Rho‐kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats

Rajasekaran, Mahadevan; Wilkes, Nathan; Kuntz, Steven; Albo, Michael

doi:10.1002/nau.20122

Cited by 70 publications

(73 citation statements)

References 32 publications

(51 reference statements)

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“…This is in agreement with previous work wherein identification of these proteins has also been demonstrated [25,27,30,31,37,45]. In addition, recent reports demonstrate that ROKβ is partly responsible for the high degree of force maintenance in the detrusor smooth muscle in overactive bladders [30][31][32]. Our experiments revealed that both ROKα and ROKβ are expressed at lower levels in the urethra compared to the detrusor and trigone.…”

Section: Discussionsupporting

confidence: 93%

“…In human, rat, rabbit and guinea pig bladder, the Rho-kinase pathway represents an important regulator of smooth muscle activity and tone [25,[27][28][29][30][31][32]. The prototype Rho-kinase inhibitor Y-27632 has been shown to attenuate contractions of bladder smooth muscle evoked by CCh, through the decrease of Ca 2+ sensitivity of the contractile apparatus [27][28][29].…”

Section: Discussionmentioning

confidence: 99%

“…The RhoA/Rho-kinase Ca 2+ sensitization pathway is involved in the regulation of bladder smooth muscle contraction and tone in humans [25,26] and animals [27][28][29]. Inhibition of Rho-kinase attenuates bladder hyperactivity in rabbits with partial outlet obstruction [30], diabetic rabbits [31] and hypertensive rats [32].…”

Section: Introductionmentioning

confidence: 99%

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Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

Teixeira

Jin

Priviero

et al. 2007

Biochemical Pharmacology

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We aimed to compare the expression and function of molecular components of the RhoA/Rho-kinase signaling pathway in the contractile responses of detrusor, trigonal and urethral smooth muscle, using selective Rho-kinase inhibitors. Contractility studies and molecular approaches were employed to demonstrate the expression patterns and functional activity of the RhoA/Rho-kinase signaling pathway in the lower urinary tract. Frequency-response curves (1-32 Hz) and concentration-response curves (CRC) to carbachol (CCh, 0.01-30 μM), phenylephrine (PE, 0.01-300 μM) and endothelin-1 (ET-1, 0.01-100 nM) were significantly attenuated (p<0.01) following incubation with the Rhokinase inhibitors H-1152 (0

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

Teixeira

Jin

Priviero

et al. 2007

Biochemical Pharmacology

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“…However, Wibberley et al 22 found that Rhokinase inhibitors (Y-27632, HA 1077) reduced basal tension of isolated bladder preparations. Furthermore, Rajasekaran et al 23 showed that Rho kinase inhibition reduced DO in spontaneous hypertensive rats.…”

Section: Spontaneous Activation Of the Myocytementioning

confidence: 99%

Detrusor myocyte activity and afferent signaling

Andersson

2009

Neurourology and Urodynamics

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Aims: To discuss (1) mechanisms involved in the generation and control of myocyte contractions and consequent afferent nerve activity and (2) these mechanisms as targets for drugs aimed for treatment of overactive bladder (OAB) symptoms and detrusor overactivity (DO). Methods: Literature review of myocyte activation, bladder afferent nerves, mediators in the bladder, and translational aspects of the findings. Results: During bladder filling, there is normally no parasympathetic outflow from the spinal cord. Despite this, the bladder develops tone during filling and also exhibits non-synchronized local contractions and relaxations that are caused by a basal myogenic mechanical activity that may be reinforced by release of, for example, acetylcholine from non-neuronal and/or neuronal sources or local mediators, such as prostaglandins and endothelins. It is suggested that these spontaneous contractions are able to generate activity in afferent nerves (''afferent noise'') that may contribute to DO and OAB. Conclusions: Spontaneous bladder myocyte contractions and factors that are able to modulate them, as well as the consequent afferent nerve activity, may be targets for drugs meant for treatment of OAB/DO. Neurourol.

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“…Overexpression or sensitization of muscarinic receptors was noted as the mechanism (Schneider et al, 2005). Moreover, intracellular calcium sensitization (Sherer et al, 2000;Rajasekaran et al, 2005) and correlation of autonomic nerve alteration (Steers et al, 1999) were also hypothesized.…”

mentioning

confidence: 99%

Alterations of Glucose-Dependent and -Independent Bladder Smooth Muscle Contraction in Spontaneously Hypertensive and Hyperlipidemic Rat

Nobe

Yamazaki²,

Kumai³

et al. 2007

J Pharmacol Exp Ther

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Alteration of bladder contractility was examined in the spontaneously hypertensive and hyperlipidemic rat (SHHR; age, 9 months; systolic blood pressure, Ͼ150 mm Hg; plasma cholesterol, Ͼ150 mg/dl). Carbachol (CCh) induced time-and dose-dependent contractions in Sprague-Dawley (age-matched control) rats and SHHR; however, maximal levels differed significantly (13.3 Ϯ 2.2 and 5.4 Ϯ 1.9 N/mm 2 following 10 M CCh treatment, respectively; n ϭ 5). This difference, which was maintained in calciumreplaced physiological salt solution (PSS), was suppressed by pretreatment with rho kinase inhibitor, 1 M Y27632 [(R)-(ϩ)-trans-N-(4-pyridyl)-4-(1-aminoethyl)-cyclohexanecarboxamide]; moreover, total activity of rho kinase was also reduced in SHHR bladder. Pretreatment of bladders under high-glucose (HG) conditions (22.2 mM glucose-contained PSS for 30 min) led to enhancement of CCh-induced contraction solely in control animals. Under HG conditions, both protein kinase C (PKC) activity and production of diacylglycerol (DG) derived from incorporated glucose declined in SHHR bladder; however, sustained elevation of plasma glucose level was not detected in SHHR. These results suggested that bladder contractility dysfunction in SHHR is attributable to alteration of rho kinase activity and the DG-PKC pathway. This dysfunction may occur prior to chronic hyperglycemia onset in progressive hypertension and hyperlipidemia.

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Rho‐kinase inhibition suppresses bladder hyperactivity in spontaneously hypertensive rats

Cited by 70 publications

References 32 publications

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

Comparative pharmacological analysis of Rho-kinase inhibitors and identification of molecular components of Ca2+ sensitization in the rat lower urinary tract

Detrusor myocyte activity and afferent signaling

Alterations of Glucose-Dependent and -Independent Bladder Smooth Muscle Contraction in Spontaneously Hypertensive and Hyperlipidemic Rat

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