Galán L, Ferrer T, Artiles A, Talavera K, Salinas E, Orta G, García-Barreto D, Alvarez J L
Laboratorio de Electrofisiología, Instituto de Cardiología y Cirugía Cardiovascular, La Habana, Cuba Laboratorio de Fisiología Cardiovascular, Instituto de Fisiología, Universidad Autónoma de Puebla, Puebla, Mexico.
Fundam Clin Pharmacol. 2001 Feb;15(1):9-17. doi: 10.1046/j.1472-8206.2001.00009.x.
In long term treatment, thiazide diuretics such as hydrochlorothiazide (HCTZ) lower blood pressure by decreasing peripheral resistance rather than by their diuretic effect. This action has been attributed to the opening of Ca2+-activated K+ channels in vascular smooth muscle cells. However, little is known about their cardiac cellular actions. Here we investigated the possible actions of HCTZ on action potential and contraction of rat ventricular muscle strips and on the ionic currents of isolated rat ventricular cardiomyocytes. HCTZ depressed ventricular contraction with an IC30 of 1.85 microM (60% decrease at 100 microM). Action potential duration at -60 mV and maximal rate of depolarization were, however, only slightly decreased by 12% and 22%, respectively, at 100 microM. At the single cell level, HCTZ (100 microM) depressed the fast Na+ current (INa) and the L-type Ca2+ current (ICaL) by 30% and 20%, respectively. The effects on ICaL were not voltage-or frequency-dependent. In cells intracellularly perfused with 50 microM cyclic adenosine, monophosphate HCTZ reduced ICaL by 33%. The transient (Ito), the delayed rectifier and the inward rectifier potassium currents were decreased by 20% at 100 microM HCTZ. The effects on Ito were voltage-dependent. In conclusion, HCTZ at high concentrations possesses a negative inotropic action that could be in part due to its blocking action on INa and ICaL. The actions of HCTZ on multiple cardiac ionic currents could explain its weak effect on action potential duration.
在长期治疗中，噻嗪类利尿剂如氢氯噻嗪（HCTZ）通过降低外周阻力而非利尿作用来降低血压。这种作用归因于血管平滑肌细胞中Ca2 +激活的K +通道的开放。然而，关于它们对心脏细胞的作用知之甚少。在这里，我们研究了HCTZ对大鼠心室肌条动作电位和收缩以及对分离的大鼠心室心肌细胞离子电流的可能作用。HCTZ抑制心室收缩，IC30为1.85 microM（100 microM时降低60%）。然而，在100 microM时，-60 mV处的动作电位持续时间和最大去极化速率仅分别略有降低，即12%和22%。在单细胞水平，HCTZ（100 microM）分别使快速钠电流（INa）和L型钙电流（ICaL）降低30%和20%。对ICaL的影响不依赖于电压或频率。在细胞内灌注50 microM环磷酸腺苷的细胞中，HCTZ使ICaL降低33%。在100 microM HCTZ时，瞬时外向电流（Ito）、延迟整流钾电流和内向整流钾电流降低20%。对Ito的影响依赖于电压。总之，高浓度的HCTZ具有负性肌力作用，这可能部分归因于其对INa和ICaL的阻断作用。HCTZ对多种心脏离子电流的作用可以解释其对动作电位持续时间的微弱影响。
