Reversal by phosphodiesterase-4 blockers of in vitro apnea in the isolated brainstem-spinal cord preparation from newborn rats.
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 mu-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 microM) 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 microM) and the phosphodiesterase-4 blockers rolipram (0.1-1 microM) and RO-201724 (1-5 microM). Blocking phosphodiesterases 3 and 5 with milrinone (25-100 microM) and zaprinast (25-100 microM), 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.
Department of Physiology and Perinatal Research Centre, Faculty of Medicine and Dentistry, 232D Heritage Medical Research Centre, University of Alberta, Edmonton, Canada T6G 2S2.
Araya
A
Ruangkittisakul
Klaus
K
Ballanyi
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000818:Animals; D000831:Animals, Newborn; D001049:Apnea / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D000242:Cyclic AMP / Q000096:biosynthesis*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004525:Efferent Pathways / Q000187:drug effects / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019204:GTP-Binding Proteins / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007231:Infant, Newborn; D007234:Infant, Premature / Q000502:physiology; D009294:Narcotics / Q000009:adverse effects; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011453:Prostaglandins / Q000009:adverse effects; D051381:Rats; D017450:Receptors, Opioid, mu / Q000187:drug effects / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000187:drug effects / Q000378:metabolism; D058308:Receptors, Prostaglandin E, EP3 Subtype; D012125:Respiratory Center / Q000187:drug effects / Q000378:metabolism*; D012131:Respiratory Insufficiency / Q000139:chemically induced / Q000188:drug therapy / Q000517:prevention & control; D012143:Respiratory Physiological Phenomena / Q000187:drug effects; D012249:Rhombencephalon / Q000187:drug effects / Q000378:metabolism*; D013116:Spinal Cord / Q000187:drug effects / Q000378:metabolism*
D004791:Enzyme Inhibitors; D009294:Narcotics; C545647:PTGER3 protein, human; D011453:Prostaglandins; D017450:Receptors, Opioid, mu; D018078:Receptors, Prostaglandin E; D058308:Receptors, Prostaglandin E, EP3 Subtype; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D019204:GTP-Binding Proteins