Alterations in the Nitric Oxide Synthase Binding Sites and Non-Adrenergic, Non-Cholinergic Mediated Smooth Muscle Relaxation in the Diabetic Rabbit Bladder Outlet: Possible Relevance to the Pathogenesis of Diabetic Cystopathy

Mumtaz, Faiz; Sullivan, M.; Thompson, CS; Dashwood, M; Naseem, KM; Bruckdorfer, K. Richard; Mikhailidis, DP; Morgan, Robert J.

doi:10.1016/s0022-5347(05)68627-2

Cited by 39 publications

(22 citation statements)

References 41 publications

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“…In a previous study, NO production was reported to be increased in the urethra of DM rabbits through the measurement of nicotinamide adenine dinucleotide phosphate diaphorase, a marker of NOS activity (24). However, in the present study, the concentration of NO was determined directly in DM rats, and the results indicated that the NO concentration was significantly decreased in DM rats.…”

Section: Discussioncontrasting

confidence: 71%

Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO‑cGMP pathway

Zhang

et al. 2017

Exp Ther Med

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Abstract.Oxidative stress is closely associated with the onset of diabetes mellitus (DM). Diabetic urethropathy is one of the most common complications of DM, but few studies have been conducted to investigate the role of oxidative stress in diabetic urethropathy. Grape seed proanthocyanidin extract (GSPE) has been previously reported to reduce oxidative injury. The present study aimed to investigate the role of oxidative stress and the protective effects of GSPE on urethral dysfunction using a streptozotocin-induced DM rat model. Female Wistar rats were divided into a control group (n=36), a DM group (n=36) and a DM + GSPE group (n=36). Urodynamic testing was performed using a PowerLab data acquisition device. The expression of neuronal nitric oxide synthase (nNOS), 3-nitrotyrosine and nuclear factor erythroid 2-related factor 2 (Nrf2) was determined using western blot analysis. The expression of 3-nitrotyrosine was also determined using immunohistochemistry. Nitric oxide (NO), cyclic guanosine monophosphate (cGMP), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) were measured using commercial ELISA kits. A significant increase was observed in the intravesical pressure thresholds for inducing urethral relaxation and the urethral perfusion pressure nadir in DM rats compared with the control group. GSPE was observed to reverse the increase of these parameters compared with the DM group. In addition, GSPE could reverse the downregulation of nNOS, NO and cGMP expression, and the decreased activities of antioxidant enzymes (SOD and GSH-Px). GSPE reversed the upregulation of 3-nitrotyrosine and MDA in DM rats. GSPE also activated Nrf2, which is a key antioxidative transcription factor. The findings of the present study demonstrated that GSPE protects urethra function in DM rats through modulating the NO-cGMP signaling pathway. The protective roles of GSPE may be associated with activation of the Nrf2 defense pathway. IntroductionDiabetes mellitus (DM) refers to a group of metabolic disorders characterized by hyperglycemia, which have a severe impact on public health. To date, the majority of studies examining DM complications have focused on the pathogenesis and management of diabetic cystopathy, one of the most common complications of DM (1,2). Diabetic cystopathy is considered to be a manifestation of polyneuropathy, involving sensory and autonomic nerve fibers 1 (3). A previous study reported that DM induces damage to the innervation of the urethra, together with reduction of urethral relaxation during micturition reflex (4). DM may also induce impairment of urethral smooth muscle, which is closely associated with urethral dysfunction. However, few studies have been conducted to investigate the mechanism of urethral dysfunction in DM, so this remains unclear.Precise coordination between smooth muscle in the urethra and bladder is crucial for the balance between urine storage and bladder emptying (4). Such coordination is largely dependent on the nitric oxide (NO) released from...

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Section: Discussioncontrasting

confidence: 71%

Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO‑cGMP pathway

Zhang

et al. 2017

Exp Ther Med

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“…TH and VAChT protein are well established and commonly employed presynaptic markers of sympathetic and parasympathetic fibers respectively [28,29]. NOS1 is also recognized as an important controller of genitourinary function via its involvement in non-adrenergic non-cholinergic pathways [15,19,27,31]. In our initial studies of control tissues we found these markers to be localized to certain mouse bladder regions, in that TH was most prevalent in the lamina propria region, while VAChT was most prevalent in the smooth muscle region, and NOS1 was widely distributed.…”

Section: Discussionmentioning

confidence: 99%

“…Diabetes-related urinary bladder dysfunction in humans has commonly been attributed to altered neuronal control and/or neuronal injury [3,4], and such changes have also been observed in several animal models (e.g., rat, guinea pig, hamster, rabbit) [7,[17][18][19]. However, a review of the literature shows no consensus since studies have reported an increase, decrease or no effect to various muscarinic and adrenergic agonists [7,10,12], and there is a lack of such investigations in any mouse model during diabetes.…”

Section: Introductionmentioning

confidence: 99%

Functional, Structural, and Neuronal Alterations in Urinary Bladder during Diabetes: Investigations of a Mouse Model

