cyclic-gmp and Diabetic-Neuropathies

Erectile dysfunction (ED) is a common, male sexual disorder that has a negative impact on the quality of life of men and their sexual partners. The prevalence of ED in diabetic men is ≥ 50%. Animal models provide a valuable perspective in the investigation of ED. Most basic science studies have utilized the rodent model of type 1 diabetes. However, an animal model for type 2 diabetes-associated ED requires verification. The streptozotocin (STZ) induced type 1 diabetic model has contributed to significant advancement in the study of ED. A Medline search using the keywords "diabetic animals and ED" was performed, and available peer-reviewed English articles between 2007-2013 were evaluated. The proposed mechanisms for developing ED in diabetics include: hyperglycemia, impaired nitric oxide (NO) synthesis, cyclic guanosine monophosphate (cGMP) pathway dysfunction, increased levels of reactive free-radicals, up-regulation of the RhoA/Rho-kinase pathway, and neuropathic damage. The current treatment regimen of diabetes-induced ED is multimodal. Modification of comorbidities and, specifically, rectifying the underlying hyperglycemia is vital to prevent or halt progression of the disease. Further research on the basic mechanisms of ED and additional studies using better animal models of ED associated with type 1 and 2 diabetes are needed. Preclinical studies using the diabetic animal model will likely provide further insight for intervention and prevention strategies for diabetic ED treatment.

Topics: Animals; Blood Glucose; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Neuropathies; Erectile Dysfunction; Intracellular Signaling Peptides and Proteins; Male; Oxidative Stress; Penis; Rats; rho-Associated Kinases; Smad Proteins; Transforming Growth Factor beta1

Diabetic men with erectile dysfunction (ED) are less responsive to therapy with type 5 phosphodiesterase (PDE5) inhibitors. Although an impairment of the nitric oxide (NO)/cyclic guanosin-monophosphate (cGMP) pathway has been shown in diabetic ED vs. non-diabetic ED, the functionality of NO/cGMP pathway in non-diabetic and diabetic ED patients with respect to non-ED patients has not been established.. The aim of this study is to evaluate the function of NO/cGMP signalling in human erectile tissues from ED patients exploring the added impact of diabetes.. Corpus cavernosum strips (human corpus cavernosum [HCC]) and penile resistance arteries (HPRA) were collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic men with ED undergoing penile prosthesis implantation.. Relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside, and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted HPRA. cGMP content in HCC was also determined.. The impairment of endothelium-dependent relaxation in HCC and HPRA from ED patients was exacerbated by diabetes (E(max) 76.1, 62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and diabetic ED, respectively). Hypertension, hypercholesterolemia, or aging did not exert a further impairment of endothelial relaxation among ED patients. Diabetes also causes a further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated content of cGMP in HCC was significantly decreased in patients with ED, but specially reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation of HPRA from ED patients.. ED is related to impaired vasodilation, reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition. Thus, an exacerbated reduction of nitric oxide/cGMP signaling could be responsible for ED in diabetic men and would explain their reduced response to treatment.

Topics: Adult; Cyclic GMP; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Neuropathies; Humans; Impotence, Vasculogenic; In Vitro Techniques; Male; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide; Penile Implantation; Penis; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Signal Transduction; Vascular Resistance; Vasodilation

Streptozocin (STZ)-induced diabetic rats show hyperalgesia that is partially attributed to altered protein kinase C (PKC) activity. Both attenuated neuronal nitric oxide synthase (nNOS)-cGMP system and tetrodotoxin-resistant (TTX-R) Na channels in dorsal root ganglion neurons may be involved in diabetic hyperalgesia. We examined whether PKCbeta inhibition ameliorates diabetic hyperalgesia and, if so, whether the effect is obtained through action on neurons by testing nociceptive threshold in normal and STZ-induced diabetic rats treated with or without PKCbeta-selective inhibitor LY333531 (LY) and by assessing the implication of LY in either nNOS-cGMP system or TTX-R Na channels of isolated dorsal root ganglion neurons. The decreased nociceptive threshold in diabetic rats was improved either after 4 weeks of LY treatment or with a single intradermal injection into the footpads. The treatment of LY for 6 weeks significantly decreased p-PKCbeta and ameliorated a decrease in cGMP content in dorsal root ganglia of diabetic rats. The latter effect was confirmed in ex vivo condition. The treatment with NO donor for 4 weeks also normalized both diabetic hyperalgesia and decreased cGMP content in dorsal root ganglions. The expressions of nNOS and TTX-R Na channels were not changed with LY treatment. These results suggest that LY is effective for treating diabetic hyperalgesia through ameliorating the decrease in the nNOS-cGMP system.

