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Durham, NC, United States

Kullmann F.A.,Urogenix Inc. Astellas | McKenna D.,Urogenix Inc. Astellas | Wells G.I.,Urogenix Inc. Astellas | Thor K.B.,Urogenix Inc. Astellas

Aims: Bombesin receptors (BB receptors) and/or bombesin related peptides are expressed in the lower urinary tract, though their function and distribution in different species is largely unknown. This study examines whether BB receptor agonists can contract bladder smooth muscle in rats, mice, pigs and humans. Methods: Bladder strips were placed in tissue baths for in vitro contractility. Neuronally evoked contractions were elicited using electric field stimulation (EFS). Effects of the BB receptor agonists, neuromedin B (NMB; BB1 receptor agonist) and gastrin-releasing peptide (GRP; BB2 receptor agonist) on baseline tone and EFS-induced contractions were monitored. Results: In rat and human bladder strips, NMB and GRP (10-11-10-6M) increased EFS-induced contractions in a concentration dependent manner. In these species, NMB and GRP also increased baseline tension. In mouse and pig bladder strips, NMB and GRP (10-8-3×10-6M) had no effects on either parameter. Conclusions: These data suggest that bombesin receptors BB receptor 1 and/or BB receptor 2 increase bladder contractions in rat and human. The site of action of these receptors may be pre- and/or post-synaptic, increasing release of transmitters or enhancing smooth muscle excitability, respectively. Thus, BB1 receptor and/or BB2 receptor may offer therapeutic targets for voiding dysfunction associated with impaired bladder contractility; however, species differences must be considered when studying these receptors.Part of this work was published in an abstract form at the SFN meeting New Orleans, 2012. © 2013 Elsevier Ltd. Source

Kullmann F.A.,Urogenix Inc. Astellas | Wells G.I.,Urogenix Inc. Astellas | McKenna D.G.,Urogenix Inc. Astellas | Thor K.B.,Urogenix Inc. Astellas
Life Sciences

Aims To determine if the muscarinic agonist, bethanechol, inhibits the non-cholinergic, atropine-resistant (i.e. putatively purinergic) component of naturally occurring (i.e. reflexogenic) bladder contractions in vivo in the rat, as previously described in vitro. Our second aim was to determine if elevation of endogenous acetylcholine (ACh) with distigmine, an acetylcholine esterase (AChE) inhibitor, could also inhibit non-cholinergic component of reflexogenic bladder contractions. Main methods Cystometry was performed in urethane anesthetized adult female Sprague Dawley rats. The nonselective muscarinic receptor (mAChR) antagonist, atropine, was administered intravenously (i.v.) before and after i.v. administration of the non-selective mAChR agonist, bethanechol, the AChE inhibitor, distigmine or the neurokinin receptor 2 agonist, [βAla8]-Neurokinin A(4-10). Intermicturition interval (IMI), bladder contraction amplitude (BCA), postvoid bladder pressure (PVBP), and voiding efficiency (VE) were measured. Key findings Atropine (0.4 mg/kg; n = 11 rats) delivered as the first drug, had insignificant effects on BCA (~ 15% reduction) or PVBP (~ 15% increase) and weakly reduced IMI and VE by ~ 40% (p < 0.05) relative to vehicle. Bethanechol and distigmine on their own produced excitatory effects on bladder activity, consistent with mAChR activation. Unexpectedly atropine, administered after bethanechol or after distigmine but not after [βAla8]-Neurokinin A(4-10), completely blocked bladder activity for 3-10 min. Partial recovery of bladder activity occurred after that time, but BCA, IMI, and VE remained significantly reduced and PVBP remained significantly increased. Significance Activation of mAChRs by an exogenous agonist or elevation of endogenous ACh levels by an AChE inhibitor inhibits the non-cholinergic, atropine-resistant, component of reflexogenic bladder contractions in vivo. © 2013 Elsevier Inc. Source

Kullmann F.A.,Urogenix Inc. Astellas | Wells G.I.,Urogenix Inc. Astellas | Langdale C.L.,Urogenix Inc. Astellas | Zheng J.,Urogenix Inc. Astellas | Thor K.B.,Urogenix Inc. Astellas

Time- and vehicle-related variability of bladder and urethral rhabdosphincter (URS) activity as well as cardiorespiratory and blood chemistry values were examined in the acetic acid-induced bladder irritation model in α-chloralose-anesthetized female cats. Additionally, bladder and urethra were evaluated histologically using Mason trichrome and toluidine blue staining. Urodynamic, cardiovascular and respiratory parameters were collected during intravesical saline infusion followed by acetic acid (0.5%) to irritate the bladder. One hour after starting acetic acid infusion, a protocol consisting of a cystometrogram, continuous infusion-induced rhythmic voiding contractions, and a 5 min "quiet period" (bladder emptied without infusion) was precisely repeated every 30 minutes. Administration of vehicle (saline i.v.) occurred 15 minutes after starting each of the first 7 cystometrograms and duloxetine (1mg/kg i.v.) after the 8th. Acetic acid infusion into the bladder increased URS-EMG activity, bladder contraction frequency, and decreased contraction amplitude and capacity, compared to saline. Bladder activity and URS activity stabilized within 1 and 2 hours, respectively. Duloxetine administration significantly decreased bladder contraction frequency and increased URS-EMG activity to levels similar to previous reports. Cardiorespiratory parameters and blood gas levels remained consistent throughout the experiment. The epithelium of the bladder and urethra were greatly damaged and edema and infiltration of neutrophils in the lamina propria of urethra were observed. These data provide an ample evaluation of the health of the animals, stability of voiding function and appropriateness of the model for testing drugs designed to evaluate lower urinary tract as well as cardiovascular and respiratory systems function. © 2013 Kullmann et al. Source

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