Valenzuela Fermín, García-Saisó Sebastián, Lemini Cristina, Ramírez-Solares Rafael, Vidrio Horacio, Mendoza-Fernández Víctor
Departamento de Farmacología, Facultad de Medicina, UNAM, Ciudad Universitaria, CP 04510, México D.F., México.
Vascul Pharmacol. 2005 Aug;43(2):120-7. doi: 10.1016/j.vph.2005.05.003.
Clinically metamizol (MZ) has been related to alteration on haemodynamic parameters and modifications on blood pressure in humans when administered intravenously. These effects have been observed at MZ therapeutic doses. Experimentally, MZ is able to induce relaxation on several types of vascular smooth muscles and modulates the contraction induced by phenylephrine. However, the mechanism underlying the MZ effects on vascular reactivity is not clear. Potassium channels (K) present on vascular smooth muscle cells closely regulate the vascular reactivity and membrane potential. There are four described types of K in vascular tissue: K voltage sensitive (K(V)), K calcium sensitive (K(Ca)2+), K ATP sensitive (K(ATP) and K inward rectification (K(IR), voltage sensitive). The aim of this work was to investigate MZ effects on angiotensin II (AT II) and noradrenaline (NA) induced contraction and to evaluate the K participation on MZ modulating effect on vascular smooth muscle contraction, using isometric and patch clamp techniques. MZ induces relaxation in a concentration dependent manner. Furthermore, MZ strongly inhibits in a concentration dependent fashion the contraction induced by AT II. However, MZ inhibition on NA induced contraction was moderated compared with that observed on AT II. MZ effects on AT II induced contraction was blocked by glybenclamide (a specific K(ATP) blocker, 3 microM, *p < 0.01). In patch clamp experiments, MZ (3 mM) induces an increase on potassium current (K+) mediated by K(ATP) in similar way as diazoxide (a specific K(ATP) opener, 3 microM). Our results suggest that MZ induces relaxation and inhibits contraction induced by AT II acting as a K(ATP) opener.
临床上，静脉注射甲灭酸（MZ）会导致人体血流动力学参数改变和血压变化。这些效应在MZ治疗剂量下即可观察到。实验表明，MZ能够使多种类型的血管平滑肌松弛，并调节去氧肾上腺素诱导的收缩。然而，MZ对血管反应性的作用机制尚不清楚。血管平滑肌细胞上的钾通道（K）密切调节血管反应性和膜电位。血管组织中已描述的钾通道有四种类型：电压敏感性钾通道（K(V)）、钙敏感性钾通道（K(Ca)2+）、ATP敏感性钾通道（K(ATP)）和内向整流钾通道（K(IR)，电压敏感性）。本研究旨在利用等长收缩和膜片钳技术，研究MZ对血管紧张素II（AT II）和去甲肾上腺素（NA）诱导收缩的影响，并评估钾通道在MZ调节血管平滑肌收缩中的作用。MZ以浓度依赖的方式诱导血管平滑肌松弛。此外，MZ以浓度依赖的方式强烈抑制AT II诱导的收缩。然而，与对AT II诱导收缩的抑制作用相比，MZ对NA诱导收缩的抑制作用较弱。格列本脲（一种特异性K(ATP)阻滞剂，3 microM，*p < 0.01）可阻断MZ对AT II诱导收缩的作用。在膜片钳实验中，MZ（3 mM）以与二氮嗪（一种特异性K(ATP)开放剂，3 microM）相似的方式诱导由K(ATP)介导的钾电流（K+）增加。我们的结果表明，MZ作为K(ATP)开放剂，诱导血管平滑肌松弛并抑制AT II诱导的收缩。
