钾通道开放剂KRN_(4884)对猪冠状微血管内皮源性超极化因子介导松弛的影响

Effects of Potassium Channel Opener KRN_(4884) on EDHF-mediated Relaxation in Porcine Coronary Micro-arteries

目的:高钾溶液能够减少血管内皮源性超极化因子(EDHF)介导的舒张,本研究拟观察ATP敏感的钾通道开放剂KRN4884(ATP-SPCOs)能否影响经高钾溶液孵育后的猪冠状微动脉中EDHF介导的舒张。方法:将猪冠状微动脉血管段(200-450μm)固定于肌张力描记装置的器官小室中,37℃下以高钾溶液(K+20 mmol/L)孵育1 h后,用血栓素类似物(U46619)收缩血管,在环氧化酶抑制剂吲哚美辛(INDO),一氧化氮合成酶抑制剂Nc-硝基-L-精氨酸(L-NNA)以及NO捕捉剂氧合血红蛋白(HbO)存在的条件下,观察缓激肽(BK,I组)诱导的EDHF介导的舒张功能,以及将不同浓度的KRN4884加入高钾溶液中对血管进行孵育后(Ⅱ-1,2,3组),这种功能的变化情况。结果:经高钾溶液孵育后,BK诱导EDHF介导的最大舒张明显被减少,(72.5±7.8)％比(41.6±10.6)％;P<0.05。KRN4884在浓度为-4log mol/L和-7log mol/L时降低U46619诱发的血管收缩力,(1.7±0.3)比(7.1±1.9)mN,P<0.05;3.2±1.6比7.8±1.7mN,P<0.05;在浓度为-8log mol/L(5.8±1.7)比(7.1±1.5)mN.n=11;P>0.05时,其降低血管收缩力的作用不明显。用KRN4884(-8log mol/L)加入高钾溶液可部分恢复这种被减少的EDHF的功能(59.9±5.6)％比(77.2±5.3)％,P<0.008。结论:在猪冠状微动脉。

Hyperkalemia-exposure could reduce endothelium-derived hyperpolarizing factor(EDHF)-mediated relaxation. The present study investigated whether the reduction could be recovered by KRN4884, a novel ATP-sensitive potassium channel opener, in porcine coronary micro-arteries. Methods: Two rings from the same micro-artery (diameter 200-450 μm) were allocated in a myograph ( n = 8 - 11 in each group) at 37 ℃. In Group 1 , one ring was incubated in hyperkalemic solution (K+ 20 mmol/L) for 1 h and the other, in Krebs'as control. In Group Ⅱ , both rings were exposed to hyperkalemia for 1 h and one of them was simultaneously incubated with KRN 4884 (-4, -7, or -8 log mol/L). The EDHF-mediated relaxation was induced by bradykinin(BK, - 10 to -6.5 log mol/L) in U46619(-8. 5 log mol/L) precontraction in the presence of indomethacin (Indo, 7 μmol/L), Nc-nitro-L-arginine(L-NNA, 300 μmol/L), and oxyhemoglobin (HbO, 20 μmol/L). Results: EDHF-mediated relaxation was reduced by hyperkalemia from (72. 5 ± 7. 8)% to (41. 6 ± 10. 6)%(P < 0. 05). KRN4884 depressed the U46619-induced contraction at - 4. 5 log mol/L[(1.7±0. 3)vs 7.1 ±1.9 mN, P < 0. 05] , - 7 log mol/L[ (3. 2±1. 6)vs (7. 8 ±1. 7)mN, P < 0. 05], and - 8 log mol/L[ (5. 8 ± 1. 7) vs (7. 1±1. 5) mN, n = 11 ; P > 0. 05). BK-induced relaxation after hyperkalemia exposure was significantly restored by KRN4884-8 log mol/L, (59. 9 ±5. 6)% vs (77.2±5.3)%, P = 0.008]. Conclusion: Addition of KRN4884 in hyperkalemic solutions may restore the EDHF-mediated relaxation impaired by hyperkalemia in porcine coronary micro-arteries.