Pharmacological actions of AH-9700 on micturition reflex in anesthetized rats

Abstract

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for σ receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for σ₁ receptors was significantly reduced in the presence of 5′-guanylyl-imidodiphosphate (GppNHp). In isolated bladder strips of rats, AH-9700 inhibited carbachol-induced contractions. In anesthetized rats, i.v. administration of AH-9700 and typical σ receptor ligands, (+)-pentazocine and 1,3-di-o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhibited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybutynin suppressed the amplitude of rhythmic bladder contractions. On the other hand, at doses lower than used i.v., the i.c.v. administration of AH-9700 or the σ receptor ligands inhibited rhythmic bladder contractions without suppressing the amplitude. This inhibitory effect of AH-9700 was markedly reduced by pretreatment with i.c.v. pertussis toxin. These results suggest that AH-9700 exerts a marked anti-micturition reflex effect through central σ receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.

Introduction

The number of patients suffering from urinary incontinence has been increasing in aging societies. The International Continence Society (1998) has defined four types of urinary incontinence: urge, genuine stress, reflex and overflow. Among them, urge incontinence is frequently observed in elderly patients. Although urinary incontinence is not a mortal disease, patients live an inconvenient life.

All existing drugs for the treatment of urge incontinence and frequent urination are characterized by their common ability to relax detrusor smooth muscles, based on anti-muscarinic and/or Ca²⁺-antagonistic properties. However, these drugs cause systemic adverse effects such as dry mouth, blurred vision, constipation and hypotension, which restrict their clinical use (Ferguson and Christopherm, 1996). For example, oxybutynin, a currently used drug for the treatment of urge incontinence and frequent urination, frequently causes (at least 50%) anti-muscarinic adverse effects Moisey et al., 1980, Yarker et al., 1995. Therefore, a new drug, which can facilitate urine storage through a different mechanism, has long been desired.

A σ-receptor was initially proposed by Martin et al. (1976) to explain the psychotomimetic actions of N-allyl-normetazocine. Following subsequent biochemical and pharmacological studies, the σ receptor has been categorized into at least two subtypes, termed σ₁ and σ₂ Walker et al., 1990, Quirion et al., 1992. Earlier studies have demonstrated that σ receptors relate to diverse pharmacological effects, for example, antipsychotic, antidepressant, anxiolytic, neuroprotective, anti-amnesic, anti-inflammatory, anti-tussive, anti-ulcer, intestinal motility modulation and anti-ion transport effects Su et al., 1988, Walker et al., 1990, Su, 1991, Junien et al., 1991, Kamei et al., 1992, Riviere et al., 1993, Maurice et al., 1998, Nakazawa et al., 1998. In addition, we have shown for the first time that i.v. or i.c.v. administration of typical σ receptor ligands such as (+)-pentazocine or 1,3-di-o-tolylguanidine (DTG) increases bladder capacity on cystometrograms in rats, and central σ receptor(s) may play an important role in the micturition controlling system (Shimizu et al., 2000).

Recently, we have found that our newly synthesized compound, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl]pyrrolidine fumarate, Fig. 1), has a high affinity for σ receptors and facilitates urine storage in experimental animals. The present paper describes the pharmacological actions of AH-9700 in comparison to those of (+)-pentazocine, DTG and oxybutynin.