Koltsova Svetlana V, Kotelevtsev Sergei V, Tremblay Johanne, Hamet Pavel, Orlov Sergei N
Research Centre, Centre Hospitalier de l'Université de Montréal (CRCHUM - Technopôle Angus), Montreal, PQ, Canada H1W 4A4.
Biochem Biophys Res Commun. 2009 Feb 20;379(4):1080-3. doi: 10.1016/j.bbrc.2009.01.018. Epub 2009 Jan 14.
Bumetanide and other high-ceiling diuretics (HCD) attenuate myogenic tone and contractions of vascular smooth muscle cells (VSMC) triggered by diverse stimuli. HCD outcome may be mediated by their interaction with NKCC1, the only isoform of Na(+), K(+), 2Cl(-) cotransporter expressed in VSMC as well as with targets distinct from this carrier. To examine these hypotheses, we compared the effect of bumetanide on contractions of mesenteric arteries from wild-type and NKCC1 knockout mice. In mesenteric arteries from wild-type controls, 100 microM bumetanide evoked a decrease of up to 4-fold in myogenic tone and contractions triggered by modest K(+)-induced depolarization, phenylephrine and UTP. These actions of bumetanide were preserved after inhibition of nitric oxide synthase with NG-nitro-l-arginine methyl ester, but were absent in mesenteric arteries from NKCC1(-/-) mice. The data show that bumetanide inhibits VSMC contractile responses via its interaction with NKCC1 and independently of nitric oxide production by endothelial cells.
布美他尼和其他高效能利尿剂（HCD）可减弱由多种刺激引发的血管平滑肌细胞（VSMC）的肌源性张力和收缩。HCD的作用可能是通过其与NKCC1的相互作用介导的，NKCC1是VSMC中表达的唯一一种钠（Na⁺）、钾（K⁺）、2氯（2Cl⁻）共转运体亚型，以及与该载体不同的靶点。为了验证这些假设，我们比较了布美他尼对野生型和NKCC1基因敲除小鼠肠系膜动脉收缩的影响。在野生型对照的肠系膜动脉中，100微摩尔布美他尼可使适度的细胞外钾离子浓度（[K⁺]o）诱导的去极化、去氧肾上腺素和三磷酸尿苷（UTP）引发的肌源性张力和收缩降低多达4倍。在用N-硝基-L-精氨酸甲酯抑制一氧化氮合酶后，布美他尼的这些作用仍然存在，但在NKCC1基因敲除（-/-）小鼠的肠系膜动脉中则不存在。数据表明，布美他尼通过与NKCC1相互作用抑制VSMC的收缩反应，且不依赖于内皮细胞产生的一氧化氮。
