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. 2011 Nov;30(8):1666-74.
doi: 10.1002/nau.21143. Epub 2011 Jun 29.

Developmental and spinal cord injury-induced changes in nitric oxide-mediated inhibition in rat urinary bladder

Debra E Artim  1 , F Aura Kullmann, Stephanie L Daugherty, Evan Bupp, Cassandra L Edwards, William C de Groat
Affiliations

Developmental and spinal cord injury-induced changes in nitric oxide-mediated inhibition in rat urinary bladder

Debra E Artim et al. Neurourol Urodyn. 2011 Nov.

Abstract

Aims: During postnatal development large amplitude spontaneous activity of the neonatal rat bladder changes to a low amplitude adult pattern of activity that leads to improved storage function. Previously, we have shown that spontaneous activity in neonatal rat bladder strips is inhibited by activation of the nitric oxide (NO)-cGMP signaling pathway. In the present experiments we determined if this inhibitory pathway is altered during postnatal development or spinal cord injury.

Methods: Baseline tone and amplitude and frequency of spontaneous contractions were measured in bladder strips from male or female neonatal (days 10-21), juvenile (days 24-39) and adult female spinal cord intact or chronic spinal cord injured Sprague-Dawley rats.

Results: The inhibitory effects of an NO donor (SNAP) and a PDE-5 inhibitor (zaprinast) on spontaneous activity of bladder strips decreased during postnatal development, while an inhibitory effect of 8-bromo-cGMP, which was blocked by a protein kinase G inhibitor, was detected at all ages tested. However, the effect of NO-cGMP signaling to reduce baseline tone emerged during postnatal development. The inhibition induced by the NO donor was blocked by an inhibitor of soluble guanylyl cyclase (sGC). Chronic spinal cord injury (cSCI), which causes the re-emergence of a neonatal-like pattern of spontaneous activity, did not restore sensitivity to NO-mediated inhibition in adult rat bladders.

Conclusions: These data indicate that while cGMP signaling inhibits activity in young and adult bladders as well as after cSCI, there is a developmental decrease in the sensitivity of bladder to NO-mediated inhibition.

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Figures

Fig. 1
Fig. 1
Developmental changes in spontaneous activity in rat bladder strips. A: Representative examples of spontaneous bladder strip activity from a neonatal (11 days old) rat, a juvenile (28 days old) rat, an adult rat and a cSCI adult rat 4 weeks post-spinal injury. The neonatal rat bladder strip is characterized by a high-amplitude, low-frequency pattern of spontaneous activity. During development this activity changes to become low-amplitude, high-frequency pattern characteristic of the adult bladder. Spinal cord injury reverses this developmental change causing the re-emergence of a neonatal-like pattern of spontaneous bladder strip activity. Average amplitude (B) and frequency (C) of spontaneous contractions for each age group. For these measurements, no strips were treated with carbachol. *P < 0.01.
Fig. 2
Fig. 2
The effects of SNAP, an NO donor, on amplitude and frequency of spontaneous contractions and on baseline tone change during postnatal development. Examples of SNAP-mediated inhibition of spontaneous activity in neonatal (A), juvenile (B), adult (C), and cSCI adult (D) rat bladder strips. Arrows indicate time of drug application. Calibration bars apply to all traces (A–D). Summary of the effects of SNAP in bladder strips from neonatal (E, hatched bars) juvenile (E, black bars), adult (F), and cSCI (H) rats. G: Summary of the effects of SNAP in adult rat bladder strips in the presence (hatched bar) and absence (solid bar) of ODQ (10 μM). *P < 0.05 versus control. #P < 0.05 between groups (with and without ODQ).
Fig. 3
Fig. 3
8-Bromo-cGMP inhibits contractile activity and reduces baseline tone in bladder strips of all ages and following spinal cord injury. 8-Bromo-cGMP-induced inhibition of bladder strip spontaneous activity from a juvenile rat (A), an untreated adult rat bladder (B, top trace), an adult rat bladder pretreated with 25 μM Rp-cGMPs (B, bottom trace), an untreated cSCI adult (C, top trace) and a cSCI adult pretreated with 25 μM Rp-cGMPs (C, bottom trace). D: Summary of the effects of 8-bromo-cGMP on the amplitude and frequency of spontaneous contractions and on baseline tone in juvenile rat bladder strips. E,F: Summary of the effects of 8-bromo-cGMP on the amplitude and frequency of spontaneous contractions and on baseline tone in untreated strips (black bars) and in strips pretreated with 25 μM Rp-cGMPs (hatched bars) from an adult rat (E) and from a cSCI adult rat (F) rat. In each experiment, strips from the same bladder were used for Rp-cGMPs treatment and untreated controls. *P < 0.05 difference between control and 8-bromo-cGMP. #P < 0.05 between 8-bromo-cGMP with and without Rp-cGMPs.
Fig. 4
Fig. 4
Effects of PDE-5 inhibition on spontaneous contractions and on the effect of subsequent application of SNAP, an NO donor. A: Example of the effect of zaprinast (top trace) and subsequent application of SNAP (bottom trace) in a juvenile rat bladder strip. B: Example of the effect of zaprinast (top trace) and subsequent application (10 min interval) of SNAP (bottom trace) in an adult rat bladder strip. C: Spontaneous activity in an cSCI rat bladder strip before (top trace) and after (bottom trace) application of zaprinast. Subsequent application of SNAP had no additional effect. Summary of the effects of zaprinast (black bars) and subsequent application of SNAP (hatched bars) on the amplitude and frequency of spontaneous contractions and baseline tone in bladder strips from juvenile (D), adult (E), and cSCI adult (F) rats. In each experiment, strips from the same bladder were used for zaprinast treatment and untreated controls. *P < 0.05 difference between control and zaprinast. #P < 0.05 between zaprinast alone and SNAP following zaprinast.
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