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

Simple Summary Inhibitors of phosphodiesterase 4 (PDE4), a group of isoenzymes that hydrolyze and inactivate the second messenger cAMP, produce promising therapeutic benefits, including anti-inflammatory and memory-enhancing effects. Here, we report that, unexpectedly, PDE4 inhibitors also reduce serum potassium levels in mice. As both the total potassium content of the body, as well as the distribution of potassium between intra- and extracellular compartments, are critical for normal cellular functions, we further explored this observation. Several structurally distinct PDE4 inhibitors reduce serum potassium levels in mice, suggesting it is a class effect of these drugs. Serum potassium levels decrease within 15 min of drug injection, suggesting that PDE4 inhibition lowers serum potassium levels by promoting a transcellular shift of potassium from the blood into cells. This shift is a characteristically fast process, compared to a loss of total-body potassium via the kidneys or digestive tract (e.g., diarrhea). Indeed, stimulating cAMP synthesis with beta-adrenoceptor agonists is known to rapidly shift potassium into cells, and PDE4 inhibitors appear to mimic this process by preventing PDE4-mediated cAMP degradation. Our findings reveal that the various acute physiologic effects of PDE4 inhibitors are paralleled and/or may be affected by reduced serum potassium levels. 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 beta-adrenoceptor agonist Isoprenaline or the alpha(2)-blocker Yohimbine, and is partially blocked by pre-treatment with the beta-blocker Propranolol. Together, these data suggest that PDE4 inhibitors reduce serum potassium levels by modulating the adrenergic regulation of cellular potassium uptake.

Automated summary

Inhibitors of phosphodiesterase 4 (PDE4) reduce serum potassium levels by promoting a transcellular shift of potassium from the blood into cells. This effect is separate from the hypothermic and hypokinetic effects of PDE4 inhibitors. PDE4 inhibitors modulate the adrenergic regulation of cellular potassium uptake.