Poladia¹,

Bauer²

2005

Pharmacology

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Urinary bladder dysfunction is a common complication in diabetes, but the mechanisms involved are undefined and treatment options are limited. Murine models provide opportunities to utilize transgenic technologies for bladder research and here we investigate the functional, structural and neuronal aspects of the bladder in a mouse model of type-1 diabetes. Mice were injected with streptozotocin (150 mg/kg) or vehicle and studied at 5 weeks. Increases in blood glucose and total urine output were observed. In vitro cystometry showed a 2-fold increase in bladder capacity and compliance and decreased intravesical plateau pressure in diabetics versus controls. Bladder structure and composition were evaluated by digital imaging; region-specific changes included increased smooth muscle and urothelium and no change in collagen content. Alterations in cholinergic, adrenergic and nitric oxide-related functional responsiveness were also observed. The prevalence of cholinergic and adrenergic neuronal tracts was determined by immunohistochemistry: decreased vesicular acetylcholine transferase was observed in smooth muscle, whereas tyrosine hydroxylase was increased in the lamina propria, demonstrating a ‘neuronal remodeling’ shift toward pro-relaxant neuronal pathways. These studies demonstrate that this mouse model of diabetes exhibits important features of urinary bladder remodeling that are similar to the findings in humans and other animal models and will therefore be useful for further mechanistic investigations.

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“…This is in good accordance with ®ndings in other uro-genital smooth muscle organs (corpus cavernosum and urethra), where it was shown that diabetes impairs nerve-mediated relaxation. 5,34 In the vascular bed, several investigators have shown that diabetes causes impaired endothelium-dependent relaxation. 35 ± 38 Possible mechanisms behind the diabetes-related impairment of the NO system may be decreased releaseaformation of NO due to decreased NOS activity, 39 de®cit in the substrate availability, 35 alterations of the NOS binding sites, 34 reduction in nerve density, 33 or decreased sensitivity to NO.…”

Section: Discussionmentioning

confidence: 99%

“…5,34 In the vascular bed, several investigators have shown that diabetes causes impaired endothelium-dependent relaxation. 35 ± 38 Possible mechanisms behind the diabetes-related impairment of the NO system may be decreased releaseaformation of NO due to decreased NOS activity, 39 de®cit in the substrate availability, 35 alterations of the NOS binding sites, 34 reduction in nerve density, 33 or decreased sensitivity to NO. 36 In order to identify a possible step of the cGMP pathway responsible for the diabetes related impairment of the NO system in our experiments, investigations were carried out to measure NOS activity in tissue from diabetic and non-diabetic animals.…”

Section: Discussionmentioning

confidence: 99%

Effects of diabetes on neurotransmission in rat vaginal smooth muscle

et al. 2001

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The aim of this work was to characterize the effect of experimental diabetes on neurotransmission in rat vagina. Female Sprague ± Dawley rats were divided into two groups: non-diabetic controls (NDM, n 38) and diabetics (DM, n 38). DM was produced by intraperitoneal injection of streptozotocin. Eight weeks later the animals were killed, the distal part of the vagina was removed, and smooth muscle strips were prepared for functional organ bath experiments and for measurement of nitric oxide synthase (NOS) activity. In DM preparations, the EC 50 value for noradrenaline (NA) was signi®cantly increased (P`0.05) and the maximal contractile response decreased (P 5 0.001). In preparations precontracted with NA, the NO donor SNAP and calcitonin gene-related peptide (CGRP) caused concentration-dependent relaxations, which were signi®cantly decreased (P`0.001) in the DM group. Electrical stimulation of nerves (EFS) caused frequency-dependent contractions, which were signi®cantly lower in DM than in NDM strips (P`0.001). SNAP and CGRP concentration-dependently inhibited EFS evoked contractions in both NDM and DM preparations. The inhibition was signi®cantly lower (P`0.05) in the DM group. In NDM preparations precontracted with NA, EFS evoked frequency-dependent relaxations; such relaxations were inhibited or reduced in DM. Treatment with the NOS inhibitor, L-NOARG 0.1 mM, abolished relaxations in all preparations or produced contraction in DM preparations. Calcium-dependent NOS activity was not signi®cantly different in the DM and NDM groups. However, the DM animals showed a small but signi®cant increase in calcium-independent NOS-activity (P`0.05). Diabetes interferes with adrenergic-, cholinergic-and NANC-neurotransmitter mechanisms in the smooth muscle of the rat vagina. The changes in the nitrergic neurotransmission are not due to reduction in NOS-activity, but seem to be due to interference with later steps in the L-arginineaNOaguanylate cyclaseacGMP system.

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Alterations in the Nitric Oxide Synthase Binding Sites and Non-Adrenergic, Non-Cholinergic Mediated Smooth Muscle Relaxation in the Diabetic Rabbit Bladder Outlet: Possible Relevance to the Pathogenesis of Diabetic Cystopathy

Abstract: Alterations of both the NOS binding sites and functional responses to NANC nerve stimulation suggest that NO may have a pathophysiological role in the urinary bladder dysfunction associated with DM.

Cited by 39 publications

References 41 publications

Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO‑cGMP pathway

Grape seed proanthocyanidin extract alleviates urethral dysfunction in diabetic rats through modulating the NO‑cGMP pathway

Functional, Structural, and Neuronal Alterations in Urinary Bladder during Diabetes: Investigations of a Mouse Model

Effects of diabetes on neurotransmission in rat vaginal smooth muscle

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