Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF

Angulo, Javier; Cuevas, Pedro; Fernández, Argentina; Gabancho, Sonia; A, Allona Almagro; Martín‐Morales, Antonio; Moncada, Ignacio; Videla, Sebastián; Tejada, Iñigo Sáenz de

doi:10.1016/j.bbrc.2003.11.034

Cited by 94 publications

(113 citation statements)

References 39 publications

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“…These findings emphasize the importance of the EDHF pathway for normal erectile function. They also provide additional support to the in vitro observation that diabetes can impair EDHF-dependent responses [9]. Activating endothelial SK3 and IK1 channels or increasing their expression could constitute a novel therapeutic strategy for the treatment of ED in diabetic men.…”

Section: Discussionmentioning

confidence: 61%

“…Diabetes can also impair endothelium-dependent relaxation of human penile vascular tissues mediated by EDHF [9], but the mechanism remains unclear. In our study, we have demonstrated that diabetes can inhibit mRNA and protein expression of SK3 and IK1, which could be related to the observed impairment in the EDHF pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, this factor has been shown to be involved in the relaxation of the vascular smooth muscle cells in penile arteries [5][6][7][8]. Angulo [9] has reported that diabetes can impair endothelium-dependent relaxation of human penile vascular tissues mediated by EDHF, but the causes remain unclear. The calcium-activated potassium channels, 600 npg particularly the small and intermediate conductance calcium-activated K + -channels (SK3 and IK1), are key players in EDHF-mediated relaxation in small arteries [10].…”

Section: Introductionmentioning

confidence: 99%

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Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

Jun¹,

Jia²,

Xu³

et al. 2010

Asian J Androl

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The small (SK3) and intermediate (IK1) conductance calcium-activated potassium channels could have key roles in the endothelium-dependent hyperpolarization factor pathway, which is believed to contribute to normal penile erection function. We aimed to investigate the expression of SK3 and IK1 in diabetic rodents. The experimental diabetes model was induced in 8-week-old male Sprague-Dawley rats (250-300 g) by a single administration of streptozotocin. Both the diabetes mellitus group (DM group, n = 20) and the control group (NDM group, n = 10) were injected with a low dose of apomorphine to allow for the measurement and comparison of the corresponding penile erections. The mRNA and protein expression levels of SK3 and IK1 were measured by reverse transcription polymerase chain reaction and western blot, respectively. Erectile function was significantly decreased in the DM group compared with control group (P < 0.05). The mRNA and protein expression levels of SK3 and IK1 were reduced in the cavernous tissue of diabetic rats compared with the control group (P < 0.05). Diabetes inhibits mRNA and protein expression of both SK3 and IK1 in the cavernous tissue of diabetic rats. This could play a key role in the development of erectile dysfunction in diabetic rats.

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Section: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

Jun¹,

Jia²,

Xu³

et al. 2010

Asian J Androl

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“…Penile resistance arteries from diabetic patients with ED exhibit decreased EDHF-mediated endothelium-dependent relaxation compared to that of nondiabetic men with ED. 93 In diabetic rats enhancement of both EDHF and NO/3 0 , 5 0 -cyclic guanosine monophosphate (cGMP) pathways is necessary to reverse erectile dysfunction. 94 However, the mechanisms underlying impaired blood flow by EDHF in penile and nonpenile vascular beds in diabetes, as well as other disease states, remain to be fully elucidated.…”

Section: No-independent Endothelium-derived Relaxing Factorsmentioning

confidence: 99%

Endothelial dysfunction in diabetic erectile dysfunction

2006

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Erectile dysfunction (ED) is highly prevalent in diabetes mellitus. Pathophysiological mechanisms underlying diabetes-associated ED are in large part due to endothelial dysfunction, which functionally refers to the inability of the endothelium to produce vasorelaxing messengers and to maintain vasodilation and vascular homeostasis. The precise mechanisms leading to endothelial dysfunction in the diabetic vasculature, including the penis, are not yet fully understood. Hyperglycemia affects endothelial nitric oxide synthase activity and nitric oxide production/ bioavailability, nitric oxide-independent relaxing factors, oxidative stress, production and/or action of hormones, growth factors and/or cytokines, and generation and activity of opposing vasoconstrictors. Considering recent advances in the field of vascular biology and diabetes, the emphasis in this review is placed on the mechanisms of hyperglycemia-induced endothelial dysfunction in the pathophysiology of diabetes-associated ED.

