Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats

Abstract

Ventilation of the lungs is mediated by neurons of the respiratory network in the lower brainstem. The activity of rhythmogenic respiratory network neurons seems to depend greatly on cellular levels of the second messenger cAMP. Accordingly, depression of breathing in (preterm) infants associated with clinical administration of opioids and prostaglandins results likely from a fall of cAMP in these cells caused by G i/o proteins that are activated via μ-opiate or EP 3 prostanoid receptors, respectively. Typically, such drug-induced depression of infant breathing is treated with high doses of methylxanthines that have notable adverse effects. It was the aim of our study to investigate whether clinically applicable blockers of cAMP-hydrolyzing phosphodiesterase-4 counteract the inhibition of the respiratory network associated with a drug-induced fall of cAMP. For this purpose, inspiratory-related cervical nerve activity was measured in isolated brainstem-spinal cord preparations from newborn rats. Respiratory frequency was depressed by >80% (from >5 bursts/min to <1 burst/min) with nociceptin (1 μM) which decreases cAMP via a G i/o protein-coupled opioid-like receptor. The nociceptin-induced respiratory depression was reversed by the activator of adenylyl cyclase, forskolin (5–25 μM) and the phosphodiesterase-4 blockers rolipram (0.1–1 μM) and RO-201724 (1–5 μM). Blocking phosphodiesterases 3 and 5 with milrinone (25–100 μM) and zaprinast (25–100 μM), respectively, was not effective. The results indicate that phosphodiesterase-4 blockers are strong stimulants of the respiratory network. We hypothesize that these or related agents may be potent tools for a treatment of drug-induced disturbances of breathing in (preterm) infants.