Rp diastereomeric analogs of cAMP inhibit both cAMP- and cGMP-induced dilation of hamster mesenteric small arteries.
Rp diastereomeric analogs of cAMP inhibit both cAMP- and cGMP-induced dilation of hamster mesenteric small arteries.
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cAMP 的 Rp 非对映体类似物抑制 cAMP 和 cGMP 诱导的仓鼠肠系膜小动脉扩张。
DOI：
10.1159/000139387
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发表时间：
1996
期刊：
影响因子：
3.1
通讯作者：
Jackson,WF
中科院分区：
文献类型：
--
作者：
Jackson,WF
在血管平滑肌中，腺苷（3 '，5'-环一磷酸）（cAMP）和鸟苷（3 '，5'-环一磷酸）（cGMP）信号传导途径之间可能发生串扰，使得cAMP可能通过cGMP依赖性蛋白激酶而不是cAMP依赖性蛋白激酶起作用，以诱导该组织的松弛。因此，假设由于这种串扰，cAMP的竞争性拮抗剂在抑制cAMP或cGMP诱导的血管舒张中可能没有显示出很大的选择性。为了验证这一假设，cAMP的Rp-非对映体硫代磷酸酯衍生物，cAMP依赖性蛋白激酶的cAMP的推定竞争性拮抗剂，对由cAMP的Sp-硫代磷酸酯衍生物，二丁酰cAMP，8-Br cGMP和硝普钠诱导的血管舒张的影响进行了评估。肠系膜动脉（200-400 µm i.d.）插管并加压至75 mm Hg，并用1 µmol/l苯乙醯胺收缩至最大值的50%。然后以累积方式加入血管扩张剂，并在不存在和存在（Rp）-腺苷（3 '，5'-环硫代磷酸）（Rp cAMP）或（Rp）-8-（对氯苯硫基）腺苷（3 '，5'-环硫代磷酸）（Rp 8 CPT cAMP）的情况下记录直径反应。Rp cAMPs（0.1-0.5 mmol/l）抑制cAMP激动剂（Sp）-腺苷（3 '，5'-环硫代单磷酸）（Sp cAMPs）和二丁酰cAMP诱导的舒张，但也抑制8-Br cGMP和硝普钠诱导的舒张（< 0.05 and n >均为p 4）。在一项更详细的研究中，我们发现Rp 8 CPT cAMPs（0.025-0.25 mmol/l）竞争性抑制Sp 8 CPT cAMPs和8-BR cGMP诱导的扩张，效力相同：Rp 8 CPT cAMPs对Sp 8 CPT cAMPs的pA 2（3.6 ± 1.2）与Rp 8 CPT cAMPs对8-Br cGMP的pA 2（4.1 ± 1.2）相似（p > 0.05，d.f.）。= 37）。这些数据支持cAMP和cGMP均通过共同的蛋白激酶起作用以引起血管舒张的假设，并敦促谨慎使用环核苷酸的Rp-非对映体类似物来剖析血管中的特定信号转导途径。
Cross talk between the adenosine (3’,5’-cyclic monophosphate) (cAMP) and the guanosine (3’,5’-cyclic monophosphate) (cGMP) signalling pathways in vascular smooth muscle may occur such that cAMP may act through cGMP-dependent protein kinase rather than cAMP-dependent protein kinase to induce relaxation of this tissue. Therefore, it was hypothesized that due to this crosstalk, competitive antagonists of cAMP may not show much selectivity in inhibition of cAMP- or cGMP-induced vasodilation. To test this hypothesis, the effects of Rp-diastereomeric phosphorothioate derivatives of cAMP, putative competitive antagonists of cAMP at cAMP-dependent protein kinase, were assessed on vasodilation induced by Sp-phosphorothioate derivatives of cAMP, dibutyryl cAMP, 8-Br cGMP and sodium nitroprusside. Hamster mesenteric arteries (200–400 µm i.d.) were cannulated and pressurized to 75 mm Hg and constricted to ∼50% of maximum with 1 µmol/l phenylephrine. Vasodilators were then added in cumulative fashion and diameter responses recorded in the absence and presence of (Rp)-adenosine (3’,5’-cyclic monophos-phorothioate) (Rp cAMPs) or (Rp)-8-(parachlorophenylthio) adenosine (3’,5’-cyclic monophosphorothioate) (Rp 8CPT cAMPs). Rp cAMPs (0.1-0.5 mmol/l) inhibited dilations induced by the cAMP agonists, (Sp)-adenosine (3’,5’-cyclic monophosphorothioate) (Sp cAMPs) and dibutyryl cAMP, but also inhibited dilations induced by 8-Br cGMP and sodium nitroprusside (p < 0.05 and n > 4 for all). In a more detailed study we found that Rp 8CPT cAMPs (0.025-0.25 mmol/l) competitively inhibited dilations induced by both Sp 8CPT cAMPs and 8-BR cGMP with equal potency: the pA2for Rp8 CPT cAMPs against Sp 8CPT cAMPs (3.6 ± 1.2) was similar to the pA2for Rp 8CPT cAMPs against 8-Br cGMP (4.1 ± 1.2) (p > 0.05, d.f. = 37). These data support the hypothesis that both cAMP and cGMP act through a common protein kinase to cause vasodilation and urge caution in the use of Rp-diastereomeric analogs of cyclic nucleotides to dissect out specific signal transduction pathways in blood vessels.