Roflumilast, a phosphodiesterase-4 (PDE4) inhibitor, induces respiratory frequency plasticity that is resistant to inflammation in neonatal rat in vitro preparations

Premature and newborn infants often have prolonged apneas and are susceptible to bacterial infections that further disrupt breathing. Phoshodiesterase-4 (PDE4) inhibitor drugs increase inspiratory motor activity and appear to induce a long-lasting increase in inspiratory frequency (“frequency plasticity”). To test whether a PDE4 inhibitor drug induces frequency plasticity, neonatal rat brainstem-spinal cords were isolated and exposed to bath-applied roflumilast (10 min, 0.02–1.0 µM). Roflumilast acutely increased burst frequency and induced frequency plasticity in a concentration-dependent manner. Blockade of protein kinase A (PKA) or exchange protein activated by cAMP (EPAC) signaling pathways abolished the induction, but not the maintenance, of roflumilast-induced frequency plasticity. Brainstem-spinal cords isolated from neonatal rats injected with lipopolysaccharide (LPS, 0.1 mg/kg, 3 h prior) expressed frequency plasticity following bath-applied roflumilast at 0.05–0.5 µM, but not at lower concentrations. This shows that roflumilast-induced frequency plasticity is largely resistant to LPS-induced inflammation. Thus, roflumilast increases inspiratory burst frequency acutely and induces frequency plasticity even during ongoing inflammation, which could have important clinical implications.