Non-Selective PDE4 Inhibition Induces a Rapid and Transient Decrease of Serum Potassium in Mice

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...

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Published in:Biology (Basel, Switzerland) Switzerland), 2022-10, Vol.11 (11), p.1582
Main Authors: Boyd, Abigail, Lochmaier, Peter, Irelan, Daniel, Fiedler, Edward, Lee, Ji, Fouty, Brian, Abou Saleh, Lina, Richter, Wito
Format: Article
Language:English
Subjects:
Adrenergic receptors
adrenergic signaling
Agonists
Anesthesia
Body temperature
cAMP-phosphodiesterase
Catecholamines
Chemistry
Cyclic AMP
Diarrhea
Drugs
Experiments
Gastrointestinal tract
Hyperkalemia
Hypokalemia
Hypothermia
Inflammation
Isoenzymes
Kidneys
Laboratory animals
Musculoskeletal system
PDE4
Phosphodiesterase
Phosphodiesterase IV
Potassium
Propranolol
Rolipram
serum potassium
Software
Yohimbine
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Summary: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 α2-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.
ISSN:2079-7737
2079-7737
DOI:10.3390/biology11111582