Institute of Vascular Medicine, Li Ka Shing Institute of Health Sciences, and School of Biomedical Sciences, Chinese University of Hong Kong, Hong Kong, China.
Pharmacol Res. 2012 Feb;65(2):239-46. doi: 10.1016/j.phrs.2011.11.006. Epub 2011 Nov 25.
H(2)S, a gaseous signalling molecule, relaxes blood vessels partly through activation of ATP-sensitive K(+) channels. It is however unclear whether H(2)S or its donors could affect other ion transporting proteins. The present study examined the hypothesis that NaHS, a H(2)S donor inhibits voltage-sensitive Ca(2+) channels and thus relaxes vascular smooth muscle cells (VSMC) in the cerebral arteries. NaHS dilated cerebral arteries from Sprague-Dawley rats with the same potency against pre-contraction by 5-HT and 60 mmol/L KCl, which were unaffected by several K(+) channel blockers, N(G)-nitro-l-arginine methyl ester or indomethacin, as assessed in wire myograph under an isometric condition. Likewise, NaHS also dilated cerebral arteries against myogenic constriction in pressurized myograph under an isobaric condition. NaHS concentration-dependently inhibited CaCl(2)-induced contraction in Ca(2+)-free, 60mM K(+)-containing Krebs solution. Patch clamp recordings showed that NaHS reduced the amplitude of l-type Ca(2+) currents in single myocytes isolated enzymatically from the cerebral artery. Calcium fluorescent imaging using fluo-4 showed a reduced Ca(2+) in 60 mmol/L KCl-stimulated rat cerebral arteries in response to NaHS. H(2)S precursor l-cysteine-induced relaxation in cerebral arteries was inhibited by cystathionine γ-lyase (CSE) inhibitor dl-propargylglycine. CSE was expressed in cerebral arteries. In summary, NaHS dilates rat cerebral arteries by reducing l-type Ca(2+) currents and suppressing Ca(2+) of arterial myocyte, indicating that NaHS relaxes cerebral arteries primarily through inhibiting Ca(2+) influx via Ca(2+) channels.
H₂S 是一种气态信号分子，它通过激活 ATP 敏感性 K⁺通道部分舒张血管。然而，H₂S 或其供体是否能影响其他离子转运蛋白尚不清楚。本研究检验了如下假说，即 H₂S 供体 NaHS 通过抑制电压敏感性 Ca²⁺通道来舒张脑血管平滑肌细胞（VSMC）。在等长条件下的血管张力测定仪中，NaHS 舒张了来自 Sprague-Dawley 大鼠的脑血管，对 5-HT 和 60mmol/L KCl 预收缩的舒张效果相同，而不受几种 K⁺通道阻滞剂（N(G)-硝基-l-精氨酸甲酯或吲哚美辛）的影响。同样，在等压条件下的加压血管张力测定仪中，NaHS 也能舒张脑血管的肌源性收缩。NaHS 浓度依赖性地抑制了无 Ca²⁺、含 60mmol/L K⁺的 Krebs 溶液中 CaCl₂诱导的收缩。膜片钳记录显示，NaHS 减少了酶分离的脑血管单个肌细胞中 L 型 Ca²⁺电流的幅度。使用 fluo-4 的钙荧光成像显示，在响应 NaHS 时，60mmol/L KCl 刺激的大鼠脑血管中的 [Ca²⁺]i 降低。H₂S 前体 l-半胱氨酸诱导的脑血管舒张被胱硫醚 γ-裂解酶（CSE）抑制剂 dl-丙炔基甘氨酸抑制。CSE 在脑血管中表达。综上所述，NaHS 通过减少 L 型 Ca²⁺电流和抑制动脉肌细胞中的 [Ca²⁺]i 来舒张大鼠脑血管，表明 NaHS 主要通过抑制 Ca²⁺通道的 Ca²⁺内流来舒张脑血管。
