title: NS-49, an alpha 1A-adrenoceptor agonist, selectively increases intraurethral pressure in dogs.
abstract: The effects of NS-49 ((R)-(-)-3'-(2-amino-1-hydroxyethyl)-4'-fluoromethane sulfonanilide hydrochloride), an alpha 1A-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 alpha 1-adrenoceptor agonists. Intravenously (i.v.) administered NS-49 at 0.3 microgram/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 micrograms/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 alpha 1A-adrenoceptor-selective antagonists 5-methyl-urapidil and WB-4101 also showed high affinity for alpha 1-adrenoceptors in the dog urethra in inhibiting [3H]prazosin binding. In conclusion, the alpha 1A-selective agonist NS-49 selectively increased intraurethral pressure in dogs, and produced selective contraction of the dog urethra. These results suggest that the alpha 1A-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.
authors.affiliation: Research Laboratories, Nippon Shinyaku Co. Ltd., Kyoto, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Taniguchi
authors.forename: K
authors.initials: K
authors.lastname: Hamada
authors.forename: T
authors.initials: T
authors.lastname: Ogasawara
authors.forename: Y
authors.initials: Y
authors.lastname: Ukai
authors.forename: Y
authors.initials: Y
authors.lastname: Yoshikuni
authors.forename: K
authors.initials: K
authors.lastname: Kimura
mesh_terms: D000316:Adrenergic alpha-Agonists / Q000494:pharmacology*; D000813:Anilides / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002339:Carotid Arteries / Q000187:drug effects; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism; D008297:Male; D008879:Midodrine / Q000031:analogs & derivatives / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011224:Prazosin / Q000494:pharmacology; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism / Q000502:physiology*; D013363:Submandibular Gland / Q000378:metabolism; D014521:Urethra / Q000187:drug effects* / Q000502:physiology
chemical_list: C092989:3'-(2-amino-1-hydroxyethyl)-4'-fluoromethanesulfonanilide; D000316:Adrenergic alpha-Agonists; D000813:Anilides; D018340:Receptors, Adrenergic, alpha-1; C006146:ST 1059; D008879:Midodrine; D011224:Prazosin