Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Penile erection depends on the balanced action between antagonist vasoactive molecules such as nitric oxide (NO) and angiotensin. Endothelial nitric oxide synthase (eNOS) and angiotensin-converting enzyme (ACE) polymorphisms have been associated with endothelial dysfunction, which is described as a cause of erectile dysfunction (ED). Endothelial NOS and ACE are both regulators of vascular and corporal smooth muscle tone, which are connected by interaction between the NO-cyclic guanosine monophosphate pathway and the renin-angiotensin system. We analyzed the frequencies of 894 G/T (Glu298Asp) eNOS and ACE I/D polymorphisms in Mexican patients with ED (n=53) and in an age-matched control group (n=62). The populations analyzed were in Hardy Weinberg equilibrium. We found significant differences in allelic (chi2=4.42; P=.03) and genotypic frequencies (chi2=3.96; P=.04) between patients and controls for the 894 G/T eNOS polymorphism. Presence of the 894T allele in carriers increased the risk of ED (odds ratio [TT + GT versus GG] = 2.37; 95% confidence interval, 1.08 to 5.21; P=.02). Multiple logistic regression analysis showed that the Glu298Asp polymorphism was an independent factor for ED, as was diabetes mellitus, hypertension, cardiac disease, and cigarette smoking. No association was found between ACE I/D polymorphism and ED in the population studied. Therefore, our results suggest that Glu298Asp eNOS polymorphism plays a role as a genetic susceptibility factor for ED.
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PMID:Glu298Asp endothelial nitric oxide synthase polymorphism is a risk factor for erectile dysfunction in the Mexican Mestizo population. 1529 2

Both diabetes mellitus (DM) and elevated plasma copper concentrations are risk factors for cardiovascular disease (CVD). DM is associated with impaired endothelial nitric oxide (NO) and with excess superoxide (O2*-) formation. Copper is also elevated in DM and is also associated with the generation of O2*-. To explore possible interactions between DM and copper, the effect of exogenous copper (CuCl2) on endothelium-dependent relaxation and cyclic guanosine monophosphate (GMP) formation was investigated in aortae from diabetic rabbits. Rabbits were rendered diabetic by intravenous injection of alloxan. Six months after induction of DM, the aortae were excised, cut into rings, and mounted in an organ bath for isometric measurement of acetylcholine (Ach)-evoked relaxation in rings precontracted with phenylephrine (PE). In parallel studies, cyclic (c)GMP formation by aortic rings following stimulation with Ach, calcium ionophore A23187 (A23187) and sodium nitroprusside (SNP) was assessed using radioimmunoassay. The effect of copper on these parameters was then studied using the same methods. Ach-evoked relaxation and Ach- and A23187-evoked cGMP formation were significantly impaired in aortae from diabetic rabbits compared to controls, effects that were reversed with superoxide dismutase (SOD) and catalase (CAT). In contrast, there were no significant differences in SNP-stimulated relaxation or cGMP formation in aortae from diabetic rabbits compared to controls. Copper (1 to 10 micromol/L) promoted a further significant inhibition of Ach-stimulated relaxation in aortae from diabetic but not control rabbits. This reduction by copper was again reversed by SOD and CAT. We conclude that copper augments the reduction of NO bioavailability, which is already impaired in aortae from diabetic rabbits due to excess production of O2*- and H2O2. These results indicate that patients with DM may be susceptible to copper-mediated vasculopathy at much lower concentrations than those that promote vasculopathy in nondiabetic patients.
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PMID:Low micromolar concentrations of copper augment the impairment of endothelium-dependent relaxation of aortae from diabetic rabbits. 1537 88

