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01.12.2015 | Research article | Ausgabe 1/2015 Open Access

BMC Urology 1/2015

Protein kinase C modulates frequency of micturition and non-voiding contractions in the urinary bladder via neuronal and myogenic mechanisms

Zeitschrift:
BMC Urology > Ausgabe 1/2015
Autoren:
Joseph A Hypolite, Shaohua Chang, Alan J Wein, Samuel Chacko, Anna P Malykhina
Wichtige Hinweise
Joseph A Hypolite and Anna P Malykhina contributed equally to this work.

Competing interests

The authors declare that they have no competing interests.

Authors’ contributions

JAH conceived of the study. JAH; SC; S.Chang; APM designed experiments. JAH; SC; S. Chang; APM and AJW interpreted and analyzed results. JAH; SC; S. Chang; APM and AJW prepared manuscript. JAH and S.Chang performed experiments. JAH; SC; APM and S. Chang prepared figures. JAH; APM; SC; S. Chang; and AJW approved final version of the manuscript. All authors read and approved the final manuscript.

Abstract

Background

Protein Kinase C (PKC) dysfunction is implicated in a variety of smooth muscle disorders including detrusor overactivity associated with frequency and urgency of micturition. In this study, we aimed to evaluate the modulatory effects of endogenous PKC-dependent pathways on bladder storage and emptying function.

Methods

We utilized in vivo cystometry and in vitro organ bath studies using isolated bladder muscle strips (BMS) from rats to measure contractility, intravesical pressure, and voided volume. Both in vitro and in vivo results were statistically analyzed using one-way repeated measures ANOVA between the groups followed by Bonferroni’s post-test, as appropriate (Systat Software Inc., San Jose, CA).

Results

Effects of PKC activators, phorbol-12,13-dibutyrate (PDBu), and phorbol-12,13-myristate (PMA), were concentration-dependent, with high concentrations increasing frequency of micturition, and sensitivity of intramural nerves to electrical field stimulation (EFS), in vitro, while lower concentrations had no effect on BMS sensitivity to EFS. The PKC inhibitors, bisindolylmaleimide1 (Bim-1), (28 nM), and Ro318220 (50 μM) triggered an increase in the number of non-voiding contractions (NVC), and a decrease in the voided volume associated with reduced ability to maintain contractile force upon EFS, but did not affect peak force in vitro. Both low (50 nM) and high PDBu 1 micromolar (1uM) decreased the sensitivity of BMS to carbachol. Application of a low concentration of PDBu inhibited spontaneous contractions, in vitro, and Bim-1-induced NVC, and restored normal voiding frequency during urodynamic recordings in vivo.

Conclusions

In summary, the effects of low PKC stimulation include inhibition of smooth muscle contractile responses, whereas high levels of PKC stimulation increased nerve-mediated contractions in vitro, and micturition contractions in vivo. These results indicate that endogenous PKC signaling displays a concentration-dependent contraction profile in the urinary bladder via both smooth muscle and nerve-mediated pathways.
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