Protease-activated receptor-2-mediated contraction in the rat urinary bladder: the role of urinary bladder mucosa

Nakahara, Tsutomu; Kubota, Yuko; Mitani, Akiko; Maruko, Takeshi; Sakamoto, Kenji; Ishii, Kunio

doi:10.1007/s00210-002-0687-y

Cited by 18 publications

(8 citation statements)

References 14 publications

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“…This could potentially also be involved in muscarinic receptor-mediated bladder contraction, since several cyclooxygenase products are known to contract the bladder (Andersson, 2000), and since it has recently been shown that rat bladder contraction elicited by protease-activated receptor-2 involves activation of a cyclooxygenase Nakahara et al, 2003). In the present study, AACOCF 3 , an inhibitor of cytosolic PLA 2 , caused only minor, if any, inhibition of rat bladder contraction.…”

Section: Phospholipases and Ca 2؉ In Muscarinic Bladder Contractionmentioning

confidence: 47%

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Schneider¹,

Hein²,

Michel³

2004

The Journal of Pharmacology and Experimental Therapeutics

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We have reexamined the muscarinic receptor subtype mediating carbachol-induced contraction of rat urinary bladder and investigated the role of phospholipase (PL)C, D, and A 2 and of intra-and extracellular Ca 2ϩ sources in this effect. Based on the nonsubtype-selective tolterodine, the highly M 2 receptorselective (R)-4-{2-[3-(4-methoxy-benzoylamino)-benzyl]-piperidin-1-ylmethyl}-piperidine-1-carboxylic acid amide , and the highly M 3 receptor-selective darifenacin and 3-(1-carbamoyl-1,1-diphenylmethyl)-1-(4-methoxyphenylethyl)pyrrolidine (APP), contraction occurs via M 3 receptors. Carbachol stimulated inositol phosphate formation in rat bladder slices, and this was abolished by the phospholipase C inhibitor 1- Carbachol had only little effect on PLD activity in bladder slices, but the PLD inhibitor butan-1-ol, relative to its negative control butan-2-ol (0.3% each), caused detectable inhibition of carbachol-induced bladder contraction. The cytosolic PLA 2 inhibitor arachidonyltrifluoromethyl ketone weakly inhibited carbacholinduced contraction at a concentration of 300 M, but the cyclooxygenase inhibitor indomethacin (1-10 M) remained without effect. The Ca 2ϩ entry blocker nifedipine (10 -100 nM) almost completely inhibited carbachol-induced bladder contraction. In contrast, 1-[␤-[3-(4-methoxyphenyl)propoxy]-4-methoxyphenethyl]-1H-imidazole HCl (SKF 96,365; 10 M), an inhibitor of storeoperated Ca 2ϩ channels, caused little inhibition. We conclude that carbachol-induced contraction of rat bladder largely depends on Ca 2ϩ entry through nifedipine-sensitive channels and, perhaps, PLD, PLA 2 , and store-operated Ca 2ϩ channels, whereas cyclooxygenase and, surprisingly, also PLC are not involved to a relevant extent.Muscarinic acetylcholine receptors are the physiologically most important mechanisms to elicit contraction of the urinary bladder (Andersson, 1993). In the bladder of various mammalian species, including humans, M 2 and M 3 muscarinic receptors coexist, but the expression of M 2 receptors is much greater than that of the M 3 receptors (Wang et al., 1995;Goepel et al., 1998;Yamanishi et al., 2000;Kories et al., 2003). Nevertheless, the contractile response to the exogenous agonist carbachol and to endogenous agonists released by field stimulation have been attributed predominantly, if not exclusively, to M 3 receptors in rats (Longhurst et al., 1995;Hegde et al., 1997;Tong et al., 1997;Braverman et al., 1998;Choppin et al., 1998;Longhurst and Levendusky, 2000;Kories et al., 2003), mice (Choppin and Eglen, 2001b), pigs (Yamanishi et al., 2000), dogs (Choppin and Eglen, 2001a), and humans (Chess-Williams et al., 2001;Fetscher et al., 2002). Moreover, at least male M 3 (but not M 2 ) receptorknockout mice exhibit bladder distension and develop urinary retention (Matsui et al., 2000). On the other hand, it should be considered that hitherto available antagonists have only modest subtype selectivity and/or do not act in a purely competitive manner; hence, they were not well suited for detecting a pot...

