In vivo and in vitro evidence of an adenosine-mediated mechanism of calcium entry blocker activities.
Drugs such as dipyridamole (200 micrograms/kg/min), an adenosine uptake inhibitor, and theophylline (300 micrograms/kg/min), an adenosine receptor antagonist, respectively increased and decreased postischemic hyperemia in normal subjects, as well as in POAD patients. Moreover, dipyridamole pretreatment was able to antagonize the reduction of peak flow induced by nifedipine, and the potentiating effect of flunarizine on postischemic hyperemia was affected significantly by theophylline, thus suggesting a possible interference of calcium entry blocker drugs with the endogenous adenosine system. In a cellular model (polymorphonuclear leukocytes--PMN) the inhibitory effect 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-receptor coupling to the calcium entry blocker channels is suggested.
Di Perri
T
T
Istituto di Patologia Speciale Medica, Universita degli Studi di Siena, Italy.
Pasini
F L
FL
Pecchi
S
S
De Franco
V
V
Damiani
P
P
Pasqui
A L
AL
Capecchi
P L
PL
Orrico
A
A
Materazzi
M
M
Domini
L
L
D000241:Adenosine / Q000494:pharmacology* / Q000502:physiology; D001157:Arterial Occlusive Diseases / Q000503:physiopathology*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology; D005260:Female; D005444:Flunarizine / Q000494:pharmacology; D006801:Humans; D007383:Intermittent Claudication / Q000503:physiopathology; D007866:Leg / Q000098:blood supply*; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D013481:Superoxides / Q000378:metabolism; D013806:Theophylline / Q000494:pharmacology
D002121:Calcium Channel Blockers; D013481:Superoxides; D004176:Dipyridamole; D013806:Theophylline; D000241:Adenosine; D005444:Flunarizine