PDE4 inhibitors induce emesis in ferrets via a noradrenergic pathway.
The objective of this work was to assess the role of alpha(2)-adrenoceptors in emesis induced by inhibitors of type 4 phosphodiesterase (PDE4) in ferrets. Pre-treatment with yohimbine, MK-912 or MK-467 (alpha(2)-adrenoceptor antagonists) caused sudden and unexpected vomiting. In contrast, clonidine (alpha(2)-adrenoceptor agonist) did not induce emesis at doses ranging from 62.5-250 microg/kg s.c. At the dose of 250 microg/kg, clonidine also provided protection against emesis induced by the PDE4 inhibitors, PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline, CT-2450 and R-rolipram. It was postulated that PDE4 inhibitors trigger emesis by mimicking the pharmacological actions of alpha(2)-adrenoceptor antagonists. This hypothesis was strengthened by the demonstration that PDE4 inhibitors can reverse the hypnotic effect of an alpha(2)-adrenoceptor mediated anaesthetic regimen in rats and ferrets. Similar to alpha(2)-adrenoceptor antagonists, PMNPQ, R-rolipram and S-rolipram dose-dependently decreased the duration of anaesthesia in rats injected with the combination xylazine/ketamine. While subcutaneous injections of CT-2450 (3-30 mg/kg) were without effect, a central infusion (6 microg i.c.v.) decreased the duration of anaesthesia. These studies suggest that the ferret is an appropriate model to study emesis induced by PDE4 inhibitors and that these compounds trigger the emetic reflex via a noradrenergic pathway, mimicking the pharmacological actions of a pre-synaptic alpha(2)-adrenoceptor inhibition.
Robichaud
A
A
Department of Pharmacology, Merck Frosst Centre for Therapeutic Research, PO Box 1005, Pointe-Claire, Dorval, Quebec, Canada H9R 4P8. annette_robichaud@merck.com
Savoie
C
C
Stamatiou
P B
PB
Tattersall
F D
FD
Chan
C C
CC
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000502:physiology*; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005289:Ferrets; D008297:Male; D010726:Phosphodiesterase Inhibitors / Q000009:adverse effects*; D011725:Pyridines / Q000009:adverse effects; D011804:Quinolines / Q000009:adverse effects; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects; D020889:Rolipram / Q000009:adverse effects; D014839:Vomiting / Q000139:chemically induced*
D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D010726:Phosphodiesterase Inhibitors; D011725:Pyridines; D011804:Quinolines; D018340:Receptors, Adrenergic, alpha-1; D018341:Receptors, Adrenergic, alpha-2; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram