Inhibition of neurally mediated nonadrenergic, noncholinergic contractions of guinea pig bronchus by isozyme-selective phosphodiesterase inhibitors

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Abstract

We studied the effect of inhibiting phosphodiesterase (PDE) isozyme types III, IV and V on the cholinergic and noncholinergic (tachykinergic) contractile responses to electrical field stimulation (EFS) in the guinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a slight (~30%) but significant inhibitory effect on the noncholinergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramatically inhibited the noncholinergic contractions by nearly 70%. The EC50 for rolipram was approximately 20 nM. Rolipram (1 μM) had no effect on contractions elicited by either capsaicin or neurokinin A. EFS, but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by rolipram. Rolipram had the same inhibitory effect on EFS- and vagus nerve stimulation-induced noncholinergic contractions. The effect of rolipram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition of PDE V with zaprinast (3 μM) had no effect on the tachykinergic contractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due to stimulation of tachykinergic fibers is significantly reduced by selective inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of the smooth muscle. It is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin release from capsaicin-sensitive fibers in the guinea pig bronchus.

Original languageEnglish (US)
Pages (from-to)811-817
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Volume271
Issue number2
StatePublished - 1994

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Rolipram
Phosphodiesterase Inhibitors
Bronchi
Isoenzymes
Guinea Pigs
Type 3 Cyclic Nucleotide Phosphodiesterases
Type 4 Cyclic Nucleotide Phosphodiesterase
Electric Stimulation
Type 5 Cyclic Nucleotide Phosphodiesterases
Vagus Nerve Stimulation
Capsaicin
Cholinergic Agents
Neurokinin A
Tachykinins
Phosphoric Diester Hydrolases
Smooth Muscle

ASJC Scopus subject areas

  • Pharmacology

Cite this

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title = "Inhibition of neurally mediated nonadrenergic, noncholinergic contractions of guinea pig bronchus by isozyme-selective phosphodiesterase inhibitors",
abstract = "We studied the effect of inhibiting phosphodiesterase (PDE) isozyme types III, IV and V on the cholinergic and noncholinergic (tachykinergic) contractile responses to electrical field stimulation (EFS) in the guinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a slight (~30{\%}) but significant inhibitory effect on the noncholinergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramatically inhibited the noncholinergic contractions by nearly 70{\%}. The EC50 for rolipram was approximately 20 nM. Rolipram (1 μM) had no effect on contractions elicited by either capsaicin or neurokinin A. EFS, but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by rolipram. Rolipram had the same inhibitory effect on EFS- and vagus nerve stimulation-induced noncholinergic contractions. The effect of rolipram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition of PDE V with zaprinast (3 μM) had no effect on the tachykinergic contractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due to stimulation of tachykinergic fibers is significantly reduced by selective inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of the smooth muscle. It is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin release from capsaicin-sensitive fibers in the guinea pig bronchus.",
author = "Undem, {Bradley J} and Sonya Meeker and J. Chen",
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T1 - Inhibition of neurally mediated nonadrenergic, noncholinergic contractions of guinea pig bronchus by isozyme-selective phosphodiesterase inhibitors

AU - Undem, Bradley J

AU - Meeker, Sonya

AU - Chen, J.

PY - 1994

Y1 - 1994

N2 - We studied the effect of inhibiting phosphodiesterase (PDE) isozyme types III, IV and V on the cholinergic and noncholinergic (tachykinergic) contractile responses to electrical field stimulation (EFS) in the guinea pig isolated bronchus. SKF 94836, a PDE III inhibitor, had a slight (~30%) but significant inhibitory effect on the noncholinergic contractions. Rolipram, an inhibitor of PDE IV isozymes, dramatically inhibited the noncholinergic contractions by nearly 70%. The EC50 for rolipram was approximately 20 nM. Rolipram (1 μM) had no effect on contractions elicited by either capsaicin or neurokinin A. EFS, but not direct vagus nerve stimulation, elicits small nonadrenergic, noncholinergic relaxations of the bronchus that were potentiated by rolipram. Rolipram had the same inhibitory effect on EFS- and vagus nerve stimulation-induced noncholinergic contractions. The effect of rolipram was mimicked by another PDE IV inhibitor, RO-201724. Inhibition of PDE V with zaprinast (3 μM) had no effect on the tachykinergic contractile response. None of the PDE inhibitors affected the EFS-induced cholinergic contractions. The data suggest that the contraction due to stimulation of tachykinergic fibers is significantly reduced by selective inhibition of PDE IV and, to a lesser extent, PDE III isozymes. This is unlikely to be due to functional antagonism at the level of the smooth muscle. It is also unlikely to be due to potentiation of the nonadrenergic relaxant response to nerve stimulation. Rather, the data are in agreement with the hypothesis that selective inhibition of PDE isozymes leads to inhibition of electrically evoked tachykinin release from capsaicin-sensitive fibers in the guinea pig bronchus.

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