Functional antagonism of substance P and related peptides by RP 67580 and CP-96,345, two novel non-peptide NK1-receptor antagonists, in the rat urinary bladder in vitro and in vivo

Neuropeptides ◽  
1993 ◽  
Vol 24 (4) ◽  
pp. 238 ◽  
Author(s):  
F. Montier ◽  
A. Carruette ◽  
S. Moussaoui ◽  
D. Boccio ◽  
C. Garret
Keyword(s):  
Substance P ◽  
Urinary Bladder ◽  
Nk1 Receptor ◽  
Receptor Antagonists ◽  
Rat Urinary Bladder ◽  
Functional Antagonism ◽  
Nk1 Receptor Antagonists

In vitro and in vivo predictors of the anti-emetic activity of tachykinin NK1 receptor antagonists

1997 ◽  
Vol 326 (2-3) ◽  
pp. 201-209 ◽  
Author(s):  
Nadia M.J. Rupniak ◽  
F.David Tattersall ◽  
Angela R. Williams ◽  
Wayne Rycroft ◽  
Emma J. Carlson ◽  
...  
Keyword(s):  
Nk1 Receptor ◽  
Receptor Antagonists ◽  
Nk1 Receptor Antagonists

Antagonism of substance P and related peptides by RP 67580 and CP-96,345, at tachykinin NK1 receptor sites, in the rat urinary bladder

1994 ◽  
Vol 251 (1) ◽  
pp. 9-14 ◽  
Author(s):  
François Montier ◽  
Anne Carruette ◽  
Saliha Moussaoui ◽  
Daniel Boccio ◽  
Claude Garret
Keyword(s):  
Substance P ◽  
Urinary Bladder ◽  
Nk1 Receptor ◽  
Rat Urinary Bladder ◽  
Receptor Sites

scholarly journals Rat Urinary Bladder Carcinogenesis by Dual-Acting PPARα+γAgonists

PPAR Research ◽  
2008 ◽  
Vol 2008 ◽  
pp. 1-14 ◽  
Author(s):  
Martin B. Oleksiewicz ◽  
Jennifer Southgate ◽  
Lars Iversen ◽  
Frederikke L. Egerod
Keyword(s):  
Urinary Bladder ◽  
Mode Of Action ◽  
Carcinogenic Effect ◽  
Attrition Rates ◽  
Rat Urinary Bladder ◽  
Mediated Effects ◽  
Kidney Pelvis ◽  
Rats And Mice

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.

New insights into the antidepressant actions of substance P (NK1 receptor) antagonists

2002 ◽  
Vol 80 (5) ◽  
pp. 489-494 ◽  
Author(s):  
Nadia M.J Rupniak
Keyword(s):  
Substance P ◽  
Species Differences ◽  
Motor Impairment ◽  
Nk1 Receptor ◽  
Receptor Antagonists ◽  
Antidepressant Efficacy ◽  
Preclinical Species ◽  
Pharmacological Blockade ◽  
Nk1 Receptor Antagonists ◽  
Made In

Considerable progress has been made in understanding the neural circuits involved the antidepressant and anxiolytic efficacy of substance P (NK1 receptor) antagonists (SPAs). Progress has been hampered by species differences in the pharmacology of the NK1 receptor, and the availability of NK1R–/– mice has been a particularly useful resource in overcoming this difficulty. Using neuroanatomical, behavioural, and electrophysiological techniques, studies have now established that pharmacological blockade or deletion of the NK1 receptor produces an antidepressant and anxiolytic-like profile in a range of behavioural assays that is distinct from that of established drugs. There is evidence from focal injection studies that some of these effects may be mediated directly by blockade of NK1 receptors in the amygdala and its projections to the hypothalamus, periaqueductal gray, and reticulopontine nucleus. Substance P and NK1 receptors are also intimately associated with ascending 5-HT and norepinephrine projections to the forebrain, and alterations in the function of these systems are also likely to be related to the antidepressant efficacy of SPAs. Unlike some established drugs, SPAs are generally well tolerated and do not induce sedation or motor impairment in preclinical species. These findings are consistent with a novel antidepressant mechanism of action of SPAs.Key words: NK1 receptor, depression, anxiety.

Kinin receptors in experimental inflammation

1980 ◽  
Vol 58 (5) ◽  
pp. 536-542 ◽  
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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