The effects of a new selective β3‐adrenoceptor agonist (GW427353) on spontaneous activity and detrusor relaxation in human bladder

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Abstract
OBJECTIVE: To examine the effects of a new selective β3‐adrenoceptor agonist, GW427353 on human detrusor function, as β2‐ and β3‐adrenoceptors have been identified in the bladder, and can mediate detrusor relaxation, but β3‐adrenoceptors are less widely distributed and β3‐adrenoceptor agonists should have the therapeutic advantage of producing fewer treatment side‐effects.PATIENTS AND METHODS: ‘Normal’ human detrusor was retrieved from 12 patients (mean age 56 years) at cystectomy and from organ donors. Detrusor strips (4 × 1 × 1 mm) were mounted in superfused organ baths. Tone was induced with carbachol (5 × 10−7m) before applying either a nonselective β‐adrenoceptor agonist (isoprenaline) or GW427353 (with or without the β3‐adrenoceptor antagonist, SR59230A). In addition, the effect of GW427353 was tested on intrinsic nerve‐evoked smooth muscle contraction over time. Effects on spontaneous activity were also recorded.RESULTS: GW427353 produced significant relaxation at concentrations of >10−7m; isoprenaline produced a significant effect from 10−6m, but otherwise both agonists had similar effects. The addition of SR59230A (10−7m), produced partial inhibition of the GW427353 response. GW427353 at 10−6msignificantly reduced spontaneous activity within 10 min of incubation, and at higher concentrations (>5 × 10−6m) inhibited detrusor contractions evoked by electrical field stimulation.CONCLUSION: Neuropathic bladder dysfunction is characterized by increased spontaneous activity and involuntary detrusor contractions, which can result in urinary frequency, urgency, nocturia and incontinence. The novel feature of GW427353 is the ability to suppress spontaneous activity and produce significant relaxation in human detrusor tissue at low concentrations, whilst also inhibiting evoked detrusor contractions at higher concentrations.