endothelin-1 and Diabetic-Angiopathies

Diabetes is not only an endocrine but also a vascular disease. Cardiovascular complications are the leading cause of morbidity and mortality associated with diabetes. Diabetes affects both large and small vessels and hence diabetic complications are broadly classified as microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (heart disease, stroke and peripheral arterial disease) complications. Endothelial dysfunction, defined as an imbalance of endothelium-derived vasoconstrictor and vasodilator substances, is a common denominator in the pathogenesis and progression of both macro and microvascular complications. While the pathophysiology of diabetic complications is complex, endothelin-1 (ET-1), a potent vasoconstrictor with proliferative, profibrotic, and proinflammatory properties, may contribute to many facets of diabetic vascular disease. This review will focus on the effects of ET-1 on function and structure of microvessels (retina, skin and mesenteric arteries) and macrovessels (coronary and cerebral arteries) and also discuss the relative role(s) of endothelin A (ET(A)) and ET(B) receptors in mediating ET-1 actions.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Diabetic Angiopathies; Endothelin-1; Humans; Microvessels; Rats

Topics: Atherosclerosis; Brachial Artery; Cardiovascular Diseases; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Humans; Ischemic Attack, Transient; Meta-Analysis as Topic; Nitric Oxide; Risk Factors; Tunica Intima; Tunica Media

Most of the late diabetic complications such as retinopathy, nephropathy, and neuropathy, have their basis in disturbed microvascular function. Structural and functional changes in the micro-circulation are present in diabetes mellitus irrespective of the organ studied, and the pathogenesis is complex. Endothelial dysfunction, characterized by an imbalance between endothelium-derived vasodilator and vasoconstrictor substances, plays an important role in the pathogenesis of diabetic microangiopathy. Increased circulating levels of endothelin-1 (ET-1), a potent vasoconstrictor peptide, has been found in patients with diabetes, and a positive correlation between plasma ET-1 levels and microangiopathy in patients with type 2 diabetes has been demonstrated. In addition to its direct vasoconstrictor effects, enhanced levels of ET-1 may contribute to endothelial dysfunction through inhibitory effects on nitric oxide (NO) production. Vascular endothelial dysfunction may precede insulin resistance, although the feature of insulin resistance syndrome includes factors that have negative effects on endothelial function. Furthermore, ET-1 induces a reduction in insulin sensitivity and may take part in the development of the metabolic syndrome. In the following, the mechanisms by which ET-1 contributes to the development of diabetic microangiopathy and the potentially beneficial effect of selective ET(A) receptor antagonists are discussed.

Topics: Cardiovascular Agents; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Endothelin Receptor Antagonists; Endothelin-1; Humans; Microcirculation; Receptors, Endothelin; Treatment Outcome; Up-Regulation

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Aspartic Acid Endopeptidases; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelin-1; Endothelin-Converting Enzymes; Humans; Metalloendopeptidases; Neprilysin; Protease Inhibitors; Rats

Since the discovery of endothelin-1 as the most potent endothelial-derived vasoconstrictor/mitogenic peptide a decade ago, considerable evidence has implicated this peptide in various cardiovascular disease states, including diabetes mellitus. Plasma and tissue concentrations of endothelin-1 as well as responses to the peptide are changed in various forms of the disease in humans and animals. Endothelin activity is also altered in atherosclerotic and ischaemic disease, nephropathy, retinopathy, erectile dysfunction, and neuropathy, many of the well-known complications of diabetes. Striking new evidence shows that antagonists of the endothelin system might beneficially affect and potentially overcome some of these complications. Despite this, lack of direct proof of causation makes this peptide's role in the disease uncertain. This review examines the current state of thought on the role of endothelin in diabetes and in the complications of the disease as well as the likely roles of altered metabolic variables in modulating endothelin-1 concentrations and its activity. It is concluded that although alterations in endothelin-1 release and action are clearly associated with the diabetic state, further studies using inhibitors of the endothelin system are warranted to determine its precise role in the complications of the disease.

Topics: Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Hemodynamics; Humans

Endothelin-1 is mainly synthesized by the vascular endothelial cells and acts on the vascular smooth muscle. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. In diabetes mellitus atherosclerosis is accelerated. The authors summarize the available data of the role of endothelin-1 in Type 1 and Type 2 diabetes mellitus and the development of diabetic complication.

Topics: Animals; Diabetes Complications; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Humans; Rats

Endothelin-1 is mainly synthesised by the vascular endothelial cells and acts on the vascular smooth muscle. There are special endothelin receptors, endothelin receptor-A and endothelin receptor-B expressed on the vascular smooth muscle cells. Endothelin-1 through second messengers mobilises the intracellular calcium storage. The level of endothein-1 was found to be higher than normal in several diseases. Because of its vasoconstrictor and mitogenic effects it plays a role in the development of vascular diseases. The most severe and most frequent complications of diabetes mellitus are micro- and macroangiopathy. The authors summarise the physiological functions of endothelin-1 and its role in the development of diabetic angiopathy.

Topics: Diabetic Angiopathies; Endothelin-1; Humans; Mitogens; Vasoconstrictor Agents

A high blood concentration of endothelin (ET)-1 may participate in the onset and progress of diabetic microangiopathy, resulting in neuropathy. We examined the therapeutic effects of prostaglandin E1 (PGE1), which possesses both a peripheral vasodilating action and inhibition of platelet aggregation, on diabetic microangiopathy. Increases in both skin temperature and peripheral never conduction velocity in diabetic patients were recorded four weeks after Lipo PGE1 administration. A quantitative decrease in urinary albumin concentration was also observed, suggesting its efficacy of action was on diabetic nephropathy. Lipo PGE1 administration reduced the elevated circulating plasma ET-1 levels in the diabetic patients. As an increase in ET-1 concentrations is thought to correlate with the onset and progress of diabetic microangiopathy, the reduction of plasma ET-1 concentration by Lipo PGE1 administration may be one reason for the improvement in diabetic neuropathy and nephropathy.

Topics: Adult; Aged; Aged, 80 and over; Albumins; Alprostadil; Angiotensins; Blood Glucose; Collagen Type IV; Cyclic AMP; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Diabetic Retinopathy; Electric Conductivity; Electrocardiography; Endothelin-1; Fasting; Female; Glycated Hemoglobin; Humans; Hypertension; Male; Middle Aged; Peptidyl-Dipeptidase A; Peripheral Nerves; Renin; Skin Temperature

Endothelin (ET) is a potent vasoconstrictive peptide that may play a role in vascular pathology in general and diabetic nephropathy in particular. The aim of this study was to investigate (1) alterations of urinary ET1 (UET1) in adolescents and young adults with insulin-dependent diabetes mellitus (IDDM) and (2) the relation of UET1 to other indices of diabetic nephropathy and to risk factors of diabetic angiopathy in general. In 130 IDDM subjects aged 15.2+/-4.9 years with a diabetes duration of 7.3+/-5.1 years, UET1 by radioimmunoassay, urinary albumin by nephelometry, plasma renin by immunoradiometric assay, hemoglobin A1c (HbA1c) by high-performance liquid chromatography, and routine biochemistry analyses were determined. Forty-eight controls, healthy siblings of the diabetics of comparable age, were similarly studied. Total 24-hour UET1 excretion was higher in diabetics than in controls (10,866+/-7,270 and 6,598+/-3,294 pg/24 h, respectively, P=.000). This difference was also noted if male and female diabetics were separately compared with controls. In diabetics with normoalbuminuria (<20 microg/min), total 24-hour UET1 excretion was also higher than in controls (P=.002). In diabetics but not in controls, 24-hour UET1 values were higher in males than in females (P=.018). In IDDM subjects, UET1 showed a linear relationship with age (P=.002), urinary albumin (P=.000), serum creatinine (P=.001), systolic blood pressure (P=.038), triglycerides (P=.003), and HbA1c (P=.041). Multiple regression analysis demonstrated that the variables interacting independently with UET1 were urinary albumin (P=.003) and serum creatinine (P=.038). UET1 is elevated early (in adolescence) in IDDM subjects, and it is positively correlated with the degree of albuminuria. These data suggest that the amount of UET1 possibly reflects the severity of diabetic renovascular damage. It may thus be speculated that UET1 could be used as another index of diabetic nephropathy or its progress.

