GABAA AND GABAB RECEPTORS IN DETRUSOR STRIPS FROM GUINEA‐PIG BLADDER DOME

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Abstract
The effects of various GABAA and GABAB receptor agonists and antagonists on electrically induced contractions of detrusor strips from guinea-pig urinary bladder dome were investigated by using both supra and submaximal parameters of stimulation. In supramaximally stimulated preparations GABA (1 mM) inhibited amplitude to contractions. This effect was mimicked, to a lesser degree, by the selective GABAB receptor agonist, (.+-.)-baclofen (0.1 mM). Exposure to (.+-.)-baclofen reduced markedly the effects of a subsequent challenge with GABA. The GABAA receptor agonists, muscimol (0.3 mM) and homotaurine (1 mM), produced a slight inhibition of contractions and reduced the effects of a subsequent challenge with GABA. The selective GABAA receptor antagonist, picrotoxin (0.1 mM), had a slight, but significant, antagonistic effect toward GABA, but had no effect against (.+-.)-baclofen. GABA inhibition of supramaximally stimulated contractions was partly reduced by previous exposure to atropine (3 .mu.M) or to the putative P2-purinoreceptor antagonist, reactive blue 2 (0.3 mM) as well as by desensitization of P2-purinoreceptors produced by the stable ATP analogue .beta.-.gamma. methylene ATP (APPCP). GABA inhibition was unaffected by phentolamine (0.2 .mu.M), propranolol (0.3 .mu.M) or hexamethonium (10 .mu.M). The inhibition produced by atropine plus reactive blue 2 or APPCP desensitization was additive or more than additive. In submaximally stimulated preparations GABA (0.01-1 mM) produced a transient, concentration related enhancment of amplitude of contractions. This effect was minicked by either muscimol (0.3 mM) or homotaurine (1 mM) but not by (.+-.)-baclofen (0.1 mM). A cross desensitization could be observed between the effects of muscimol or homotaurine on one hand and GABA on the other, but not between (.+-.)-baclofen and GABA. Picrotoxin (0.03-0.1 mM) produced a concentration dependent antagonism of a noncompetitive type against the excitatory effect of GABA in submaximally stimulated preparations. Previous exposure to either atropine (3 .mu.M), phentolamine (0.2 .mu.M) or hexamethonium (10 .mu.M) failed to affect GABA induced enhancement of submaximally stimulated contractions. On the other hand the effects of GABA were reduced by reactive blue 2 (0.1-0.9 mM) or by desensitization of P2-purinoreceptors. In preparations exposed to tetrodotoxin (TTX, 0.3 .mu.M), field stimulation induced contractions are attributable to a direct excitation of smooth muscle cells. Under these conditions GABA (1 mM) was ineffective, indicating that, in the absence of TTX, it affects the excitability of neural elements in the bladder wall. Results indicate that activation of GABAA and GABAB receptors modulates the release of neurotransmitter(s) from postganglionic nerve endings in the dome of the guine-pig urinary bladder. In supramaximally stimulated preparations the activation of GABAB receptors reduces both the cholinergic and the nonadrenergic-noncholinergic (NANC) component of the excitatory neurotransmission. However a slight component of the effect of GABA is ascribable to the activation of GABAA receptors. On the other hand, in submaximally stimulated preparations activation of GABAA receptors appears to produce a transient enhancement of the NANC component of the excitatory neurotransmission.