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Section: Phospholipases and Ca 2؉ In Muscarinic Bladder Contractionmentioning

confidence: 47%

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Schneider¹,

Hein²,

Michel³

2004

The Journal of Pharmacology and Experimental Therapeutics

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“…In vitro experiments indicate that both trypsin and PAR-2 activating peptide (SLIGRL-NH(2)) produced a concentration-dependent contractile response in the rat urinary bladder preparations. These contractions were abolished by removal of the urinary bladder mucosa and were significantly reduced by the non-steroidal anti-inflammatory drug indomethacin [57]. The release of prostaglandins by PAR-2 activators seems to be partly mediated by the phospholipase A 2 (iPLA2) [58].…”

Section: Discussionmentioning

confidence: 99%

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

et al. 2007

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BackgroundIn general, inflammation plays a role in most bladder pathologies and represents a defense reaction to injury that often times is two edged. In particular, bladder neurogenic inflammation involves the participation of mast cells and sensory nerves. Increased mast cell numbers and tryptase release represent one of the prevalent etiologic theories for interstitial cystitis and other urinary bladder inflammatory conditions. The activity of mast cell-derived tryptase as well as thrombin is significantly increased during inflammation. Those enzymes activate specific G-protein coupled proteinase-activated receptors (PAR)s.Four PARs have been cloned so far, and not only are all four receptors highly expressed in different cell types of the mouse urinary bladder, but their expression is altered during experimental bladder inflammation. We hypothesize that PARs may link mast cell-derived proteases to bladder inflammation and, therefore, play a fundamental role in the pathogenesis of cystitis.ResultsHere, we demonstrate that in addition to the mouse urinary bladder, all four PA receptors are also expressed in the J82 human urothelial cell line. Intravesical administration of PAR-activating peptides in mice leads to an inflammatory reaction characterized by edema and granulocyte infiltration. Moreover, the inflammatory response to intravesical instillation of known pro-inflammatory stimuli such as E. coli lipopolysaccharide (LPS), substance P, and antigen was strongly attenuated by PAR1-, and to a lesser extent, by PAR2-deficiency.ConclusionOur results reveal an overriding participation of PAR1 in bladder inflammation, provide a working model for the involvement of downstream signaling, and evoke testable hypotheses regarding the role of PARs in bladder inflammation. It remains to be determined whether or not mechanisms targeting PAR1 gene silencing or PAR1 blockade will ameliorate the clinical manifestations of cystitis.

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“…Prostaglandins may play a role in bladder contraction by several agents such as protease‐activated receptors or bradykinin (Nakahara et al ., 2003; 2004; Chopra et al ., 2005). Therefore, it is surprising that prostaglandins were also postulated to play a permissive role for β‐adrenoceptor‐mediated relaxation of the urinary bladder (Bolle et al ., 1999).…”

Section: Bladdermentioning

confidence: 99%

“…Michel & W. Vrydag Adrenoceptors in the lower urinary tract latter two studies also report that relaxation against passive tension is not sensitive to those toxins. Prostaglandins may play a role in bladder contraction by several agents such as protease-activated receptors or bradykinin (Nakahara et al, 2003;2004;Chopra et al, 2005). Therefore, it is surprising that prostaglandins were also postulated to play a permissive role for b-adrenoceptormediated relaxation of the urinary bladder (Bolle et al, 1999).…”

Section: Protein Expressionmentioning

confidence: 99%

α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Michel

Vrydag

2006

British J Pharmacology

413

320

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1 We have systematically reviewed the presence, functional responses and regulation of a 1 -, a 2 -and b-adrenoceptors in the bladder, urethra and prostate, with special emphasis on human tissues and receptor subtypes. 2 a 1 -Adrenoceptors are only poorly expressed and play a limited functional role in the detrusor. a 1 -Adrenoceptors, particularly their a 1A -subtype, show a more pronounced expression and promote contraction of the bladder neck, urethra and prostate to enhance bladder outlet resistance, particularly in elderly men with enlarged prostates. a 1 -Adrenoceptor agonists are important in the treatment of symptoms of benign prostatic hyperplasia, but their beneficial effects may involve receptors within and outside the prostate. 3 a 2 -Adrenoceptors, mainly their a 2A -subtype, are expressed in bladder, urethra and prostate. They mediate pre-junctional inhibition of neurotransmitter release and also a weak contractile effect in the urethra of some species, but not humans. Their overall post-junctional function in the lower urinary tract remains largely unclear. 4 b-Adrenoceptors mediate relaxation of smooth muscle in the bladder, urethra and prostate. The available tools have limited the unequivocal identification of receptor subtypes at the protein and functional levels, but it appears that the b 3 -and b 2 -subtypes are important in the human bladder and urethra, respectively. b 3 -Adrenoceptor agonists are promising drug candidates for the treatment of the overactive bladder. 5 We propose that the overall function of adrenoceptors in the lower urinary tract is to promote urinary continence. Further elucidation of the functional roles of their subtypes will help a better understanding of voiding dysfunction and its treatment.

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Protease-activated receptor-2-mediated contraction in the rat urinary bladder: the role of urinary bladder mucosa

Cited by 18 publications

References 14 publications

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

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Protease-activated receptor-2-mediated contraction in the rat urinary bladder: the role of urinary bladder mucosa

Cited by 18 publications

References 14 publications

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Signal Transduction Underlying Carbachol-Induced Contraction of Rat Urinary Bladder. I. Phospholipases and Ca2+ Sources

Mandatory role of proteinase-activated receptor 1 in experimental bladder inflammation

α1‐, α2‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate

Contact Info

Product

Resources

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α₁‐, α₂‐ and β‐adrenoceptors in the urinary bladder, urethra and prostate