In Vivo and in Vitro Evidence of an Adenosine-Mediated Mechanism of Calcium Entry Blocker Activities

Abstract

Drugs such as dipyridamole (200 μg/kg/min), an adenosine uptake in hibitor, and theophylline (300 μg/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hypere mia in normal subjects, as well as in POAD patients. Moreover, dipyrida mole pretreatment was able to antag onize the reduction of peak flow in duced by nifedipine, and the potenti ating effect of flunarizine on postis chemic hyperemia was affected sig nificantly by theophylline, thus sug gesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes — PMN) the inhibitory ef fect of calcium entry blockers on stimulated functions (degranulation and free radical production) was highly antagonized by theophylline. Finally, a ¹H-NMR spectroscopy study showed a binding interaction between adenosine and flunarizine on the cell membrane. An adenosine-re ceptor coupling to the calcium entry blocker channels is suggested.