Topics: Adolescent; Adult; Albuminuria; Blood Pressure; Child; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Humans; Male

To examine a possible role for endothelin-1 in the pathophysiology of diabetic microangiopathy, we measured plasma levels of endothelin-1 and big endothelin-1, a precursor peptide of endothelin-1, in 33 untreated patients with non-insulin-dependent diabetes mellitus. There was no significant difference among the mean plasma endothelin-1 concentrations in 18 patients with microangiopathy, in 15 patients without microangiopathy and in 33 age-matched normal subjects. In contrast, the mean plasma big endothelin-1 concentration in patients with microangiopathy was significantly higher than in those without microangiopathy or in normal subjects. As a consequence, the mean big endothelin-1 to endothelin-1 ratio in patients with microangiopathy was significantly higher than in the other two groups. There was no significant correlation between plasma levels of endothelin-1 or big endothelin-1 and fasting blood glucose, HbA1c, mean blood pressure, or period of duration of diabetes mellitus in the patient groups. The results indicate that elevation of plasma big endothelin-1 levels with diminished conversion of big endothelin-1 to endothelin-1 is associated with diabetic microangiopathy, which may be the effect rather than the cause of endothelial dysfunction.

Topics: Adult; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Endothelins; Female; Glycated Hemoglobin; Humans; Male; Middle Aged; Protein Precursors; Time Factors

Diabetes elevates endothelin-1 (ET-1) in the vitreous and enhances constriction of retinal venules to this peptide. However, mechanisms contributing to ET-1-induced constriction of retinal venules are incompletely understood. We examined roles of sodium-hydrogen exchanger 1 (NHE1), protein kinase C (PKC), mitogen-activated protein kinases (MAPKs), and extracellular calcium (Ca

Topics: Animals; Calcium; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Retinopathy; Endothelin-1; Imidazoles; Male; Mitogen-Activated Protein Kinases; p38 Mitogen-Activated Protein Kinases; Pyridines; Retinal Vein; Signal Transduction; Sodium-Hydrogen Exchanger 1; Swine; Vasoconstriction

Hyperglycemia-induced production of endothelin (ET)-1 is a hallmark of endothelial dysfunction in diabetes. Although the detrimental vascular effects of increased ET-1 are well known, the molecular mechanisms regulating endothelial synthesis of ET-1 in the setting of diabetes remain largely unidentified. Here, we show that adapter molecule TRAF3 interacting protein 2 (TRAF3IP2) mediates high glucose-induced ET-1 production in endothelial cells and ET-1-mediated endothelial cell inflammation. Specifically, we found that high glucose upregulated TRAF3IP2 in human aortic endothelial cells, which subsequently led to activation of JNK and IKKβ. shRNA-mediated silencing of TRAF3IP2, JNK1, or IKKβ abrogated high-glucose-induced ET-converting enzyme 1 expression and ET-1 production. Likewise, overexpression of TRAF3IP2, in the absence of high glucose, led to activation of JNK and IKKβ as well as increased ET-1 production. Furthermore, ET-1 transcriptionally upregulated TRAF3IP2, and this upregulation was prevented by pharmacological inhibition of ET-1 receptor B using BQ-788, or inhibition of NADPH oxidase-derived reactive oxygen species using gp91ds-tat and GKT137831. Notably, we found that knockdown of TRAF3IP2 abolished ET-1-induced proinflammatory and adhesion molecule (IL-1β, TNF-α, monocyte chemoattractant protein 1, ICAM-1, VCAM-1, and E-selectin) expression and monocyte adhesion to endothelial cells. Finally, we report that TRAF3IP2 is upregulated and colocalized with CD31, an endothelial marker, in the aorta of diabetic mice. Collectively, findings from the present study identify endothelial TRAF3IP2 as a potential new therapeutic target to suppress ET-1 production and associated vascular complications in diabetes. NEW & NOTEWORTHY This study provides the first evidence that the adapter molecule TRAF3 interacting protein 2 mediates high glucose-induced production of endothelin-1 by endothelial cells as well as endothelin-1-mediated endothelial cell inflammation. The findings presented herein suggest that TRAF3 interacting protein 2 may be an important therapeutic target in diabetic vasculopathy characterized by excess endothelin-1 production.

Topics: Adaptor Proteins, Signal Transducing; Animals; Cell Adhesion; Cell Adhesion Molecules; Cells, Cultured; Coculture Techniques; Cytokines; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Female; Glucose; Humans; I-kappa B Kinase; Inflammation; Inflammation Mediators; Male; Mice, Inbred NOD; Mitogen-Activated Protein Kinase 8; Monocytes; Signal Transduction; Tumor Necrosis Factor Receptor-Associated Peptides and Proteins

The aim of this study was to determine if weight loss following Roux-en-Y gastric bypass (RYGB) surgery in morbidly obese patients is associated with a decrease in plasma concentrations of neprilysin, mediators of the renin angiotensin system (RAS), catecholamines and endothelin-1, and also with an increase in the concentrations of vasodilators. Fasting blood samples were obtained from 15 patients with morbid obesity and diabetes prior to and 6 months after RYGB surgery. Circulating levels of neprilysin, vasoconstrictors, vasodilators, and the mRNA expression of related genes in circulating mononuclear cells (MNC) were measured. Six months after RYGB surgery the concentrations of neprilysin, angiotensinogen, angiotensin II, renin and endothelin-1 fell significantly by 27 ±16%, 22 ±10%, 22 ±8%, 35 ±13% and 17 ±6% (P < .05 for all), respectively, while ANP concentrations increased significantly by 24 ±13%. There was no significant change in aldosterone, BNP, cAMP or cGMP concentrations, or angiotensin converting enzyme (ACE) expression. These changes may contribute to the reduction of congestive cardiac failure and blood pressure risks after RYGB surgery.

Topics: Bariatric Surgery; Body Mass Index; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Cardiomyopathies; Endothelin-1; Female; Glycated Hemoglobin; Heart Failure; Humans; Hypertension; Insulin Resistance; Male; Middle Aged; Neprilysin; Obesity, Morbid; Postoperative Period; Prospective Studies; Renin-Angiotensin System; Risk; Weight Loss

It is unclear whether diabetic angiopathy is related to oxidative stress-associated endothelial dysfunction. The authors investigated whether alteration of endothelin-1 and lipid peroxide production and activation of nuclear factor-κB expression were involved in lower limb amputation in type 2 diabetes mellitus patients.. A total of 135 subjects including 51 type 2 diabetes mellitus patients with major lower extremity amputations and 36 diabetes mellitus patients without limb and vascular complication and 48 normal controls were recruited for this study. The authors measured the plasma soluble endothelin-1 concentrations by a sandwich enzyme immunoassay, and measured oxidative stress as determined by the lipid peroxide byproduct malondialdehyde. Histologic staining and nuclear factor-κB activation determined by electrophoretic mobility shift assay of the amputated vessels were examined.. Histologic staining revealed that severe arteriosclerosis with atheroma formation in the amputated diabetic arteries was significantly prominent compared with normal controls. Soluble endothelin-1 concentrations and malondialdehyde levels were increased significantly in diabetic amputation patients compared with other groups (p < 0.001). The nuclear factor-κB binding activity in amputated diabetic stump vessels was more prominent compared with healthy vessels without diabetes mellitus. There was a positive correlation between endothelin-1 and malondialdehyde in patients with diabetic amputation (r = 0.46, p = 0.001).. These results suggest that elevation of endothelin-1 and lipid peroxide levels is involved in the pathogenesis of diabetic foot amputation. An increase of lipid peroxide and endothelin-1 associated with nuclear factor-κB activation plays an important role in the development of diabetic angiopathies.

Topics: Adult; Aged; Aged, 80 and over; Amputation, Surgical; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Electrophoresis; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Gene Expression Regulation; Humans; Leg; Lipid Peroxidation; Male; Middle Aged; NF-kappa B; Polymerase Chain Reaction; Retrospective Studies; RNA

To study the relationship between plasma soluble klotho (sKlotho) and pro-endothelin-1 (proET-1) in patients with type 2 diabetes (T2DM).. In this cross-sectional study, we recruited 175 T2DM subjects and 56 non-diabetic controls. Plasma sKlotho, proET-1 and extracellular superoxide dismutase (SOD) were measured by ELISA and ILMA, respectively.. Plasma sKlotho level in patients with T2DM was lower compared to that in non-diabetic controls (416.8±148.1 vs. 494.6±134.3 pg/ml, p=0.001) and showed significant interaction with diabetes status in its association with proET-1. Plasma sKlotho was inversely correlated with proET-1 in T2DM (Rho=-0.410, p<0.0001) but not in non-diabetic controls (Rho=0.091, p=0.505). Multivariable linear regression models revealed that sKlotho was independently associated with proET-1 after adjustment for renal filtration function, albuminuria, diabetes duration, HbA1c, systolic and diastolic blood pressure.. Plasma sKlotho was associated with proET-1 independent of renal function in patients with T2DM.

