Modulatory activity of GABAB receptors on cholinergic tone in guinea-pig distal colon.
The effect of gamma-aminobutyric acid (GABA) administration was studied in both in vitro and in vivo preparations of the guinea-pig distal colon. In in vitro preparations GABA (10(-7) - 10(-3) M) elicited a dose-dependent relaxation; a decrease in the spontaneous contractions was sometimes observed. The effect of GABA was mimicked by (-)-baclofen, which gave a dose-response curve overlapping that of GABA, while (+)-baclofen was about one hundred times less potent. The relaxation responses induced by the above drugs were antagonized by 5-aminovaleric acid (5 X 10(-4) M), which did not affect adenosine-induced relaxation, but they were insensitive to bicuculline (10(-5) M) and picrotoxin (10(-5) M). Moreover, they were prevented by tetrodotoxin (6 X 10(-7) M). In hyoscine (10(-7) M)-pretreated preparations, GABA still evoked a small relaxation response (approx. 10% of the maximum) that was bicuculline-sensitive. Desensitization to GABA (10(-5) M) was observed. A specific cross-desensitization occurred between GABA (10(-5) M) and (-)-baclofen (10(-5) M). In in vivo preparations, GABA (10 mumol kg-1) and (-)-baclofen (5 mumol kg-1) produced a dose-related inhibition of basal tone, while (+)-baclofen (5 mumol kg-1) had much less effect (about 25%). A decrease in the spontaneous contractions was sometimes observed. The relaxant effect of GABA and (-)-baclofen persisted in guinea-pigs pretreated (1-2 min) with picrotoxin (1.6 mumol kg-1), whereas it was significantly reduced in animals injected 1 min beforehand with 5-aminovaleric acid (0.2 mmol). The maximal relaxant effect induced by GABA and (-)-baclofen did not differ from that of atropine (0.9 mumol kg-1) and after atropine administration GABA had no further inhibitory effect. Relaxation responses induced by GABA and (-)-baclofen still occurred after blockade of nicotinic receptors by hexamethonium (0.17 mmol kg-1), which itself caused an increase in the basal tone. When the tone was increased by topical application of physostigmine (40 micrograms), GABA and (-)-baclofen induced a greater relaxation than that obtained in basal conditions. It is concluded that GABA, both in vitro and in vivo administration, inhibits cholinergic tone in guinea-pig distal colon and that this effect is mediated mainly by activation of GABAB receptors. Further experiments are required to ascertain the possible physiological role of a GABA-releasing neuronal system in the colon in vivo.
Giotti
A
A
Luzzi
S
S
Maggi
C A
CA
Spagnesi
S
S
Zilletti
L
L
D000596:Amino Acids / Q000494:pharmacology; D021542:Amino Acids, Neutral; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001418:Baclofen / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D006168:Guinea Pigs; D006584:Hexamethonium Compounds / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D010275:Parasympathetic Nervous System / Q000187:drug effects*; D010852:Picrotoxin / Q000494:pharmacology; D011963:Receptors, GABA-A / Q000187:drug effects*; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
D000596:Amino Acids; D021542:Amino Acids, Neutral; D001285:Atropine; D001418:Baclofen; D001640:Bicuculline; D006584:Hexamethonium Compounds; D010852:Picrotoxin; D011963:Receptors, GABA-A; D005680:gamma-Aminobutyric Acid; C013809:5-aminovaleric acid