Long Yuan, Fu Cai-Yun, Tian Xiao-Zhu, Chen Juan, Han Min, Wang Rui
Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Institute of Biochemistry and Molecular Biology, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, PR China.
Eur J Pharmacol. 2007 Aug 13;569(1-2):119-25. doi: 10.1016/j.ejphar.2007.04.049. Epub 2007 May 22.
Rat and mouse hemokinin-1(r/m hemokinin-1) is a recently described member of the tachykinin family whose cardiovascular functions are not fully understood. In this study, we investigated the mechanisms of the relaxing response induced by r/m hemokinin-1 in isolated porcine coronary arteries by using a specific antagonist of tachykinin NK(1) receptor (SR140333), a nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (L-NNA), and 1H-[1,2,4] Oxadiazolo [4,3-a] quinoxalin-1-one (ODQ), a blocker of cGMP production. r/m Hemokinin-1 (10(-12)-10(-6 )M) evoked a marked endothelium-dependent vasodilatation (E(max)=121.12+/-10.6% and 91.79+/-2.39% in 10(-6) M PGF(2)alpha and 30 mM KCl precontracted arterial rings, respectively) of coronary arteries mediated by activation of endothelial tachykinin NK(1) receptors. Two components contributed to this r/m hemokinin-1-elicited vasodilatation, the first of which was endothelium-derived hyperpolarizing factor (EDHF), which played a major role. This EDHF was identified as a potassium current through certain kinds of potassium channels on the endothelial cell membrane of porcine coronary arteries. Specific antagonists of Ca(2+)-activated K(+) channels (dequalinium and clotrimazole) did not have an inhibitory effect on the r/m hemokinin-1-induced vasodilatation, whereas they did on the substance P-induced vasodilatation. When potassium ion efflux was impaired by a high K(+) concentration (30 mM) or removal of K(+) from the surroundings, NO synthesis was triggered by r/m hemokinin-1 to produce an equivalent EDHF (K(+))-independent vasorelaxation as a compensatory mechanism.
大鼠和小鼠的血管活性肠肽-1（r/m血管活性肠肽-1）是速激肽家族中最近被描述的成员，其心血管功能尚未完全明了。在本研究中，我们通过使用速激肽NK(1)受体的特异性拮抗剂（SR140333）、一氧化氮合酶抑制剂N(ω)-硝基-L-精氨酸（L-NNA）以及cGMP生成阻滞剂1H-[1,2,4]恶二唑并[4,3-a]喹喔啉-1-酮（ODQ），研究了r/m血管活性肠肽-1在离体猪冠状动脉中诱导舒张反应的机制。r/m血管活性肠肽-1（10(-12)-10(-6 )M）引起了明显的内皮依赖性血管舒张（在分别用10(-6) M前列腺素F2α和30 mM氯化钾预收缩的动脉环中，E(max)分别为121.12±10.6%和91.79±2.39%），这是由内皮速激肽NK(1)受体激活介导的冠状动脉舒张。两个因素促成了这种r/m血管活性肠肽-1引起的血管舒张，其中第一个是内皮衍生的超极化因子（EDHF），它起主要作用。这种EDHF被确定为通过猪冠状动脉内皮细胞膜上某些种类钾通道的钾电流。钙激活钾通道的特异性拮抗剂（地喹氯铵和克霉唑）对r/m血管活性肠肽-1诱导的血管舒张没有抑制作用，而对P物质诱导的血管舒张有抑制作用。当高钾浓度（30 mM）或去除周围环境中的钾离子损害钾离子外流时，r/m血管活性肠肽-1会触发一氧化氮合成，以产生同等的不依赖EDHF（钾离子）的血管舒张作为一种补偿机制。
