Uptake inhibitors potentiate gamma-aminobutyric acid-induced contractile responses in the isolated ileum of the guinea-pig

Abstract

The gamma-aminobutyric acid (GABA)-induced contractile responses in the guinea-pig isolated ileum, maintained in Krebs-bicarbonate solution (pH 7.4, 37 degrees C), were significantly potentiated by inhibitors of GABA uptake, with a greater potentiation of the responses in the presence of (+/-)-cis-3-aminocyclohexane-carboxylic acid (ACHC) greater than L-2,4-diaminobutyric acid (DABA) greater than (+/-)-nipecotic acid greater than beta-alanine, whilst simultaneous addition of DABA with beta-alanine caused a greater potentiation of the GABA-induced responses than did nipecotic acid with beta-alanine, or any of the uptake blockers applied alone. The concentration-response curves for the GABA-induced ileal contraction were shifted to the left in the presence of the uptake inhibitors, this shift being more prominent over the lower concentration range of GABA (1-20 microM). By contrast, contractile responses to muscimol or 3-amino-1-propanesulphonic acid (3APS) were not potentiated by the uptake blockers, neither were their concentration-response curves altered. Bicuculline methochloride shifted the GABA concentration-response curve to the right, whilst picrotoxinin both shifted the concentration-response curve for GABA to the right and depressed the maximum response. In the presence of the uptake inhibitors, the rightward shift of the concentration-response curves for GABA induced by bicuculline was less than that induced by bicuculline alone. The rightward shift with picrotoxinin was similarly reduced in the presence of the uptake inhibitors, without altering the depression of the maximum by picrotoxinin. Bicuculline caused a rightward shift of the concentration-response curves for 3APS and muscimol, with the curve for 3APS most affected. Picrotoxinin similarly shifted the concentration-response curves for 3APS and muscimol but depressed the maximum, with the curve for 3APS again being most affected. None of the inhibitors of GABA uptake influenced the concentration-response curves for 3APS or muscimol in the presence of bicuculline or picrotoxinin. 5. In conclusion, a saturable GABA uptake system is present in the enteric nervous system of the guinea-pig intestine, where neuronal GABA uptake appears to predominate over glial uptake.