A standardised mini pig model for in vivo investigations of anticholinergic effects on bladder function and salivation.
OBJECTIVE
The objective was to validate an in vivo model for evaluation of pharmacological effects on bladder function taking the most predominant anticholinergic side effect (hyposalivation) into account. Therefore, two anticholinergic properties (propiverine hydrochloride and tolterodine-L(+)-tartrate) were used to test the in vivo model. Sacral anterior root stimulation (SARS) was performed to induce reproducible and standardized bladder contractions. To evaluate hyposalivation standardised salivavary flow measurements by stimulating the lingual nerve was performed in addition to SARS.


METHODS
10 male mini pigs were anaesthetised. The carotid artery was cannulated for blood pressure measurement and the jugular vein for administration of propiverine 0.4 mg kg(-1) b.w. and tolterodine 0.06 mg kg(-1) b.w. For stimulation-induced salivary flow measurements both lingual nerves were exposed and a cuff electrode was placed around the nerves. The bladder was exposed and a cystostomy catheter was inserted to performed cystometrographic measurements during SARS.


RESULTS
In all experiments, for each animal reproducible intravesical pressure values (pves) and salivary flow rates were elicited during electrostimulation before administration of the drug. Bladder pressure: After administration of propiverine, neurostimulation-induced rise in pves had fallen by 60% from the initial value. After administration of tolterodine pves had fallen by about 50%. After additional administration of atropine pves decreased to about 15% of the initial value for both drugs. Salivation: After propiverine salivary flow had fallen by 61%. Inhibition of salivary flow under tolterodine was about 56%. Additional administration of atropine led in both drugs to a nearly complete blockade of salivation. Heart rate (HR) and blood pressure (BP): Directly following intravenous administration of both drugs, a short-term and reversible period of mild but significant fluctuations in HR was observed. There was also a slight but non-significant rise in blood pressure.


CONCLUSIONS
This model allows comparative investigations of various drugs with bladder inhibitory properties in terms of acute efficacy and side effects.
Scheepe
Jeroen Ronald
JR
Department of Urology and Paediatric Urology, Erasmus MC, University Medical Centre, Rotterdam, The Netherlands. j.scheepe@erasmusmc.nl
van den Hoek
Joop
J
Jünemann
Klaus-Peter
KP
Alken
Peter
P
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D001559:Benzhydryl Compounds / Q000494:pharmacology; D001561:Benzilates / Q000494:pharmacology; D001794:Blood Pressure / Q000187:drug effects; D018680:Cholinergic Antagonists / Q000494:pharmacology* / Q000633:toxicity; D003408:Cresols / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods / Q000592:standards*; D004558:Electric Stimulation; D006339:Heart Rate / Q000187:drug effects; D008036:Lingual Nerve; D008297:Male; D023421:Models, Animal; D009119:Muscle Contraction / Q000187:drug effects*; D010665:Phenylpropanolamine / Q000494:pharmacology; D015203:Reproducibility of Results; D012469:Salivary Glands / Q000187:drug effects* / Q000294:innervation / Q000503:physiopathology; D012472:Salivation / Q000187:drug effects*; D013552:Swine; D013556:Swine, Miniature; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects* / Q000294:innervation; D014987:Xerostomia / Q000139:chemically induced* / Q000503:physiopathology
D001559:Benzhydryl Compounds; D001561:Benzilates; D018680:Cholinergic Antagonists; D003408:Cresols; D010665:Phenylpropanolamine; C015586:propiverine; D000068737:Tolterodine Tartrate; D001285:Atropine