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

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.

Bladder Smooth Muscle Strip Contractility as a Method to Evaluate Lower Urinary Tract Pharmacology

“…, SCI, BOO) 3–5 . Because this activity is believed to contribute to the symptoms of overactive bladder (OAB) 2 , an evaluation of receptors, intracellular pathways and pharmacological agents that modulate it, is of high interest for developing effective treatments for OAB and other smooth muscle dysfunctions.…”

“…, mucosa, Figure 7B). Additional applications not illustrated here include evaluation of intracellular pathways using pharmacological agents 3,10,11 , structure-activity relationships of various drugs 22–24 , or evaluation/quantification of transmitter release after neural stimulation 25 .…”

“…They were used to evaluate changes in myogenic spontaneous activity induced by pathology. This activity is believed to contribute to the urgency and frequency symptoms of overactive bladder (OAB), and is therefore a target for drugs being developed for OAB 3–9 . Bladder strips were also used to investigate myogenic and neuronal factors that modulate smooth muscle tone with the aim of discovering ion channels and/or receptors and/or intracellular pathways that could be targeted to induce either relaxation or contraction of the smooth muscle 3,10–13 .…”

“…This activity is believed to contribute to the urgency and frequency symptoms of overactive bladder (OAB), and is therefore a target for drugs being developed for OAB 3–9 . Bladder strips were also used to investigate myogenic and neuronal factors that modulate smooth muscle tone with the aim of discovering ion channels and/or receptors and/or intracellular pathways that could be targeted to induce either relaxation or contraction of the smooth muscle 3,10–13 . Other studies have focused on the nature of neurotransmission, including transmitters and receptors involved and changes induced by pathology 14,15 .…”

Nitric oxide modulates bladder afferent nerve activity in the in vitro urinary bladder–pelvic nerve preparation from rats with cyclophosphamide induced cystitis

“…Nitric oxide synthase (NOS) is expressed at various sites in the urinary bladder including afferent nerves (Vizzard et al, 1995, 1996; Vizzard, 1997), parasympathetic efferent nerves (Andersson and Persson, 1995; Vizzard et al, 1994), urothelial cells (Birder et al, 1998,2008; Birder, 2005); and smooth muscle (Andersson and Persson, 1993, 1995; Andersson and Wein, 2004; Birder et al, 1998, 2005,2008; Birder, 2005; de Groat, 2006; Moncada et al, 1991; Vizzard et al, 1994, 1997) suggesting that nitric oxide (NO) could have complex functions in the bladder. The smooth muscles of the bladder outlet and urethra are inhibited by NO, but detrusor muscle is relatively insensitive to these inhibitory effects (Andersson and Wein, 2004) except in neonatal bladders (Artim et al, 2009, 2011). However, in adult bladders intravesical administration of an NO donor suppresses bladder overactivity induced by chemical irritation with cyclophosphamide (CYP) (Ozawa et al, 1999); while intravesical administration of an NO scavenger (oxyhemoglobin) enhances reflex bladder activity (Pandita et al, 2000).…”