背景:在几种病理情况下,K+通道表达/功能的变化与血管反应性的破坏有关,包括高血压,糖尿病,和动脉粥样硬化。Gasotransmitters通过调节离子通道来实现其在生物体中的部分作用,特别是K+频道。它们是否参与硫化氢(H2S)介导的血管舒张尚不清楚,关于人类血管的数据是有限的。
目的:确定K+通道亚型在H2S供体血管舒张机制中的作用,硫氢化钠(NaHS),分离的人乳内动脉(HIMA)。
结果:NaHS(1×10-6-3×10-3mol/L)诱导了去氧肾上腺素和高K预收缩的HIMA的浓度依赖性松弛。在K+通道阻滞剂中,伊贝毒素,格列本脲,4-氨基吡啶(4-AP),和margatoxin显著抑制NaHS诱导的去氧肾上腺素收缩HIMA的松弛(P<0.01),而在存在阿帕明/1-[(2-氯苯基)二苯基甲基]-1H-吡唑(TRAM-34)组合的情况下,HIMA松弛部分减少(P<0.05)。NaHS的作用被NO途径抑制剂拮抗,L-NAME和KT5823,以及环氧合酶抑制剂,吲哚美辛(P<0.01)。在阻断NO/前列环素合成和释放的条件下,阿帕明/TRAM-34和格列本脲导致NaHS诱导的血管舒张进一步减少(P<0.01),而伊贝毒素,4-AP,和margatoxin无额外作用(P>0.05)。在硝苯地平存在的情况下,NaHS诱导HIMA部分舒张(P<0.01)。
结论:我们的结果表明,H2S供体,NaHS,诱导分离的HIMA的浓度依赖性弛豫。H2S的血管松弛机制包括直接或间接开放不同的K+通道亚型,KATP,BKCa,SKCa/IKCa,和KV(KV1.3亚型),除了NO通路激活和干扰细胞外Ca2+内流。
BACKGROUND: Changes in K+ channel expression/function are associated with disruption of vascular reactivity in several pathological conditions, including hypertension, diabetes, and atherosclerosis. Gasotransmitters achieve part of their effects in the organism by regulating ion channels, especially K+ channels. Their involvement in hydrogen sulfide (H2S)-mediated vasorelaxation is still unclear, and data about human vessels are limited.
OBJECTIVE: To determine the role of K+ channel subtypes in the vasorelaxant mechanism of H2S donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).
RESULTS: NaHS (1 × 10-6-3 × 10-3 mol/L) induced a concentration-dependent relaxation of HIMA pre-contracted by phenylephrine and high K+. Among K+ channel blockers, iberiotoxin, glibenclamide, 4-aminopyridine (4-AP), and margatoxin significantly inhibited NaHS-induced relaxation of phenylephrine-contracted HIMA (P < 0.01), whereas in the presence of apamin/1-[(2-chlorophenyl) diphenylmethyl]-1H-pyrazole (TRAM-34) combination, the HIMA relaxation was partially reduced (P < 0.05). The effect of NaHS was antagonized by NO pathway inhibitors, L-NAME and KT5823, and by cyclo-oxygenase inhibitor, indomethacin (P < 0.01). Under conditions of blocked NO/prostacyclin synthesis and release, apamin/TRAM-34 and glibenclamide caused further decrease in NaHS-induced vasorelaxation (P < 0.01), while iberiotoxin, 4-AP, and margatoxin were without additional effect (P > 0.05). In the presence of nifedipine, NaHS induced partial relaxation of HIMA (P < 0.01).
CONCLUSIONS: Our results demonstrated that H2S donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of H2S included direct or indirect opening of different K+ channel subtypes, KATP, BKCa, SKCa/IKCa, and KV (subtype KV1.3), in addition to NO pathway activation and interference with extracellular Ca2+ influx.