Results AP 5 A evoked a dose‐dependent forearm vasodilator response equal to that of adenosine but less than that of adenosine triphosphate (ATP) at equimolar doses. The P 1 ‐purinoceptor antagonist theophylline (0.28 μmol/min per deciliter) reduced the percentage decrease in forearm vascular resistance (FVR) to AP 5 A (0.6, 6, and 20 nmol/min/dL): −8% ± 6%, −50% ± 6%, and −68% ± 4% during saline solution versus −7% ± 4%, −33% ± 5%, and −45% ± 6% during theophylline (mean ± standard error [SE]; ANOVA for repeated measures; P < .05 for the interaction between purine dose and theophylline; n = 10). An inhibitor of equilibrative nucleoside transport, dipyridamole (7.4 nmol/min per deciliter), augmented the AP 5 A (0.6 and 6 nmol/min per deciliter)‐induced reduction in FVR as follows: −34% ± 6% and −67% ± 5% during saline versus −49% ± 5% and −80% ± 3% during dipyridamole ( P < .05 for the effect of dipyridamole; n = 6). The bivalent cation chelator ethylenediaminetetra‐acetic acid (EDTA) inhibited the rapid degradation of AP 5 A in vitro. In vivo, the highest tolerated intra‐arterial EDTA dose was not sufficient to inhibit AP 5 A metabolism. Conclusion Intra‐arterial AP 5 A caused a dose‐dependent reduction in FVR. This is, at least in part, mediated by its degradation product adenosine. The data do not support an in vivo vasoconstrictor action of AP 5 A, and as such AP 5 A does not seem likely to contribute to the pathogenesis of primary hypertension in humans. Clinical Pharmacology & Therapeutics (2002) 71 , 448–456; doi: 10.1067/mcp.2002.124469