1-(2-pyrimidinyl)-piperazine, a buspirone metabolite, modulates bladder function in the anesthetized rat.
OBJECTIVE
To examine the effects of 1-(2-pyrimidinyl)-piperazine (1-PP), a buspirone metabolite, on bladder function in vivo.


METHODS
Micturition reflexes in the rat were evaluated in two models of bladder function; a constant infusion model employing 0.5% acetic acid and an isovolumic model.


RESULTS
In the constant infusion model, 1-PP (0.14-1.32 mg/kg) dose-dependently and significantly decreased the number of bladder contractions measured during a 30 min recording period, with little effect on the pressure developed during each contraction. 1-PP is an alpha2-adrenergic receptor antagonist. The alpha2 antagonists BRL44408 (alpha2A vs. alpha2B selective; 0.3 and 1 mg/kg), imiloxan (alpha(2B) vs. alpha2A selective; 1 mg/kg), and yohimbine (non-subtype selective; 1 mg/kg; but not 0.3 mg/kg) also significantly reduced the number of contractions. Vehicle was without effect. In the isovolumic model, 1-PP (0.03-1.0 mg/kg) produced a dose-dependent and significant reduction in the number of bladder contractions recorded during a 15 min assessment period, with the maximum effect observed at 0.3 mg/kg. 1-PP had little effect on blood pressure; the only effect was observed at the highest dose (1 mg/kg) where it produced a transient 17% decrease in pressure. Cromakalim and tolterodine served as comparitors in all studies.


CONCLUSIONS
1-PP decreased the number of bladder contractions evoked by the micturition reflex at doses that had little effect on either the pressure developed during each bladd er contraction or on blood pressure. The effects of 1-PP are likely mediated primarily by alpha2 receptor antagonism.
Myers
Robert A
RA
Bristol-Myers Squibb Pharmaceutical Research Institute, Neuroscience Drug Discovery, Wallingford, Connecticut 06492, USA.
Plym
Mary Jane
MJ
Signor
Laura J
LJ
Lodge
Nicholas J
NJ
D018528:ATP-Binding Cassette Transporters; D019342:Acetic Acid; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000758:Anesthesia; D000818:Animals; D001559:Benzhydryl Compounds / Q000494:pharmacology; D002065:Buspirone / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003408:Cresols / Q000494:pharmacology; D019806:Cromakalim / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D054833:Isoindoles; D054086:KATP Channels; D018727:Muscarinic Antagonists / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010665:Phenylpropanolamine / Q000494:pharmacology; D015221:Potassium Channels / Q000819:agonists; D024661:Potassium Channels, Inwardly Rectifying; D051381:Rats; D017208:Rats, Wistar; D000068737:Tolterodine Tartrate; D001743:Urinary Bladder / Q000187:drug effects*; D014563:Urodynamics / Q000187:drug effects; D015016:Yohimbine / Q000494:pharmacology
D018528:ATP-Binding Cassette Transporters; D058669:Adrenergic alpha-2 Receptor Antagonists; D000317:Adrenergic alpha-Antagonists; D001559:Benzhydryl Compounds; D003408:Cresols; D007093:Imidazoles; D007211:Indoles; D054833:Isoindoles; D054086:KATP Channels; D018727:Muscarinic Antagonists; D015221:Potassium Channels; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel; D019806:Cromakalim; D015016:Yohimbine; D010665:Phenylpropanolamine; D000068737:Tolterodine Tartrate; C037921:1-(2-pyrimidinyl)piperazine; D019342:Acetic Acid; D002065:Buspirone; C072125:BRL 44408; C044484:Imiloxan