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Assessing the emetic potential of PDE4 inhibitors in rats.

Abstract
1. Type 4 phosphodiesterase (PDE4) inhibitors mimic the pharmacological actions of alpha(2)-adrenoceptor antagonists. This has been postulated as the mechanism by which PDE4 inhibitors induce emesis and was also demonstrated by their ability to reverse xylazine/ketamine-induced anaesthesia. We further characterized this latter effect since it appears to reflect the emetic potential of PDE4 inhibitors. 2. Selective inhibitors of PDE 1, 2, 3, 4 and 5 were studied in rats, on the duration of anaesthesia induced by the combination of xylazine (10 mg kg(-1), i.m.) and ketamine (10 mg kg(-1), i.m.). PMNPQ (i.e. 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline) - PDE4 inhibitor: 0.01 - 3 mg kg(-1)), like MK-912 (alpha(2)-adrenoceptor antagonist: 0.01 - 3 mg kg(-1)), dose-dependently reduced the duration of anaesthesia. In contrast, vinpocetine (PDE1 inhibitor), EHNA (PDE2 inhibitor), milrinone (PDE3 inhibitor) and zaprinast (PDE5 inhibitor) had no significant effect at the doses tested (1 - 10 mg kg(-1)). Analysis of plasma and cerebrospinal fluid (CSF) of treated animals confirmed the absorption and distribution to the brain of the inactive inhibitors. 3. Neither MK-912 (3 mg kg(-1)) nor PMNPQ (0.1 - 1 mg kg(-1)) altered the duration of anaesthesia induced via a non-alpha(2)-adrenoceptor pathway (sodium pentobarbitone 50 mg kg(-1), i.p.). 4. Central NK(1) receptors are involved in PDE4 inhibitor-induced emesis. Consistently, [sar(9), Met(O(2))(11)]-substance P (NK(1) receptor agonist, 6 microg i.c.v.) reduced the duration of anaesthesia induced by xylazine/ketamine. 5. In summary, this model is functionally coupled to PDE4, specific to alpha(2)-adrenoceptors and relevant to PDE4 inhibitor-induced emesis. It therefore provides a novel way of evaluating the emetic potential of PDE4 inhibitors in rats.
AuthorsA Robichaud, C Savoie, P B Stamatiou, N Lachance, P Jolicoeur, R Rasori, C C Chan
JournalBritish journal of pharmacology (Br J Pharmacol) Vol. 135 Issue 1 Pg. 113-8 (Jan 2002) ISSN: 0007-1188 [Print] England
PMID11786486 (Publication Type: Journal Article)
Chemical References
  • Adjuvants, Anesthesia
  • Adrenergic alpha-Agonists
  • Adrenergic alpha-Antagonists
  • Phosphodiesterase Inhibitors
  • Quinolizines
  • Receptors, Adrenergic, alpha-1
  • Receptors, Adrenergic, alpha-2
  • Receptors, Neurokinin-3
  • substance P, Sar(9)-Met(O2)(11)-
  • L 657743
  • Substance P
  • 3',5'-Cyclic-AMP Phosphodiesterases
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Pentobarbital
Topics
  • 3',5'-Cyclic-AMP Phosphodiesterases (antagonists & inhibitors, physiology)
  • Adjuvants, Anesthesia (pharmacology)
  • Adrenergic alpha-Agonists (pharmacology)
  • Adrenergic alpha-Antagonists (pharmacology)
  • Animals
  • Cyclic Nucleotide Phosphodiesterases, Type 1
  • Cyclic Nucleotide Phosphodiesterases, Type 4
  • Dose-Response Relationship, Drug
  • Male
  • Pentobarbital (pharmacology)
  • Phosphodiesterase Inhibitors (adverse effects, blood, pharmacology)
  • Quinolizines (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, Adrenergic, alpha-1 (drug effects)
  • Receptors, Adrenergic, alpha-2 (drug effects)
  • Receptors, Neurokinin-3 (antagonists & inhibitors)
  • Substance P (administration & dosage, analogs & derivatives)
  • Vomiting (chemically induced)

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