Topics: Aged; Albuminuria; Blood Glucose; Blood Pressure; Body Mass Index; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Nephropathies; Diabetic Neuropathies; Endothelin-1; Female; Glomerular Filtration Rate; Glucuronidase; Glycated Hemoglobin; Humans; Klotho Proteins; Lipids; Male; Middle Aged; Oxidative Stress; Protein Precursors; Superoxide Dismutase

We studied the impact of diabetes mellitus (DM) on the radial artery (RA) in 30 patients with DM and 30 non-diabetic patients undergoing coronary artery bypass grafting with autologous RA. RAs were recorded as normal if there was no cellular or stromal tissue between the endothelium and the internal elastic lamina. The RA was normal in 26.7% of diabetic and 76.7% of non-diabetic patients (p = 0.000298). Intimal thickness index and intima:media ratio were higher in the former than in the latter (p < 0.05; p < 0.05), with no significant difference in luminal narrowing (p > 0.05). Electron microscopy scores were lower in the non-diabetic group (p < 0.001); endothelial nitric oxide synthase (eNOS) protein expression and optical density were higher (p < 0.001). Von Willebrand factor and endothelin-1 messenger RNA (mRNA) levels were higher in the DM patients (p < 0.001). The quality of the RA in patients with DM was thus inferior to that in non-diabetic patients. Care should be taken when selecting RA as a conduit in patients with DM.

Topics: Aged; Carotid Intima-Media Thickness; Carotid Stenosis; Coronary Artery Bypass; Coronary Artery Disease; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Hyperplasia; Male; Microscopy, Electron, Transmission; Middle Aged; Nitric Oxide Synthase Type III; Radial Artery; RNA, Messenger; Transplantation, Autologous; Up-Regulation; von Willebrand Factor

Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.

Topics: Animals; Blood Glucose; Bradykinin; Coronary Artery Disease; Coronary Vessels; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Male; Nitric Oxide; Nitric Oxide Donors; Receptors, Endothelin; S-Nitroso-N-Acetylpenicillamine; Swine; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Endothelial dysfunction plays a key role in the pathogenesis of diabetic vascular disease. Herein, we have analyzed if the peroxisome proliferator-activated receptor-β/-δ (PPARβ/δ) agonist GW0742 exerts protective effects on endothelial function in type 1 diabetic rats. The rats were divided into 4 groups: control, control-treated (GW0742, 5 mg kg(-1)day(-1) for 5 weeks), diabetic (streptozotocin injection), and diabetic-treated. GW0742 administration in diabetic rats did not alter plasma glucose, systolic blood pressure, or heart rate, but reduced plasma triglyceride levels. The vasodilatation induced by acetylcholine was decreased in aortas from diabetic rats. GW0742 restored endothelial function, increasing eNOS phosphorylation. Superoxide production, NADPH oxidase activity, and mRNA expression of prepro endothelin-1, p22(phox), p47(phox), and NOX-1 were significantly higher in diabetic aortas, and GW0742 treatment prevented these changes. In addition, GW0742 prevented the endothelial dysfunction and the upregulation of prepro endothelin-1 and p47(phox) after the in vitro incubation of aortic rings with high glucose and these effects were prevented by the PPARβ/δ antagonist GSK0660. PPARβ/δ activation restores endothelial function in type 1 diabetic rats. This effect seems to be related to an increase in nitric oxide bioavailability as a result of reduced NADPH oxidase-driven superoxide production and downregulation of prepro endothelin-1.

Topics: Acetylcholine; Animals; Aorta; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Gene Expression; Gene Expression Regulation; In Vitro Techniques; Macrophages; NADPH Oxidases; Neutrophil Infiltration; Peroxidase; PPAR delta; PPAR-beta; Rats; Rats, Wistar; Reactive Oxygen Species; Streptozocin; Thiazoles; Triglycerides; Vasodilation; Vasodilator Agents

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. In the present study, we hypothesized that treatment with pravastatin (an inhibitor of 3-hydroxy-3-methylglutaryl-CoA reductase) would normalize the ET-1-induced contraction in aortas isolated from type 2 diabetic Otsuka Long-Evans Tokushima fatty (OLETF) rats. Contractile responses were examined by measuring isometric force in endothelium-denuded aortic helical strips from four groups: Long-Evans Tokushima Otsuka (LETO; genetic control), OLETF (type 2 diabetic), pravastatin-treated LETO, and pravastatin-treated OLETF rats. Both immunoblot analysis and immunoprecipitation assays were used to examine Src, protein phosphatase (PP)2A, kinase suppressor of Ras (KSR)1, and ERK signaling pathway protein levels and activities. In endothelium-denuded aortas isolated from OLETF rats at the chronic stage of diabetes (56-60 wk) (vs. those from age-matched LETO rats), we found the following: 1) ET-1-induced contraction was enhanced, 2) ERK1/2 phosphorylation was increased, 3) phosphorylations of KSR1 and PP2A were reduced (i.e., enhancement of the kinase active state), 4) ERK1/2-KSR1 complexes were increased, and 5) Src tyrosine kinase activity was diminished. Endothelium-denuded aortas isolated from OLETF rats treated with pravastatin (10 mg/kg po, daily for 4 wk) exhibited normalized ET-1-induced contractions and suppressed ET-1-stimulated ERK phosphorylation, with the associated phosphorylated KSR1 and phosphorylated PP2A levels being increased toward normal levels. These results suggest that in type 2 diabetic rats, pravastatin normalizes ET-1-induced contraction in aortic smooth muscle via a suppression of PP2A/KSR1/ERK activities after an enhancement of Src kinase activity.

Topics: Animals; Aorta, Thoracic; Aortic Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Male; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Phosphorylation; Pravastatin; Protein Kinases; Protein Phosphatase 2; Rats; Rats, Inbred OLETF; Signal Transduction; src-Family Kinases; Time Factors; Vasoconstriction; Vasoconstrictor Agents

The study aim was to investigate NOS3 VNTR, NOS3 G894T, EDN1 C8002T, ACE I/D, AGT M235T and AGTR1 A1166C in nonobese and obese T2DM patients, and their interaction with the incidence of microangiopathy. T2DM subjects (n=250; 166 nonobese, and 84 obese) were genotyped for the gene variants by PCR/RFLP. The interaction of these polymorphisms with obesity and their contribution to microangiopathy were analyzed by multivariate regression analysis. A higher frequency of NOS3 4a allele was found in obese (P=0.027) vs. nonobese subjects. ACE D (P=0.009) and AGT 235T (P=0.026) alleles were associated with the reduced risk of diabetic nephropathy in nonobese and obese patients, respectively. In obese subjects, NOS3 4a (P=0.011) had a converse effect to NOS3 894T (P=0.043), and EDN1 8002T (P=0.035) on the prevalence of combined microangiopathy (neuropathy/retinopathy/nephropathy) vs. microangiopathy-negative subjects. The study indicates association of RAS variants with obesity and nephropathy, and an opposite effect of NOS3 VNTR and NOS3 G894T on the occurrence of combined microangiopathy.

Topics: Adult; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Female; Humans; Male; Middle Aged; Nitric Oxide Synthase Type III; Obesity; Polymorphism, Genetic; ras Proteins; Receptor, Angiotensin, Type 1

Transient receptor potential vanilliod 1 (TRPV1) channels have recently been postulated to play a role in the vascular complications/consequences associated with diabetes despite the fact that the mechanisms through which TRPV1 regulates vascular function are not fully known. Accordingly, our goal was to define the mechanisms by which TRPV1 channels modulate vascular function and contribute to vascular dysfunction in diabetes. We subjected mice lacking TRPV1 [TRPV1((-/-))], db/db, and control C57BLKS/J mice to in vivo infusion of the TRPV1 agonist capsaicin or the α-adrenergic agonist phenylephrine (PE) to examine the integrated circulatory actions of TRPV1. Capsaicin (1, 10, 20, and 100 μg/kg) dose dependently increased MAP in control mice (5.7 ± 1.6, 11.7 ± 2.1, 25.4 ± 3.4, and 51.6 ± 3.9%), which was attenuated in db/db mice (3.4 ± 2.1, 3.9 ± 2.1, 7.0 ± 3.3, and 17.9 ± 6.2%). TRPV1((-/-)) mice exhibited no changes in MAP in response to capsaicin, suggesting the actions of this agonist are specific to TRPV1 activation. Immunoblot analysis revealed decreased aortic TRPV1 protein expression in db/db compared with control mice. Capsaicin-induced responses were recorded following inhibition of endothelin A and B receptors (ET(A) /ET(B)). Inhibition of ET(A) receptors abolished the capsaicin-mediated increases in MAP. Combined antagonism of ET(A) and ET(B) receptors did not further inhibit the capsaicin response. Cultured endothelial cell exposure to capsaicin increased endothelin production as shown by an endothelin ELISA assay, which was attenuated by inhibition of TRPV1 or endothelin-converting enzyme. TRPV1 channels contribute to the regulation of vascular reactivity and MAP via production of endothelin and subsequent activation of vascular ET(A) receptors. Impairment of TRPV1 channel function may contribute to vascular dysfunction in diabetes.

