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

Abstract

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.

TNF-α, Erectile Dysfunction, and NADPH Oxidase-Mediated ROS Generation in Corpus Cavernosum in High-Fat Diet/Streptozotocin-Induced Diabetic Rats

“…Decreased eNOS protein expression was reported both in STZ‐induced type 1 diabetic rats [52] and genetic type 2 diabetic rats [53], but some other studies reported no change [18,50,51]. Although previous studies reported that TNF‐α could significantly decrease eNOS expression by enhancing mRNA degradation [54], we found no significant changes in the total expression of eNOS in control or diabetic rats regardless of treatment in the current study.…”

Yidiyin, a Chinese Herbal Decoction, Improves Erectile Dysfunction in Diabetic Patients and Rats through the NO-cGMP Pathway

“…STZ-induced diabetic ED rats showed a decrease in the activity of NOS and the contents of NO as well as cGMP in the corpus cavernosum tissue, and thus was responsible for the impaired erectile function, consistently with the literature. [8][9][10] Administration of Yidiyin increased diabetic ED rats' erection numbers, enhanced NOS activity, and boosted the contents of NO and cGMP in the corpus cavernosum penis, and the indexes in the Yidiyin group were similar to that in the control group. In sum, increased NOS activity led to elevated NO levels, which resulted in increases in the content of cGMP, causing relaxation of the smooth muscle and triggering penile erection.…”

“…[36][37][38] Studies on corpus cavernosum tissue from type 1 and type 2 diabetic patients and animals have also disclosed low activity of NOS, diminished NO-mediated function, impaired GC, reduced cGMPgenerating capacity, and deficient PKG. [8][9][10]39) On the other hand, enhancing the activity of the NO-cGMP pathway by inhibiting PDE5, stimulating GC, or overexpressing PKG-1 improve the erectile function of patients and animals with diabetic ED. [40][41][42] According to reports, [43][44][45] some herbs, including Rehmannia glutinosa Steud., Epimedium brevicornum Maxim., and Cynomorium songaricum Rupr.…”

“…5,7) Increasing evidence also indicates that diabetic ED also results from downregulation of the NO-cGMP signaling in the corpora cavernosum, including impaired NOS activity, low levels of NO and cGMP, and deficient activity of cGMP-dependent kinase. [8][9][10] It is a remedy for diabetic ED to preserve or strengthen the activity of the NO-cGMP pathway. At present, inhibitors of phosphodiesterase type 5 (PDE5) are the most effective oral drugs.…”

Effect of short‐ and long‐term sildenafil treatment on erectile dysfunction in rats with partial bladder outlet obstruction

“…Inhibition of PDE5 enzyme might enhance nNOS enzyme activity and thereby augment neuronal NO synthesis and release. Earlier research showed that PDE5 enzyme interacts with nNOS and modulates nitrergic neurotransmission . Hence improvement in neurogenic relaxation might result from both increased NO release from nitrergic nerves and a direct action of sildenafil to prolong such CCSM relaxation.…”