Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis
A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors.
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2002 |
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| Erschienen: |
2002 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:110 |
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| Enthalten in: |
The Journal of clinical investigation - 110(2002), 7 vom: 07. Okt., Seite 1045-52 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Robichaud, Annette [VerfasserIn] |
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| Anmerkungen: |
Date Completed 04.11.2002 Date Revised 18.03.2022 published: Print Citation Status MEDLINE |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM121598659 |
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| 100 | 1 | |a Robichaud, Annette |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Deletion of phosphodiesterase 4D in mice shortens alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis |
| 264 | 1 | |c 2002 | |
| 336 | |a Text |b txt |2 rdacontent | ||
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| 500 | |a Date Completed 04.11.2002 | ||
| 500 | |a Date Revised 18.03.2022 | ||
| 500 | |a published: Print | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a A combination of pharmacological and genetic approaches was used to determine the role of type 4 cAMP-specific cyclic nucleotide phosphodiesterase 4 (PDE4) in reversing alpha(2)-adrenoceptor-mediated anesthesia, a behavioral correlate of emesis in non-vomiting species. Among the family-specific PDE inhibitors, PDE4 inhibitors reduced the duration of xylazine/ketamine-induced anesthesia in mice, with no effect on pentobarbital-induced anesthesia. The rank order of the PDE4 inhibitors tested was 6-(4-pyridylmethyl)-8-(3-nitrophenyl)quinoline (PMNPQ) > (R)-rolipram > (S)-rolipram >> (R)-N-[4-[1-(3-cyclopentyloxy-4-methoxyphenyl)-2-(4-pyridyl)ethyl]phenyl]N'-ethylurea (CT-2450). The specific roles of PDE4B and PDE4D in this model were studied using mice deficient in either subtype. PDE4D-deficient mice, but not PDE4B-deficient mice, had a shorter sleeping time than their wild-type littermates under xylazine/ketamine-induced anesthesia, but not under that induced with pentobarbital. Concomitantly, rolipram-sensitive PDE activity in the brain stem was decreased only in PDE4D-deficient mice compared with their wild-type littermates. While PMNPQ significantly reduced the xylazine/ketamine-induced anesthesia period in wild-type mice and in PDE4B-null mice, it had no effect in PDE4D-deficient mice. These findings strongly support the hypothesis that inhibition of PDE4D is pivotal to the anesthesia-reversing effect of PMNPQ and is likely responsible for emesis induced by PDE4 inhibitors | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Research Support, U.S. Gov't, P.H.S. | |
| 650 | 7 | |a Phosphodiesterase Inhibitors |2 NLM | |
| 650 | 7 | |a Receptors, Adrenergic, alpha-2 |2 NLM | |
| 650 | 7 | |a 3',5'-Cyclic-AMP Phosphodiesterases |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 650 | 7 | |a Cyclic Nucleotide Phosphodiesterases, Type 4 |2 NLM | |
| 650 | 7 | |a EC 3.1.4.17 |2 NLM | |
| 650 | 7 | |a Pentobarbital |2 NLM | |
| 650 | 7 | |a I4744080IR |2 NLM | |
| 700 | 1 | |a Stamatiou, Panagiota B |e verfasserin |4 aut | |
| 700 | 1 | |a Jin, S-L Catherine |e verfasserin |4 aut | |
| 700 | 1 | |a Lachance, Nicholas |e verfasserin |4 aut | |
| 700 | 1 | |a MacDonald, Dwight |e verfasserin |4 aut | |
| 700 | 1 | |a Laliberté, France |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Susana |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Zheng |e verfasserin |4 aut | |
| 700 | 1 | |a Conti, Marco |e verfasserin |4 aut | |
| 700 | 1 | |a Chan, Chi-Chung |e verfasserin |4 aut | |
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