Mini-pig urinary bladder function: comparisons of in vitro anticholinergic responses and in vivo cystometry with drugs indicated for urinary incontinence.
1. Studies of carbachol-induced contractions on mini-pig bladder tissue strips in vitro demonstrated that antagonist drugs produced a rank order of potency similar to that observed in guinea-pig tissues: propantheline approximately atropine greater than oxybutynin greater than dicyclomine greater than HHSiD greater than imipramine greater than terodiline approximately AF-DX 116. The drugs appeared to show competitive antagonism and the tissues exhibited resistance to complete cholinergic blockade. 2. Cytometry performed in vivo on awake mini-pigs also showed that i.v. cholinergic antagonists produced a dose-dependent depression of peak intravesical bladder pressure (PvesP) during slow filling of the bladder using urethral catheters, with a rank order of potency: atropine greater than oxybutynin approximately propantheline greater than HHSiD approximately dicyclomine greater than terodiline. Other parameters of the cystometrogram were unaffected by the antagonists, except for residual volume, which generally increased after drug treatment. 3. Hexahydrosiladifenidol (HHSiD), an ileal-selective competitive muscarinic antagonist, was about as effective an antagonist as the clinically useful drugs oxybutynin or dicyclomine, both in vitro and in vivo, suggesting that HHSiD may have useful therapeutic effects for the treatment of urinary incontinence. 4. Correlation of the rank order of potency for muscarinic antagonism between mini-pigs and guinea-pigs was very high in vitro (r = 0.97, P less than 0.05), as was the correlation among the drugs for their ability to depress PvesP of the cystometrogram in vivo (r = 0.89, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Peterson
J S
JS
Nova Pharmaceutical Corporation, Baltimore, Maryland 21224-2788.
Patton
A J
AJ
Noronha-Blob
L
L
D000818:Animals; D002217:Carbachol / Q000494:pharmacology; D005260:Female; D006168:Guinea Pigs; D009119:Muscle Contraction / Q000187:drug effects; D010276:Parasympatholytics / Q000494:pharmacology*; D013552:Swine; D013556:Swine, Miniature; D001743:Urinary Bladder / Q000033:anatomy & histology* / Q000187:drug effects; D014549:Urinary Incontinence / Q000188:drug therapy*
D010276:Parasympatholytics; D002217:Carbachol