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

Selective type II (inducible) nitric oxide synthase (NOS) inhibitors have several potential therapeutic applications, including treatment of sepsis, diabetes, and autoimmune diseases. The ability of two novel, selective inhibitors of type II NOS, S-ethylisothiourea (EIT) and 2-amino-5,6-dihydro-6-methyl-4H-1,3-thiazine (AMT), to inhibit type II NOS function in vivo was studied in lipopolysaccharide (LPS) treated rats. Type II NOS activity was assessed by measuring changes in plasma nitrite and nitrate concentrations ([NOx]). Both EIT and AMT elicited a dose-dependent and > 95% inhibition of the LPS-induced increase in plasma [NOx]. The ED50 values for EIT and AMT were 0.4 and 0.2 mg/kg, respectively. In addition, the administration of LPS and either NOS inhibitor resulted in a dose-dependent increase in animal mortality; neither compound was lethal when administered alone. Pretreatment with L-arginine (but not D-arginine) prevented the mortality, while not affecting the type II NOS-dependent NO production, suggesting the toxicity may be due to inhibition of one of the other NOS isoforms (endothelial or neuronal). Thus, although EIT and AMT are potent inhibitors of type II NOS function in vivo, type II NOS inhibitors of even greater selectivity may need to be developed for therapeutic applications.
 ...
PMID:In vivo pharmacological evaluation of two novel type II (inducible) nitric oxide synthase inhibitors. 758 35

Improved understanding of the pathogenesis of symptomatic and silent myocardial ischemia has led to important advances in the prevention and treatment of these syndromes. For example, recognition of the role of platelets in the atherogenic process and of thrombosis in acute myocardial ischemia has led to extensive use of aspirin and thrombolytic therapy, with resultant decreases in mortality. Both nitrates and beta-adrenergic blockers effectively alleviate myocardial ischemia. However, long-term nitrate use is limited by the occurrence of tolerance. beta blockers have been shown to decrease subsequent cardiovascular events in patients with acute myocardial infarction; however, adverse effects are often associated with their use. Calcium antagonists have been shown to be effective in the treatment of stable and vasospastic angina. In patients with coronary artery disease and symptoms resulting from either fixed obstruction or vasospasm, these agents decrease the frequency of angina episodes. The 3 types of calcium antagonists currently available--phenylalkylamine, benzothiazepine, and dihydropyridine derivatives--while chemically a heterogeneous group, share the common property of decreasing depolarization of smooth muscle, albeit to varying degrees. Nonetheless, other characteristics, including varying electrophysiologic effects, distinguish these groups. The novel calcium antagonist amlodipine is effective and well tolerated as an antianginal agent, and offers the advantage of once-daily dosing. Calcium antagonists appear to be well tolerated in patients with concomitant conditions such as diabetes and are effective in commonly coexistent cardiovascular disorders such as hypertension.
 ...
PMID:Emerging options in the management of myocardial ischemia. 790 91

To evaluate the role of nitric oxide (NO) in diabetic hyperfiltration, renal hemodynamic changes and changes in urinary excretion of NO2/NO3 in response to the NO inhibitor nitro-L-arginine methyl ester (L-NAME) and the NO-donating agent glyceryl trinitrate (GTN) were investigated in conscious streptozocin-induced diabetic (D) and age-matched control (C) rats. In all experiments, D rats demonstrated increased glomerular filtration rate (GFR), renal plasma flow (RPF), polyuria, and an increased urinary sodium excretion when compared with C rats. An intravenous bolus of low-dose L-NAME (1 mg/kg body wt) increased modestly systolic blood pressure (sBP) in C rats but had no effect on sBP in D rats. L-NAME induced a marked decrease in GFR and RPF in D rats with no change in filtration fraction (FF). In C rats, no change in GFR was observed, and RPF decreased, resulting in a rise in FF. A supramaximal dose of L-NAME (10 mg/kg body wt) increased sBP in C and D rats to a similar degree. With high-dose L-NAME, GFR decreased in D but not in C rats. There was a greater decrease in RPF in D rats when compared with C animals. An intravenous infusion of GTN induced a modest decrease in sBP in both C and D rats (P < 0.01). There were no changes in GFR and RPF in D rats, but in the C group, GTN increased RPF (P < 0.05) with a tendency for a rise in GFR (P = 0.09). Basal urinary NO2/NO3 excretion was increased in D rats in all experiments.(ABSTRACT TRUNCATED AT 250 WORDS)
Diabetes 1994 Oct
PMID:Role of endothelium-derived nitric oxide in the pathogenesis of the renal hemodynamic changes of experimental diabetes. 792 87