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“…Impairments in neurogenic and endothelium-dependent corporal smooth muscle relaxation is observed in diabetes mellitus and is responsible for erectile impairment in diabetic patients (4,5).…”

mentioning

confidence: 99%

RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction

Bivalacqua

Champion

Usta

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

296

276

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Significant impairment in endothelial-derived nitric oxide is present in the diabetic corpus cavernosum. RhoA͞Rho-kinase may suppress endothelial nitric oxide synthase (eNOS). Here, we tested the hypothesis that RhoA͞Rho-kinase contributes to diabetesrelated erectile dysfunction and down-regulation of eNOS in the streptozotocin (STZ)-diabetic rat penis. Colocalization of Rhokinase and eNOS protein was present in the endothelium of the corpus cavernosum. RhoA͞Rho-kinase protein abundance and MYPT-1 phosphorylation at Thr-696 were elevated in the STZdiabetic rat penis. In addition, eNOS protein expression, cavernosal constitutive NOS activity, and cGMP levels were reduced in the STZ-diabetic penis. To assess the functional role of RhoA͞Rho-kinase in the penis, we evaluated the effects of an adenoassociated virus encoding the dominant-negative RhoA mutant (AAVTCMV19NRhoA) on RhoA͞Rho-kinase and eNOS and erectile function in vivo in the STZ-diabetic rat. STZ-diabetic rats transfected with AAVCMVT19NRhoA had a reduction in RhoA͞Rho-kinase and MYPT-1 phosphorylation at a time when cavernosal eNOS protein, constitutive NOS activity, and cGMP levels were restored to levels found in the control rats. There was a significant decrease in erectile response to cavernosal nerve stimulation in the STZ-diabetic rat. AAVT19NRhoA gene transfer improved erectile responses in the STZ-diabetic rat to values similar to control. These data demonstrate a previously undescribed mechanism for the down-regulation of penile eNOS in diabetes mediated by activation of the RhoA͞Rho-kinase pathway. Importantly, these data imply that inhibition of RhoA͞Rho-kinase improves eNOS protein content and activity thus restoring erectile function in diabetes.gene therapy ͉ neuronal NO synthase ͉ endothelium R elaxation of corporal smooth muscle is essential for normal erectile function, and evidence exists to implicate neuronaland endothelial-derived nitric oxide (NO) as the principal mediator of corporal smooth muscle relaxation (1-3). Impairments in neurogenic and endothelium-dependent corporal smooth muscle relaxation is observed in diabetes mellitus and is responsible for erectile impairment in diabetic patients (4, 5).Contraction of smooth muscle is primarily mediated by phosphorylation of the regulatory myosin light chain (MLC) by the Ca 2ϩ ͞calmodulin-dependent activation of MLC kinase and actin͞myosin cross-bridge formation (6). Relaxation is mediated by the dephosphorylation of MLC by smooth muscle myosin phosphatase. Recent evidence has established the importance of Ca 2ϩ -sensitization through the Ca 2ϩ -independent stimulation of MLC kinase or the attenuation of MLC phosphatase activity (7). A principle regulator of MLC phosphatase is the serine͞ threonine kinase, Rho-kinase. Data from peripheral arteries suggest that RhoA, a GTP-binding protein, mediates agonistinduced activation of Rho-kinase (8). The exchange of GDP for GTP on RhoA and translocation of RhoA from the cytosol to the membrane are markers of activation, and enable the downstr...

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Diabetes impairs endothelium-dependent relaxation of human penile vascular tissues mediated by NO and EDHF

Cited by 94 publications

References 39 publications

Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats

Endothelial dysfunction in diabetic erectile dysfunction

RhoA/Rho-kinase suppresses endothelial nitric oxide synthase in the penis: A mechanism for diabetes-associated erectile dysfunction

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