Vascular reactivity to nitric oxide (NO) is mediated by NO-sensitive soluble guanylyl cyclase (sGC). Since a diminished activity of vascular sGC has been reported in an animal model of type 2 diabetes, the sGC activity was assayed in vitro in internal mammary artery specimens obtained during bypass surgery from patients with and without type 2 diabetes. The sensitivity of sGC to NO, which is dependent on Fe(2+)-containing heme, was measured in vitro using stimulation with diethylamine NONOate (DEA/NO). In addition, the novel cyclic guanosine monophosphate-elevating compound HMR-1766 was used to test the stimulation of the oxidized heme-Fe(3+)-containing form of sGC. Basal activity of sGC and its sensitivity to stimulation by DEA/NO and HMR-1766 were not different between control and type 2 diabetic patients: maximum stimulation by DEA/NO amounted to 475 +/- 67 and 418 +/- 59 pmol. mg(-1). min(-1) in control and type 2 diabetic patients, respectively. The maximum effects of HMR-1766 were 95 +/- 18 (control subjects) and 83 +/- 11 pmol. mg(-1). min(-1) (type 2 diabetic patients). Hypertension, hyperlipidemia, drug treatment with statins, ACE inhibitors, or nitrates had no effect on sGC activity. In conclusion, the present findings do not support the hypothesis that desensitization of sGC contributes to the pathogenesis of diabetic vascular dysfunction in humans.
Diabetes 2004 Oct
PMID:Nitric oxide-sensitive soluble guanylyl cyclase activity is preserved in internal mammary artery of type 2 diabetic patients. 1544 95

The purpose of this study was to investigate the effects of diabetes and insulin resistance during pregnancy on the ex vivo vascular reaction to magnesium. Female Sprague-Dawley rats were made diabetic by intravenous injection of alloxan, or insulin resistant by fructose feeding. The rats were allowed to mate and sacrificed on Day 19 of pregnancy. Aortic rings were isolated and mounted in organ baths for measurement of isometric tension. The rings were contracted with 10(-7) M phenylephrine and cumulative concentration-response curves for magnesium (1-12 mM) were determined in the presence and absence of 10(-4) M Nomega-nitro-L-arginine methyl ester (L-NAME) or 10(-5) M indomethacin. The relaxation response to magnesium was significantly decreased in pregnant rats compared with non-pregnant rats. Pregnant rats with diabetes or insulin resistance had greater impairment in the relaxation responses to magnesium compared with normal pregnant rats. The effects of diabetes and insulin resistance on magnesium-induced relaxation in pregnant rats were not altered in the presence of L-NAME and indomethacin. The results suggest that diabetes and insulin resistance aggravate the alteration in magnesium-induced vascular relaxation observed in pregnancy, and this may be due in part to impairment to mechanisms other than the nitric oxide-cyclic guanosine monophosphate and cyclooxygenase pathways.
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PMID:Effects of diabetes and insulin resistance in pregnant rats on ex vivo vascular reaction to magnesium. 1572 3

Increased oxidative stress has been suggested to be involved in the pathogenesis and progression of diabetic tissue damage. The aim of this study was to investigate the effect of different phosphodiesterase inhibitors on lipid peroxidation and total antioxidant capacity (TAC) of plasma in streptozotocin-induced diabetic rats (Rattus norvegicus). Rats became diabetic by a single administration of streptozotocin (STZ, 45 mg/kg). The effects of 15-days treatment by milrinone, sildenafil, and theophylline as cyclic-AMP and -GMP phosphodiesterase inhibitors (PDEIs) on diabetes-induced oxidative stress were studied. The levels of glucose, malonedialdehyde (MDA) the by product of lipid peroxides, and TAC (FRAP test) were estimated in plasma of control and experimental groups of rats. A significant increase in the levels of plasma glucose, and MDA and a concomitant decrease in the levels of TAC were observed in diabetic rats. These alterations were reverted back to near normal level after the treatment with PDEIs. Treatment of diabetic rats by PDEIs reduced MDA levels and increased TAC in the order of milrinone>sildenafil>theophylline. In conclusion, the present investigation show that PDIS possesses antioxidant activities, which may be attributed to their enhancing effect on cellular cyclic nucleotides contributing to the protection against oxidative stress in streptozotocin-induced diabetes. Exact mechanism of protective actions of cAMP- and cGMP-phosphodiesterase remains to be elucidated by further studies. This finding may suggest a place for PDEIs in maintaining health in diabetes.
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PMID:Reduction of diabetes-induced oxidative stress by phosphodiesterase inhibitors in rats. 1590 69

