Prejunctional M<sub>1</sub> facilitory and M<sub>2</sub> inhibitory  muscarinic receptors mediate rat bladder contractility

Braverman, Alan S.; Kohn, Ira J.; Luthin, Gary R.; Ruggieri, Michael R.

doi:10.1152/ajpregu.1998.274.2.r517

Cited by 36 publications

(45 citation statements)

References 22 publications

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“…Prejunctional autoreceptors have been identified on the nerves innervating the rat bladder (3,26,28). Activation of the M 1 subtype increases acetylcholine release and contraction while activation of the M 2 subtype reduces acetylcholine release and inhibits contraction.…”

Section: Discussionmentioning

confidence: 99%

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Braverman¹,

Ruggieri²

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. Am J Physiol Regul Integr Comp Physiol 285: R701-R708, 2003. First published May 22, 2003 10.1152/ajpregu.00009.2003.-Major pelvic ganglion electrocautery (MPGE) and spinal cord injury in the rat induce bladder hypertrophy and a change in muscarinic receptor subtypes mediating bladder contraction from predominantly M 3 to a combination of M2 and M3. To determine whether this is a result of bladder hypertrophy or denervation, we studied the following groups: sham-operated controls, urinary diversion (DIV), MPGE together with urinary diversion (DIV-DEN), bilateral MPGE (DEN), bladder outlet obstruction (BOO), and MPG decentralization (MPG-DEC). The degree of bladder denervation was determined by the maximal carbachol response normalized to the response to electric field stimulation. Receptor subtype density was determined by immunoprecipitation. The affinity of subtypeselective muscarinic antagonists for inhibition of carbacholinduced contractions was used to determine the subtypemediating contraction. DEN, MPG-DEC, and BOO bladders were hypertrophic whereas DIV bladders were atrophic compared with sham operated. Bladder contraction in shamoperated, DIV, and DIV-DEN was mediated by the M3 receptor subtype, whereas the M 2 subtype participated in contraction in the DEN, MPG-DEC, and BOO groups. The hypertrophied bladders had an increase in total and M 2 receptor density while all experimental groups showed a reduction in M3 receptor density. Thus bladder hypertrophy, independent from bladder denervation, causes a shift in the muscarinic receptor subtype mediating bladder contraction from M3 toward M2. denervation; outlet obstruction; urinary diversion PHARMACOLOGICAL DATA, based on the actions of subtypeselective antimuscarinic agents, can distinguish four subtypes of muscarinic acetylcholine receptors (M 1 -M 4 ). Molecular techniques have identified five muscarinic receptor subtypes (M 1 -M 5 ) arising from five separate genes (7,8). Both M 2 and M 3 muscarinic receptor subtypes are found in most smooth muscles. The M 2 receptor preferentially couples to the inhibition of adenylyl cyclase through the G i family of proteins, while the M 3 receptor preferentially couples to IP 3 generation and calcium mobilization through the G q family of proteins (7,8). Pertussis toxin (PTX), which ADP ribosylates and therefore inactivates the G i family of proteins, has no apparent effect on contraction (23). Even though the M 2 muscarinic receptor density is greater than the M 3 receptor density in bladder and other smooth muscles, the affinity of subtype-selective muscarinic receptor antagonist drugs indicates that contraction is mediated by the M 3 receptor in most smooth muscles under normal conditions (7,9).A number of studies have shown that under certain conditions the M 2 receptor subtype can contribute to the contractile response. This includes selective alkylation of M 3 receptors in an environment of increased intrac...

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Section: Discussionmentioning

confidence: 99%

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Braverman¹,

Ruggieri²

2003

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Similarly, the M 2 and M 3 receptor mRNA has been identified in this tissue by Northern hybridization [Maeda et al, 1988]. With the advent of the highly sensitive reverse-transcriptase polymerase chain reaction assay for the identification of mRNA, the M 1-4 transcripts have been shown to be present in urinary bladder smooth muscle from rats [Braverman et al, 1998a], while transcripts for all five subtypes has been demonstrated in samples of human bladder [Sigala et al, 2002].…”

Section: Introductionmentioning

confidence: 95%

Muscarinic receptor transcript and protein density in hypertrophied and atrophied rat urinary bladder

Braverman

Ruggieri

2005

Neurourology and Urodynamics

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Aims-Our previous studies showed that bladder hypertrophy shifts the muscarinic receptor subtype mediating contraction from M 3 towards M 2 along with increased M 2 and decreased M 3 protein concentration. We quantified mRNA for M 1 through M 5 receptors to determine whether the changes in M 2 and M 3 protein levels was due to changes in transcription.Methods-Bladder hypertrophy was induced by bladder outlet obstruction (BOO), major pelvic ganglion electrocautery (DEN), and major pelvic ganglion decentralization (DEC). Bladder atrophy was induced by ureteral diversion (DIV). Additional groups included denervated and diverted (DEN-DIV), sham operated (SHAM), and normal (NOR) controls. Transcripts were quantified using a multiplex ribonuclease protection assay (RPA) and receptor protein density was determined by immunoprecipitation. Receptor transcripts were expressed per unit total RNA.Results-Although all five receptor subtype transcripts were detected in all experimental groups, the densities of M 1 , M 4 , and M 5 were much lower than for the M 2 and M 3 subtype. There were more M 2 receptor transcripts than all the others, consistent with M 2 protein determinations. M 2 transcripts were significantly increased in DEN and BOO bladders. Surprisingly, M 3 transcripts were also significantly increased in BOO. There was a significant correlation (r = 0.98, P < 0.001) between protein density and transcript density for the M 2 but not the M 3 receptor among the different experimental groups.Conclusions-Changes in mRNA concentration are reflected by changes in protein density for the M 2 receptor but not for the M 3 receptor. Extrapolation of functional effects from transcript density data is invalid for M 3 mediated bladder contractions.

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“…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). An increase in bladder smooth muscle M3 receptor mRNA expression has recently been demonstrated in rats with bladder outlet obstruction (Kim et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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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Prejunctional M₁ facilitory and M₂ inhibitory muscarinic receptors mediate rat bladder contractility

Cited by 36 publications

References 22 publications

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Muscarinic receptor transcript and protein density in hypertrophied and atrophied rat urinary bladder

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

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Prejunctional M1 facilitory and M2 inhibitory muscarinic receptors mediate rat bladder contractility

Cited by 36 publications

References 22 publications

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M3 toward M2

Muscarinic receptor transcript and protein density in hypertrophied and atrophied rat urinary bladder

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

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Prejunctional M₁ facilitory and M₂ inhibitory muscarinic receptors mediate rat bladder contractility

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂

Hypertrophy changes the muscarinic receptor subtype mediating bladder contraction from M₃ toward M₂