Pharmacologic evaluation of pressor and visceromotor reflex responses to bladder distension

Su, Xin; Riedel, Erin S.; Leon, Lisa A.; Laping, Nicholas J.

doi:10.1002/nau.20469

Cited by 20 publications

(26 citation statements)

References 36 publications

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“…However, they do have many features in common (Steers, 2002;Andersson and Wein, 2004). In fact, because OAB is a phenomenon of "hypersensitivity" , it is reasonable to use VMR and pressor responses to bladder distension as a tool to study pure afferent mechanisms in bladder hypersensitivity (Su et al, 2008b).…”

Section: Discussionmentioning

confidence: 99%

“…Polyethylene 90 tubing was inserted into the urinary bladder via the urethra and secured by a tight ligature around the distal urethral orifice. The bladder catheter was also linked to a bladder distension control device (B482C-1; Department of Biomedical Engineering, University of Iowa, Iowa City, IA) (Su et al, 2008b). The bladder was distended with saline by regulating air inflow into a Marriott bottle from a valve interface distension control device.…”

Section: Methodsmentioning

confidence: 99%

“…SRFs to graded UBD were plotted for each experiment, and a least-squares regression line was obtained from the linear part of the SRF. The regression line was then extrapolated to the ordinate (representing distension pressure) to estimate the response threshold (Su et al, 2008b). After drug administration, response was modified to the percentile of mean control response: the average of four UBD responses before drug treatment.…”

Section: Methodsmentioning

confidence: 99%

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Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

Leon¹,

Hoffman²,

Gardner³

et al. 2008

J Pharmacol Exp Ther

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The present study investigated whether ␤3-adrenoceptor activation acts on the bladder afferent pathway by examination of the visceromotor reflex (VMR) and pressor responses to urinary bladder distension (UBD) and whether ␤3-adrenoceptor activation produces urinary bladder relaxation in hyperactive spontaneously hypertensive rats (SHRs) in comparison with their normotensive control rats [Wistar-Kyoto (WKY)]. Using the VMR responses to noxious UBD as a measure of bladder afferent signal transmission, SHRs did not present a sensitized bladder phenotype. However, reduced bladder compliance accompanied by a reduced void threshold was detected in the SHR detrusor. Furthermore, the selective ␤3-adrenoceptor agonist) failed to attenuate VMR or pressor responses to UBD in either SHRs or WKY rats, but it dose-dependently inhibited rhythmic contraction (RC) in SHRs. The minimal effective dose was 0.001 mg/kg. Using the same model in WKY rats, CL-316243 did not elicit significant inhibition of contractions in the bladder RC assay. These results suggest that SHRs represent abnormal efferent/ detrusor function (detrusor overactivity) without mechanosensory afferent hypersensitivity. The ␤3-adrenoceptor agonist CL-316243 acts on the detrusor muscle to increase urine storage in SHRs.The overactive bladder (OAB) is defined by the symptom of urgency (Abrams et al., 2002), which is the complaint of a sudden compelling desire to pass urine. The evaluation of urgency as a sensation is not easy in humans; however, several scales are available to measure the intensity of urgency. In animals, "urgency" cannot be used as a measurement, and only a few parameters of physiological endpoints, which are unique to humans as a consequence of urgency, can be measured by urodynamic studies. For example, spontaneously hypertensive rats (SHRs) exhibit such an animal model that mimics the pathophysiology of OAB patients with increased voiding frequency and lower bladder capacity (Persson et al., 1998;Spitsbergen et al., 1998). The mechanism behind the detrusor overactivity (DO) in SHRs and how the model simulates urgency in humans is not known. The alternations of both the afferent pathway and the efferent pathway in SHRs compared with their normotensive controls [Wistar-Kyoto (WKY)] have been proposed. The evidence for an enhanced afferent limb of the micturition reflex pathway in SHRs was based on an increased production of nerve growth factor by bladder smooth muscle Clemow et al., 1999). The consequence of an increased nerve growth factor level includes enlargement of bladder sensory neuron size (Clemow et al., 1997) and sensitization of the bladder afferent nerve activity (Dmitrieva and McMahon, 1996). However, direct evidence of enhanced afferent activity in SHRs is still lacking.The function of adrenoceptors (ARs) in the efferent limb (efferent outflow/bladder function) may also underlie the DO in SHRs. Blockade of spinal ␣1-AR removed the abnormal bladder contractions, and activation of peripherally postjuncArticle, publication date...

