Qi R, Ozaki Y, Satoh K, Yang L B, Asazuma N, Yatomi Y, Kume S
Department of Clinical and Laboratory Medicine, Yamanashi Medical University, Japan.
J Cardiovasc Pharmacol. 1996 Aug;28(2):215-22. doi: 10.1097/00005344-199608000-00006.
We investigated the effects on human platelet aggregation of several agents that increase either intracellular cyclic AMP or cyclic GMP, using a platelet aggregometer that allows quantification of the size and number of platelet aggregates. During the initial phase of aggregation induced by epinephrine and ADP, small aggregates consisting of < 100 cells predominated; large aggregates formed later. Prostaglandin I2 (PGI2), which increases intracellular cyclic AMP, suppressed the formation of small as well as large aggregates induced by epinephrine, with ID50 values of 10.7 +/- 2.8 and 3.8 +/- 0.5 nM, respectively. ADP-induced formation of small and large aggregates was also inhibited by PGI2, with similar ID50 values. Dibutyryl cyclic AMP (db cyclic AMP), a cell-permeant form of cyclic AMP, also inhibited small and large aggregate formation induced by epinephrine or ADP, with ID50 values of 420-560 microM for small aggregates and 139-166 microM for large aggregates, respectively. On the other hand, nitroprusside, which increases intracellular cyclic GMP, inhibited only the formation of large aggregates, with an ID50 value of 454 +/- 191 nM for epinephrine-induced activation and of 2.1 +/- 0.6 microM for ADP-induced activation. Nitroprusside at 1 mM did not affect the formation of small aggregates induced by epinephrine, whereas that of large aggregates was completely blocked at 10 microM. 8-Bromo cyclic GMP (8-br cyclic GMP) also inhibited only the formation of large aggregates, with ID50 values of 140-170 microM, but not that of small aggregates induced by epinephrine and ADP. Milrinone, which increases the intracellular level of both cyclic AMP and cyclic GMP, suppressed the formation of small and large aggregates induced by epinephrine and ADP. These findings suggest that cyclic AMP and cyclic GMP differentially modify the size of aggregates formed during epinephrine or ADP activation.
我们使用一种能够对血小板聚集体的大小和数量进行量化的血小板聚集仪，研究了几种可增加细胞内环磷酸腺苷（cAMP）或环磷酸鸟苷（cGMP）的药物对人血小板聚集的影响。在由肾上腺素和二磷酸腺苷（ADP）诱导的聚集初始阶段，主要是由少于100个细胞组成的小聚集体；大聚集体随后形成。增加细胞内cAMP的前列腺素I2（PGI2）抑制了由肾上腺素诱导的小聚集体和大聚集体的形成，其半数抑制浓度（ID50）值分别为10.7±2.8 nM和3.8±0.5 nM。PGI2也抑制了由ADP诱导的小聚集体和大聚集体的形成，ID50值相似。二丁酰环磷酸腺苷（db cAMP），一种可穿透细胞的cAMP形式，也抑制了由肾上腺素或ADP诱导的小聚集体和大聚集体的形成，小聚集体的ID50值为420 - 560 μM，大聚集体的ID50值为139 - 166 μM。另一方面，增加细胞内cGMP的硝普钠仅抑制大聚集体的形成，对肾上腺素诱导的激活，其ID50值为454±191 nM，对ADP诱导的激活，ID50值为2.1±0.6 μM。1 mM的硝普钠不影响由肾上腺素诱导的小聚集体的形成，而10 μM时大聚集体的形成则被完全阻断。8 - 溴环磷酸鸟苷（8 - br cGMP）也仅抑制大聚集体的形成，ID50值为140 - 170 μM，但不抑制由肾上腺素和ADP诱导的小聚集体的形成。米力农可增加细胞内cAMP和cGMP的水平，抑制了由肾上腺素和ADP诱导的小聚集体和大聚集体的形成。这些发现表明，cAMP和cGMP对肾上腺素或ADP激活过程中形成的聚集体大小有不同的调节作用。
