The effects of long‐term oral administration of l‐arginine on the erectile response of rabbits with alloxan‐induced diabetes

Yıldırım, Seda; Ayan, Semih; Sarıoğlu, Yusuf; Gültekin, Yener; Bütüner, C.

doi:10.1046/j.1464-410x.1999.00962.x

Cited by 32 publications

(21 citation statements)

References 39 publications

(47 reference statements)

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“…In addition to the alloxan-induced diabetes studies described above, decreased CCSM relaxation has also been reported in streptozotocin-induced diabetic rats (27,29,30,32) and recently in streptozotocin-induced diabetic mice (43). Although some studies reported no effect of diabetes on SNPinduced CCSM relaxation (22,30,65), the duration of diabetes in these studies was generally less than 8 wk. The duration of diabetes in our study was 6 mo and we found that shorter periods of diabetes have less of an effect on CCSM contractility (unpublished observation by DiSanto and Chacko).…”

Section: Discussionmentioning

confidence: 75%

Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits

Chang

Hypolite

Velez

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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DiSanto. Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits. Am J Physiol Regul Integr Comp Physiol 287: R950 -R960, 2004. First published June 17, 2004 10.1152/ajpregu.00639.2003.-Increased guanosine 3Ј,5Ј-cyclic monophosphate (cGMP), induced by nitric oxide release, is crucial for corpus cavernosum smooth muscle (CCSM) relaxation within the penis. This CCSM relaxation (necessary for penile erection) is impaired in men with erectile dysfunction (ED), especially those men with diabetes. One of the effector proteins for cGMP is cGMP-dependent protein kinase-1 (PKG-1). PKG-1 knockout mice exhibit detrusor overactivity (Am J Physiol Regul Integr Comp Physiol 279: R1112-R1120, 2000 and, more relevant to this study, ED (Proc Natl Acad Sci USA 97: 2349 -2354, 2000, suggesting an in vivo role for PKG-1 in urogenital smooth muscle relaxation. In the current study, using normal rabbit CCSM, Western blot analysis revealed high expression of PKG-1 at levels almost equivalent to aorta (previously shown to have high PKG-1 expression) and that the two known alternatively spliced isoforms of PKG-1 (␣ and ␤) are expressed in nearly equal amounts in the CCSM. However, in response to alloxan-induced diabetes, there was a decrease in expression of both PKG-1 isoforms at the mRNA and protein levels as determined by real-time RT-PCR and Western blotting, respectively, but with the PKG-1␣ isoform expression decreased to a greater extent. Moreover, diabetes was associated with significantly decreased PKG-1 activity of CCSM in vitro, correlating with decreased CCSM relaxation. Immunofluorescence microscopy revealed a diabetes-associated decrease in PKG-1 in the CCSM cells. In conclusion, our results demonstrate for the first time a significant downregulation of PKG-1 expression associated with decreased PKG-1 activity in the CCSM in response to diabetes. Furthermore, these results suggest a mechanistic basis for the decreased efficacy of phosphodiesterase V inhibitors in treating diabetic patients with ED. diabetes; erectile dysfunction; alloxan; isoforms; PDE5 inhibitors PENILE TUMESCENCE (erection) and detumescence (return to flaccid state) are regulated by a complex neurophysiological process of relaxation and contraction, respectively, of corpus cavernosum smooth muscle (CCSM) (for a review, see Ref. 15). Failure of the CCSM to relax properly results in the inability of men to obtain an erection sufficient for sexual satisfaction and has been termed erectile dysfunction (ED). The incidence of ED throughout the world is expected to reach 322 million worldwide by the year 2025 (41).Guanosine 3Ј,5Ј-cyclic monophosphate (cGMP) is the direct intracellular mediator of the CCSM relaxation (60). In response to sexual stimuli, release of nitric oxide (NO) causes elevation of cGMP levels via stimulation of guanylate cyclase activity (34), which leads to relaxation of the CCSM and ultimately to penile erection (4). However, the exact molecular mechanism by which cGMP causes...

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Section: Discussionmentioning

confidence: 75%

Downregulation of cGMP-dependent protein kinase-1 activity in the corpus cavernosum smooth muscle of diabetic rabbits

Chang

Hypolite

Velez

et al. 2004

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Oral administration of L-arginine to diabetic rabbits and rats increases endothelium-dependent and neurogenic relaxation of cavernosal tissue by improving NO biosynthesis. 20,21 Decreased L-arginine may be due to competitive interaction with asymmetric dimethylarginine, an endogenous NOS inhibitor, possibly due to its increased levels in association with ROS production. 22 Recent in vitro studies proposed that oxidized LDL in particular is able to decrease local endothelial L-arginine uptake, ultimately leading to both local depletion of L-arginine and eNOS uncoupling.…”

Section: Enos Expressionmentioning

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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“…This increases penile blood flow, causes dilation of the lacunar space and, eventually, an erection. In DM, it has been shown that endothelium-dependent smooth muscle relaxation is impaired, although the exact mechanism is not known (12,13). Endothelial dysfunction (the small ed) then leads to erectile dysfunction (the big ED) through smooth muscle dysfunction in the microvascular tree of the penis.…”

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confidence: 99%