NS-49, an α1A-adrenoceptor agonist, selectively increases intraurethral pressure in dogs

The effects of NS-49 ((R)-(−)-3′-(2-amino-1-hydroxyethyl)-4′-fluoromethane sulfonanilide hydrochloride), an α1A-adrenoceptor-selective agonist, on intraurethral pressure and blood pressure were investigated in anesthetized dogs. In addition, the contractile effects of NS-49 on the isolated dog urethra and carotid artery were compared with those of non-selective α1-adrenoceptor agonists. Intravenously (i.v.) administered NS-49 at 0.3 μg/kg or more significantly increased intraurethral pressure in a dose-dependent manner. Much higher doses of NS-49 were needed to increase blood pressure. In contrast, ST-1059 (1-(2′,5′-dimethoxyphenyl)-2-aminoethanol) (an active metabolite of midodrine) at 30 μg/kg or more significantly increased both intraurethral pressure and blood pressure. NS-49 was 11-fold more selective for intraurethral pressure than ST-1059. NS-49, ST-1059, phenylephrine and noradrenaline caused concentration-dependent contraction of the isolated dog urethra. NS-49 caused only a slight contraction of the dog carotid artery even at high concentrations, whereas the reference drugs caused contractions of the artery with high efficacy. The α1A-adrenoceptor-selective antagonists 5-methylurapidil and WB-4101 also showed high affinity for α1-adrenoceptors in the dog urethra in inhibiting [3H]prazosin binding. In conclusion, the α1A-selective agonist NS-49 selectively increased intraurethral presure in dogs, and produced selective contraction of the dog urethra. These results suggest that the α1A-adrenoceptor subtype is responsible for the contraction of the urethra and the regulation of intraurethral pressure, and that NS-49 might be useful for the treatment of stress incontinence with little effect on the cardiovascular system.