LUNAM Université, Oniris, UPSP 5304 de physiopathologie animale et de pharmacologie fonctionnelle, Atlanpole La Chantrerie, BP 40706, Nantes F-44307, France.
Vet J. 2012 Jun;192(3):368-73. doi: 10.1016/j.tvjl.2011.09.005. Epub 2011 Oct 8.
The direct vasodilatory action of pentoxifylline (1-(5-oxohexyl)-3,7-dimethylxanthine) and its signalling pathway was evaluated in equine digital veins. Cumulative concentration-response curves to pentoxifylline (1 nM to 300 μM) were recorded in phenylephrine-precontracted equine digital vein rings under different experimental conditions. Relaxation to pentoxifylline was partially inhibited by endothelium removal, but was unaltered by CGS-15943 (a non-xanthine adenosine receptor antagonist; 3 μM). Nitric oxide synthase (NOS), soluble guanylate cyclase and cyclooxygenase (COX) inhibitors (Nω-nitro-L-arginine methyl ester (100 μM), ODQ (30 μM) and indomethacin (10 μM), respectively) significantly reduced the maximum relaxation induced by pentoxifylline. Moreover, pentoxifylline-induced relaxation was strongly reduced by Rp-8-Br-PET-cyclic guanosine monophosphate-S (a protein kinase G inhibitor; 3 μM), but remained unaffected by H-89 (a protein kinase A inhibitor; 2 μM). Pentoxifylline-induced relaxation was associated with a 3.4-fold increase in tissue cGMP content. To investigate whether pentoxifylline can affect cAMP- and cGMP-mediated relaxations, curves to forskolin, to sodium nitroprusside (SNP) and 8-bromo-cGMP were also recorded in endothelium-denuded equine digital vein rings pretreated with pentoxifylline (10 and 100 μM). Pentoxifylline only potentiated the SNP-mediated relaxation at the highest concentration (100 μM). Thus, pentoxifylline relaxed equine digital veins via endothelium-dependent and endothelium-independent components. The effect was mediated through both the NOS and COX pathways and could also result from inhibition of cGMP specific-phosphodiesterase activity at the highest concentrations used.
己酮可可碱（1-（5-氧代己基）-3,7-二甲基黄嘌呤）的直接血管舒张作用及其信号通路在马的数字静脉中进行了评估。在不同的实验条件下，记录了在苯肾上腺素预收缩的马数字静脉环中，对己酮可可碱（1 nM 至 300 μM）的累积浓度-反应曲线。内皮细胞去除部分抑制了对己酮可可碱的舒张作用，但对 CGS-15943（非黄嘌呤腺嘌呤受体拮抗剂；3 μM）无影响。一氧化氮合酶（NOS）、可溶性鸟苷酸环化酶和环氧化酶（COX）抑制剂（Nω-硝基-L-精氨酸甲酯（100 μM）、ODQ（30 μM）和吲哚美辛（10 μM））显著降低了己酮可可碱诱导的最大舒张作用。此外，己酮可可碱诱导的舒张作用被 Rp-8-Br-PET-环鸟苷单磷酸-S（蛋白激酶 G 抑制剂；3 μM）强烈抑制，但不受 H-89（蛋白激酶 A 抑制剂；2 μM）的影响。己酮可可碱诱导的舒张作用与组织 cGMP 含量增加 3.4 倍有关。为了研究己酮可可碱是否可以影响 cAMP 和 cGMP 介导的舒张作用，还在己酮可可碱预处理（10 和 100 μM）的去内皮马数字静脉环中记录了福司可林、硝普钠（SNP）和 8-溴-cGMP 的曲线。己酮可可碱仅在最高浓度（100 μM）时增强 SNP 介导的舒张作用。因此，己酮可可碱通过内皮依赖性和非依赖性成分舒张马的数字静脉。该作用是通过 NOS 和 COX 途径介导的，也可能是由于在最高浓度下抑制 cGMP 特异性磷酸二酯酶活性所致。
