Characteristics of the NANC post‐stimulus (‘rebound’) contraction of the urinary bladder neck muscle in sheep

Thornbury, Keith D.; Donaghy, K.M.; Peake, Jennifer

doi:10.1111/j.1476-5381.1995.tb15095.x

Cited by 17 publications

(15 citation statements)

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“…In the rabbit urethra and the sheep bladder outlet regions, zaprinast was reported to increase the duration of the relaxant responses to EFS [11,32,33]. In the current investigation, sildenafil, vardenafil or tadalafil increased the duration of EFS‐induced relaxations by 30–60%.…”

Section: Discussionsupporting

confidence: 46%

Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

et al. 2006

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OBJECTIVES To characterize the distribution of phosphodiesterase 5 (PDE‐5), cGMP and cGMP‐dependent protein kinase I (PKG1), and to evaluate the effect of pharmacological inhibition of PDE‐5 in isolated preparations of pig and human urethra, as the nitric oxide (NO)/cGMP pathway generates the main inhibitory signals to reduce resistance in the bladder outlet and urethra during emptying of the bladder. MATERIALS AND METHODS After obtaining ethics committee approval, urethral specimens were obtained from three female patients during cystectomy, and from young female pigs. The specimens were prepared for immunohistochemical investigations and for functional studies in organ baths. Effects of sildenafil, vardenafil and tadalafil (1 nm to 30 µm) were studied in l‐noradrenaline (1 µm)‐activated or spontaneously contracted preparations, and on relaxations induced by electrical‐field stimulation (EFS). Levels of cGMP were determined by radioimmunoassay. RESULTS After stimulation with the NO donor, DETA NONO‐ate (1 mm), there was greater cGMP‐immunoreactivity (IR) in urethral and vascular smooth muscles. There was a wide distribution of cGMP‐ and vimentin‐positive interstitial cells between pig urethral smooth muscle bundles. There was also cGMP‐IR within NO‐synthase‐IR endothelium. There was PDE‐5 IR within the urethral and vascular smooth muscle cells, but also in vascular endothelial cells that expressed cGMP‐IR. In pig and human sections, there was strong PKG1‐IR in α‐actin‐IR urethral smooth muscle cells that also contained IR for cGMP. Sildenafil, vardenafil and tadalafil caused mean (sem) concentration‐dependent relaxations of the pig urethra which, at 30 µm, were 80 (3)% (11 samples), 81 (5)% (12 samples) and 64 (4)% (10 samples) of the spontaneous tone. The relaxation of L‐noradrenaline‐contracted female human urethra was 100% in response to 10 µm sildenafil, and 85 (15)% and 47 (13)% for 30 µm of vardenafil and tadalafil, respectively (three samples). Vardenafil or sildenafil (30 µm) doubled cGMP levels in pig specimens. There were no effects on cGMP levels with tadalafil. EFS (1–32 Hz) caused l‐NG‐nitroarginine‐sensitive relaxations of pig urethral muscle that were increased in amplitude and duration by PDE‐5 inhibition. At 0.1 µm, sildenafil, vardenafil or tadalafil significantly prolonged the mean (sem) duration of the relaxation at 4 Hz by 55 (19)%, 45 (14)% and 51 (12)%, respectively. CONCLUSIONS PDE‐5‐, cGMP‐ and PKG1‐IR is widely distributed in human and pig urethral tissues. Nerve‐induced relaxations of urethral preparations were enhanced at low concentrations of sildenafil, vardenafil and tadalafil, whereas there were direct smooth muscle‐relaxant actions of the PDE‐5 inhibitors at high concentrations. Inhibition of PDE‐5 might be an interesting option to facilitate cGMP‐mediated relaxation of the outflow region.

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Section: Discussionsupporting

confidence: 46%

Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

et al. 2006

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“…However, the Ca 2+ -release itself seems not to directly evoke muscle contraction; rather, it seems to be linked to a relaxing mechanism and to act as a signal to induce Ca 2+ -influx through L-type channels in LM-PGF (discussed in detail in the following section). These findings are distinct from the observations in sheep bladder neck and rat ileum where only one Ca 2+ source is necessary for NO-induced contraction (3,5).…”

Section: +contrasting

confidence: 54%

“…For example, NO-induced contraction is reduced slightly by nifedipine but suppressed strongly by ryanodine in sheep urinary bladder neck (5). Comparatively, it is unaffected by ryanodine but reduced by nifedipine in rat ileum (3).…”

Section: The Camentioning

confidence: 89%

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Rebound Contraction by Nitric Oxide in the Longitudinal Muscle of Porcine Gastric Fundus

