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-naphthalenyl)ethyl]pyrrolidine fumarate) had high affinity for sigma receptors and moderate affinity for muscarinic receptors. The affinity of AH-9700 for sigma(1) 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 sigma 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 sigma 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 sigma receptors possibly related to pertussis toxin-sensitive Gi/o-proteins and a moderate spasmolytic effect based on its peripheral anti-muscarinic activity.
Shimizu
I
I
Department of Pharmacology I, Discovery Research Laboratories, Dainippon Pharmaceutical Co., Ltd., 33-94 Enoki-cho, Osaka 564-0053, Suita, Japan. isao-shimizu@dainippon-pharm.co.jp
Kawashima
K
K
Ishii
D
D
Oku
S
S
Kohayakawa
H
H
Oka
M
M
D000758:Anesthesia; D000818:Animals; D018680:Cholinergic Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005650:Fumarates / Q000494:pharmacology; D006801:Humans; D008297:Male; D008333:Mandelic Acids / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009281:Naphthalenes / Q000494:pharmacology; D009292:Narcotic Antagonists / Q000494:pharmacology*; D010423:Pentazocine / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017480:Receptors, sigma / Q000187:drug effects* / Q000378:metabolism; D012018:Reflex / Q000187:drug effects*; D001743:Urinary Bladder / Q000187:drug effects* / Q000502:physiology; D014554:Urination
D018680:Cholinergic Antagonists; D005650:Fumarates; D008333:Mandelic Acids; D009281:Naphthalenes; D009292:Narcotic Antagonists; D017480:Receptors, sigma; C437044:1-(2-(3,4-dihydro-6,7-dimethyl-2-naphthalenyl)ethyl) pyrrolidine fumarate; C005419:oxybutynin; D010423:Pentazocine