Boyd Abigail, Lochmaier Peter, Irelan Daniel, Fiedler Edward, Lee Ji Young, Fouty Brian, Abou Saleh Lina, Richter Wito
Department of Biochemistry & Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Center for Lung Biology, College of Medicine, University of South Alabama, Mobile, AL 36688, USA.
Biology (Basel). 2022 Oct 27;11(11):1582. doi: 10.3390/biology11111582.
The analysis of blood samples from mice treated with the PDE4 inhibitor Roflumilast revealed an unexpected reduction in serum potassium levels, while sodium and chloride levels were unaffected. Treatment with several structurally distinct PAN-PDE4 inhibitors, including Roflumilast, Rolipram, RS25344, and YM976 dose-dependently reduced serum potassium levels, indicating the effect is a class-characteristic property. PDE4 inhibition also induces hypothermia and hypokinesia in mice. However, while general anesthesia abrogates these effects of PDE4 inhibitors, potassium levels decrease to similar extents in both awake as well as in fully anesthetized mice. This suggests that the hypokalemic effects of PDE4 inhibitors occur independently of hypothermia and hypokinesia. PDE4 inhibition reduces serum potassium within 15 min of treatment, consistent with a rapid transcellular shift of potassium. Catecholamines promote the uptake of potassium into the cell via increased cAMP signaling. PDE4 appears to modulate these adrenoceptor-mediated effects, as PDE4 inhibition has no additional effects on serum potassium in the presence of saturating doses of the β-adrenoceptor agonist Isoprenaline or the α-blocker Yohimbine, and is partially blocked by pre-treatment with the β-blocker Propranolol. Together, these data suggest that PDE4 inhibitors reduce serum potassium levels by modulating the adrenergic regulation of cellular potassium uptake.
对用磷酸二酯酶4（PDE4）抑制剂罗氟司特处理的小鼠的血样分析显示，血清钾水平意外降低，而钠和氯水平未受影响。用几种结构不同的泛PDE4抑制剂（包括罗氟司特、咯利普兰、RS25344和YM976）处理后，血清钾水平呈剂量依赖性降低，表明该效应是该类药物的特性。PDE4抑制还会在小鼠中诱发体温过低和运动减少。然而，虽然全身麻醉消除了PDE4抑制剂的这些作用，但在清醒和完全麻醉的小鼠中，钾水平均下降到相似程度。这表明PDE4抑制剂的低钾血症作用独立于体温过低和运动减少而发生。PDE4抑制在治疗后15分钟内降低血清钾，这与钾的快速跨细胞转移一致。儿茶酚胺通过增加环磷酸腺苷（cAMP）信号促进钾进入细胞。PDE4似乎调节这些肾上腺素能受体介导的作用，因为在存在饱和剂量的β肾上腺素能受体激动剂异丙肾上腺素或α阻滞剂育亨宾的情况下，PDE4抑制对血清钾没有额外影响，并且被β阻滞剂普萘洛尔预处理部分阻断。总之，这些数据表明PDE4抑制剂通过调节细胞钾摄取的肾上腺素能调节来降低血清钾水平。