Topics: Adrenergic alpha-Agonists; Analysis of Variance; Animals; Azepines; Biphenyl Compounds; Blood Pressure; Capsaicin; Cells, Cultured; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Dipeptides; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelial Cells; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Femoral Artery; Indoles; Infusions, Intravenous; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Phenylephrine; Receptor, Endothelin A; Receptor, Endothelin B; TRPV Cation Channels; Vasoconstriction; Vasoconstrictor Agents

Diabetes is a risk factor for female sexual dysfunction (FSD). FSD has several etiologies, including a vasculogenic component that could be exacerbated in diabetes. The internal pudendal artery supplies blood to the vagina and clitoris and diabetes-associated functional abnormalities in this vascular bed may contribute to FSD.. The Goto-Kakizaki (GK) rat is a non-obese model of type 2 diabetes with elevated endothelin-1 (ET-1) activity. We hypothesize that female GK rats have diminished sexual responses and that the internal pudendal arteries demonstrate increased ET-1 constrictor sensitivity.. Female Wistar and GK rats were used. Apomorphine (APO)-mediated genital vasocongestive arousal (GVA) was measured. Functional contraction (ET-1 and phenylephrine) and relaxation (acetylcholine, ACh) in the presence or absence of the ETA receptor antagonist (ETA R; atrasentan) or Rho-kinase inhibitor (Y-27632) were assessed in the internal pudendal and mesenteric arteries. Protein expression of ET-1 and RhoA/Rho-kinase signaling pathway was determined in the internal pudendal and mesenteric arteries.. APO-mediated GVAs; contraction and relaxation of internal pudendal and mesenteric arteries; ET-1/RhoA/Rho-kinase protein expression.. GK rats demonstrated no APO-induced GVAs. Internal pudendal arteries, but not mesenteric arteries, from GK rats exhibited greater contractile sensitivity to ET-1 compared with Wistar arteries. ETA R blockade reduced ET-1-mediated constriction in GK internal pudendal and mesenteric arteries. Rho-kinase inhibition reduced ET-1-mediated constriction of GK internal pudendal but not mesenteric arteries; however, it had no effect on arteries from Wistar rats. RhoA protein expression was elevated in GK internal pudendal arteries. At the highest concentrations, ACh-mediated relaxation was greater in the GK internal pudendal artery; however, no difference was observed in the mesenteric artery.. Female GK rats demonstrate decreased sexual responses that may be because of increased constrictor sensitivity to the ET-1/RhoA/Rho-kinase signaling in the internal pudendal artery.

Topics: Animals; Apomorphine; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Estradiol; Female; Mesenteric Arteries; Rats; Rats, Inbred Strains; Rats, Wistar; rhoA GTP-Binding Protein; Sexual Behavior, Animal; Signal Transduction; Vagina; Vasoconstriction

Endothelin-1 (ET-1) and oxidative stress are involved in the development of hypertension-induced cardiovascular complications. The aim of this study was to evaluate the relationship between plasma ET-1 level and plasma antioxidant capacity and carotid atherosclerosis. In 61 treated patients with hypertension (44 women, 35 diabetics, mean age 72.4+/-7.2 years) medical histories, ambulatory blood pressure, blood tests (glucose, creatinine, cholesterol, haemoglobin A1c (HbA1c), ET-1) and common carotid artery intima-media thickness (CCA-IMT) measurement were carried out. Plasma antioxidant capacity was assessed by the ferric-reducing ability of plasma (FRAP). Subjects with diabetes presented with higher concentrations of glucose (7.01+/-2.3 vs 5.14+/-0.6 mmol l(-1), P<0.001), HbA1c (7.75+/-2.1 vs 6.1+/-1.2%, P<0.001) and ET-1 (1.36+/-0.53 vs 1.01+/-0.4 pg ml(-1), P<0.01), and lower cholesterol level (5.02+/-0.8 vs 5.86+/-1.3 mmol l(-1), P<0.01). A significant positive correlation between CCA-IMT and ET-1 plasma concentration (r=0.40, P<0.001) and reverse relationship between CCA-IMT and FRAP (r=-0.36, P<0.01) was observed. In a stepwise regression analysis, after adjustment for all confounders, CCA-IMT was independently influenced by age, systolic blood pressure (SBP), HbA1c and ET-1. When FRAP was included in the regression model, CCA-IMT was significantly influenced by age, FRAP, HbA1c and SBP. ET-1 promotes the increase in CCA-IMT contributing to the development of end-organ damage. Plasma antioxidant capacity may modulate this deleterious effect, but whether better antioxidant defence may prevent against the development of atherosclerosis remains to be elucidated.

Topics: Aged; Antioxidants; Carotid Artery Diseases; Carotid Artery, Common; Diabetic Angiopathies; Endothelin-1; Female; Humans; Hypertension; Male; Multivariate Analysis; Oxidative Stress; Regression Analysis; Signal Transduction; Tunica Intima; Tunica Media; Ultrasonography

Emerging evidence demonstrates the involvement of endothelin-1 (ET-1) in the pathophysiology of cardiovascular disorders associated with diabetes mellitus. The molecular mechanisms accountable for the increased production of ET-1 are not completely defined. The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is an essential pathogenic mechanism leading to endothelial cell dysfunction. Our aim has been to investigate the role of JAK/STAT in the regulation of ET-1 synthesis in human endothelial cells (EAhy926 cells line). EAhy926 cells were exposed to normal (5 mM) or high (25 mM) glucose concentrations in the presence/absence of various JAK/STAT inhibitors. Using real-time polymerase chain reaction, enzyme-linked immunosorbent assay, and gene reporter assay, we found that JAK/STAT inhibitors (STAT1 decoy oligodeoxynucleotides, AG490, S3I201, WP1066) significantly diminished the high-glucose-dependent up-regulation of ET-1 mRNA, peptide synthesis, and promoter activity. In silico analysis of the human ET-1 promoter revealed the presence of typical STAT1-gamma-activated sequence (STAT1-GAS) elements. Transient overexpression of STAT1 indicated an up-regulation of ET-1 promoter activity. Chromatin immunoprecipitation demonstrated the physical interaction of STAT1 proteins with the predicted GAS sites. Regulation of ET-1 synthesis by the JAK/STAT pathway thus represents a novel mechanism by which high glucose induces endothelial cell dysfunction in diabetes. Since the JAK/STAT system is an important regulator of the response of endothelial cells to injury, the modulation of this system and the subsequent decrease in ET-1 level may represent a key pharmacological target in diabetes-associated cardiovascular disorders.

Topics: Cells, Cultured; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Enzyme Inhibitors; Glucose; Humans; Hyperglycemia; Janus Kinases; Promoter Regions, Genetic; RNA, Messenger; Signal Transduction; STAT Transcription Factors; STAT1 Transcription Factor; Up-Regulation

Endothelin (ET)-1 is a likely candidate for a key role in diabetic vascular complications. However, no abnormalities in the vascular responsiveness to ET-1 have been identified in the chronic stage of type 2 diabetes. Our goal was to look for abnormalities in the roles played by ET receptors (ET(A) and ET(B)) in the mesenteric artery of the type 2 diabetic Goto-Kakizaki (GK) rat and to identify the molecular mechanisms involved. Using mesenteric arteries from later-stage (32-38 wk old) individuals, we compared the ET-1-induced contraction and the relaxation induced by the selective ET(B) receptor agonist IRL1620 between GK rats and control Wistar rats. Mesenteric artery ERK activity and the protein expressions for ET receptors and MEK were also measured. In GK rats (vs. age-matched Wistar rats), we found as follows. 1) The ET-1-induced contraction was greater and was attenuated by BQ-123 (ET(A) antagonist) but not by BQ-788 (ET(B) antagonist). In the controls, BQ-788 augmented this contraction. 2) Both the relaxation and nitric oxide (NO) production induced by IRL1620 were reduced. 3) ET-1-induced contraction was enhanced by N(G)-nitro-l-arginine (l-NNA; NO synthase inhibitor) but suppressed by sodium nitroprusside (NO donor). 4) The enhanced ET-1-induced contraction was reduced by MEK/ERK pathway inhibitors (PD-98059 or U0126). 5) ET-1-stimulated ERK activation was increased, as were the ET(A) and MEK1/2 protein expressions. 6) Mesenteric ET-1 content was increased. These results suggest that upregulation of ET(A), a defect in ET(B)-mediated NO signaling, and activation of the MEK/ERK pathway together represent a likely mechanism mediating the hyperreactivity to ET-1 examined in this study.

