Selective potentiating effect of RS14203 on a serotoninergic pathway in anesthetized rats.
The usefulness of selective inhibitors of type 4 phosphodiesterase (PDE4) in the treatment of inflammation and pulmonary diseases is limited by their side effects: nausea and vomiting. We studied the effect of three structurally diverse PDE4 inhibitors on the vagal nerve afferent and efferent fibers in anesthetized rats. The effects of RS14203, (R)-rolipram, and CT-2450 were evaluated on the von Bezold-Jarisch reflex (vagal afferent fibers) and in a model of vagal electrical stimulation (vagal efferent fibers). All three PDE4 inhibitors were administered at 1, 10, or 100 microg/kg (iv) 15 min prior to the induction of bradycardia by an iv injection of 2-methyl-5-HT (von Bezold-Jarisch reflex) or by vagal electrical stimulation. At 100 microg/kg, RS14203 significantly potentiated the 2-methyl-5-HT response. No statistically significant effects were observed with (R)-rolipram or CT-2450 at the doses studied. RS14203, (R)-rolipram, or CT-2450 (1-100 microg/kg iv) did not affect the bradycardia induced by vagal electrical stimulation. Consequently, our results show that RS14203 selectively facilitates serotoninergic neurotransmission in vagal afferent fibers. The emetic action of RS14203 may be mediated by this mechanism.
Savoie
C
C
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, Pointe-Claire-Dorval, QC, Canada.
Chan
C C
CC
Rodger
I W
IW
Robichaud
A
A
D000344:Afferent Pathways; D000818:Animals; D001919:Bradycardia / Q000139:chemically induced; D004525:Efferent Pathways; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D008297:Male; D009578:Nitrobenzenes / Q000494:pharmacology*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020889:Rolipram / Q000494:pharmacology; D012701:Serotonin / Q000031:analogs & derivatives / Q000378:metabolism; D014628:Vagotomy; D014630:Vagus Nerve / Q000187:drug effects* / Q000502:physiology
D009578:Nitrobenzenes; D010671:Phenylurea Compounds; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D015363:Quinolones; C119518:RS 14203; D012701:Serotonin; C045918:2-methyl-5-HT; D020889:Rolipram; C119519:CT 2450