Michel H, Caen J P, Born G V, Miller R, D'Auriac G A, Meyer P
Br J Haematol. 1976 May;33(1):27-38. doi: 10.1111/j.1365-2141.1976.tb00969.x.
Adenosine inhibits the aggregation of human but not of rat platelets whereas both are inhibited by prostaglandin E1 or by the pyrimido-pyrimidine compound RA233. In human platelets all three agents increase adenosine-3'-5'-cyclic monophosphate (cAMP). If the inhibition of aggregation depended on this increase, adenosine might be expected not to increase cAMP in rat platelets. Under conditions in which adenosine inhibited aggregation and increased cAMP in human platelets, adenosine caused a similar increase in cAMP in rat platelets without inhibiting their aggregation. The aggregation of rat platelets was inhibited as effectively as that of human platelets by PGE1 or RA233 at concentrations which caused greater increases in cAMP than did the highest concentrations (2.8 X 10(-4) M) of adenosine it was possible to use. When the increase of cAMP in rat platelets by PGE1 was limited to that produced by adenosine, PGE1 like adenosine failed to inhibit aggregation. Therefore, the difference in the inhibitory effectiveness of adenosine on rat and human platelets was quantitative rather than qualitative and apparently depended on the inability of adenosine to increase cAMP sufficiently in rat platelets. When cAMP had been increased by adenosine, PGE1 or RA233, the addition of ADP caused cAMP to decrease rapidly in both human and rat platelets to between +22 and -18% of control values, except that the decrease in rat platelets was to +40% after RA233 had been present for 0.5 min before ADP. The increase in cAMP produced in rat platelets by adenosine at 5 X 10(-6) to 2.8 X 10(-4) M for 3 min was associated with a small increase in aggregation velocity. It is suggested that the comparative ineffectiveness of adenosine as an inhibitor of platelet aggregation, particularly with rat but less so also with human platelets, is because, unlike PGE1 or RA233, adenosine has two opposing actions on aggregation; one being inhibition by activating adenylate cyclase and increasing cAMP, and the other being potentiation by uptake. This hypothesis accounts for the present results as well as for the earlier observation that dipyridamole which prevents the uptake of adenosine potentiates its inhibitory effect on the aggregation of human platelets.
腺苷可抑制人血小板的聚集，但对大鼠血小板无此作用，而前列腺素E1或嘧啶并嘧啶化合物RA233则可抑制两者的血小板聚集。在人血小板中，这三种物质均可使腺苷-3'-5'-环磷酸（cAMP）增加。如果聚集的抑制取决于这种增加，那么腺苷在大鼠血小板中可能不会使cAMP增加。在腺苷抑制人血小板聚集并使其cAMP增加的条件下，腺苷在大鼠血小板中也引起了类似的cAMP增加，但并未抑制其聚集。前列腺素E1或RA233在导致cAMP升高幅度大于腺苷所能使用的最高浓度（2.8×10⁻⁴M）的浓度下，对大鼠血小板聚集的抑制效果与人血小板一样有效。当前列腺素E1使大鼠血小板中cAMP的增加量限制在腺苷所产生的增加量时，前列腺素E1和腺苷一样无法抑制聚集。因此，腺苷对大鼠和人血小板抑制效果的差异是定量的而非定性的，显然取决于腺苷在大鼠血小板中无法充分增加cAMP。当cAMP因腺苷、前列腺素E1或RA233而增加后，加入二磷酸腺苷（ADP）会使人和大鼠血小板中的cAMP迅速下降至对照值的+22%至 -18%之间，只是在RA233在ADP加入前0.5分钟存在的情况下，大鼠血小板中的cAMP下降至+40%。腺苷在5×10⁻⁶至2.8×10⁻⁴M浓度下作用3分钟使大鼠血小板中产生的cAMP增加与聚集速度的小幅增加有关。有人提出，腺苷作为血小板聚集抑制剂相对无效，特别是对大鼠血小板，对人血小板的作用稍弱，是因为与前列腺素E1或RA233不同，腺苷对聚集有两种相反的作用；一种是通过激活腺苷酸环化酶和增加cAMP来抑制，另一种是通过摄取来增强。这一假设解释了目前的结果以及早期的观察结果，即双嘧达莫可阻止腺苷摄取，从而增强其对人血小板聚集的抑制作用。