Topics: Angiotensin II; Animals; Arginine Vasopressin; Butadienes; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Endothelin-1; Endothelins; Enzyme Inhibitors; Extracellular Signal-Regulated MAP Kinases; Flavonoids; Male; MAP Kinase Kinase Kinases; Mesenteric Arteries; Nitric Oxide; Nitric Oxide Donors; Nitric Oxide Synthase; Nitriles; Nitroarginine; Nitroprusside; Oligopeptides; Peptide Fragments; Peptides, Cyclic; Piperidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Signal Transduction; Vasoconstriction; Vasodilation

We investigated the role of leptin and its interaction with endothelin 1 (ET-1) in fibronectin (FN) synthesis and cardiomyocyte hypertrophy, two characteristic features of diabetic cardiomyopathy.. Endothelial cells [human umbilical vein endothelial cells (HUVECs)] were examined for FN production and neonatal rat cardiomyocytes for hypertrophy, following incubation with glucose, ET-1, leptin and specific blockers. FN, ET-1, leptin and leptin receptors mRNA expression and FN protein were measured. Myocytes were also morphometrically examined. Furthermore, hearts from streptozotocin-diabetic rats were analysed.. Glucose caused increased FN mRNA and protein expression in HUVECs and cardiomyocytes hypertrophy along with upregulation of ET-1 mRNA, leptin mRNA and protein. Glucosemimetic effects were seen with leptin and ET-1. Leptin receptor antagonist (leptin quadruple mutant) and dual endothelin A endothelin B (ETA/ETB) receptor blocker bosentan normalized such abnormalities. Hearts from the diabetic animals showed hypertrophy and similar mRNA changes.. These data indicate that in diabetes increased FN production and cardiomyocyte hypertrophy may be mediated through leptin with its interaction with ET-1.

Topics: Analysis of Variance; Animals; Cells, Cultured; Diabetic Angiopathies; Endothelial Cells; Endothelin-1; Extracellular Matrix Proteins; Fibronectins; Humans; Hypertrophy; Leptin; Male; Myocytes, Cardiac; Rats; Rats, Sprague-Dawley; Receptors, Leptin; RNA, Messenger; Statistics, Nonparametric; Umbilical Veins

Endothelin-1 levels are elevated in patients with type 2 diabetes mellitus and may contribute to impaired microvascular function. We investigated the effect of selective endothelin-A (ET(A)) receptor blockade (BQ123) on skin microcirculation in patients with type 2 diabetes and albuminuria.. Ten type 2 diabetes patients and 8 non-diabetic controls were investigated. Nutritive skin capillary circulation, investigated by videophotometric capillaroscopy, and total skin microcirculation, assessed by laser Doppler flux-metry (LDF), were studied during intra-arterial infusion of saline for 15 min, followed by BQ123 infusion for 60 min.. Following BQ123 infusion there was a significant increase in resting capillary blood cell velocity (CBV) in patients with type 2 diabetes from 0.24 (0.20-0.34) mm/s at baseline to 0.61 (0.46-0.88) mm/s at 60 min, but no significant change in the control subjects [0.55 (0.10-0.68) vs. 0.38 (0.13-0.88) mm/s; p < 0.005 for difference between groups]. Peak CBV following arterial occlusion and skin temperature increased significantly in the type 2 diabetes group but not in the control group during BQ123 infusion. There were no significant changes in LDF parameters during infusion of BQ123 in either group.. ET(A) receptor blockade improves nutritive skin capillary circulation in patients with type 2 diabetes and microangiopathy.

Topics: Aged; Albuminuria; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin A Receptor Antagonists; Endothelin-1; Female; Humans; Male; Microcirculation; Middle Aged; Peptides, Cyclic; Skin

To evaluate the relationship of plasma endothelin-1 (ET-1) levels, a marker of endothelial dysfunction, and urinary albumin excretion in patients with type 2 diabetes mellitus (DM).. Cross-sectional study was conducted in 279 patients (132 males, mean age: 58.7+/-11.0 years, mean DM duration: 11.3+/-8.1 years). Urinary albumin excretion, ET-1, and insulin were measured. Insulin sensitivity was estimated by homeostasis model assessment (HOMA-ir) index.. ET-1 was associated with urinary albumin excretion after controlling for age, gender, body mass index, blood pressure, HbA1c test, and total cholesterol (R=0.436; adjusted R(2)=0.190, P<0.01). Furthermore, there was a progressive increase in plasma ET-1 levels from patients with normoalbuminuria (n=187, 0.92+/-0.50pg/ml), microalbuminuria (n=68, 1.13+/-0.52pg/ml) to macroalbuminuria (n=24, 1.93+/-1.10pg/ml, P<0.01).. There is an independent association of plasma ET-1 levels with urinary albumin excretion. In addition, plasma ET-1 levels started to increase in the normal values of urinary albumin excretion suggesting that in patients with type 2 DM endothelial dysfunction is already present, in urinary albumin excretion values considered normal.

Topics: Age of Onset; Aged; Albuminuria; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diabetic Retinopathy; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged

Vascular dysfunction, which presents either as an increased response to vasoconstrictors or an impaired relaxation to dilator agents, results in worsened cardiovascular outcomes in diabetes. We have established that the mesenteric circulation in Type 2 diabetes is hyperreactive to the potent vasoconstrictor endothelin-1 (ET-1) and displays increased nitric oxide-dependent vasodilation. The current study examined the individual and/or the relative roles of the ET receptors governing vascular function in the Goto-Kakizaki rat, a mildly hyperglycemic, normotensive, and nonobese model of Type 2 diabetes. Diabetic and control rats received an antagonist to either the ET type A (ETA; atrasentan; 5 mg x kg(-1) x day(-1)) or type B (ET(B); A-192621; 15 or 30 mg x kg(-1) x day(-1)) receptors for 4 wk. Third-order mesenteric arteries were isolated, and vascular function was assessed with a wire myograph. Maximum response to ET-1 was increased in diabetes and attenuated by ETA antagonism. ETB blockade with 15 mg/kg A-192621 augmented vasoconstriction in controls, whereas it had no further effect on ET-1 hyperreactivity in diabetes. The higher dose of A-192621 showed an ETA-like effect and decreased vasoconstriction in diabetes. Maximum relaxation to acetylcholine (ACh) was similar across groups and treatments. ETB antagonism at either dose had no effect on vasorelaxation in control rats, whereas in diabetes the dose-response curve to ACh was shifted to the right, indicating a decreased relaxation at 15 mg/kg A-192621. These results suggest that ETA receptor blockade attenuates vascular dysfunction and that ETB receptor antagonism exhibits differential effects depending on the dose of the antagonists and the disease state.

Topics: Acetylcholine; Animals; Atrasentan; Cardiovascular Agents; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Male; Mesenteric Arteries; Microcirculation; Myography; Peptides, Cyclic; Pyrrolidines; Rats; Rats, Wistar; Receptor, Endothelin A; Receptor, Endothelin B; Up-Regulation; Vasoconstriction; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents; Viper Venoms

The JAK/STAT pathway is activated in vitro by angiotensin II (ANG II) and endothelin-1 (ET-1), which are implicated in the development of diabetic complications. We hypothesized that ANG II and ET-1 activate the JAK/STAT pathway in vivo to participate in the development of diabetic vascular complications. Using male Sprague-Dawley rats, we performed a time course study [days 7, 14, and 28 after streptozotocin (STZ) injection] to determine changes in phosphorylation of JAK2, STAT1, and STAT3 in thoracic aorta using standard Western blot techniques. On day 7 there was no change in phosphorylation of JAK2, STAT1, and STAT3. Phosphorylation of JAK2, STAT1, and STAT3 was significantly increased on days 14 and 28 and was inhibited by treatment with candesartan (AT(1) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), atrasentan (ET(A) receptor antagonist, 10 mg x kg(-1) x day(-1) orally in drinking water), and AG-490 (JAK2 inhibitor, 5 mg x kg(-1) x day(-1) intraperitoneally). On day 28, treatment with all inhibitors prevented the significant increase in systolic blood pressure (SBP; tail cuff) of STZ-induced diabetic rats (SBP: 157 +/- 9.0, 130 +/- 3.3, 128 +/- 6.8, and 131 +/- 10.4 mmHg in STZ, STZ-candesartan, STZ-atrasentan, and STZ-AG-490 rats, respectively). In isolated tissue bath studies, diabetic rats displayed impaired endothelium-dependent relaxation in aorta (maximal relaxation: 95.3 +/- 3.0, 92.6 +/- 7.4, 76.9 +/- 12.1, and 38.3 +/- 13.1% in sham, sham + AG-490, STZ + AG-490, and STZ rats, respectively). Treatment of rats with AG-490 restored endothelium-dependent relaxation in aorta from diabetic rats at 14 and 28 days of treatment. These results demonstrate that JAK2 activation in vivo participates in the development of vascular complications associated with STZ-induced diabetes.

