1 The effects of y-aminobutyric acid (GABA) and related substances were examined in guinea-pig ileum longitudinal muscle. 2 GABA at doses ranging from 1O-7M to 3 x 10-6M elicited a relaxation while at higher doses (3 x 10-6M_10-4 M), as previously described, it caused a contraction followed by relaxation.3 GABA-induced relaxation was bicuculline-insensitive, was mimicked by (-)-baclofen but not by homotaurine and muscimol. The effect of baclofen was stereospecific. GABA-and (-)-baclofeninduced relaxations were dose-dependent and their ED50 values were similar. A specific crossdesensitization occurred between GABA and (-)-baclofen.4 The bicuculline-insensitive relaxation induced by GABA and (-)-baclofen was prevented by tetrodotoxin and hyoscine but not by phentolamine plus propranolol, naloxone or theophylline. 5 In preparations in which the muscle tone was raised by histamine or prostaglandin F2X, GABA and (-)-baclofen induced relaxation to the same extent as before increasing the tone. If the tone was raised by DMPP, a greater bicuculline-insensitive relaxation occurred. 6 Contraction caused by GABA was bicuculline-sensitive and was mimicked by homotaurine and muscimol. Contraction was dose-dependent and muscimol was about three times more potent than GABA or homotaurine. A specific cross-desensitization occurred between the contractile effects of GABA and those of homotaurine or muscimol. 7 Bicuculline competitively antagonized the contractile effects of GABA, homotaurine and muscimol and gave closely similar pA2 values. The slope of the Schild plot for the above drugs was near 1, confirming the competitive nature of the antagonism.8 The bicuculline-sensitive contraction induced by GABA, homotaurine and muscimol was abolished by tetrodotoxin and was non-competitively antagonized by hyoscine, while it was unaffected by hexamethonium, mepyramine and methysergide. 9 It is concluded that two receptors mediate the GABA effects in guinea-pig ileum: a bicucullinesensitive GABAA receptor, which elicits contraction through an excitatory action on cholinergic post-ganglionic neurones; and a bicuculline-insensitive GABAB receptor which causes relaxation through an inhibitory presynaptic action on cholinergic post-ganglionic neurones. We confirm that GABA, homotaurine and muscimol are GABAA agonists, while GABA and (-)-baclofen are GABAB agonists.
Seven aerobic bacterial strains capable of degrading several of the monocyclic aromatic compounds occurring in the phenolic fraction of olive-mill wastewaters (OMWs) were isolated from an Italian OMW. The results of the 16S rDNA restriction analysis evidenced that these strains are distributed among four different groups. One strain of each group was taxonomically characterized by sequencing the amplified 16S rDNA, and the four strains were assigned to the genera Comamonas (strain AV1A), Ralstonia (strain AV5BG), Pseudomonas (strain AV2A) and Sphingomonas (strain AV6C). The four strains, when checked for the ability to degrade nine monocyclic aromatic compounds abundant in OMWs, were found to significantly metabolize five to eight of them, both as resting cells and growing cells. Specific enzyme analyses of the same selected strains showed: (1) the occurrence of O-demethylating activities towards four methoxylated mono-aromatic acids in three of the four studied strains (strains AV1A, AV5BG and AV6C), (2) ring-cleavage activity towards protocatechuic acid in all of the strains, and (3) a ring-cleavage activity towards catechol in strain AV6C. The isolates described here exhibit a biodegradation potential towards monocyclic aromatic compounds of OMWs that is markedly broader and higher than that displayed by other aerobic bacteria described previously. These features make them excellent candidates for removing the low-molecular-weight phenolic compounds persisting in the effluent following anaerobic digestion of OMWs.
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.
Homotaurine (3‐aminopropane sulphonic acid) did not inhibit the twitch response in guinea‐pig ileum longitudinal muscle whilst γ‐aminobutyric acid (GABA) and (−)‐baclofen evoked dose‐dependent inhibitions. The inhibitory effects of GABA and (−)‐baclofen were prevented in the presence of homotaurine 2 × 10−4 and 10−3 M. The log dose‐effect curves of GABA and (−)‐baclofen were shifted in a parallel manner compatible with competitive antagonism. The pA2 of homotaurine with GABA (4.22 ± 0.05) and (−)‐baclofen (4.26 ± 0.1) were the same. Homotaurine did not antagonize the inhibitory effects of morphine (ED50 4 × 10−7 M), noradrenaline (ED50 10−6 M) or ATP (ED50 1.5 × 10−5 M). The inferior homologue of homotaurine, taurine 10−3 M, did not modify the inhibitory effects of GABA and (−)‐baclofen. Picrotoxin 5 × 10−5 M antagonized GABAA receptor‐mediated contraction but did not affect GABAB receptor‐mediated inhibition. At the same concentration the drug did not influence the antagonistic action of homotaurine, thus showing no GABAA receptor‐mediated interference. It may be concluded that homotaurine is a competitive antagonist of GABAB mediated effects in the guinea‐pig ileum.
The potential interaction of 5-aminovaleric acid (5-AVA) on GABAA and GABAB receptors was investigated on the guinea-pig isolated ileum myenteric plexus preparation. In the unstimulated preparation 5-AVA (0.1-3 mM) produced a transient contraction which was abolished by previous exposure to picrotoxin (0.1 mM), atropine (3 microM) or tetrodotoxin (0.3 microM). Cross desensitization was observed between the contractile effects of 5-AVA and GABA, while a previous exposure to (+/-)-baclofen did not affect 5-AVA induced contractions. 5-AVA antagonized the relaxant effect of (+/-)-baclofen in unstimulated preparations. 5-AVA (1 mM) had no effect on amplitude of twitches in supramaximally stimulated preparations while GABA produced a concentration related inhibition. In the presence of 5-AVA (1 mM) the concentration response curve to GABA was shifted to the right without a reduction of the maximal effect attainable. These observations indicate that 5-AVA interacts with both GABAA and GABAB receptors in guinea-pig ileum. The concentrations required to observe a GABAA effect are of the same order as those which are effective in producing a blockade of GABAB mediated responses.
In this preliminary report an unreported inhibitory action of GABA on anaphylactic reaction has been described. In a functional model (Schultz-Dale reaction) GABA has been demonstrated to inhibit the antigen-evoked contraction. This effect depends on a modulation of anaphylactic histamine release. The phenomenon is dose-dependent and requires a period of time to develop. Since GABAergic neurons are present in the preparation, it is possible to speculate that GABA receptors are involved in this inhibitory action. However, pharmacological analysis of the phenomenon has to be carried out, especially in view of the latency of GABA to develop its effect.
Inhibitory effect of GABA on anaphylactic histamine release in vitro is not mimicked by 2-aminoethansulphonic acid (taurine), an aminoacid unrelated to GABA neuro-transmission. Tetrodotoxin (TTX) 6 X 10(-7) M, a concentration known to block neuronal mechanism but not to modify muscle membrane and anaphylactic histamine release, strongly prevented the inhibition caused by GABA in the Schultz-Dale reaction and in anaphylactic histamine release. The inhibitory effect of GABA on anaphylactic reaction in vitro thus appears to be specific for this aminoacid and is neurogenic in nature, in that it requires integrity of neuronal mechanisms.
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