The intakes of nitrate and nitrite of children and their parents from food and drinking water were estimated in a Finnish nation-wide case-control study on the epidemiology of Type 1 diabetes. The study population consisted of 684 case and 595 control children; 548 case-control pairs of fathers; and 620 case-control pairs of mothers. The consumption frequencies of foods which are important sources of nitrate and nitrite were assessed by structured questionnaire. Nitrate and nitrite concentration data were collected from Finnish water works. Diabetic children's and their mothers' daily dietary intake of nitrite was greater compared with that of control children and mothers (for case and control children 0.9 mg vs 0.8 mg, for case and control mothers 0.9 mg vs 0.8 mg, p < 0.001). Case mothers compared with control mothers received less (p < 0.05) nitrate from their diet. No differences were observed in the intake of nitrate or nitrite from drinking water. Dietary nitrite intake of children (odds ratios and 95% confidence intervals for the second, third, and fourth quartile 1.16, 0.82-1.65; 1.49, 1.06-2.10; 2.32, 1.67-3.24, respectively) and mothers (odds ratios and 95% confidence intervals for the second, third, and fourth quartile 1.15, 0.76-1.74; 1.29, 0.87-1.91; 1.98, 1.35-2.90, respectively) was positively associated with the risk for Type 1 diabetes independently from length of mother's education, child's or mother's age, place of residence or mother's smoking status.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:Nitrate and nitrite intake and the risk for type 1 diabetes in Finnish children. Childhood Diabetes in Finland Study Group. 795 90

Three cases of diabetic myocardiopathy having history of diabetes, angina and left ventricular dysfunction of various degrees and confirmed by coronary angiography and endomyocardial biopsy were reported. Electrocardiography showed significant ST-T changes simulating coronary insufficiency but without definite localization. As to the treatment, nitrate preparations, inotropic agents such as strophanthin K, digoxin etc. were used to relieve the symptoms; insulin was also administered to control the blood glucose level. Diltiazem, a calcium blocker, is also of help in alleviating the symptoms. It is shown in the present study and in the literatures as well that diabetic myocardiopathy is a disease showing intramural microvascular endothelial proliferation and swelling as well as subendothelial accumulation of acid glycogen deposition cells. The transportation of intracellular calcium ions and the cellular metabolism are thus affected, so there are extensive ischemia, focal necrosis and fibrosis in the myocardium with resulting cardiac dysfunction. The authors are, therefore, of the opinion that diabetic myocardiopathy is a specific and separate clinical entity.
 ...
PMID:[Diabetic myocardiopathy]. 804 81

The effect(s) of L-arginine administration on the renal function of rats with untreated diabetes mellitus was examined. Rats received streptozotocin (N = 11) or vehicle (N = 12): Group 1 (normal rats, N = 6) drank tap water; Group 2 (normal rats, N = 6) drank tap water containing 1% L-arginine; Group 3 (diabetic rats, N = 5) drank tap water; and Group 4 (diabetic rats, N = 6) drank tap water with 1% L-arginine. Rats were fed a standard rat chow diet (22.8% protein, 142% L-arginine) with free access to food and water for 14 wk. Diabetic rats gained less weight, had significantly lower plasma levels of albumin and L-arginine, and had greater values for 24-h urine volumes and urine excretion of glucose, protein, urea, creatinine, nitrate, and nitrite than control rats. Diabetic rats given L-arginine (Group 4) had significantly lower protein and cGMP excretion in the urine than did rats of Group 3. The administration of L-arginine did not affect the plasma levels of glucose or L-arginine in Groups 2 or 4 compared with those of their respective controls. Group 3 had significantly higher values for GFR than did the other three groups of rats, but values for effective RPF, mean arterial pressure, hematocrit, and renal vascular resistance were not significantly different between Groups 3 and 4. There was no significant difference in glomerular morphology among the four groups of rats as determined by light microscopy, and both groups of diabetic rats exhibited the Armanni-Ebstein lesion in their tubules.(ABSTRACT TRUNCATED AT 250 WORDS)
 ...
PMID:L-arginine administration prevents glomerular hyperfiltration and decreases proteinuria in diabetic rats. 828 12

The activity of the arginine-citrulline cycle was investigated in macrophages from the spontaneous immunologically mediated diabetic BB rat. Peritoneal macrophages were prepared from male diabetes-prone (BBdp), diabetic (BBd) and age-matched non-diabetes-prone (BBn) rats. Cells were incubated at 37 degrees C for 2 h in Krebs-Henseleit bicarbonate buffer containing 0.5 mM L-arginine, 0.1 mM L-[ureido-14C]citrulline and 5 mM D-glucose to measure the activity of the arginine-citrulline cycle. The uptakes of citrulline and arginine by macrophages were measured during a 5 min incubation period with L-[ureido-14C]citrulline and L-[2,3-3H] arginine respectively. The production of NO3- (the major stable oxidation product of NO) increased (P < 0.01) by 112% and 151% in 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The conversion of [14C]citrulline into [14C]arginine increased (P < 0.01) by 704%, 892% and 904% in 50- and 75-day-old BBdp and 115-day-old BBd macrophages respectively, compared with age-matched BBn cells. The enhanced NO synthesis in BBdp and BBd macrophages was associated with a 25-35% increase in the uptake of L-arginine. However, there were no differences in the uptake of citrulline between BBdp or BBd macrophages and age-matched BBn cells. Our results demonstrate for the first time the activation of the arginine-citrulline cycle in macrophages in an autoimmune condition. The inherent increase in the recycling of L-citrulline to L-arginine in BBdp and BBd macrophages may reflect an innate metabolic disorder in these cells. This increased L-arginine synthesis from L-citrulline may play a role in sustaining a sufficient intracellular L-arginine concentration for prolonged generation of NO in BBdp and BBd macrophages. A role for NO in the autoimmune destruction of pancreatic beta-cells in insulin-dependent diabetes mellitus warrants further investigation.
 ...
PMID:The activation of the arginine-citrulline cycle in macrophages from the spontaneously diabetic BB rat. 836 61

