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)