Macháček Martin, Švecová Olga, Bébarová Markéta
Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czechia.
Front Pharmacol. 2022 Apr 25;13:829952. doi: 10.3389/fphar.2022.829952. eCollection 2022.
Sildenafil (Viagra) is a vasodilator mainly used in the treatment of erectile dysfunction. Atrial or ventricular fibrillation may rarely occur as a side effect during sildenafil therapy. Although changes in inward rectifier potassium currents including are known to contribute to the pathogenesis of fibrillation, the effect of sildenafil on has not been studied. In experiments, Ba is used as a specific inhibitor of at high concentrations (usually 100 µM). Being an environmental contaminant, it is also present in the human body; Ba plasmatic concentrations up to 1.5 µM are usually reported in the general population. This study was primarily aimed to investigate changes of induced by sildenafil in a wide range of concentrations (0.1-100 µM). Additionally, the effect of combination of sildenafil and Ba at selected clinically-relevant concentrations was tested, at 0.1 µM both on and on the action potential duration (APD). Experiments were performed by the whole-cell patch-clamp technique on enzymatically isolated rat ventricular cardiomyocytes, mostly at 23°C with the exception of APD measurements which were performed at 37°C as well. Sildenafil caused a significant, reversible, and concentration-dependent inhibition of that did not differ at -50 and -110 mV. Simultaneous application of sildenafil and Ba at 0.1 µM revealed a massive inhibition of both inward and outward components of (this synergy was missing at other tested combinations). The combined effect at 0.1 µM (45.7 ± 5.7 and 43.0 ± 6.9% inhibition at -50 and -110 mV, respectively) was significantly higher than a simple sum of almost negligible effects of the individual substances and it led to a significant prolongation of APD at both 23 and 37°C. To our knowledge, similar potentiation of the drug-channel interaction has not been described. The observed massive inhibition of induced by a combined action of the vasodilator sildenafil and environmental contaminant Ba at a low concentration and resulting in a significant APD prolongation may contribute to the genesis of arrhythmias observed in some patients treated with sildenafil.
西地那非（万艾可）是一种血管扩张剂，主要用于治疗勃起功能障碍。在西地那非治疗期间，心房或心室颤动作为一种副作用很少发生。尽管已知包括内向整流钾电流变化在内的因素会导致心律失常的发病机制，但西地那非对内向整流钾电流的影响尚未得到研究。在实验中，钡在高浓度（通常为100μM）下用作内向整流钾电流的特异性抑制剂。作为一种环境污染物，它也存在于人体中；一般人群中通常报告的血浆钡浓度高达1.5μM。本研究的主要目的是研究西地那非在广泛浓度范围（0.1 - 100μM）下引起的内向整流钾电流变化。此外，测试了西地那非和钡在选定的临床相关浓度（均为0.1μM）下联合使用对内向整流钾电流和动作电位时程（APD）的影响。实验采用全细胞膜片钳技术在酶分离的大鼠心室心肌细胞上进行，除APD测量在37°C进行外，大部分实验在23°C进行。西地那非对内向整流钾电流产生了显著、可逆且浓度依赖性的抑制作用，在 - 50和 - 110 mV时无差异。同时应用0.1μM的西地那非和钡显示出对内向整流钾电流的内向和外向成分均有大量抑制（在其他测试组合中不存在这种协同作用）。0.1μM时的联合作用（在 - 50和 - 110 mV时分别抑制45.7±5.7%和43.0±6.9%）显著高于各物质几乎可忽略不计的效应的简单相加，并且在23°C和37°C时均导致APD显著延长。据我们所知，尚未描述过类似的药物 - 通道相互作用增强情况。观察到血管扩张剂西地那非和环境污染物钡在低浓度下联合作用对内向整流钾电流产生大量抑制并导致APD显著延长，这可能有助于解释在一些接受西地那非治疗的患者中观察到的心律失常的发生。
