Relaxant influence of phosphodiesterase inhibitors in the cat gastric fundus.
The breakdown of the relaxation-inducing second messengers cAMP and cGMP is mediated by phosphodiesterases. Inhibitors of functionally present phosphodiesterases can be expected to induce relaxation by increasing the basic amount of cAMP and/or cGMP. In the cat gastric fundus, vinpocetine, which has some selectivity for phosphodiesterase type I, only induced contractions, but the inhibitors of type III [5-(4-acetimidophenyl)pyrazin-(1H)-one; SKF 94120], type IV (rolipram) and type V (zaprinast) phosphodiesterase all caused concentration-dependent relaxation, as did the non-specific phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (IBMX). The most potent relaxant agent was rolipram (EC50 9 +/- 5 x 10(-7) M and 3 +/- 1 x 10(-7) M in longitudinal and circular smooth muscle strips, respectively). These results suggest that type III, IV and V phosphodiesterases are functionally present in the cat gastric fundus and are involved in the regulation of tone. The possible influence of the phosphodiesterase inhibitors on non-adrenergic non-cholinergic (NANC) relaxation induced by nitric oxide (NO), vasoactive intestinal polypeptide (VIP) and train and sustained electrical field stimulation was then tested. Rolipram (3 x 10(-8) M), SKF 94120 (10(-5) M) and IBMX (10(-6) M) did not potentiate any of the relaxant stimuli studied. Zaprinast (10(-5) M), the cGMP specific type V phosphodiesterase inhibitor, caused a significant increase of the relaxation induced by exogenous NO and by train electrical field stimulation. These stimuli are thought to induce relaxation via an increase of intracellular cGMP.(ABSTRACT TRUNCATED AT 250 WORDS)
Barbier
A J
AJ
Heymans Institute of Pharmacology, University of Gent Medical School, Belgium.
Lefebvre
R A
RA
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D002415:Cats; D006152:Cyclic GMP / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005748:Gastric Fundus / Q000187:drug effects* / Q000502:physiology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000502:physiology; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000502:physiology*; D011688:Purinones / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D011760:Pyrrolidinones; D009569:Nitric Oxide; D014660:Vasoactive Intestinal Peptide; D010727:Phosphoric Diester Hydrolases; C011145:zaprinast; D006152:Cyclic GMP; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine