CYSTOMETRIC FINDINGS IN MICE LACKING MUSCARINIC M
            <sub>2</sub>
            OR M
            <sub>3</sub>
            RECEPTORS

Igawa, Yasuhiko; Zhang, Xiaoyang; Nishizawa, Osamu; Umeda, Masaomi; Iwata, Atsuko; Taketo, Makoto Mark; Manabe, Toshiya; Matsui, Masanao; Andersson, Karl Erik

doi:10.1097/01.ju.0000138054.77785.4a

Cited by 65 publications

(56 citation statements)

References 16 publications

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“…Whereas the M2 subtype is most common, the M3 is functionally more important in producing contraction of isolated bladder, with M2 thought to act by inhibiting beta-adrenergic relaxation in-vivo (Hegde et al, 1997). This is supported by the observation that contractions of bladders from knockout mice without M3 receptors are greatly reduced (Matsui et al, 2000;Igawa et al, 2004). Whereas studies with immunological and Northern Blot techniques have failed to reveal M1 and M4 subtypes, the genes responsible for synthesis of the receptor subtypes M1-M4 have been identified by reverse transcription-polymerase chain reaction (RT-PCR) on whole extracts of rat bladder wall (Braverman et al, 1998a).…”

Section: Introductionsupporting

confidence: 55%

“…However, cholinergic contractile responses and their antagonism were similar in male and female rats with comparable pA2 values for darifenacin. A study by Kories et al (Kories et al, 2003) found a similar situation in human and rat tissue using KCl and carbachol challenge, and while it has been shown in M3 receptor knock-out mice that males, but not females, had difficulty urinating, the response of bladder strips were comparable (Matsui et al, 2000;Igawa et al, 2004). Differences between males and females might therefore be explained by urethral properties, as there are important sexual differences in the urethral muscles (Van der Werf and Creed, 2002).…”

Section: Rat Functional Responsesmentioning

confidence: 89%

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Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Creed

Loxley

Phillips

2010

J. Smooth Muscle Res.

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Purpose: The objectives of this study were to compare the functional expression of muscarinic and purinergic receptors in the urinary bladder of 2 species, rat and guinea pig under comparable experimental conditions; and to test whether the receptors in males and females differ. Methods: Reverse transcription-polymerase chain reaction (RT-PCR) techniques were used to identify gene expression profiles in bladder smooth muscle (total n=8 rats, 7 guinea pigs) and mechanical responses to nerve stimulation and applied acetylcholine (ACh) in the presence of specific antagonists were used to identify functional receptor sub-types (total n=12 rats, 16 guinea pigs). Results: RT-PCR indicated that M2 and M3 were the predominant muscarinic receptor genes in both the male and female rat and guinea pig bladders. M) caused a significant reduction in the amplitude of the phasic response to nerve stimulation in all groups, and this effect was significantly greater in male vs. female rats. mRNA for the purinergic P2X1, P2X2, P2X4, P2X5 and P2X7 receptors was detected in both male and female rats, whereas P2X3 and P2X6 were inconsistently detected in male rats. The P2X1 purinoceptor antagonist pyridoxal-5'-phosphate-6-(2'-naphthylazo-6'-nitro-4', 8'-disulphonate) (PPNDS), only inhibited nerve induced contractions at high concentrations (up to 10 -4 M). Conclusions: While only minor functional differences were documented in cholinergic and purinergic bladder contractile responses between male and female animals, and between rats and guinea pigs, data such as presented in this study are critical in determining how relative functional contributions may change in the diseased state, providing valuable information towards new treatment options.

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Section: Introductionsupporting

confidence: 55%

Section: Rat Functional Responsesmentioning

confidence: 89%

Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Creed

Loxley

Phillips

2010

J. Smooth Muscle Res.

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“…These observations suggest that the M 3 muscarinic receptor subtype is solely responsible for the cholinergic component of nerve-mediated contraction and that compensatory changes by up-regulation of other muscarinic receptor subtypes do not occur in prostates taken from M3R(Ϫ/Ϫ) mice. This does not exclude the possibility of up-regulation of noncholinergic mechanisms such as purinergic mechanisms, as observed in the bladders of M3R(Ϫ/Ϫ) mice (Igawa et al, 2004). However, this seems unlikely in the prostate because the residual contractile response to electrical-field stimulation in prostates taken from M3R(Ϫ/Ϫ) mice is abolished by the ␣ 1 -adrenoceptor antagonist prazosin.…”