Topics: Animals; Arginine; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Ganglia, Spinal; Immunohistochemistry; Indoles; Male; Maleimides; NAV1.9 Voltage-Gated Sodium Channel; Neuropeptides; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Nociceptors; Protein Kinase C; Protein Kinase C beta; Rats; Rats, Sprague-Dawley; Sodium Channels; Tetrodotoxin

To evaluate the role of nitric oxide synthase (nNOS) in the pathogenesis of diabetic neuropathy, we investigated nociception and nNOS expression in dorsal root ganglion (DRG) of rats with streptozocin-induced diabetes. Paw withdrawal threshold to noxious mechanical stimuli was decreased in both L-NAME-treated and diabetic rats. The number of NADPH-diaphorase positive neurons was significantly decreased in untreated diabetic compared with control rats. Decreased expression of nNOS protein was confirmed by immunoblotting. Insulin treatment completely prevented decreases in withdrawal threshold and nNOS expression. Cyclic GMP content paralleled nNOS expression in experimental animals. These results suggest that decreased nNOS-cGMP system in DRG may play a role in the pathogenesis of diabetic sensory neuropathy.

Topics: Animals; Blotting, Western; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Enzyme Inhibitors; Ganglia, Spinal; Histocytochemistry; Hyperalgesia; Male; Neurons; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Pain Measurement; Rats; Rats, Sprague-Dawley

Defective tissue perfusion and nitric oxide production and altered myo-inositol metabolism and protein kinase C activation have been invoked in the pathogenesis of diabetic complications including neuropathy. The precise cellular compartmentalization and mechanistic interrelationships of these abnormalities remain obscure, and nitric oxide possesses both neurotransmitter and vasodilator activity. Therefore the effects of ambient glucose and myo-inositol on nitric oxide-dependent cGMP production and protein kinase C activity were studied in SH-SY5Y human neuroblastoma cells, a cell culture model for peripheral cholinergic neurons. D-Glucose lowered cellular myo-inositol content, phosphatidylinositol synthesis, and phosphorylation of an endogenous protein kinase C substrate, and specifically reduced nitric oxide-dependent cGMP production a time- and dose-dependent manner with an apparent IC50 of approximately 30 mM. The near maximal decrease in cGMP induced by 50 mM D-glucose was corrected by the addition of protein kinase C agonists or 500 microM myo-inositol to the culture medium, and was reproduced by protein kinase C inhibition or downregulation, or by myo-inositol deficient medium. Sodium nitroprusside increased cGMP in a dose-dependent fashion, with low concentrations (1 microM) counteracting the effects of 50 mM D-glucose or protein kinase C inhibition. The demonstration that elevated D-glucose diminishes basal nitric oxide-dependent cGMP production by myo-inositol depletion and protein kinase C inhibition in peripheral cholinergic neurons provides a potential metabolic basis for impaired nitric oxide production, nerve blood flow, and nerve impulse conduction in diabetes.

Topics: Base Sequence; Cholinergic Fibers; Cyclic GMP; Diabetic Neuropathies; Glucose; Humans; Inositol; Models, Neurological; Molecular Sequence Data; Neuroblastoma; Nitric Oxide; Nitric Oxide Synthase; Peripheral Nervous System; Protein Kinase C; Sorbitol; Tumor Cells, Cultured

Topics: Animals; Cyclic GMP; Diabetic Neuropathies; Dinoprostone; Heart Failure; Humans; Hypertension; Receptors, Angiotensin; Renin-Angiotensin System

The effects of a stable prostacyclin analog, Iloprost, and aldose reductase inhibitors (ONO-2235 and isoliquiritigenin) were studied to elucidate the role of cAMP in diabetic neuropathy in relation to polyol metabolism. In in vivo experiments, the cAMP and myoinositol contents in sciatic nerves and motor nerve conduction velocity were significantly reduced in diabetic rats. Iloprost significantly restored the reduced cAMP content in sciatic nerves and improved motor nerve conduction velocity in diabetic rats. However, the contents of sorbitol or myoinositol in sciatic nerves were not affected by Iloprost in diabetic rats. On the other hand, aldose reductase inhibitors significantly reduced the sorbitol content and increased the cAMP and myoinositol contents in the sciatic nerves of diabetic rats. The motor nerve conduction velocity was also slightly but significantly improved by treatment with aldose reductase inhibitors. There was a negative correlation between cAMP and sorbitol in the sciatic nerves of diabetic rats treated with aldose reductase inhibitors and a positive correlation between cAMP and motor nerve conduction velocity. In in vitro experiments, Iloprost significantly increased cAMP, but did not affect the sorbitol content in sciatic nerves. Aldose reductase inhibitors inhibited sorbitol accumulation and increased cAMP in sciatic nerves. Our data suggest that polyol pathway activation somehow results in cAMP reduction in sciatic nerves and that the reduction of cAMP in peripheral nerves may be closely related to the pathogenesis of diabetic neuropathy.

Topics: Aldehyde Reductase; Animals; Blood Glucose; Chalcone; Chalcones; Cyclic AMP; Cyclic GMP; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Iloprost; Inositol; Male; Neural Conduction; Rats; Rats, Inbred WKY; Rhodanine; Sciatic Nerve; Sorbitol; Thiazolidines