Desensitisation of pig urethral but not internal anal sphincter (IAS) smooth muscle by aplha1-adrenoceptor agonists

Russell Chess-Williams, Jian Liu & Kathryn Bagot. Department of Biomedical Science, University of Sheffield, Sheffield S10 2TN.

The internal anal sphincter (IAS) contracts in response to α1-adrenoceptor agonists and variable success has been reported in studies where α1-adrenoceptor agonists have been used to treat faecal incontinence. Our previous studies have shown that incubation of pig urethra with α1-adrenoceptor agonists results in desensitisation of this tissue (Bagot et al., 2005). The present study investigates whether a similar mechanism also operates in the IAS of the pig.

Strips (with epithelium removed) of urethra and IAS from female pigs were set up at 37°C under 1g tension in gassed Krebs solution containing cocaine (1µM), corticosterone (10µM) and propranolol (1µM). Concentration-response curves to noradrenaline were obtained before and after incubation of tissues with EC50 concentrations of methoxamine or A61603 for 120min. Control experiments (no agonist during the incubation) were used to correct for time dependent changes in tissues sensitivity and responsiveness. Paired Students t test was used for statistical analysis.

When the IAS was incubated with an EC50 concentration of methoxamine (9.5µM) or A61603 (25nM), tissues contracted and maintained the contraction during the full 120min incubation. After incubation with the agonist and washout of the drug, subsequent concentration-response curves to noradrenaline were similar to controls. Thus, pEC50 values and maximum responses for noradrenaline following incubation of IAS strips were similar before (5.50±0.12 & 8.14±0.49g respectively) and after (5.28±0.09 & 8.13±0.40g) incubation with methoxamine (n=15). Similarly, IAS tissues were not desensitised by incubation with an EC50 concentration of A61603 for 120min (n=15), with the mean pEC50 value and maximum responses to noradrenaline after incubation with A61603 (5.29±0.10 & 7.13±0.38g respectively) being similar to control values obtained before incubation (5.62±0.17 & 6.45±0.52g).

In contrast, urethral tissues were readily desensitised. During the 120min incubation, tissues contacted initially but then tension declined by 25-60% during the incubation. Incubation of these smooth muscle strips with EC50 concentrations of methoxamine (9.4µ) or A61603 (50nM) caused a desensitisation of subsequent responses to noradrenaline with maximum responses being depressed by 55.8±7.3% (P<0.01, n=7) by incubation with methoxamine and by 41.7±6.1% (P<0.05, n=8) after incubation with A61603.

These data demonstrate a difference in the susceptibility of urethral and IAS smooth muscle to desensitisation by α1-adrenoceptor agonists and suggests that desensitisation may be less of a problem if these drugs were used to treat faecal incontinence than if they were used for stress incontinence.

Bagot et al. (2005) Eur. Urol. Supplements 4(3), p207, 820.