ENDOTHELIUM-DEPENDENT AND INDEPENDENT RELAXATION OF THE RAT AORTA BY CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS
ENDOTHELIUM-DEPENDENT AND INDEPENDENT RELAXATION OF THE RAT AORTA BY CYCLIC-NUCLEOTIDE PHOSPHODIESTERASE INHIBITORS
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DOI：
10.1111/j.1476-5381.1991.tb12457.x
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发表时间：
1991-10-01
影响因子：
7.3
通讯作者：
STOCLET, JC
中科院分区：
文献类型：
--
作者：
KOMAS, N;LUGNIER, C;STOCLET, JC
1研究选择性腺苷3‘：5’-环一磷酸(CAMP)和鸟苷3‘：5’-环一磷酸(CGMP)磷酸二酯酶(PDE)的选择性抑制剂对分离的大鼠主动脉环的作用以及对去甲肾上腺素(1-mU-M)预收缩的大鼠主动脉环的松弛作用。2用DEAE-Seacel柱层析从去内皮的大鼠主动脉中分离出四种PDE形式：一种优先水解环GMP的PDE(PDE I)，两种环AMP PDE(PDE III和PDE IV)和一种环GMP特异性PDE(PDE V)。后者可被扎普司特选择性而有效地抑制。两种环状AMP PDE被特异性抑制剂区分：一种被环鸟苷酸(PDEⅢ)和新的强心剂(米力农、CI 930、LY 195115和SK&F 94120)抑制，另一种被布非林和罗利普兰(PDE IV)抑制。这些药物均不能显著抑制PDE I。3 PDE III抑制剂可引起大鼠主动脉环非内皮依赖性松弛，其EC50值(产生50%松弛的MU-M浓度)如下：LY 195115：3.4，米力农：5.7，CI 930；7.8，SK&F 94120：14.7。N(G)-单甲基-L-精氨酸(L-NMMA，300mU-M)和L-精氨酸(1 MM)均不影响PDE III抑制剂的作用。然而，除化合物CI 930.4外，可溶性鸟苷环化酶抑制剂亚甲蓝(10-mU-M)均可阻断PDEⅢ类抑制剂引起的内皮依赖性松弛，其作用可被L和亚甲蓝(10-mU-M)所抑制。在L-NMMA存在下，通过随后添加L-精氨酸来恢复松弛。5在刺激腺苷环化酶(Forsklin和异丙肾上腺素)或可溶性鸟苷环化酶(硝普钠，SNP)或抑制PDE III(米力农)的药物存在下，研究了登布福林和罗利普兰的松弛作用。在去内皮的环上，米力农(EC50值分别为1.7和12mU-M)或SNP(EC50值分别为12.3和124mU-M)均有舒缩效应，而Forsklin和异丙肾上腺素则无此作用。然而，在有功能内皮存在的情况下，Forskolin、异丙肾上腺素、米力农和SNP显著增强PDE IV抑制剂产生的松弛(登布菲林的EC50值分别为2、2、0.4和0.7 mU-M，罗利普兰的EC50值分别为7、13、7和1.2 mU-M)。6这些结果表明，环状GMP提高剂和PDE III抑制剂米力农显著增强环状AMP特异性PDE IV抑制剂的松弛效应。他们支持这样的假设，即环状GMP增强环状AMP介导的松弛，可能是通过抑制环状GMP抑制的PDE III。
1 The effects of selective inhibitors of adenosine 3':5'-cyclic monophosphate (cyclic AMP) and guanosine 3':5'-cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1-mu-M) precontracted rat aortic rings, with and without functional endothelium.2 Four PDE forms were isolated by DEAE-sephacel chromatography from endothelium-denuded rat aorta: a calmodulin-activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP-specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I.3 The PDE III inhibitors caused endothelium-independent relaxations of rat aortic rings with the following EC50 values (mu-M concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither N(G)-monomethyl-L-arginine (L-NMMA, 300-mu-M), an inhibitor of the L-arginine-NO pathway, nor L-arginine (1 mM) modified the effect of PDE III inhibitors. However, methylene blue (10-mu-M) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930.4 The specific PDE IV and PDE V inhibitors both produced endothelium-dependent relaxations which were inhibited by L-NMMA and by methylene blue (10-mu-M). In the presence of L-NMMA, relaxation was restored by subsequent addition of L-arginine.5 The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium-denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC50 values 1.7 and 12-mu-M, respectively) or SNP (EC50 values 12.3 and 124-mu-M, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7-mu-M and for rolipram: 7, 13, 7 and 1.2-mu-M).6 These results indicate that the relaxant effects of inhibitors of the cyclic AMP-specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP-mediated relaxation, possibly through the inhibition of the cyclic GMP-inhibited PDE III.