A substantial part of urethral tone, which is an important factor for the maintenance of intra-urethral pressure, is mediated through stimulation of -adrenoceptors. The pharmacological treatment of stress incontinence aims at increasing intra-urethral pressure by increasing tone in the urethral smooth muscle with
₁-adrenoceptor agonists (Andersson et al 1999). To date such agonists have lacked sufficient efficacy in clinical trials. This study investigates the role of desensitisation as a possible reason for the failure of these agonists as therapeutic agents.

Strips of pig urethral circular smooth muscle and human prostate chips from trans-urethral resection of the prostrate operations were set up under 1g tension in gassed Krebs-bicarbonate solution at 37°C. An initial concentration-response curve was obtained to noradrenaline. After washout the tissues were incubated for 2-hours with an EC₅₀ concentration of noradrenaline, methoxamine or A61603. Following a 30 minute washout, a second concentration-response curve to noradrenaline was then obtained. All stages of the experiments were performed in the presence of cocaine (10µM), corticosterone (10µM) and propranolol (1µM) to inhibit amine uptake and ß-adrenoceptors respectively. Results are expressed as the mean ± sem, with paired student's t-test used for statistical comparisons.

On pig urethra noradrenaline and A61603 were full agonists with pEC₅₀ values of 6.01±0.06 (n=50) and 7.31±0.11 (n=4), whilst methoxamine was a partial agonist (82%), with a pEC₅₀ value of 5.01±0.10 (n=7). In the human prostate noradrenaline and A61603 were full agonists with a mean pEC50 of 5.74±0.07 (n=6) and 6.85±0.08 (n=6) whilst methoxamine was a partial agonist (35%) with a pEC50 value of 4.55±0.03 (n=6).

During incubation of the pig urethra with EC₅₀ concentrations of the agonists, over the 120 minutes tension fell by 63.7±17.6% for noradrenaline, 36.9±15.5% for A61603 and 77.15±8.10% for methoxamine. Similarly in the human prostate over the 120 minute incubation tension fell by 45.4±7.9% for noradrenaline, 45.5±3.2% for A61603 and 68.1±6.8% for methoxamine.

Table 1 Effect of agonist incubation on responses to noradrenaline. Results are means ± sem * significantly different P<0.05; # P<0.01 paired student t-test.

In contrast to the incubation with the endogenous agonist noradrenaline, A61603 and methoxamine significantly depress subsequent responses to noradrenaline in the pig urethra and human prostate (Table 1). It appears these agonists have the ability to desensitise the ₁-adrenoceptors with a desensitisation potency order of methoxamine > A61603 > noradrenaline. Further investigation is required to determine the mechanisms behind this desensitisation.

Andersson KE. et al., (1999) BJU Int. 84, 923-947.