Inhibition of cAMP-phosphodiesterase 4 (PDE4) potentiates the anesthetic effects of Isoflurane in mice

Aragon

Saleh

et al. 2021

Biochemical Journal

Self Cite

Saliva, while often taken for granted, is indispensable for oral health and overall well-being, as inferred from the significant impairments suffered by patients with salivary gland dysfunction. Here, we show that treatment with several structurally-distinct PAN-PDE4 inhibitors, but not a PDE3 inhibitor, induces saliva secretion in mice, indicating it is a class-effect of PDE4 inhibitors. In anesthetized mice, while neuronal regulations are suppressed, PDE4 inhibition potentiates a β-adrenoceptor-induced salivation, that is ablated by the β-blocker Propranolol and is absent in homozygous ΔF508-CFTR mice lacking functional CFTR. These data suggest that PDE4 acts within salivary glands to gate saliva secretion that is contingent upon the cAMP/PKA-dependent activation of CFTR. Indeed, PDE4 contributes the majority of total cAMP-hydrolytic capacity in submandibular-, sublingual-, and parotid glands, the three major salivary glands of the mouse. In awake mice, PDE4 inhibitor-induced salivation is reduced by CFTR deficiency or β-blockers, but also by the muscarinic blocker Atropine, suggesting an additional, central/neuronal mechanism of PDE4 inhibitor action. The PDE4 family comprises four subtypes, PDE4A-D. Ablation of PDE4D, but not PDE4A-C, produced a minor effect on saliva secretion, implying that while PDE4D may play a predominant role, PDE4 inhibitor-induced salivation results from the concurrent inactivation of multiple (at least two) PDE4 subtypes. Taken together, our data reveal a critical role for PDE4/PDE4D in controlling CFTR function in an in vivo model and in inducing salivation, hinting at a therapeutic potential of PDE4 inhibition for cystic fibrosis and conditions associated with xerostomia.

Section: Measurement Of Saliva Secretion Ratementioning

confidence: 99%

The cAMP-phosphodiesterase 4 (PDE4) controls β-adrenoceptor- and CFTR-dependent saliva secretion in mice

Aragon

Saleh

et al. 2021

Biochemical Journal

Self Cite

“…Treatment with PAN-PDE4 inhibitors, such as Roflumilast, produces several acute physiologic effects in mice, including hypokinesia, hypothermia, and gastroparesis, that reach a maximal amplitude between 30 and 60 min after drug injection [ 32 , 33 , 34 , 40 ]. To explore potential underlying mechanisms, blood samples were collected from mice 45 min after treatment with the PDE4 inhibitor Roflumilast for basic blood chemistry analysis.…”

Section: Resultsmentioning

confidence: 99%

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

Lochmaier

Irelan

et al. 2022

Biology

Self Cite

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.

“…Neither of these properties are shared by the second-generation PDE4 inhibitors, such as Roflumilast or Piclamilast [ 53 , 59 , 78 , 79 ] ( Figure 5 ). Rolipram and RS25344 are arguably also more brain-penetrant [ 54 , 77 ]. Thus, it seems plausible that a preference for HARBS and/or PKA-phosphorylated/activated PDE4 and/or high brain-penetrance may increase the emetic potential of PDE4 inhibitors such that they should be avoided in drug development.…”

Section: Discussionmentioning

confidence: 99%

“…First-generation inhibitors are distinguished from second-generation drugs by high emetic potential, selectivity for HARBS ( H igh- a ffinity R olipram- b inding s tate—a unique conformation of PDE4 proteins) and their preference for inhibition of PKA-phosphorylated/activated PDE4 [ 12 , 53 , 59 , 76 ]. While all listed PDE4 inhibitors do engage in paradigms that require brain-penetrance (e.g., anesthesia, hypokinesia, hypothermia [ 42 , 77 ]), the effects of Rolipram and RS25344 appear more rapid in onset and more potent compared to second-generation PAN-PDE4 inhibitors, suggesting that Rolipram and RS25344 exhibit a more rapid and profound brain-penetrance.…”

Section: Figurementioning

confidence: 99%

Assessment of PDE4 Inhibitor-Induced Hypothermia as a Correlate of Nausea in Mice

Aragon

Rich

et al. 2021

Biology

Self Cite

Treatment with PAN-PDE4 inhibitors has been shown to produce hypothermia in multiple species. Given the growing body of evidence that links nausea and emesis to disturbances in thermoregulation in mammals, we explored PDE4 inhibitor-induced hypothermia as a novel correlate of nausea in mice. Using knockout mice for each of the four PDE4 subtypes, we show that selective inactivation of individual PDE4 subtypes per se does not produce hypothermia, which must instead require the concurrent inactivation of multiple (at least two) PDE4 subtypes. These findings contrast with the role of PDE4s in shortening the duration of α2-adrenoceptor-dependent anesthesia, a behavioral surrogate previously used to assess the emetic potential of PDE4 inhibitors, which is exclusively affected by inactivation of PDE4D. These different outcomes are rooted in the distinct molecular mechanisms that drive these two paradigms; acting as a physiologic α2-adrenoceptor antagonist produces the effect of PDE4/PDE4D inactivation on the duration of α2-adrenoceptor-dependent anesthesia, but does not mediate the effect of PDE4 inhibitors on body temperature in mice. Taken together, our findings suggest that selective inhibition of any individual PDE4 subtype, including inhibition of PDE4D, may be free of nausea and emesis.