Section: Discussionmentioning

confidence: 85%

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M₃ Muscarinic Receptors

White¹,

Short²,

Haynes³

et al. 2011

J Pharmacol Exp Ther

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Increased smooth muscle tone in the human prostate contributes to the symptoms associated with benign prostatic hyperplasia. In the mouse prostate gland, cholinergic innervation is responsible for a component of the nerve-mediated contractile response. This study investigates the muscarinic receptor subtype responsible for the cholinergic contractile response in the mouse prostate gland. To characterize the muscarinic receptor subtype, mouse prostates taken from wild-type or M 3 muscarinic receptor knockout mice were mounted in organ baths. The isometric force that tissues developed in response to electricalfield stimulation or exogenously applied cholinergic agonists in the presence or absence of a range of muscarinic receptor antagonists was evaluated. Carbachol elicited reproducible and concentration-dependent contractions of the isolated mouse prostate, which were antagonized by the presence of muscarinic receptor antagonists. Calculation of antagonist affinities (pA 2 values) indicated a rank order of antagonist potencies in the mouse prostate of: darifenacin (9.08) ϭ atropine (9.07) ϭ 1,1-dimethyl-4-diphenylacetoxypiperidinium iodide (9.02) Ͼ cyclohexyl-hydroxy-phenyl-(3-piperidin-1-ylpropyl)silane (7.85) Ͼ cyclohexyl-(4-fluorophenyl)-hydroxy-(3-piperidin-1-ylpropyl)silane (7.39) Ͼ himbacine (7.19) Ͼ pirenzipine (6.88) Ͼ methoctramine (6.20). Furthermore, genetic deletion of the M 3 muscarinic receptor inhibited prostatic contractions to electrical-field stimulation or exogenous administration of acetylcholine. In this study we identified that the cholinergic component of contraction in the mouse prostate is mediated by the M 3 muscarinic receptor subtype. Pharmacological antagonism of the M 3 muscarinic receptor may be a beneficial additional target for the treatment of benign prostatic hyperplasia in the human prostate gland.

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“…Surprisingly it is the minor population of M3-receptors that mediates detrusor muscle contraction in vitro in all species so far examined (for review see ref 14) including human [15,16] and mouse bladder [17]. Recent studies using mutant mice lacking M2 [18], M3 [19] or both [20] also suggest that the M3 receptor is the predominant muscarinic receptor subtype mediating detrusor contraction in vivo. The present study further supports the idea that M3 receptors are responsible for detrusor contraction in the mouse, since responses to carbachol were antagonised more potently by the M3-antagonist 4-DAMP than the M2-antagonist methoctramine.…”

Section: Discussionmentioning

confidence: 99%

Pharmacologic responses of the mouse urinary bladder

2009

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AbstractThe aim of the study was to determine pathways involved in contraction and relaxation of the mouse urinary bladder. Mouse bladder strips were set up in gassed Krebs-bicarbonate solution and responses to various drugs and electrical field stimulation were obtained. Isoprenaline (b-receptor agonist) caused a 63% inhibition of carbachol precontracted detrusor (EC50=2nM). Carbachol caused contraction (EC50=0.3µM), responses were antagonised more potently by 4-DAMP (M3-antagonist) than methoctramine (M2-antagonist). Electrical field stimulation caused contraction, which was inhibited by atropine (60%) and less by guanethidine and α,β-methylene-ATP. The neurogenic responses were not potentiated by inhibition of nitric oxide synthase. Presence of an intact urothelium significantly depressed responses to carbachol (p=0.02) and addition of indomethacin and L-NNA to remove prostaglandin and nitric oxide production respectively did not prevent the inhibitory effect of the urothelium. In conclusion, b-receptor agonists cause relaxation and muscarinic agonists cause contraction via the M3-receptor. Acetylcholine is the main neurotransmitter causing contraction while nitric oxide has a minor role. The mouse and human urothelium are similar in releasing a factor that inhibits contraction of the detrusor muscle which is unidentified but is not nitric oxide or a prostaglandin. Therefore, the mouse may be used as a model to study the lower urinary tract.

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CYSTOMETRIC FINDINGS IN MICE LACKING MUSCARINIC M ₂ OR M ₃ RECEPTORS

Cited by 65 publications

References 16 publications

Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M₃ Muscarinic Receptors

Pharmacologic responses of the mouse urinary bladder

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CYSTOMETRIC FINDINGS IN MICE LACKING MUSCARINIC M 2 OR M 3 RECEPTORS

Cited by 65 publications

References 16 publications

Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Functional expression of muscarinic and purinoceptors in the urinary bladder of male and female rats and guinea pigs

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M3 Muscarinic Receptors

Pharmacologic responses of the mouse urinary bladder

Contact Info

Product

Resources

About

CYSTOMETRIC FINDINGS IN MICE LACKING MUSCARINIC M ₂ OR M ₃ RECEPTORS

Contractions of the Mouse Prostate Elicited by Acetylcholine Are Mediated by M₃ Muscarinic Receptors