The Postganglionic Excitatory Innervation of the Mouse Urinary Bladder and Its Modulation by Prejunctional Gababreceptors

Field stimulation produced reproducible contractions of the mouse isolated urinary bladder whose amplitude was frequency‐related. These contractions were partially sensitive to atropine (3 μM), unaffected by hexamethonium (10 μM.) and almost abolished by tetrodotoxin (0.5 μM ). Atropine (3 μM) suppressed contractions produced by exogenous acetylcholine thereby indicating atropine‐resistance of the nerve‐mediated contractions. Nerve‐mediated contractions of the mouse urinary bladder were enhanced by physostigmine (0.1‐0.5 μM) and inhibited by hemicholinium‐3 (0.5 mM) thus confirming the presence of a cholinergic component in the excitatory postganglionic innervation. Atropine (3 μM) inhibition of the nerve‐mediated contractions increased with increasing duration and strength of the train of stimulation. The nerve‐mediated contractions of the mouse bladder were unaffected by phentolamine (0.2 μM), propranolol (0.3 μM) or indomethacin (5 μM).ATP (1mM) the major candidate for the role of nonadrenergic‐noncholinegic (NANC) excitatory neurotransmitter in the mammalian urinary bladder produced a contraction of the mouse isolated bladder. Exposure to the stable ATP analogue α,β‐methylene ATP (APCPP) or β,γ‐methylene ATP (APPCP) produced a partial desensitization of the nerve‐mediated response which, for APCPP, was greater in the presence than in the absence of atropine (3 μM). In the presence of atropine (3 /zM) and after APCPP desensitization the amplitude of the response to field stimulation amounted to about 20% of the original response and was sensitive to tetrodotoxin, indicating that it is nerve‐mediated. GABA (0.001‐0.3 mM) inhibited the amplitude of field stimulation induced contractions of mouse urinary bladder. This effect was mimicked by the selective GABA B receptor agonist, (±)‐baclofen, but not by the selective GABA A receptor agonist, homotaurine. GABA and (±)‐baclofen exhibited cross‐desensitization. The GABA‐ or (±)‐baclofen‐induced inhibition of the nerve‐mediated contractions were reduced by previous exposure to homotaurine (1 mM) or to 5‐aminovaleric acid (2 mM), two GABA B receptor antagonists. On the other hand the inhibitory effects of GAB A or (±)‐baclofen were unaffected by picrotoxin (0.1 mM), a selective GABA A receptor antagonist. The inhibitory effect of GABA on nerve‐mediated contractions was reduced in the presence of atropine or hemicholinium‐3 as well as following desensitization of P 2 ‐purinoreceptors. The action of GABA was unaffected by phentolamine, propranolol or indomethacin. GABA had no effect toward field stimulation‐induced contractions in the presence of tetrodotoxin (0.5 μM.) (pulse width 30 msec) thus indicating the neurogenic origin of its inhibitory effect. GABA had no effect on bladder contractions induced by acetylcholine or ATP. These findings indicate that the postganglionic excitatory innervation of the mouse urinary bladder involves a cholinergic as well as a NANC component which may be due to release of endogenous ATP. It appears that in this preparation GABA inhibits the nerve‐mediated contractions through prejunctional GABA B receptors whose activation reduces neurotransmitter release from postganglionic nerve endings.