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

Abstract

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.

Carnitines Increase Plasma Levels of Adenosine and ATP in Humans

“…and of myocytes.Pv'" The biologic significance of extracellular adenosine increase is related to its local vasodilating and tissue-protecting properties during ischaemia and inflammatory reactions. 24,25,36,37,41,42 Moreover, adenosine regenerates the intracelIular adenine nucleotide pool after membrane uptake.P Restoration of intracellular ATP content helps preservation of cell viability during ischaemia and reperfusion. ":" ATP also contributes to endothelium-dependent vasodilation during ischaemic events."…”

Cyclosporin and tacrolimus increase plasma levels of adenosine in kidney transplanted patients

“…The ADO increase may be of pharmacological interest since following CsA and FK506 administration, ADO reaches values high enough to be of physiological relevance [36,37]. The biological significance of extracellular ADO increase is related to its vasodilating and tissue protecting properties during ischaemia and inflammatory reactions [36–43], mediated by the interaction with four specific membrane receptors, termed A1, A2A, A2B and A3 [18,44,45]. Moreover, ADO is also provided with natural immunosuppressive activities including inhibition of cytokine release, namely tumor necrosis factor (TNF)‐ α , interleukin (IL)‐2 and IL‐6 [14,15,17,18,46,47].…”

Dipyridamole inhibits intracellular calcium transients in isolated rat arteriole smooth muscle cells

“…In the present study, we further demonstrated that, in the presence of adenosine, an ATP-induced [Ca 2+ ]i response was observed in arteriole smooth muscle cells -although this reaction was partially inhibited. Because adenosine A1 receptors mediate the inhibition of L-type Ca 2+ channels (Di Perri et al, 1989;Rocher et al, 1999), the effects of dipyridamole on resistance vessels may be partly explained by the potentiation of adenosine mechanisms rather than the potentiation of NO or other cGMP-mediated actions (Gamboa et al, 2005).…”