A case-control study of 168 cases with endometrial cancer and 334 controls was conducted in Birmingham, Alabama, between June 1985 and December 1988. Cases were identified at the University of Alabama Hospital and in a private practice; controls were selected from among women who attended the University optometry clinic. A food frequency questionnaire that evaluated the intake of 55 nutrients and 116 foods was obtained for 103 cases and 236 controls. Logistic regression was used to evaluate the effect of diet on endometrial cancer after adjustment for total calories, age, race, education, obesity, smoking status, age at menarche, number of pregnancies, age at menopause, diabetes, hypertension, and use of exogenous estrogens. High intake of certain micronutrients was associated with a decreased risk of endometrial cancer: the odds ratio for subjects in the upper tertile versus those in the lower tertile was 0.4 for both carotene and nitrate (95% confidence interval (CI) 0.2-0.8 and 0.2-0.9, respectively). There also was an inverse association between endometrial cancer and protein consumption (trend test; p = 0.002), and a moderate direct association with cholesterol intake (OR = 1.9, 95% CI 0.9-3.7) when terms for both these macronutrients were included in a logistic model. Total intake of animal and vegetable fat were not associated with endometrial cancer. More frequent consumption of several vegetables and certain dairy products was associated with a statistically significant decreased risk of endometrial cancer. These results suggest that diet plays an important role in the etiology of endometrial cancer.
 ...
PMID:Diet and endometrial cancer: a case-control study. 846 Jun 21

Sixty-four diabetic patients suffering an acute myocardial infarct were retrospectively matched, by age, gender and smoking habit, to non-diabetic controls. The two groups were compared for cardiovascular risk factors, pre-admission and discharge drug treatment, in-hospital drug treatment, and complication and mortality rates. Hypertension was more prevalent in the diabetic (63%) than in the control (42%) group. When comparing drugs on admission to those at discharge, there was a significant increase in antiplatelet and nitrate usage in both groups (P < 0.001), in beta-blocker usage in the control group (P < 0.001) and in loop diuretic usage in the diabetic group (P < 0.001). The usage of angiotensin converting enzyme inhibitors was low: 16% of diabetic patients and 5% of controls at discharge. Thrombolytic therapy was used in 29 diabetics and 37 controls. There was a significantly higher complication rate in the diabetic group than in the control group (P < 0.006), the most common being congestive cardiac failure (59% vs 30%, P < 0.001). Four controls and 13 diabetic patients died; three of the latter had their diabetes diagnosed during the admission. This study did not clearly demonstrate any underlying risk factors or treatment variables to account for the increased morbidity or mortality in diabetic patients with acute myocardial infarct, when compared to a matched non-diabetic population. However, modest associations not detected by this relatively small study are still possible.
 ...
PMID:A survey of drug treatment and outcomes in diabetic patients with acute myocardial infarcts. 855 84

Changes in nitric oxide (NO) levels were determined in ischaemic acute renal failure in streptozotocin-induced diabetes mellitus rats. Two weeks after streptozotocin administration and immediately after right nephrectomy, the left renal artery was occluded for 60 min. Similar procedures were carried out in non-diabetic rats. The nitrite (NO2) + nitrate (NO3) levels were measured in plasma and urine. The effects of chronic oral supplementation with L-arginine and an NO synthase inhibitor (N-omega-nitro-L-arginine) were also studied in both diabetic and non-diabetic rats before and after renal artery clamping. The rats with diabetic acute renal failure had a much lower creatinine clearance (90 +/- 22 microliters.min-1. 100g body weight-1, p < 0.005), and higher fractional excretion of sodium (FENa)% (10.90 +/- 4.2, p < 0.001) and protein excretion (2078 +/- 69 micrograms/ml creatinine clearance, p < 0.001) compared with the respective values in the non-diabetic groups (163 +/- 30; 1.46 +/- 86; 453.3 +/- 31). The plasma and urine NO2 + NO3 levels were significantly higher in the untreated diabetic rats compared with the untreated normal rats before ischaemia (p < 0.001). The ischaemic acute renal failure in non-diabetic rats increased the plasma and urinary NO2 + NO3 excretion after ischaemia. The urinary excretion of these metabolites decreased significantly and their plasma levels remained unchanged in the ischaemic diabetic rats. The L-arginine administration resulted in a small but significantly higher creatinine clearance after clamping in the non-diabetic rats. The NO synthase inhibitor caused deterioration in renal function in all ischaemic and non-ischaemic groups. In summary, the greater vulnerability to ischaemia of the diabetic kidney seems to be associated with both impaired response to and impaired production of NO.
 ...
PMID:Nitric oxide in ischaemic acute renal failure of streptozotocin diabetic rats. 887 86


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>