Topics: Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Aorta, Thoracic; Atrasentan; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blood Pressure; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Endothelin A Receptor Antagonists; Endothelin-1; Enzyme Activation; Intracellular Signaling Peptides and Proteins; Janus Kinase 2; Male; Phosphorylation; Protein Kinase Inhibitors; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Protein Tyrosine Phosphatases; Pyrrolidines; Rats; Receptor, Angiotensin, Type 1; Receptor, Endothelin A; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Tetrazoles; Time Factors; Tyrphostins; Vasodilation

To investigate the relationship between syndrome differentiation of traditional Chinese medicine (TCM) and characteristic changes of vascular endothelial function in patients with diabetic arterial occlusion (DAO) of lower extremities.. Forty patients with DAO were selected as trial group. Twenty patients among them were attributed to blood stasis syndrome (group A1), and the others were attributed to syndrome of pathogenic dampness-heat attacking the lower limb (group A2) according to syndrome differentiation type of TCM. Patients with diabetes (group B), arteriosclerosis obliterans (group C) and healthy people (group D) were observed as the control groups, respectively. There were 20 cases in each group. Endothelium-dependent dilation (EDD) and endothelium-independent dilation (EID) were measured by high resolution ultrasound in the 100 subjects and the changes of vascular tension factors were also studied.. The results showed that EDD in group A was reduced significantly as compared with that in the groups B, C and D. The levels of vascular contractile factors such as endothelin-1 (ET-1) and thromboxane B2 (TXB2) in group A were higher than those in the groups B, C and D, while the levels of vascular dilatory factors such as nitric oxide (NO) and 6-keto-prostaglandin F1alpha(6-Keto-PGF1alpha) were declined significantly as compared with those in the groups B and D. Linear correlation analysis showed that EDD was correlated positively with the levels of NO and 6-Keto-PGF1alpha, while the levels of ET-1 and TXB2 had negative correlation with EDD. EDD and EID in group A2 were declined significantly as compared with those in group A1.. Our findings indicate that endothelial dysfunction may play an important role in the pathogenesis of DAO and may be associated with syndrome differentiation of TCM.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Arterial Occlusive Diseases; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Diagnosis, Differential; Endothelin-1; Endothelium, Vascular; Female; Humans; Lower Extremity; Male; Medicine, Chinese Traditional; Middle Aged; Nitric Oxide; Thromboxane B2

This study investigated the role of endothelin-1 for hyperglycemia, vascular, and pancreatic injury in early type I diabetes in non-obese-diabetic (NOD) mice. Endothelium dependent relaxation to acetylcholine and vascular gene expression of endothelin converting enzyme (ECE) isoforms 1 and 2 were studied as indicators of vascular injury. Endothelial NO bioactivity in the aorta was reduced in diabetic NOD mice while vascular expression of ECE-1 and ECE-2 mRNA was increased compared with controls (all p<0.05). Vascular histology was normal in all animals. Unexpectedly, treatment of prediabetic NOD mice for 6 weeks with the orally active ET(A) receptor antagonist BSF461314 prevented onset of diabetes without affecting insulitis severity. ET(A) receptor blockade also restored abnormal endothelial NO bioactivity and reduced ECE-1 and ECE-2 gene expression in NOD mice to levels comparable with healthy controls (p<0.05). Moreover, secretion of endothelin-1 in a time-dependent fashion was observed by pancreatic islet beta-cells cultured in vitro. These data suggest a critical role for ET(A) receptor signaling in the development of autoimmune forms of diabetes and the early vascular injury associated with it.

Topics: Animals; Cells, Cultured; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Hyperglycemia; Islets of Langerhans; Mice

Two endothelium-derived factors, endothelin (ET), a vasoconstrictor, and vascular endothelial growth factor (VEGF), an angiogenic factor are thought to be involved in the pathogenesis of diabetic vascular complications. The aim of this study was to determine the effects of an angiotensin II type I (AT-1) receptor antagonist and an ACE inhibitor on the pathogenesis of VEGF and ET-1-mediated kidney disease in STZ-induced diabetic rats. Two days after STZ administration, diabetic rats were treated for 8 weeks with enalapril maleate, an ACE inhibitor, candesartan cilexetil, an AT-1 receptor antagonist, or saline. Urinary albumin and N-acetyl beta-D glucosaminidase (NAG) excretion as well as the VEGF protein content in the kidney were all found to be elevated in diabetic rats. Administration of enalapril maleate or candesartan cilexetil decreased the level of microalbuminuria and NAG excretion in diabetic rats. Administration of enalapril maleate also suppressed the elevated renal VEGF protein content in these animals while candesartan cilexetil treatment had no effect. Serum ET-1 and VEGF levels were unchanged by these treatments. These data support a role for AT-1 receptor antagonists and ACE inhibitors in the prevention of diabetic nephropathy, and suggest that the former may work by reducing renal VEGF levels.

Topics: Albuminuria; Analysis of Variance; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Antihypertensive Agents; Benzimidazoles; Biphenyl Compounds; Blood Glucose; Blotting, Western; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Diabetic Nephropathies; Disease Progression; Enalapril; Endothelin-1; Kidney; Male; Rats; Rats, Wistar; Streptozocin; Tetrazoles; Vascular Endothelial Growth Factor A

To study the change of vascular tension factors (VTF), including vascular contractile factors as endothelin-1 (ET-1), thromboxane A2 (TXA2) and vascular dilatory factors as nitric oxide (NO), prostacyclin (PGI2), in different stage of peripheral diabetic arterial occlusion (PDAO), and to preliminarily explore the clinical significance of these changes.. VTF in 40 diabetic patients, 15 of 2nd stage and 25 of 3rd stage, were observed by measuring level of ET-1, NO, TXB2 and 6-keto-PGF1alpha in blood plasma with RIA assay.. (1) ET-1 and TXB2 levels in all patients were higher than those in control (P < 0.05 and P < 0.01), those in patients of 3rd stage was higher than those of 2nd stage, showing significant difference (P < 0.05). (2) NO and 6-keto-PGF1alpha levels in all patients was lower than those in control, but showed no significant difference between patients of various stages (P > 0.05).. There are changes of VTF in patients with PDAO, manifesting as increase of vascular contractive factors and decrease of vascular dilative factor. The changes are diffrent in various stages, the vascular contractive and thrombotic factors in patients of 3rd stage are higher than those in patients of 2nd stage, but the injury on vascular dilative factors in the two stages showed insignificant difference.

Topics: 6-Ketoprostaglandin F1 alpha; Aged; Aged, 80 and over; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Epoprostenol; Female; Humans; Lower Extremity; Male; Middle Aged; Nitric Oxide; Thromboxane A2; Thromboxane B2; Vasomotor System

Human endothelial cells cultured under high glucose (HG) conditions were shown before to upregulate several basement membrane proteins, including fibronectin (FN), thus mimicking effects of diabetes. Using human macrovascular (HUVEC) and microvascular (HMEC) endothelial cell lines, we evaluated in the present study some of the key molecular signaling events involved in HG-induced FN overexpression. This expression was shown to be dependent on endogenous endothelin (ET) receptor-mediated signaling. We also examined the roles played by protein kinase C (PKC) and the transcription factors nuclear factor kappaB (NF-kappaB) and activating protein (AP)-1 with respect to such changes. HG, PKC activators, and ETs (ET-1 and ET-3) that increased FN expression also caused activation of NF-kappaB and AP-1. Inhibitors of both NF-kappaB and AP-1 prevented HG- and ET-induced FN production. ET receptor blockade also prevented these HG- and ET-mediated changes. The results of this study indicate that glucose-induced increased FN production in diabetes may be mediated via ET-dependent NF-kappaB and AP-1 activation.

Topics: Active Transport, Cell Nucleus; Basement Membrane; Cell Division; Cell Survival; Cells, Cultured; Diabetic Angiopathies; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Endothelins; Endothelium, Vascular; Enzyme Inhibitors; Fibronectins; Gene Expression Regulation; Glucose; Humans; NF-kappa B; Protein Kinase C; Receptors, Endothelin; RNA, Messenger; Transcription Factor AP-1; Up-Regulation

The imbalance between vasoconstrictors and vasodilators may play an important role in the pathogenesis of erectile dysfunction (ED). A total of 36 patients with ED, organogenic [diabetic (n=12) and nondiabetic (n=12)] and psychogenic (n=12) etiology, and 12 healthy adult men as controls were included. The levels of endothelin-1 (ET-1), growth hormone (GH), angiotensin-converting enzyme activity (ACE), nitric oxide (NO) and cyclic guanosine monophosphate (cGMP) were determined in the flaccid penis cavernosal blood of patients and in cubital blood of patients and controls. In psychogenic ED, systemic ACE activity was elevated compared to controls (P<0.05). In diabetic and nondiabetic ED patients, systemic levels of ET-1 (P<0.0001 for both) and ACE activity (P<0.01 and <0.05) were higher while GH (P<0.0001 and <0.001), NO (P<0.0001 for both) and cGMP (P<0.01 for both) levels were lower compared to controls. In diabetic patients, systemic and cavernosal ET-1 levels (P<0.0001 for both) and cavernosal ACE activity levels (P<0.05) were significantly elevated while systemic and cavernosal NO (P<0.0001 for both) and GH (<0.001 and <0.05) levels were declined compared to psychogenic. In nondiabetic patients, systemic and cavernosal ET-1 levels (P<0.0001 for both) were significantly elevated while systemic and cavernosal NO (P<0.0001 for both) and systemic GH levels (P<0.05) were declined compared to psychogenic. Systemic NO was positively correlated with GH in psychogenic (r=0.616, P<0.05), diabetic (r=0.583, P<0.05) and nondiabetic (r=0.615, P<0.05) patients and correlated positively with cGMP (r=0.605, P<0.05) but negatively with ACE activities (r=-0.585, P<0.05) in diabetic patients. In conclusion, plasma levels of ET-1, ACE activities are elevated and associated with reduction of GH, NO and cGMP levels in the systemic and cavernous blood of ED patients. This disturbance may indicate endothelial dysfunction that may hind at their significance in the pathophysiology of ED.

