Pharmacologic Characterization of Human Male Urethral Smooth Muscle: An In Vitro Approach

Kedia, George T.; Oelke, Matthias; Sohn, Michael; Kuczyk, Markus A.; Ückert, Stefan

doi:10.1016/j.urology.2013.08.023

Cited by 6 publications

(4 citation statements)

References 25 publications

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“…In the organ bath-assay in vitro we demonstrated that the PDE5 inhibitor vardenafil, but also the sGC stimulator BAY 41–2272, significantly and dose-dependently reduced noradrenaline-induced spontaneous oscillations of isolated rat ureter. These data are in line with the recently published data of Kedia et al (2013), Liatsikos et al (2013), and Miyaoka et al (2014)[ 39 , 40 , 41 ], showing a significant and concentration-dependent relaxation in human ureteral tissue with the NO-donnor sodiumnitroprusside (SNP), the PDE5 inhibitors vardenafil and sildenafil [ 40 , 41 ] and the sGC stimulator BAY 41–2272 [ 39 ]. In human ureteral tissue, the relaxing effects of vardenafil were also accompanied by cGMP increase, which suggests a cGMP-driven mode of action [ 41 ].…”

Section: Discussionsupporting

confidence: 88%

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

et al. 2015

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Urinary colics from calculosis are frequent and intense forms of pain whose current pharmacological treatment remains unsatisfactory. New and more effective drugs are needed to control symptoms and improve stone expulsion. Recent evidence suggested that the Nitric Oxide (NO) / cyclic guanosine monophosphate (cGMP) / phosphodiesterase type 5 (PDE5) system may contribute to ureteral motility influencing stone expulsion. We investigated if PDE5 inhibitors and sGC stimulators influence ureteral contractility, pain behaviour and stone expulsion in a rat model of ureteral calculosis. We investigated: a)the sex-specific PDE5 distribution in the rat ureter; b)the functional in vitro effects of vardenafil and sildenafil (PDE5 inhibitors) and BAY41-2272 (sGC stimulator) on induced ureteral contractility in rats and c)the in vivo effectiveness of vardenafil and BAY41-2272, alone and combined with ketoprofen, vs hyoscine-N-butylbromide alone or combined with ketoprofen, on behavioural pain indicators and stone expulsion in rats with artificial calculosis in one ureter. PDE5 was abundantly expressed in male and female rats’ ureter. In vitro, both vardenafil and BAY41-2272 significantly relaxed pre-contracted ureteral strips. In vivo, all compounds significantly reduced number and global duration of “ureteral crises” and post-stone lumbar muscle hyperalgesia in calculosis rats. The highest level of reduction of the pain behaviour was observed with BAY41-2272 among all spasmolytics administered alone, and with the combination of ketoprofen with BAY41-2272. The percentage of stone expulsion was maximal in the ketoprofen+BAY41-2272 group. The NO/cGMP/PDE5 pathway is involved in the regulation of ureteral contractility and pain behaviour in urinary calculosis. PDE5 inhibitors and sGC stimulators could become a potent new option for treatment of urinary colic pain.

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Section: Discussionsupporting

confidence: 88%

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

et al. 2015

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“…A cAMP‐dependent pathway has been suggested to be involved in the relaxant response in urethra . We demonstrated here that both PGE 2 and CP‐533,533 increased cAMP accumulation in urethral tissues of rats in a concentration‐dependent manner.…”

Section: Discussionmentioning

confidence: 49%

“…A cAMP-dependent pathway has been suggested to be involved in the relaxant response in urethra. 9,10 We demonstrated here that both PGE 2 and CP-533,533 increased cAMP accumulation in urethral tissues of rats in a concentration-dependent manner. Further, at the concentrations of PGE 2 and CP-533,536 that significantly raised cAMP levels in urethral tissues, the compounds also induced relaxation of the tissue.…”

Section: Discussionmentioning

confidence: 59%

Study on Physiological Roles of Stimulation of Prostaglandin E₂ Receptor Subtype EP2 in Urethral Function in Rats

Kurihara

Ishizu

Takamatsu

et al. 2014

LUTS

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“…; Chen & Brading, ; Andersson, ; Kedia et al . ). Genes encoding all three α1 adrenoceptors were expressed in sorted USMCs (Fig.…”

Section: Resultsmentioning

confidence: 97%

Ca²⁺ signalling in mouse urethral smooth muscle in situ: role of Ca²⁺ stores and Ca²⁺ influx mechanisms

Drumm

Rembetski

Cobine

et al. 2018

The Journal of Physiology

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Urethral smooth muscle cells (USMCs) generate myogenic tone and contribute to urinary continence. Currently, little is known about Ca signalling in USMCs in situ, and therefore little is known about the source(s) of Ca required for excitation-contraction coupling. We characterized Ca signalling in USMCs within intact urethral muscles using a genetically encoded Ca sensor, GCaMP3, expressed selectively in USMCs. USMCs fired spontaneous intracellular Ca waves that did not propagate cell-to-cell across muscle bundles. Ca waves increased dramatically in response to the α1 adrenoceptor agonist phenylephrine (10 μm) and to ATP (10 μm). Ca waves were inhibited by the nitric oxide donor DEA NONOate (10 μm). Ca influx and release from sarcoplasmic reticulum stores contributed to Ca waves, as Ca free bathing solution and blocking the sarcoplasmic Ca -ATPase abolished activity. Intracellular Ca release involved cooperation between ryanadine receptors and inositol trisphosphate receptors, as tetracaine and ryanodine (100 μm) and xestospongin C (1 μm) reduced Ca waves. Ca waves were insensitive to L-type Ca channel modulators nifedipine (1 μm), nicardipine (1 μm), isradipine (1 μm) and FPL 64176 (1 μm), and were unaffected by the T-type Ca channel antagonists NNC-550396 (1 μm) and TTA-A2 (1 μm). Ca waves were reduced by the store operated Ca entry blocker SKF 96365 (10 μm) and by an Orai antagonist, GSK-7975A (1 μm). The latter also reduced urethral contractions induced by phenylephrine, suggesting that Orai can function effectively as a receptor-operated channel. In conclusion, Ca waves in mouse USMCs are a source of Ca for excitation-contraction coupling in urethral muscles.

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Pharmacologic Characterization of Human Male Urethral Smooth Muscle: An In Vitro Approach

Cited by 6 publications

References 25 publications

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

Study on Physiological Roles of Stimulation of Prostaglandin E₂ Receptor Subtype EP2 in Urethral Function in Rats

Ca²⁺ signalling in mouse urethral smooth muscle in situ: role of Ca²⁺ stores and Ca²⁺ influx mechanisms

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Pharmacologic Characterization of Human Male Urethral Smooth Muscle: An In Vitro Approach

Cited by 6 publications

References 25 publications

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

Effects of PDE5 Inhibitors and sGC Stimulators in a Rat Model of Artificial Ureteral Calculosis

Study on Physiological Roles of Stimulation of Prostaglandin E2 Receptor Subtype EP2 in Urethral Function in Rats

Ca2+ signalling in mouse urethral smooth muscle in situ: role of Ca2+ stores and Ca2+ influx mechanisms

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Study on Physiological Roles of Stimulation of Prostaglandin E₂ Receptor Subtype EP2 in Urethral Function in Rats

Ca²⁺ signalling in mouse urethral smooth muscle in situ: role of Ca²⁺ stores and Ca²⁺ influx mechanisms