Urinary bladder smooth muscle is innervated by both sympathetic and parasympathetic nerves. Acetylcholine released from postganglionic parasympathetic nerve terminals activates postjunctional muscarinic receptors in urinary bladder, which modulate urinary bladder contraction during the voiding phase and control detrusor tone during the filling phase. Five muscarinic receptor subtypes (M 1 -M 5 ) have been identified by both molecular biological and pharmacological investigations.1) The urinary bladder smooth muscle contains a mixed population of muscarinic M 2 and M 3 receptors.2) Although muscarinic M 2 receptors are numerically predominant, muscarinic M 3 receptors are considered to predominate in the mediation of bladder contraction.3,4) An important functional role of the muscarinic M 3 receptor in mediating bladder contraction has also been suggested in experiments using mutant mice lacking the muscarinic M 3 receptor gene. 5)Overactive bladder is characterized by symptoms of urgency and urinary frequency with or without urge incontinence. It has a profoundly negative effect on the quality of life of those affected. Muscarinic receptor antagonists are the most widely used therapy for overactive bladder.6-8) Solifenacin succinate [YM905; (3R)-1-azabicyclo[2.2.2]oct-3-yl(1S)-1-phenyl-3,4-dihydroisoquinoline-2(1H)-carboxylate monosuccinate] is a new muscarinic receptor antagonist developed for the treatment of overactive bladder. Affinity constants (K i values) of this drug for human muscarinic M 1 , M 2 and M 3 receptors only have been reported, along with its antagonism of the contractile effect of carbachol in isolated guinea pig urinary bladder.9) The present study was therefore undertaken to investigate the affinity of solifenacin for all human muscarinic receptor subtypes (M 1 -M 5 ) and its functional muscarinic M 3 receptor antagonism in rats, and to compare the results with those for tolterodine, oxybutynin, darifenacin, propiverine and atropine. Additionally, we also investigated the effect of solifenacin on voiding function in anesthetized rats. MATERIALS AND METHODS MaterialsSolifenacin succinate (YM905, Vesicare ® ), tolterodine tartrate, darifenacin and propiverine hydrochloride were prepared by Astellas Pharma Inc. (Tokyo, Japan). Oxybutynin chloride, atropine sulfate and carbachol (carbamylcholine chloride) were purchased from Sigma-Aldrich (St. Louis, MO, U.S.A.). Darifenacin was dissolved in dimethyl sulfoxide and the others were dissolved in dimethyl sulfoxide, Krebs-Henseleit solution or physiological saline.Animals Male Wistar rats and male Sprague-Dawley rats were purchased from Charles River Laboratories Japan (Kanagawa, Japan) and Japan SLC (Shizuoka, Japan), respectively. In in vitro studies, rats were sacrificed by exsanguination under ether anesthesia. All animal experiments were performed in compliance with the regulations of the Institutional Animal Ethical Committee of Astellas Pharma Inc.Radioligand Receptor Binding Assay Membranes of Chinese hamster ovary (CHO)-K1 cells expressi...

No abstract

Bladder over distention/emptying induced bladder blood flow decrease/partial recovery and caused bladder overactivity via a mechanism other than capsaicin sensitive C-fiber activation. Findings in tamsulosin treated rats confirmed the potency of tamsulosin to increase bladder blood flow and ameliorate bladder overactivity.

No abstract

Alpha1-adrenoceptors mediate contraction of iris dilator smooth muscle and hence pupil dilatation. We compared the ability of i.v. bolus injections of alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin to antagonise phenylephrine-induced mydriasis relative to their potency for inhibiting phenylephrine-induced elevations of intraurethral pressure (IUP) in rabbits. Moreover, we compared the ability of these drugs to induce miosis in conscious rabbits in the absence of phenylephrine. All antagonists inhibited the effects of phenylephrine on pupil size and IUP, and the ratio of the respective ED50 values was close to unity in all cases. The doses required to induce statistically significant miosis in the absence of phenylephrine were 30- to 100-fold higher than those inhibiting phenylephrine-induced mydriasis for all antagonists, except for naftopidil. Moreover, the miotic effects of all alpha1-adrenoceptor antagonists were fully reversible within 8 h. We conclude that alfuzosin, doxazosin, naftopidil, prazosin, tamsulosin and terazosin inhibit phenylephrine-induced mydriasis in the same dose range as they inhibit elevations in IUP. Higher doses of all antagonists are required to induce miosis in the absence of an exogenous agonist, and such miosis is always reversible within hours.

No abstract

No abstract

Activation of mu-opioid receptors in the nucleus accumbens (NAc) is known to increase accumbal dopamine efflux in rats. Endomorphin-2 (Tyr-Pro-Phe-Phe-NH 2 ; EM-2) and endomorphin-1 (Tyr-Pro-Trp-Phe-NH 2 ; EM-1) are suggested to be the endogenous ligands for the mu-opioid receptor. As the ability of EM-2 and EM-1 to alter the accumbal extracellular dopamine level has not yet been studied in freely moving rats, the present study was performed, using a microdialysis technique that allows on-line monitoring of the extracellular dopamine with a temporal resolution of 5 min. A 25 min infusion of either EM-2 or EM-1 into the NAc (5, 25, and 50 nmol) produced a dose-dependent increase of the accumbal dopamine level. The EM-2 (50 nmol)-and EM-1 (25 and 50 nmol)-induced dopamine efflux were abolished by intra-accumbal perfusion of tetrodotoxin (2 mM). Intra-accumbal perfusion of the mu-opioid receptor antagonist CTOP (D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Phe-Thr-NH 2 ; 3 nmol) failed to affect the EM-2 (50 nmol)-induced dopamine release, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine release. The EM-1 (50 nmol)-induced accumbal dopamine efflux was significantly reduced by the systemic administration of the putative mu1-opioid receptor antagonist naloxonazine (15 mg/kg, intraperitoneally (i.p.), given 24 h before starting the perfusion). Systemic administration of the aspecific opioid receptor antagonist naloxone (1 mg/kg, i.p., given 10 or 20 min before starting the perfusion) also failed to affect the EM-2 (50 nmol)-induced dopamine efflux, whereas it significantly inhibited the EM-1 (25 and 50 nmol)-induced dopamine efflux. The present study shows that the intra-accumbal infusion of EM-2 and EM-1 increases accumbal dopamine efflux by mechanisms that fully differ. It is concluded that the effects of EM-2 are not mediated via opioid receptors in contrast to the effects of EM-1 that are mediated via mu1-opioid receptors in the NAc.