Topics: Adult; Cyclic GMP; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Erectile Dysfunction; Human Growth Hormone; Humans; Male; Middle Aged; Nitric Oxide; Penis; Peptidyl-Dipeptidase A; Sexual Dysfunctions, Psychological; Vasoconstriction; Vasodilation

Evidence has accrued to suggest that diabetic patients face an increased risk of ischemic events and low output syndrome and might mount an inordinate response to ischemia and reperfusion. Because hyperglycemia is a potent stimulus for endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 in diabetes might represent an important mediator of endothelial dysfunction in patients with that disease. To this aim, we compared the effects of cardioplegic arrest and reperfusion on coronary sinus effluent endothelin-1 levels and atrial arteriolar vascular responses in diabetic and case-matched nondiabetic patients undergoing coronary artery bypass grafting.. In study 1 coronary sinus effluent endothelin-1 levels were assessed at baseline and at 1 and 10 minutes after reperfusion in 13 diabetic and 12 nondiabetic patients matched for age, ejection fraction, Parsonnet score, and crossclamp time. In study 2 vascular responses of atrial arterioles subjected to perioperative ischemia-reperfusion were evaluated with videomicroscopy. Atrial microvessels (from appendages) were obtained before and after removal of the aortic crossclamp, and vascular responses to exogenously administered endothelin-1 (10(-10) mol/L) and substance P (10(-8) mol/L) were studied in the presence or absence of BQ-123, an endothelin A receptor antagonist.. Diabetic patients elaborated more endothelin-1 at 1 and 10 minutes after reperfusion (P =.01). Endothelin-1-mediated vasoconstriction was similar in diabetic and nondiabetic atrial microvessels before cardioplegic arrest and cardiopulmonary bypass. After cardiopulmonary bypass and reperfusion, endothelin-1-mediated vasoconstriction was enhanced in both groups; however, this response was greater in microvessels from diabetic patients (P =.02). BQ-123, the endothelin A antagonist, attenuated the effects of bypass and reperfusion on endothelin-1-mediated vasoconstriction in both groups (P =.01). Substance P-mediated vasodilatation was similar in diabetic and nondiabetic atrial microvessels before bypass. After bypass and reperfusion, substance P-mediated vasodilatation was diminished in both groups; however, this response was more pronounced in the diabetic group (P =.003). BQ-123 coincubation restored substance P-mediated vasodilatation in both groups.. We determined the following: (1) the coronary effluent release of endothelin-1 is higher in diabetic than in nondiabetic patients after cardiopulmonary bypass and reperfusion; (2) diabetic coronary microvessels respond to bypass and reperfusion with greater endothelin-1-mediated vasoconstriction and diminished nitric oxide-mediated vasodilatation; and (3) these effects are attenuated by endothelin antagonism. Endothelin-1 might be an important mediator of ischemia-reperfusion injury in patients with diabetes. Furthermore, use of endothelin receptor antagonists might be a novel strategy for improving the resistance of the diabetic heart to cardioplegic arrest and reperfusion.

Topics: Aged; Coronary Artery Bypass; Coronary Vessels; Diabetic Angiopathies; Endothelin Receptor Antagonists; Endothelin-1; Endothelium, Vascular; Heart Arrest, Induced; Humans; Middle Aged; Peptides, Cyclic; Postoperative Period

We have previously demonstrated an importance of endothelin-1 in diabetic patients undergoing bypass surgery. Recent evidence suggests that cardiomyocytes might also produce endothelin-1, which might directly impair myocyte contractility by increasing intracellular calcium levels. Because hyperglycemia is a potent stimulus of endothelin-1 production, we hypothesized that increased production, action, or both of endothelin-1 might be a mediator of direct cardiomyocyte injury in diabetes. Therefore we studied the effects of endothelin receptor blockers (BQ-123 and bosentan) on hyperglycemia-induced endothelin-1 production and cellular injury after ischemia-reperfusion.. Using a human ventricular heart cell model of simulated ischemia-reperfusion, we studied the effects of normoglycemia (5 mmol/L, 48 hours) and hyperglycemia (25 mmol/L, 48 hours) on cellular injury and endothelin-1 production. Furthermore, the effects of selective endothelin-A and mixed endothelin-A/B receptor antagonism (with BQ-123 and bosentan, respectively) were evaluated.. Cellular injury, as assessed by means of trypan blue uptake, was higher in human ventricular heart cells subjected to hyperglycemia and simulated ischemia-reperfusion injury (P =.01); this effect was prevented with both BQ-123 and bosentan (P =.01). In addition, heart cells from the hyperglycemic group elaborated more endothelin-1 after ischemia-reperfusion (P =.02).. Endothelin-1 production and cellular injury were greater in human ventricular heart cells subjected to hyperglycemic conditions and simulated ischemia-reperfusion. These effects are mediated by endothelin-A receptors because both BQ-123 and bosentan exerted similar degrees of protection. Endothelin receptor blockade is a novel strategy to improve the resistance of the diabetic heart to cardioplegic arrest and reperfusion.

Topics: Antihypertensive Agents; Bosentan; Cells, Cultured; Diabetic Angiopathies; Endothelin Receptor Antagonists; Endothelin-1; Humans; Myocardial Reperfusion Injury; Peptides, Cyclic; Sulfonamides

Type I diabetes mellitus is associated with abnormal vascular function, but few studies have documented its effects on human resistance arteries. This study aimed to determine whether endothelial cell and smooth muscle cell function was impaired in resistance arteries isolated from patients with this condition. Biopsies of subcutaneous gluteal fat were taken from 12 patients with Type I diabetes (age 32.3+/-1.9 years; duration of diabetes 13.9+/-2.5 years) and 12 matched controls (age 31.5+/-2.2 years). Levels of glycosylated haemoglobin were higher (P<0.0001) in patients (9.38+/-0.35%) than in controls (5.48+/-0.11%), but most (11 out of 12) patients showed no evidence of microvascular disease. Small resistance arteries were isolated from the biopsies, and isometric responses to vasoconstrictors and vasodilators were measured in a small-vessel myograph. The magnitude and sensitivity of responses to noradrenaline and potassium were not different in diabetic patients compared with controls. In contrast, the sensitivity (pD(2); negative logarithm of the concentration of the vasoconstrictor required to produce 50% of the maximum effect), but not the magnitude, of contraction in response to endothelin-1 in vessels from patients (8.87+/-0.12) was significantly (P=0.02) greater than in those from controls (8.40+/-0.13). Endothelium-dependent (acetylcholine, bradykinin, A23187) and -independent (3'-morpholinosydnonimine) relaxation responses were unaltered in patients with Type I diabetes. These results suggest a selective alteration in receptor activity in the endothelium, and contrast strikingly with the considerable evidence of impaired endothelium-dependent relaxation in Type I diabetes. The present study indicates, therefore, that endothelial cell function is largely maintained in resistance arteries from patients with well controlled Type I diabetes. The increased response to endothelin-1 supports the possibility that more significant abnormalities would be evident in patients with severe microvascular complications.

