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

Teixeira, Cleber E.; Jin, Liming; Priviero, Fernanda; Zhao, Ying; Webb, R.

doi:10.1016/j.bcp.2007.06.004

Cited by 33 publications

(26 citation statements)

References 53 publications

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“…For example, Deplanne et al found that α,β -methylene ATP contracted all regions of rabbit urethra 7 and Teixeira et al noted that α,β -methylene ATP also contracted strips of rat USM. 19 Hashitani and Edwards reported that EFS of intramural nerves in guinea pig USM yielded excitatory junction potentials and slow waves, which were inhibited by α,β -methylene ATP. 9 Bradley et al described a transient inward current in urethral SMCs that was activated by ATP but not mimicked by the P2Y agonist 2-MeSADP.…”

Section: Discussionmentioning

confidence: 99%

P2X Receptor Currents in Smooth Muscle Cells Contribute to Nerve Mediated Contractions of Rabbit Urethral Smooth Muscle

et al. 2011

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Purpose Adenosine triphosphate is capable of relaxing and contracting urethral smooth muscle. The mechanisms responsible for the relaxing effects of adenosine triphosphate have been well studied but those involved in the contractile response are still unclear. We investigated the contributions of interstitial cells of Cajal and smooth muscle cells to nerve mediated, adenosine triphosphate dependent contractions of urethral smooth muscle. Materials and Methods Tension recordings were made from strips of rabbit urethral smooth muscle. Recordings were made of membrane potential and ionic currents from freshly isolated smooth muscle cells and interstitial cells of Cajal using the patch clamp technique. Results Stimulating intramural nerves in urethral smooth muscle yielded contractions that were inhibited by the broad spectrum P2 receptor inhibitor pyri-doxal-phosphate-6-azophenyl-2′,4′-disulfonate and the P2X receptor agonist α,β-methylene adenosine triphosphate but not by the P2Y receptor antagonist MRS2500. When studied under voltage clamp at a holding potential of −60 mV, interstitial cells of Cajal showed spontaneous transient inward currents that were increased in frequency by adenosine triphosphate but not by α,β-methylene adenosine triphosphate. In contrast, smooth muscle cells were quiescent but responded to adenosine triphosphate and α,β-methylene adenosine triphosphate by producing a single transient inward current. Currents evoked by adenosine triphosphate in smooth muscle cells were inhibited by α,β-methylene adenosine triphosphate, pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate and suramin, and by a decrease in extracellular Na+ from 130 to 13 mM. Conclusions Stimulating purinergic nerves in rabbit urethral smooth muscle induces contractions via the activation of P2X receptors on smooth muscle cells.

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Section: Discussionmentioning

confidence: 99%

P2X Receptor Currents in Smooth Muscle Cells Contribute to Nerve Mediated Contractions of Rabbit Urethral Smooth Muscle

et al. 2011

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“…In addition, components of the RhoA-Rho-kinase signaling pathway are expressed in detrusor, trigonal and urethral smooth muscle and dynamically regulate contraction and tone. Moreover, Rho-kinase inhibitors also markedly reduced the contractions evoked by either KCl or α , β -methylene ATP with H-1152 was approximately 9 -16 times more potent than Y-27632 or HA-1077 [107] .…”

Section: Rho Kinasesmentioning

confidence: 96%

Premature ejaculation: focus on therapeutic targets

Abdel‐Hamid

Jannini

Andersson

2009

Expert Opinion on Therapeutic Targets

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Background : Premature ejaculation (PE) is poorly defined but the most common male sexual complaint. It can be treated with strategies including oral pharmacotherapy, topical anaesthetics, behavioural therapy and surgery. Although PE is treatable in most, but not all, patients by currently available modalities, long term success rates have been disappointing. An approved treatment so far does not exist. Objective : To review literature on the current and potential therapeutic targets for PE. Methods : Available English-language published literature is reviewed. Results/conclusions : There are many targets for future therapeutic approaches to PE that may address the shortcomings of existing therapy. Selecting the best targets depends heavily on their playing a prominent role in PE. Exploiting the full therapeutic potential of these targets will require additional basic and clinical research.

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“…A role for RhoA and ROK in urethral tone was indicated by the demonstration that inhibition of RhoA with Clostridium difficile toxin B or of ROK with Y27632 abolished porcine urethral tone without affecting [Ca 2ϩ ] i (28). ROK inhibition also inhibited the contractile response of rat urethral smooth muscle to phenylephrine, endothelin-1, ␣,␤-methylene ATP, and membrane depolarization but had no significant effect on baseline tension (37).…”

mentioning

confidence: 99%

Rho-associated kinase plays a role in rabbit urethral smooth muscle contraction, but not via enhanced myosin light chain phosphorylation

Walsh

Thornbury

Cole

et al. 2011

American Journal of Physiology-Renal Physiology

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Walsh MP, Thornbury K, Cole WC, Sergeant G, Hollywood M, McHale N. Rho-associated kinase plays a role in rabbit urethral smooth muscle contraction, but not via enhanced myosin light chain phosphorylation. Am J Physiol Renal Physiol 300: F73-F85, 2011. First published September 22, 2010 doi:10.1152/ajprenal.00011.2010.-The involvement of Rho-associated kinase (ROK) in activation of rabbit urethral smooth muscle contraction was investigated by examining the effects of two structurally distinct inhibitors of ROK, Y27632 and H1152, on the contractile response to electric field stimulation, membrane depolarization with KCl, and ␣ 1-adrenoceptor stimulation with phenylephrine. Both compounds inhibited contractions elicited by all three stimuli. The protein kinase C inhibitor GF109203X, on the other hand, had no effect. Urethral smooth muscle strips were analyzed for phosphorylation of three potential direct or indirect substrates of ROK: 1) myosin regulatory light chains (LC 20) at S19, 2) the myosintargeting subunit of myosin light chain phosphatase (MYPT1) at T697 and T855, and 3) cofilin at S3. The following results were obtained: 1) under resting tension, LC 20 was phosphorylated to 0.65 Ϯ 0.02 mol P i/mol LC20 (n ϭ 21) at S19; 2) LC20 phosphorylation did not change in response to KCl or phenylephrine; 3) ROK inhibition had no effect on LC 20 phosphorylation in the absence or presence of contractile stimuli; 4) under resting conditions, MYPT1 was partially phosphorylated at T697 and T855 and cofilin at S3; 5) phosphorylation of MYPT1 and cofilin was unaffected by KCl or phenylephrine; and 6) KCl-and phenylephrine-induced contraction-relaxation cycles did not correlate with actin polymerization-depolymerization. We conclude that ROK plays an important role in urethral smooth muscle contraction, but not via inhibition of MLCP or polymerization of actin. urethra; urinary continence; myosin light chain phosphatase; cofilin

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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

Cited by 33 publications

References 53 publications

P2X Receptor Currents in Smooth Muscle Cells Contribute to Nerve Mediated Contractions of Rabbit Urethral Smooth Muscle

P2X Receptor Currents in Smooth Muscle Cells Contribute to Nerve Mediated Contractions of Rabbit Urethral Smooth Muscle

Premature ejaculation: focus on therapeutic targets

Rho-associated kinase plays a role in rabbit urethral smooth muscle contraction, but not via enhanced myosin light chain phosphorylation

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