Kim

Sung

et al. 2002

Japanese Journal of Pharmacology

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ABSTRACT-The rebound contraction induced by electrical field stimulation (EFS) and nitric oxide (NO) donor, S-nitroso-L-cysteine (cysNO), were investigated in the longitudinal muscle of porcine gastric fundus (LM-PGF). Under the presence of atropine and guanethidine, cysNO and EFS produced sequential relaxation-contraction in LM-PGF. Tetrodotoxin abolished the EFS-induced response, while leaving the cysNOinduced one unaffected. A soluble guanylate cyclase inhibitor, lH-[1,2,4]-oxadiazolo-[4,3-a]-quinoxalin-1-one, inhibited both cysNO and EFS-induced biphasic response. A cGMP analogue only relaxed LM-PGF. A phosphodiesterase V inhibitor, zaprinast, prolonged the cysNO and the EFS-induced relaxation and inhibited the rebound contraction. The rebound contraction was inhibited by verapamil, an L-type Ca 2+ channel blocker. The cysNO and the EFS-induced biphasic response were inhibited by ryanodine plus cyclopiazonic acid or by ruthenium red, a ryanodine-receptor blocker. LM-PGF was relaxed on exposure to caffeine and then produced a verapamil-sensitive rebound contraction during the washout period. CysNO and EFS did not induce the rebound contraction in the presence of caffeine. These results suggest that the NO-induced rebound contraction involves both Ca 2+-release from the ryanodine-sensitive store and Ca 2+-influx through L-type channels. Although the NO-induced biphasic response is dependent on cGMP, rapid removal of cGMP seems necessary for the rebound contraction.

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“…We do not think that these responses were a direct myogenic effect of EFS because they were observed only after the tone of the tissue was elevated with serotonin. Moreover, they were resistant to treatment with L-NAME, suggesting that they are not NO-mediated rebound contractions observed by others (40). Therefore, we assume that these rebound contractions are due to EFS-induced changes in the sensitivity of smooth muscle to exogenous serotonin.…”

Section: Discussionmentioning

confidence: 90%

Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats

2003

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The distinction between metabolic and structural changes occurring in autonomic neurons during diabetes has not been fully clarified. Here we demonstrate that nitric oxide synthase-containing (nitrergic) neurons innervating the penis and gastric pylorus of streptozotocin-induced diabetic rats undergo a selective degenerative process in two phases. In the first phase, nitrergic nerve fibers lose some of their neuronal nitric oxide synthase content and function. In the second phase, nitrergic degeneration takes place in the cell bodies in the ganglia, leading to complete loss of nitrergic function. The changes in the first phase are reversible with insulin replacement; however, the neurodegeneration in the second phase is irreversible. Neurodegeneration is due to apoptotic cell death in the ganglia, which is selective for the nitrergic neurones. Diabetes 52:2353-2362, 2003 D iabetes is a common disorder that leads to complications affecting the retina, kidney, vascular, gastrointestinal, peripheral, and autonomic nervous systems. The mechanism through which diabetic complications develop is unclear. The generally accepted view for most diabetic complications is that the disease is accompanied by metabolic changes in the affected organ that, in the long term, result in structural alterations. Thus, if insulin replacement is started before the structural lesions occur, then it should reverse the metabolic changes and prevent the development of the complication. Once the structural lesions occur, however, the process should become less reversible with insulin replacement. Although from early studies in vivo "a point of no return" had been suggested during the course of diabetic peripheral neuropathy, cardiomyopathy, and nephropathy (1-3), most of the subsequent work has concentrated either on cellular dysfunction or on cell death without addressing the distinction between metabolic and structural alterations.Nitric oxide (NO) is a well-characterized neurotransmitter in the central and peripheral nervous systems. In many tissues of the urogenital and gastrointestinal tract, NO mediates nonadrenergic noncholinergic (NANC) relaxant responses (4). Nerves that release NO are now known as nitrergic (5). NO is generated in these nerves by activation of the neuronal NO synthase (nNOS) and diffuses into the smooth muscle to activate the soluble guanylyl cyclase (sGC), producing an increase in the intracellular cyclic guanosine-3Ј, 5Ј-monophosphate concentration, leading to relaxation (6).Impaired nitrergic transmission has been shown to be responsible for erectile dysfunction and gastropathy in diabetes (7-12). To investigate the mechanisms by which the metabolic changes lead to structural disturbances in autonomic neuropathy, we studied the structure and function of nitrergic nerve fibers and neuronal cell bodies in the gastric pylorus, penis, and major pelvic ganglia in streptozotocin (STZ)-induced diabetic rats. In addition, we investigated the effect of different schedules of insulin treatment on this process. RESEARCH DE...

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Characteristics of the NANC post‐stimulus (‘rebound’) contraction of the urinary bladder neck muscle in sheep

Cited by 17 publications

References 17 publications

Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

Phosphodiesterase 5 in the female pig and human urethra: morphological and functional aspects

Rebound Contraction by Nitric Oxide in the Longitudinal Muscle of Porcine Gastric Fundus

Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats

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