Erectile dysfunction (ED) and vascular disease are thought to be linked at the level of the endothelium. Endothelial dysfunction, resulting in the inability of the smooth muscle cells lining the arterioles to relax, prevents vasodilatation. Likewise, penile erection depends on the relaxation of smooth muscle in the corpus cavernosum and the wall of small arteries. The aim was to assess the systemic vascular function in patients with ED. In all, 32 ED patients diagnosed with Doppler Ultrasound and the International Index of Erectile Function-5-item questionnaire and 25 healthy men as a control group enrolled to the study. They all underwent the tests including serum glucose and lipid levels. Echocardiography and exercise stress test was performed routinely. Baseline demographics (body mass index, heart rate and blood pressures), fasting glucose and lipid levels were not significantly different between ED and control groups. Endothelial-dependent brachial artery flow-mediated vasodilatation and brachial artery response to 0.4 mg nitroglycerine (NTG) were measured. Participants were negative on exercise stress test, and echocardiographic parameters including ejection fraction were similar. Endothelial-dependent brachial artery percent diameter change with flow-mediated dilatation (6.01+/-2.9 vs 12.3+/-3.5) and brachial artery response to NTG (12.8+/-4.2 vs 17.8+/-5.2) were significantly different between groups (P<0.001). We found that endothelial function was impaired in ED patients with no apparent cardiovascular disease and diabetes mellitus. This impaired function might be explained by the abnormality in systemic nitric oxide-cyclic guanosine monophosphate vasodilator system and suggest that ED and vascular disease may be linked at the level of the endothelium.
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PMID:Is endothelial function impaired in erectile dysfunction patients? 1604 23

Inhibition of phosphodiesterase-5 (PDE5) reduces the degradation of cyclic guanosine monophosphate, which allows erectile function to occur by relaxation of penile smooth muscle. Three PDE5 inhibitors (sildenafil, tadalafil, and vardenafil) in a range of doses are available. PDE5 therapy, compared with placebo, significantly improves scores on the International Index of Erectile Function and has been found to be effective in special clinical populations, such as those with prostate cancer, diabetes, and cardiovascular disease. Sildenafil and vardenafil show some interaction with food intake. Time to onset of action is usually 30-120 minutes, but there are reports of shorter times to onset of action. The duration of action of sildenafil and vardenafil is about 4 hours, whereas that of tadalafil is about 36 hours. The overall safety of the treatments is good, even in patients with a history of cardiovascular disease. However, there is a risk of hypotension if nitrates are given concurrently. Increased QTc intervals have been reported, the longest with vardenafil, shortest with tadalafil, and intermediate with sildenafil. Priapism and prolonged erection are rare adverse events. Common side-effects include headache, facial flushing, nasal congestion, and dyspepsia. There may be interactions with other medications metabolized in a similar way, such as erythromycin and HIV protease inhibitors.
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PMID:The efficacy and safety of PDE5 inhibitors. 1615 23

