Cortisone: a potent GABAA antagonist in the guinea‐pig isolated ileum

— In the guinea-pig isolated ileum, cortisone at 0.001–10 nM induced a non-competitive, dose-dependent antagonism of GABAA-receptor-mediated contractile responses to applied GABA, depressing the maximum contractile response to GABA (100 μM), without affecting contractile responses to acetylcholine or cholinergic twitch contractions. At higher concentrations (>10 nM), cortisone depressed contractile responses to acetylcholine (10–100 nM) and cholinergic twitch responses to transmural stimulation. Cortisone is thus the most potent non-competitive antagonist at GABAA-receptor complexes in the guinea-pig ileum. From molecular modelling, sterically there appeared little difference between cortisone and cortisol, the latter being an enhancer of GABAA-receptor-mediated action in the ileum. However, there were significant differences in electrostatic potentials between the two steroids, due to the different levels of oxidation at C11 which may contribute to such opposing actions.