The Protective Effect of Aminoguanidine on Erectile Function in Streptozotocin Diabetic Rats

Usta, Mustafa F.; Bivalacqua, Trinity J.; Yang, Dae Yul; Ramanitharan, Anshiya; Sell, David R.; Viswanathan, Ashiwini; Monnier, Vincent M.

doi:10.1097/01.ju.0000077557.45582.f3

Cited by 56 publications

(60 citation statements)

References 18 publications

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“…43,44 AGEs accumulate in diabetic tissue, and AGE concentrations are increased in the penile cavernosal smooth muscle tissues and the vascular beds of diabetic ED patients. 45 AGEs interfere with ion channels, gap junctions and receptors so that calcium ion release and blood flow both decrease; as a result, the SMC relaxation mechanism is impaired. 46 Seftel et al 47 reported that AGEs quenched the production of epoxide and NO in endotheliocytes and speculated on a pathophysiologic mechanism for AGEmediated ED via the upregulation of iNOS and the downregulation of eNOS.…”

Section: Discussionmentioning

confidence: 99%

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

Zhang¹,

Li²,

Liu³

et al. 2012

Asian J Androl

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Erectile dysfunction (ED) is a major complication of diabetes mellitus. Icariin has been shown to enhance erectile function through its bioactive form, icarisid II. This study investigates the effects of icarisid II on diabetic rats with ED and its potential mechanism via the assessment of advanced glycosylation end products (AGEs), autophagy, mTOR and the NO-cGMP pathway. Icarisid II was extracted from icariin by an enzymatic method. In the control and diabetic ED groups, rats were administered normal saline; in the icarisid II group, rats were administered icarisid II intragastrically. Erectile function was evaluated by measuring intracavernosal pressure/mean arterial pressure (ICP/MAP). AGE concentrations, nitric oxide synthase (NOS) activity and cGMP concentration were assessed by enzyme immunoassay. Cell proliferation was analysed using methyl thiazolyl tetrazolium assay and flow cytometry. Autophagosomes were observed by transmission electron microscopy, monodansylcadaverine staining and GFP-LC3 localisation. The expression of NOS isoforms and key proteins in autophagy were examined by western blot. Our results have shown that Icarisid II increased ICP/MAP values, the smooth muscle cell (SMC) growth curve, S phase and SMC/collagen fibril (SMC/CF) proportions and decreased Beclin 1 (P,0.05). Icarisid II significantly increased the proliferative index and p-p70S6K(Thr389) levels and decreased the numbers of autophagosomes and the levels of LC3-II (P,0.01). Icarisid II decreased AGE concentrations and increased cGMP concentration, NOS activity (P,0.05) and cNOS levels (P,0.01) in the diabetic ED group. Therefore, Icarisid II constitutes a promising compound for diabetic ED and might be involved in the upregulation of SMC proliferation and the NO-cGMP pathway and the downregulation of AGEs, autophagy and the mTOR pathway.

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Section: Discussionmentioning

confidence: 99%

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

Zhang¹,

Li²,

Liu³

et al. 2012

Asian J Androl

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show abstract

“…Reactive oxygen species from non-enzymatic glycosylation and increased NADPH oxidase activity impair endothelial function in erectile tissue and quench NO. In turn, this causes a reduction in the bioavailability of NO and peroxinitrite formation by nitrosative stress, which is highly toxic and damaging to the erectile tissue [25][26][27].…”

Section: Discussionmentioning

confidence: 99%

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical diabetogenesis

Gj¹,

Hk²,

Ch³

et al. 2009

Asian J Androl

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Erectile dysfunction (ED) is a major complication of diabetes mellitus (DM). This study investigates the relationship between ED and the downregulation of constitutive nitric oxide synthase (cNOS) in the corpus cavernosum (CC) of diabetic rats. It also examines the effects of udenafil, a phosphodiesterase type 5 (PDE5) inhibitor, on ED and cNOS expression levels. After 16 weeks of daily oral treatment with udenafil in diabetic rats, the intracavernous pressure/mean arterial pressure (ICP/MAP) ratio was recorded to measure erectile function, and cNOS expression was measured using reverse transcriptase (RT)-PCR and immunoblots. Although the ICP/ MAP ratio and the expression levels of endothelial NOS (eNOS) and neuronal NOS (nNOS) in the CC were markedly decreased in diabetic rats, long-term udenafil treatment improved the erectile function and increased cNOS expression compared with diabetic controls. These findings suggest that ED in DM is closely related to decreased cNOS expression in the CC and that udenafil has the ability to compensate for this pathological change by modulating cNOS expression. Udenafil also has an inhibitory role in cyclic guanosine monophosphate (cGMP) degradation.

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“…Aminoguanidine, a potent inhibitor of AGE-mediated crosslinking, has been shown to prevent the development of nitrergic dysfunction in the penis [39,40] and to prevent depletion of nitrergic neurones in the retina of diabetic rats [41]. However aminoguanidine also inhibits nNOS [42] and iNOS [43].…”

Section: Discussionmentioning

confidence: 99%

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

et al. 2004

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Aims/hypothesis. We have previously shown that in diabetes nitrergic neurones innervating the urogenital and gastrointestinal organs undergo a selective degenerative process. This comprises an initial insulin-reversible decrease in neuronal nitric oxide synthase (nNOS) in the axons, followed by apoptosis of the nitrergic neurones, a process that is not reversible by insulin. Since apoptosis was independent of serum glucose concentrations, and advanced glycation endproducts (AGEs) have been implicated in the pathogenesis of diabetic complications, we have now measured AGEs in the serum and penis, pyloric sphincter and pelvic ganglia of diabetic animals at different times after streptozotocin treatment. Furthermore, we have studied their effect in vitro on human neuroblastoma (SH-SY5Y) cells in the presence or absence of nNOS expression. Methods. Serum AGEs were measured using fluorometry and ELISA. Accumulation of AGEs in the tissues was evaluated with immunohistochemistry. The viability, apoptosis and oxidative stress in SH-SY5Y cells were measured upon exposure to AGEs or high concentrations of glucose. Results. AGEs increased gradually in the serum and tissues of streptozotocin-induced diabetic rats; this process was not affected by delayed insulin treatment. In SH-SY5Y cells, AGEs, but not high glucose concentrations, increased the reactive oxygen species and caspase-3-dependent apoptosis in a synergistic fashion with endogenous nitric oxide (NO). Apoptosis was prevented by treatment with a NOS inhibitor, a pan-caspase inhibitor, a soluble receptor of AGEs or an anti-oxidant, but not an inhibitor of soluble guanylate cyclase. Conclusions/interpretation. The synergistic actions of NO and AGEs account for the irreversible nitrergic degeneration in diabetes. [Diabetologia (2004) 47: 331-339]

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The Protective Effect of Aminoguanidine on Erectile Function in Streptozotocin Diabetic Rats

Cited by 56 publications

References 18 publications

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

Effect of icarisid II on diabetic rats with erectile dysfunction and its potential mechanism via assessment of AGEs, autophagy, mTOR and the NO–cGMP pathway

Increased expression of the nitric oxide synthase gene and protein in corpus cavernosum by repeated dosing of udenafil in a rat model of chemical diabetogenesis

Synergistic action of advanced glycation end products and endogenous nitric oxide leads to neuronal apoptosis in vitro: A new insight into selective nitrergic neuropathy in diabetes

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