Nitric oxide (NO) is produced from amino acid L-arginine via the catalytic action of NO synthases, which use dioxygen and NADH or NADPH as cofactor. This simple molecule acts at nanomolar concentrations and demonstrates a wide spectrum of physiological effects, a primary of which is vasodilatation. The production of NO in endothelium cells is induced by mechanical action (increased blood-vessels wall tension) and chemical agents (catecholamines, acetylcholine, bradykinin, histamine). The endothelium-released NO easily diffuses to the underlying smooth muscles and triggers their relaxation by increasing cyclic guanosine monophosphate level and subsequent opening of endothelial potassium channels (K(ATP), K(Ca)). NO on the endothelium surface inhibits adhesion and aggregation of platelets, regulates the main functions of myocardium, modulates the permeability of endothelium, and weakens the interaction of endothelium cells and leukocytes by reducing the expression of adhesion-stimulating proteins. Direct evidence suggests that free radicals and related reactive oxygen species mostly as O2-, HO-, ONOO-, ROO- are associated with an endothelium dysfunction, which manifests itself as an impairment of endothelium-dependent vasorelaxation. Though reactive oxygen species in a small amount are produced constantly, the decreased metabolic turnover of homocysteine, poor performance of antioxidants or high level of angiotensin II alters the balance between production of free radicals and their neutralization. Such events decrease NO bioavailability and thus condition the development of various diseases like arteriosclerosis, hypertension, diabetes, heart and renal failure. Agents increasing NO bioavailability and depressing the endothelial dysfunction would be the most useful for the treatment above-mentioned pathologies.
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PMID:[The main determinants of endothelial dysfunction]. 1677 63

The nitric oxide/guanylyl cyclase, cyclic guanosine monophosphate/phosphodiesterase 5 (NO/cGMP/PDE5) pathways play a key role in physiological and pathological situations, such as synaptic plasticity, learning and memory formation, diabetic gastropathy and neuropathy, long-term potentiation (LTP), epilepsy, cerebral ischemia, and neurodegenerative diseases. Several studies have demonstrated the alteration of NO-cGMP pathway in cognitive impairment. The present study was aimed to study the effect of sildenafil, a PDE5 inhibitor on diabetes and electroconvulsive shock (ECS)-induced cognitive dysfunction in rat using one-trial step-through type of passive avoidance and elevated plus-maze task. Diabetic and ECS-treated rats showed poor learning performance in step-through passive avoidance and plus-maze task. Acute administration of sildenafil significantly reversed the diabetes and ECS-induced retention deficits in both the test paradigms. Sildenafil also significantly improved the cognitive performance in young rats in both the paradigms. Furthermore, L-NAME, a non-selective NOS inhibitor and methylene blue, a guanylate cyclase inhibitor blocked the effect of sildenafil. The results thus suggest that cognitive impairment might be due to the modulatory effect of nNOS or PDE5 enzyme on cGMP levels. Moreover, sildenafil-induced reversal of cognitive impairment suggests the protective role of PDE5 inhibitors in neurodegenerative disorders.
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PMID:Modulatory effect of sildenafil in diabetes and electroconvulsive shock-induced cognitive dysfunction in rats. 1684 11

The pathophysiology of diabetes is multifactorial and no single etiology is at the forefront. The proposed mechanisms of erectile dysfunction (ED) in diabetic patients includes elevated advanced glycation end-products (AGEs) and increased levels of oxygen free radicals, impaired nitric oxide (NO) synthesis, increased endothelin B receptor binding sites and ultrastructural changes, upregulated RhoA/Rho-kinase pathway, NO-dependent selective nitrergic nerve degeneration and impaired cyclic guanosine monophosphate (cGMP)-dependent kinase-1 (PKG-1). The treatment of diabetic ED is multimodal. Treatment of the underlying hyperglycemia and comorbidities is of utmost importance to prevent or halt the progression of the disease. The peripherally acting oral phosphodiesterase type 5 (PDE5) inhibitors are the mainstay of oral medical treatment of ED in diabetics. Vacuum erection devices are an additional treatment as a non-invasive treatment option. Local administration of vasoactive medication via urethral suppository or intracorporal injection can be effective with minimal side-effects. Patients with irreversible damage of the erectile mechanism are candidates for penile implantation. Future strategies in the evolution of the treatment of ED are aimed at correcting or treating the underlying mechanisms of ED. With an appropriate vector, researchers have been able to transfect diabetic animals with agents such as neurotrophic factors and nitric oxide synthase (NOS). Further studies in gene therapy are needed to fully ascertain its safety and utility in humans.
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PMID:Pathophysiology and treatment of diabetic erectile dysfunction. 1689 68


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