Selectivity of oxymetazoline for urethral pressure vs blood pressure in the anaesthetized female rabbit.

OBJECTIVE: The aim of this study was to test alpha-adrenergic reference agonists for tissue selectivity in the urethra and to pharmacologically characterize the functional alpha-adrenoceptor type of the female rabbit urethra in vivo. MATERIAL AND METHODS: The effect of alpha-adrenergic agonists and antagonists on the urethral pressure was compared with that on blood pressure and heart rate measured simultaneously in the anaesthetized female rabbit. RESULTS: Oxymetazoline, NS-49, phenylephrine and phenylpropanolamine enhanced the urethral pressure in a dose-dependent manner. Phenylephrine and phenylpropanolamine also enhanced the blood pressure with significantly lower ED50 (dose that gives half of the maximal enhancing effect) values than for the urethral pressure. This was in contrast to oxymetazoline and NS-49. The ED50 values for oxymetazoline on urethral pressure, and systolic and diastolic blood pressure were 0.00067, 0.0030 and 0.0020 mg/kg, respectively. The ED50 values for NS-49 on urethral pressure, and systolic and diastolic blood pressure were 0.019, 0.21 and 0.18 mg/kg, respectively. Clonidine and UK 14,304 had no effect on urethral or blood pressure. The oxymetazoline-evoked increase in urethral pressure was inhibited by WB-4101 with an ID50 (dose that gives half of the inhibitory effect) significantly lower than that for rauwolscine. CONCLUSIONS: The results suggest that in the female rabbit in vivo activation of alpha1-adrenoceptors increased the urethral pressure. Phenylephrine and phenylpropanolamine, in contrast to oxymetazoline and NS-49, selectively enhanced blood pressure as compared with urethral pressure. Provided that the present results also have validity in humans, it would seem possible to develop urethra-selective drugs for treatment of stress incontinence with few or no cardiovascular side-effects.

Characterisation of the functional alpha-adrenoceptor subtype in the isolated female pig urethra.

The aim of the present study is to characterise the contraction-mediating functional alpha-adrenoceptor of the female pig urethra. Alpha-adrenoceptor reference agonists were used to contract the isolated female pig urethra. The relative intrinsic activity was noradrenaline (1.0), phenylephrine (0.91), methoxamine (0.74), (+/-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethane-sulfonanilid e hydrochloride (NS-49) (0.68), oxymetazoline (0.60), dopamine (0.50), clonidine (0.43), midodrine (0.32), ephedrine (0.30), 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK 14,304) (0.11), and phenylpropanolamine (0.11). The 21 competitive antagonists used caused parallel rightward shifts in the alpha-adrenoceptor agonist concentration-response curves, giving linear Schild-plots with slopes not significantly different from unity, suggesting that contraction was mediated by a single receptor. The antagonist pK(B) values calculated were R(-)-tamsulosin (9.68), risperidone (9.19), 2-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-4,4-dimethyl-1,3(2H,4H)-+ ++isoquinolinedione (AR-C 239) (9.09), 2-([2,6-dimethoxyphenoxyethyl]aminomethyl)-1,4-benzodioxane (WB-4101) (8.87), N-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-methyl-4-oxo-2-phenyl- 4H-1-benzopyran-8-carboxamide monomethanesulfonate (Rec 15/2739/3) (8.81), 5-methylurapidil (8.59), prazosin (8.57), benoxathian (8.56), S(+)-tamsulosin (8.27), indoramin (8.11), doxazosin (7.96), alfuzosine (7.82), phentolamine (7.70), terazosin (7.52), spiperone (7.48), oxymetazoline (7.40), 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]deca ne-7,9-dione dihydrochloride (BMY 7378) (7.05), corynanthine (6.98), rauwolscine (6.40), yohimbine (6.22), and N-[2-(2-cyclopropylmethoxyphenoxy)ethyl]-5-chloro-alpha,alpha-dime thyl-1H-indole-3-ethanamine hydrochloride (RS 17053) (6.07). Correlation of subtype-selective antagonist pK(B) values was best with published values for the alpha1a/1A-adrenoceptor subtype. Therefore, the present results suggest that contraction of the female pig urethra is caused by activation of the alpha1A-adrenoceptor.

The effect of phenylpropanolamine on the urethral pressure and heart rate is retained after repeated short-term administration in the unanaesthetized, conscious dog.

The present study was performed to test whether high dose agonist (phenylpropanolamine) administration twice a day causes desensitization of urethral alpha-adrenoceptors in vivo. Urethral pressure was measured on five consecutive days of phenylpropanolamine treatment of the unanaesthetized, conscious dog, and the method is described in detail. Phenylpropanolamine hydrochloride proper (75 mg, 5.1-6.1 mg kg-1), and a sustained-release formulation, both significantly increased urethral pressure and decreased heart rate. Interruption of administration for two to three days did not alter the effect. The present results suggest that the effect of phenylpropanolamine was retained, and that the alpha-adrenoceptors of dog urethra did not desensitize after repeated administration of the alpha-adrenoceptor agonist phenylpropanolamine twice a day.