GABA mediation of the dual effects of somatostatin on guinea pig ileal myenteric cholinergic transmission.
Somatostatin (SS) has both excitatory and inhibitory actions on myenteric cholinergic transmission, which are mimicked by gamma-aminobutyric acid (GABA). We hypothesized that both effects of SS are mediated by neural GABA pathways. In guinea pig ileal longitudinal muscle-myenteric plexus, SS evoked [3H]-GABA release verifying GABA neural activation. SS (10(-9)-10(-5) M) stimulation of atropine-sensitive ileal contraction and evocation of tetrodotoxin-sensitive [3H]acetylcholine (ACh) release was mimicked by the GABAA agonist muscimol but not the GABAB agonist baclofen. SS (10(-7) M)-evoked contraction and [3H]ACh release were markedly reduced by the GABAA antagonist bicuculline (10(-5) M) but not the GABAB antagonist phaclofen. Cholecystokinin (CCK) evokes ileal contraction via an atropine-sensitive pathway and stimulates ACh release via adenylate cyclase activation. SS inhibited contraction and release evoked by CCK (10(-7) M). These inhibitory actions were reversed by phaclofen but not bicuculline and were mimicked by baclofen but not muscimol. Pertussis toxin (200 ng/ml for 3 h) reversed the inhibitory effects of SS and baclofen on CCK-stimulated contraction and release. In conclusion, SS modulates ileal cholinergic pathways by stimulation of GABA neural pathways. The excitatory action of SS is mediated by GABAA receptors, whereas the inhibitory action utilizes GABAB receptors via a pertussis toxin-sensitive G protein.
Roberts
D J
DJ
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor 48109.
Hasler
W L
WL
Owyang
C
C
D000109:Acetylcholine / Q000378:metabolism; D037361:Adenylate Cyclase Toxin; D000818:Animals; D001418:Baclofen / Q000031:analogs & derivatives / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology*; D002766:Cholecystokinin / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D005769:Gastrointestinal Motility / Q000187:drug effects; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology*; D009197:Myenteric Plexus / Q000187:drug effects / Q000502:physiology*; D037342:Pertussis Toxin; D011963:Receptors, GABA-A / Q000187:drug effects / Q000502:physiology*; D013004:Somatostatin / Q000494:pharmacology*; D010566:Virulence Factors, Bordetella / Q000494:pharmacology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D037361:Adenylate Cyclase Toxin; D058787:GABA-A Receptor Antagonists; D011963:Receptors, GABA-A; D010566:Virulence Factors, Bordetella; C052329:phaclofen; D013004:Somatostatin; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; D037342:Pertussis Toxin; D001418:Baclofen; D000109:Acetylcholine; D001640:Bicuculline