Phosphodiesterase inhibitors suppress alpha2-adrenoceptor-mediated 5-hydroxytryptamine release from tracheae of newborn rabbits.
The outflow of 5-hydroxytryptamine (5-HT) from isolated tracheae of newborn rabbits was determined by high pressure liquid chromatography with electrochemical detection. This 5-HT outflow reflects release from neuroendocrine epithelial cells of the airway mucosa, as previously shown. Phenylephrine, via alpha2B-adrenoceptors, caused a transient increase in 5-HT outflow, maximally by about 250%, an effect mediated by liberation of intracellular Ca2+, as previously shown. The non-selective phosphodiesterase inhibitor 2-isobutyl-1-methylxanthine (IBMX) concentration-dependently inhibited phenylephrine-induced 5-HT release (completely at 100 microM, IC50: 1.3 microM). Likewise, benzafentrine (inhibitor of phosphodiesterase 3 and 4) and siguazodan (inhibitor of phosphodiesterase 3) also almost completely inhibited phenylephrine-induced 5-HT release with IC50 values of 1.7 and 4.2 microM, respectively. Rolipram (inhibitor of phosphodiesterase 4), in a concentration of 10 microM, which exceeds more than 10-fold the reported IC50 for phosphodiesterase 4, did not significantly affect phenylephrine-induced 5-HT release. 5-HT release induced by depolarizing concentrations of K+ (45 mM), which largely depends on extracellular Ca2+, was not affected by IBMX. In conclusion, phosphodiesterases, with characteristics of phosphodiesterase 3, appear to play an important role in the control of cyclic nucleotide mediated inhibition of 5-HT release from neuroendocrine epithelial cells.
Freitag
A
A
Institute of Pharmacology and Toxicology, University of Bonn, Germany.
Wessler
I
I
Racké
K
K
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism; D005260:Female; D008297:Male; D010069:Oxadiazoles / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology; D011817:Rabbits; D018343:Receptors, Adrenergic, beta-2 / Q000187:drug effects* / Q000502:physiology*; D012701:Serotonin / Q000378:metabolism*; D014132:Trachea / Q000187:drug effects* / Q000378:metabolism*
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000316:Adrenergic alpha-Agonists; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D010726:Phosphodiesterase Inhibitors; D011810:Quinoxalines; D018343:Receptors, Adrenergic, beta-2; D010656:Phenylephrine; D012701:Serotonin; D015056:1-Methyl-3-isobutylxanthine