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

Abstract

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 GABA_B receptors. Further experiments are required to ascertain the possible physiological role of a GABA-releasing neuronal system in the colon in vivo.