全反式维甲酸对大鼠肠系膜动脉的舒张作用及其机制

Effects of all-trans retinoic acid and its mechanisms on rat mesenteric artery

目的观察全反式维甲酸(ATRA)对阻力血管的舒张效应并探讨其相关机制。方法采用离体微血管张力测定系统,取健康雄性SpragueDawley(SD)大鼠肠系膜动脉随机分为:内皮完整ATRA处理组(n=8)、内皮去除后ATRA处理组(n=5)以及溶剂对照组(n=8),观察ATRA(1×10-8至3×10-6mol/L)对苯肾上腺素(PE,1×10-5mol/L)预收缩血管的影响。分别以左旋单甲基精氨酸(l-NMMA,1×10-5mol/L,n=4)、可溶性鸟苷酸环化酶(sGC)特异性拮抗剂(ODQ,1×10-5mol/L,n=5)及钾离子通道拮抗剂[4氨基吡啶(1×10-4mol/L)、格列苯脲(1×10-5mol/L)、蜂毒明肽+蝎毒素(1×10-5mol/L),n=6]孵育血管环30min,观察ATRA对血管的反应以进一步探讨其作用机制。结果在内皮完整肠系膜动脉上,ATRA呈浓度依赖性地降低PE(1×10-5mol/L)预收缩的肠系膜动脉环的张力;与内皮完整ATRA处理组比较,去内皮后ATRA最大舒张效应明显减弱[(17.1±6.7)%比(65.5±10.9)%,P<0.05]。l-NMMA、ODQ或蜂毒明肽+蝎毒素孵育后明显降低ATRA的舒血管作用,而4氨基吡啶和格列苯脲对ATRA舒血管作用影响不大。结论 ATRA能舒张由PE引起的血管收缩。其舒张机制可能是通过血管内皮细胞产生一氧化氮,进而活化下游的sGC,促使环磷酸鸟苷合成增加而激活平滑肌细胞上的KCa通道,导致细胞膜超极化从而抑制平滑肌细胞中游离Ca2+浓度的升高。

Objective To investigate the relaxation effect of all-trans retinoic acid （ATRA} and its related mecha- nisms on the resistance vessel. Methods The mesenteric arteries of health male Sprague Dawley { SD） rats were randomly divided into three groups： ATRA treated group with intact endothelium （n ~ 8 }, ATRA treated group with denuded endothelium （n= 5） and solvent control group （n~ 8}; Than evaluate the effects of ATRA （1 X 10-a to 3 X 10-6 mol/L} on phenylephedrine { PE, 1 X 10-s mol/L} pre-vasoconstriction by in vitro microvascular tesion measurement system. Arterial rings were respectively incubated for 30 minutes with nitric oxide inhibitor： N（G）-monomethyl-l-arginine （/-NMMA, 1 ~ 10-5 mol/L, n = 4 }, soluble Guanylyl Cyclase （ sGC） specificity inhibi- tor （ODQ, 1 X 10-5 mol/L, n= 5） and different types of potassium inhibitors such as 4-aminopyridine { 1 10-4 mol/L）, glibenclamide （1~ 10-s tool/L） and charybdotoxin plus apamin （1 X 10-5 tool/L, n= 6}. The effects of ATRA on vessel were observed and its mechanisms were investigated. Results ATRA caused concentration-dependent re- laxation on endothelium-intact mesenteric arterial rings pre-contracted by PE （1 ~ 10-＇ mol/L}. Compared with ATRA treated group with intact endothelium, the maximal relaxant effect of ATRA was significantly weakened after the removal of endothelium [ （ 1 7. 1 =J= 6.7 ） ~/00 vs （ 65.5 _＋ 10. 9 ） %, P^0. 05]. The vasodilation effect of ATRA was evidently reduced after being incubated with I-NMMA, ODQ and charybdotoxin plus apamin, while 4-aminopyridine and glibenclamide didn＇t have the same effect. Conclusions The vessel contraction caused by PE can be eased by ATRA. Its diastolic mechanism may be related to the nitric oxide production in vessel endothelia cell which acti- vates the sGC, accelerates the synthesis of cyclic guanosine monophosphate {cGMP} to activate the Kc, channel in smooth musclce cells which leads to cvtomembrane hvDerDolarization, and eventually restrains the accumulation of free Ca2＋ in smooth musclce cells.