Modulatory activity of GABAB receptors on cholinergic tone in guinea‐pig distal colon

1 The effect of γ‐aminobutyric acid (GABA) administration was studied in both in vitro and in vivo preparations of the guinea‐pig distal colon. 2 In in vitro preparations GABA (10−7 − 10−3m) elicited a dose‐dependent relaxation; a decrease in the spontaneous contractions was sometimes observed. 3 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. 4 The relaxation responses induced by the above drugs were antagonized by 5‐aminovaleric acid (5 × 10−4m), which did not affect adenosine‐induced relaxation, but they were insensitive to bicuculline (10−5m) and picrotoxin (10−5m). Moreover, they were prevented by tetrodotoxin (6 × 10−7m). In hyoscine (10−7m)‐pretreated preparations, GABA still evoked a small relaxation response (approx. 10% of the maximum) that was bicuculline‐sensitive. 5 Desensitization to GABA (10−5m) was observed. A specific cross‐desensitization occurred between GABA (10−5m) and (—)‐baclofen (10−5m). 6 In in vivo preparations, GABA (10 μmol kg−1) and (—)‐baclofen (5 μmol kg−1) produced a dose‐related inhibition of basal tone, while (+)‐baclofen (5 μmol kg−1) had much less effect (about 25%). A decrease in the spontaneous contractions was sometimes observed. 7 The relaxant effect of GABA and (—)‐baclofen persisted in guinea‐pigs pretreated (1–2 min) with picrotoxin (1.6 μmol kg−1), whereas it was significantly reduced in animals injected 1 min beforehand with 5‐aminovaleric acid (0.2 mmol). 8 The maximal relaxant effect induced by GABA and (—)‐baclofen did not differ from that of atropine (0.9 μmol kg−1) and after atropine administration GABA had no further inhibitory effect. 9 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. 10 When the tone was increased by topical application of physostigmine (40 μg), GABA and (—)‐baclofen induced a greater relaxation than that obtained in basal conditions. 11 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.