Pharmacological analysis of the local and reflex responses to bradykinin on rat urinary bladder motility in vivo

Despite clinical promise, dual-acting activators of PPARαandγ(here termed PPARα+γagonists) have experienced high attrition rates in preclinical and early clinical development, due to toxicity. In some cases, discontinuation was due to carcinogenic effect in the rat urothelium, the epithelial layer lining the urinary bladder, ureters, and kidney pelvis. Chronic pharmacological activation of PPARαis invariably associated with cancer in rats and mice. Chronic pharmacological activation of PPARγcan in some cases also cause cancer in rats and mice. Urothelial cells coexpress PPARαas well as PPARγ, making it plausible that the urothelial carcinogenicity of PPARα+γagonists may be caused by receptor-mediated effects (exaggerated pharmacology). Based on previously published mode of action data for the PPARα+γagonist ragaglitazar, and the available literature about the role of PPARαandγin rodent carcinogenesis, we propose a mode of action hypothesis for the carcinogenic effect of PPARα+γagonists in the rat urothelium, which combines receptor-mediated and off-target cytotoxic effects. The proposed mode of action hypothesis is being explored in our laboratories, towards understanding the human relevance of the rat cancer findings, and developing rapid in vitro or short-term in vivo screening approaches to faciliate development of new dual-acting PPAR agonist compounds.

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Kinin receptors in experimental inflammation

Canadian Journal of Physiology and Pharmacology ◽

10.1139/y80-088 ◽

1980 ◽

Vol 58 (5) ◽

pp. 536-542 ◽

Cited By ~ 83

Author(s):

F. Marceau ◽

J. Barabé ◽

S. St-Pierre ◽

D. Regoli

Keyword(s):

Urinary Bladder ◽

De Novo ◽

Rabbit Aorta ◽

Initial Response ◽

Rat Urinary Bladder ◽

Chemical Mediation ◽

Intravesical Injection ◽

Triton X

The contractile response of the rat isolated urinary bladder to kinins is mediated by receptors of the B1 and of the B2 types, as this preparation responds to des-Arg9-bradykinin (des-Arg9-BK), a fairly selective stimulant of receptor B1 and to [Tyr(Me)8]-BK, a potent agonist on receptor B2. Des-Arg10-[Leu9]-kallidin, a specific and competitive antagonist of the action of kinins on receptor B1, has been found to block the effect of des-Arg9-BK in concentrations similar to those required in the rabbit aorta; therefore, the B1 receptor of the rat urinary bladder is analogous to that of the rabbit vascular tissue.The response of the rat urinary bladder to des-Arg9-BK increases progressively from near null level during the incubation in vitro and can be abolished by cycloheximide; this suggests that receptor B1 of the rat urinary bladder is formed de novo.The inflammation of the bladder induced by intravesical injection of the detergent Triton X-100 enhances the initial response to des-Arg9-BK without modifying the response to other agents. The B1 receptor is formed in vivo in the rat urinary bladder submitted to the Triton X-100 treatment but not in the control untreated organ. The local de novo synthesis of B1 receptors for kinins that follows a noxious stimulus is proposed as a possible mechanism implicated in the chemical mediation of the inflammatory process.

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Kinin B1 receptor-mediated motor responses in normal or inflamed rat urinary bladder in vivo

Regulatory Peptides ◽

10.1016/s0167-0115(99)00009-9 ◽

1999 ◽

Vol 80 (1-2) ◽

pp. 41-47 ◽

Cited By ~ 13

Author(s):

Alessandro Lecci ◽

Stefania Meini ◽

Manuela Tramontana ◽

Sandro Giuliani ◽

Marco Criscuoli ◽

...

Keyword(s):

Urinary Bladder ◽

Rat Urinary Bladder ◽

Motor Responses ◽

B1 Receptor ◽

Kinin B1 Receptor

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Ketamine, an N -methyl-d-aspartate Receptor Antagonist, Inhibits the Reflex Responses to Distension of the Rat Urinary Bladder

Anesthesiology ◽

10.1097/00000542-200206000-00020 ◽

2002 ◽

Vol 96 (6) ◽

pp. 1401-1409 ◽

Cited By ~ 11

Author(s):

Pablo J. Castroman ◽

Timothy J. Ness

Keyword(s):

Nmda Receptor ◽

Urinary Bladder ◽

Visceral Pain ◽

Electromyographic Activity ◽

Rat Urinary Bladder ◽

Available N ◽

Reflex Responses ◽

Dose Dependent Fashion ◽

Dose Dependent ◽

Intravenous Ketamine

Background Ketamine is analgesic in experimental and clinical studies of inflammatory, neuropathic, and postoperative pain. Its role in the treatment of visceral pain is less known. The authors investigated the effect and site of action of ketamine on reflex responses evoked by urinary bladder distension (UBD). The effects of other clinically available N-methyl-d-aspartate (NMDA) receptor antagonists on these responses were also studied. Methods The effect of intravenous ketamine (1, 3, and 10 mg/kg), dextromethorphan (5 mg/kg), and memantine (16 mg/kg) on mean arterial pressure changes (Delta MAP) and abdominal electromyographic activity (EMG) evoked by UBD was measured in anesthetized rats. Ketamine was also administered intravesically and intrathecally and its effect on Delta MAP and EMG responses to UBD recorded. The effect of pretreatment with intravenous ketamine on these responses was also assessed. Results The Delta MAP and EMG responses to UBD were reduced in a dose-dependent fashion by ketamine. Memantine and dextromethorphan also inhibited these responses. Ketamine administered intrathecally produced marked inhibition of Delta MAP and EMG responses to UBD. Pretreatment with ketamine only transiently reduced the vigor of responses to UBD. Conclusions Ketamine inhibited, in a dose-dependent fashion, the Delta MAP and EMG responses to UBD, an effect likely caused by actions within the spinal cord. Similar inhibition observed with systemic dextromethorphan and memantine treatments suggests that the analgesic effect of ketamine is caused by antagonism of the NMDA receptor. Pretreatment with ketamine did not have a preventive effect in this model of bladder nociception.

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