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

Leon¹,

Hoffman²,

Gardner³

et al. 2008

J Pharmacol Exp Ther

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“…The bladder was distended with saline by regulating air inflow into a Mariott bottle from a valve interface distension control device (University of Iowa, Bioengineering, B482C-1; see Ref. 37). Two needle electrodes were sutured in the oblique abdominal musculature just above the inguinal ligament.…”

Section: Methodsmentioning

confidence: 99%

An excitatory role for peripheral EP₃ receptors in bladder afferent function

Su¹,

Lashinger²,

Leon³

et al. 2008

American Journal of Physiology-Renal Physiology

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The excitatory roles of EP3 receptors at the peripheral afferent nerve innervating the rat urinary bladder have been evaluated by using the selective EP3 antagonist (2E)-3-{1-[(2,4-dichlorophenyl)methyl]-5-fluoro-3-methyl-1H-indol-7-yl}-N-[(4,5-dichloro-2-thienyl)sulfonyl]-2-propenamide (DG-041). The bladder rhythmic contraction model and a bladder pain model measuring the visceromotor reflex (VMR) to urinary bladder distension (UBD) have been used to evaluate DG-041 in female rats. In addition, male rats [spontaneously hypertensive rat (SHR), WistarKyoto (WKY), and Sprague-Dawley (SD)] were anesthetized with pentobarbital sodium, and primary afferent fibers in the L 6 dorsal root were isolated for recording the inhibitory response to UBD following intravenous injection of DG-041. Intravenous injection of DG-041 (10 mg/kg), a peripherally restricted EP 3 receptor antagonist, significantly reduced the frequency of bladder rhythmic contraction and inhibited the VMR response to bladder distension. The magnitude of reduction of the VMR response was not different in the different strains of rats (SD, SHR, and WKY). Furthermore, quantitative characterization of the mechanosensitive properties of bladder afferent nerves in SHR, WKY, and SD rats did not show the SHR to be supersensitive to bladder distension. DG-041 selectively attenuated responses of mechanosensitive afferent nerves to UBD, with strong suppression on the slow-conducting, high-threshold afferent fibers, with equivalent activity in the three strains. We conclude that sensitization of afferent nerve activity was not one of the mechanisms of bladder hypersensitivity in SHR. EP 3 receptors are involved in the regulation of bladder micturition and bladder nociception at the peripheral level.EP3; viscermotor reflex; bladder rhythmic contraction; bladder distension; afferent nerve SENSATION ASSOCIATED WITH the urinary bladder is conveyed primarily by pelvic and hypogastric nerves, by which the signal is relayed to the central nervous system (CNS). Most afferent fibers innervating the musculature of the bladder body pass through the pelvic nerve, whereas the majority of afferent endings in the bladder submucosa are derived from the hypogastric nerve (41), suggesting that the afferent fibers in the pelvic and hypogastric nerves have different roles, signaling mechanical stimulation (e.g., bladder distension) and chemical stimulation (e.g., inflammation), respectively (20,22,30,34). Bladder distension is a natural mechanical stimulus to evoke sensations such as fullness, urgency, and pain while the literature suggests a complex regulatory role of prostaglandins (PGs) in multiple aspects of urinary bladder physiology/pathophysiology. PGE 2 , one of the principal PGs, is synthesized in urothelium and detrusor smooth muscle (19,24,25,27) as well as in neurons and glial cells (18,23) and is released in response to various physiological (e.g., bladder distension) and pathological (e.g., mediators of inflammation) stimulation. PGE 2 interacts with four EP receptor subt...

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“…For example, pressor and visceromotor reflex (VMR) responses to noxious urinary bladder distension (UBD) in halothane/ isoflurane anesthetized rats have been reported to be a reliable indicator of bladder pain in humans. [1][2][3] This model was built on Sherrington's 4 original theory of pseudoaffective responses (also see Ref. 5) as a consequence to a noxious stimulus and the work of Ness and Gebhart 6 on their colorectal distension model in conscious rats.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats

Blatt

Lashinger

Laping

et al. 2008

Neurourology and Urodynamics

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Pharmacologic evaluation of pressor and visceromotor reflex responses to bladder distension

Cited by 20 publications

References 36 publications

Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

An excitatory role for peripheral EP₃ receptors in bladder afferent function

Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats

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Pharmacologic evaluation of pressor and visceromotor reflex responses to bladder distension

Cited by 20 publications

References 36 publications

Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

Effects of the β3-Adrenergic Receptor Agonist Disodium 5-[(2R)-2-[[(2R)-2-(3-Chlorophenyl)-2-hydroxyethyl]amino]propyl]-1,3-benzodioxole-2,2-dicarboxylate (CL-316243) on Bladder Micturition Reflex in Spontaneously Hypertensive Rats

An excitatory role for peripheral EP3 receptors in bladder afferent function

Evaluation of pressor and visceromotor reflex responses to bladder distension in urethane anesthetized rats

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An excitatory role for peripheral EP₃ receptors in bladder afferent function