Anticholinergic and calcium antagonistic activities of NS-21 contribute to the inhibition of rat urinary bladder contractions.
1. Pharmacological characteristics of NS-21 and its main metabolite, RCC-36, in the inhibition of rat urinary bladder contractions were investigated both in vitro and in vivo. 2. NS-21 and RCC-36 inhibited muscarinic receptor bindings to rat bladder membranes with [3H]3-quinuclidinyl bezilate (pKi 6.19 and 7.24, respectively), whereas they failed to inhibit the following receptor bindings: adrenergic (alpha 1, alpha 2 and beta), dopaminergic (D1 and D2), adenosine (A1 and A2), histaminergic (H1) and opioid (mu, delta and kappa) receptors. 3. NS-21 and RCC-36 suppressed carbachol-induced contractions of isolated rat detrusor strips in competitive (pA2 6.80 and 7.93, respectively) and noncompetitive (pD'2 5.93 and 5.77, respectively) manners. 4. NS-21 and RCC-36 inhibited CaCl2-induced contractions of rat detrusor strips in the presence of 100 mM K+ (pIC50 6.54 and 5.76, respectively), as well as the 100 mM K(+)-induced 45Ca influx into the isolated bladder strips at > or = 1 microM. 5. Electrical stimulation of the peripheral end of the pelvic nerve in anesthetized rats induced bladder contractions composed of two phases: an initial phasic contraction that was weakly suppressed by atropine, and a tonic contraction that was strongly suppressed by atropine. NS-21 suppressed both contractions to the same degree (ID50 2.65 and 2.19 mg/kg, i.v., respectively). RCC-36 suppressed the tonic contraction (ID50 1.20 mg/kg, i.v.) more markedly than the initial contraction (ID50 7.43 mg/kg, i.v.). 6. These results suggest that NS-21 and RCC-36 suppressed bladder contractions owing to their anticholinergic and calcium antagonistic activities.
Hamada
K
K
Research Laboratories, Nippon Shinyaku Co., Ltd., Kyoto, Japan.
Sasaki
Y
Y
Taniguchi
N
N
Fukui
H
H
Miyatsuka
Y
Y
Kimura
Y
Y
Ukai
Y
Y
Yoshikuni
Y
Y
Kimura
K
K
D000818:Animals; D002121:Calcium Channel Blockers / Q000493:pharmacokinetics / Q000494:pharmacology*; D002122:Calcium Chloride / Q000494:pharmacology; D002132:Calcium Radioisotopes; D002217:Carbachol / Q000494:pharmacology; D018680:Cholinergic Antagonists / Q000493:pharmacokinetics / Q000494:pharmacology*; D004558:Electric Stimulation; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010277:Parasympathomimetics / Q000494:pharmacology; D010648:Phenylacetates / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000378:metabolism; D001743:Urinary Bladder / Q000187:drug effects* / Q000378:metabolism
D002121:Calcium Channel Blockers; D002132:Calcium Radioisotopes; D018680:Cholinergic Antagonists; D010277:Parasympathomimetics; D010648:Phenylacetates; D017981:Receptors, Neurotransmitter; D002217:Carbachol; C105354:temiverine; D002122:Calcium Chloride