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

In radioligand binding assays, AH-9700 (1-[2-(3,4-dihydro-6,7-dimethyl-2-na phthalenyl)ethyl]pyrrolidine fumarate) had high affinity for sigma receptor s and moderate affinity for muscarinic receptors. The affinity of AH-9700 f or sigma (1) receptors was significantly reduced in the presence of 5'-guan ylyl-imidodiphosphate (GppNHp). In isolated bladder strip s of rats, AH-970 0 inhibited carbachol-induced contractions. In anesthetized rats, i.v. admi nistration of AH-9700 and typical sigma receptor ligands, (+)-pentazocine a nd 1,3-di-o-tolylguanidine (DTG), but not oxybutynin, dose-dependently inhi bited rhythmic isovolumetric reflex bladder contractions. AH-9700 and oxybu tynin suppressed the amplitude of rhythmic bladder contractions. On the oth er hand, at doses lower than used i.v., the i.c.v. administration of AH-970 0 or the sigma receptor ligands inhibited rhythmic bladder contractions wit hout suppressing the amplitude. This inhibitory effect of AH-9700 was marke dly reduced by pretreatment with i.c.v. pertussis toxin. These results sugg est that AH-9700 exerts a marked anti-micturition reflex effect through cen tral sigma receptors possibly related to pertussis toxin-sensitive Gi/o-pro teins and a moderate spasmolytic effect based on its peripheral anti-muscar inic activity. (C) 2001 Elsevier Science B.V. All rights reserved.