Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Faculty of Medicine, University of Belgrade, Belgrade, Serbia.
Fundam Clin Pharmacol. 2024 Dec;38(6):1155-1167. doi: 10.1111/fcp.13036. Epub 2024 Sep 9.
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 (HS)-mediated vasorelaxation is still unclear, and data about human vessels are limited.
To determine the role of K channel subtypes in the vasorelaxant mechanism of HS donor, sodium-hydrosulfide (NaHS), on isolated human internal mammary artery (HIMA).
NaHS (1 × 10-3 × 10 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).
Our results demonstrated that HS donor, NaHS, induced concentration-dependent relaxation of isolated HIMA. Vasorelaxant mechanisms of HS included direct or indirect opening of different K channel subtypes, K, BK, SK/IK, and K (subtype K1.3), in addition to NO pathway activation and interference with extracellular Ca influx.
在包括高血压、糖尿病和动脉粥样硬化在内的几种病理条件下，K 通道表达/功能的变化与血管反应性的破坏有关。气体递质通过调节离子通道，特别是 K 通道，在机体中发挥部分作用。它们在硫化氢（HS）介导的血管舒张中的作用尚不清楚，并且关于人体血管的数据有限。
确定 K 通道亚型在 HS 供体，硫氢化钠（NaHS）对分离的人内乳动脉（HIMA）的血管舒张机制中的作用。
NaHS（1×10-3×10mol/L）诱导 HIMA 对苯肾上腺素和高 K 预收缩的浓度依赖性松弛。在 K 通道阻滞剂中，iberiotoxin、glibenclamide、4-氨基吡啶（4-AP）和 margatoxin 显著抑制 NaHS 诱导的苯肾上腺素收缩的 HIMA 松弛（P<0.01），而在 apamin/1-（2-氯苯基）二苯甲基-1H-吡唑（TRAM-34）组合存在的情况下，HIMA 松弛部分减少（P<0.05）。NaHS 的作用被 NO 途径抑制剂 L-NAME 和 KT5823 以及环氧化酶抑制剂吲哚美辛（P<0.01）拮抗。在阻断 NO/前列环素合成和释放的条件下，apamin/TRAM-34 和 glibenclamide 导致 NaHS 诱导的血管舒张进一步减少（P<0.01），而 iberiotoxin、4-AP 和 margatoxin 没有额外的作用（P>0.05）。在硝苯地平存在的情况下，NaHS 诱导 HIMA 的部分松弛（P<0.01）。
我们的结果表明，HS 供体 NaHS 诱导分离的 HIMA 浓度依赖性松弛。HS 的血管舒张机制包括不同 K 通道亚型的直接或间接开放，K、BK、SK/IK 和 K（亚型 K1.3），除了 NO 途径的激活和干扰细胞外 Ca 内流。