Topics: Adult; Biopsy; Case-Control Studies; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Glycated Hemoglobin; Humans; Isometric Contraction; Male; Muscle, Smooth, Vascular; Myography; Vascular Resistance; Vasoconstrictor Agents; Vasodilator Agents

Patients with insulin-dependent diabetes mellitus (IDDM) are well known to be at high risk of vascular disease, and dysfunction of vascular endothelium is considered as an early step in the development of diabetic complications. Because of the involvement of autoimmunity in the pathogenesis of IDDM, our aim was to assess, in 45 IDDM patients without clinically evident vascular complications, whether early signs of endothelial cell dysfunction were correlated to alterations of the immune system. IDDM patients were characterized by significantly increased serum levels of C-reactive protein, of polymorphonuclear cells-derived elastase, of endothelin-1 (ET-1) and of thrombomodulin, while plasma concentrations of fibronectin (FNT) were significantly decreased, with a statistically significant inverse correlation between ET-1 and FNT values. The presence of circulating immune complexes (CIC) was investigated in 36 out of our 45 IDDM patients, and values above the cut-off were found in 17 (47.2%) of them. One-third of all patients showed values above the cut-off for IgG-aCL. In IDDM patients, at variance from the control group, the levels of ET-1 were directly correlated to those of von Willebrand factor, of anticardiolipin beta(2)-GPI and of CIC, with an inverse correlation with plasma FNT. An association between antiphospholipid antibodies and endothelial dysfunction and/or activation is therefore suggested, pointing to a synergism, in the early phases of IDDM vascular disease, between generation of autoantibodies and endothelial activation.

Topics: Adult; Antibodies, Anticardiolipin; Antigen-Antibody Complex; Autoantibodies; C-Reactive Protein; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Fibronectins; Humans; Immunoglobulin G; Immunoglobulin M; Male; Thrombomodulin; von Willebrand Factor

Plasma endothelin-1, the nitric oxide (NO) mediator intraplatelet cyclic guanosine monophosphate (cGMP), the prostacyclin mediator cyclic adenosine monophosphate (cAMP) and the macrophage derived inflammatory mediator plasma neopterin were measured in men with Type 2 diabetes mellitus (n=91), impaired glucose tolerance (IGT; n=51), previously abnormal glucose tolerance (PAGT; n=20), and 34 healthy control men. Plasma endothelin-1was higher in men with Type 2 diabetes mellitus than in controls [4.1 (1.0-14.3) vs. 2.1 (0.2-8. 7) ng/l; P<0.001). Intraplatelet cGMP was higher in men with PAGT [0. 84 (0.57-2.76) pmol/10(9) platelets; P<0.05], IGT [0.85 (0.48-3.53); P<0.001] and Type 2 diabetes mellitus [0.90 (0.47-3.86); P<0.001] than in controls [0.70 (0.42-1.70]. No differences existed between groups concerning intraplatelet cAMP or plasma neopterin. Plasma endothelin-1 correlated with fasting plasma glucose (r=0.33; P<0.001) and HbA1(c) (r=0.29; P<0.001). In conclusion, elevated plasma endothelin-1 in Type 2 diabetes mellitus and its relationship to glucose and HbA1(c) suggest a putative role for endothelin-1 in diabetic endothelial cell damage. Increased cGMP indicating enhanced production/activity of NO suggests that factors other than reduced NO activity contribute to enhanced platelet aggregation in diabetes.

Topics: Aged; Blood Glucose; Blood Platelets; Blood Pressure; Cholesterol; Cyclic GMP; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Glucose Intolerance; Glycated Hemoglobin; Humans; Leukocyte Count; Lipoproteins, HDL; Lipoproteins, LDL; Male; Middle Aged; Reference Values; Smoking; Vascular Diseases

The damage of endothelial integrity is an important step in the atherogenic process. To evaluate the role of circulating endothelin-1 (ET-1) in Type 1 diabetes mellitus (T1DM), plasma ET-1 levels were evaluated in T1DM patients either with (n=9) or without hyperlipidaemia (n=11), or with (n=9) and without (n=11) late diabetic complications, in non-diabetic hyperlipidaemic patients (n=17) and in healthy volunteers. Groups were matched for age, sex and body mass index.. Serum total cholesterol and apolipoprotein B were significantly higher in the diabetic group (p<0.05). Plasma ET-1 level was similar in controls and in non-diabetic hyperlipidaemic subjects (5.77+/-1.74 ng/l vs 4.97+/-1.58 ng/l); however, diabetic hyperlipidaemic patients had a significantly higher plasma ET-1 concentration compared to control subjects (6.67+/-2.44 ng/l vs 4.97+/-1.58 ng/l, p<0.05). Diabetic patients with vascular complications had a significantly higher plasma ET-1 concentration than found in diabetic patients without complications (6.99+/-2.17 ng/l vs 4.74+/-1.27 ng/l, p<0.01) and in controls (6.99+/-2.17 ng/l vs 4.97+/ 1.58 ng/l, p<0.01). Patients with diabetic complications also had a significantly higher apolipoprotein B level compared to healthy controls (0.94+/-0.37 g/l vs 0.66+/-0.12 g/l, p<0.005).. The susceptibility of T1DM patients to the development of atherosclerosis might be attributed to the relationship between elevated lipid levels and ET-1.

Topics: Adolescent; Adult; Apolipoprotein A-I; Apolipoproteins B; Blood Glucose; Body Mass Index; Cholesterol; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Glycated Hemoglobin; Humans; Hyperlipidemias; Lipids; Male; Middle Aged; Triglycerides

Abnormalities in vascular reactivity in the micro- and macrocirculation are well established in type 2 diabetes. However, little is known about changes in vascular reactivity in those at risk for developing type 2 diabetes. To address this situation, the vascular reactivity in both the micro- and macrocirculation was studied in four age and sex comparable groups: 30 healthy normoglycemic subjects with no history of type 2 diabetes in a first-degree relative (controls), 39 healthy normoglycemic subjects with a history of type 2 diabetes in one or both parents (relatives), 32 subjects with impaired glucose tolerance (IGT), and 42 patients with type 2 diabetes without vascular complications (diabetes). Laser Doppler perfusion imaging was used to measure vasodilation in the forearm skin in response to iontophoresis of 1% acetylcholine chloride (Ach) (endothelium-dependent) and 1% sodium nitroprusside (SNP) (endothelium-independent), whereas high-resolution ultrasound images were used to measure brachial artery diameter changes during reactive hyperemia. Plasma concentrations of endothelin-1 (ET-1), von Willebrand factor (vWF), soluble intercellular adhesion molecule (sICAM), and soluble vascular cell adhesion molecule (sVCAM) were also measured as indicators of endothelial cell activation. The vasodilatory responses to Ach, expressed as percent increase of blood flow over baseline, were reduced in relatives (98 +/- 48, mean +/- SD), IGT (94 +/- 52), and diabetes (74 +/- 45) compared with controls (126 +/- 67) (P < 0.001 controls versus relatives, IGT, and diabetes). The responses to SNP were similarly reduced: controls (123 +/- 46), relatives (85 +/- 46), IGT (83 +/- 48), and diabetes (65 +/- 31) (P < 0.001 controls versus relatives, IGT, and diabetes) as were the responses in the brachial artery diameter during reactive hyperemia: controls (13.7 +/- 6.1), relatives (10.5 +/- 6.7), IGT (9.8 +/- 4.5), and diabetes (8.4 +/- 5.0) (P < 0.01 controls versus relatives, IGT, and diabetes). Women had greater responses than men in both the micro- and macrovascular circulatory tests, but a similar progressive reduction was observed in both sexes with increasing degrees of glucose intolerance. A significant inverse correlation was found between microvascular reactivity and systolic blood pressure, fasting plasma glucose, HDL cholesterol, fasting plasma insulin, and homeostasis model assessment (HOMA) values, an index of insulin resistance. BMI and diastolic blood pressu

Topics: Acetylcholine; Adult; Aged; Biomarkers; Case-Control Studies; Cell Adhesion Molecules; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Endothelium, Vascular; Female; Humans; Iontophoresis; Male; Microcirculation; Middle Aged; Nitroprusside; Risk Factors; Skin; Solubility; Vascular Cell Adhesion Molecule-1; von Willebrand Factor

Endothelin-1 (ET-1), a vasoconstrictor and mitogenic endothelium-derived peptide, has been considered as a marker for endothelial damage and potential contributor to the development of the atherogenic process.. To evaluate the pattern of plasma ET-1 secretion in non-insulin-dependent diabetes mellitus (NIDDM) and nondiabetic patients with chronic arterial obstructive disease (CAOD) of the lower limbs, plasma levels of ET-1 were determined in 12 NIDDM patients (10 men and 2 women; mean age 63+/-8 years) with CAOD of the lower limbs at Fontaine stage II and in 12 nondiabetic patients (11 men and 1 woman; mean age 62+/-4 years) with comparable arteriopathy. Ten normal subjects comprised the control population.. The plasma levels of ET-1 in NIDDM patients with CAOD of the lower limbs were 5.7+/-0.3 pmol/L, which represented a significant (p<0.001) difference from the values in nondiabetic patients with comparable arteriopathy (4.1+/-0.6 pmol/L) and those in the control group (2.7+/-0.7 pmol/L). Plasma levels of ET-1 showed a significant (p<0.0001) positive correlation with the levels of fasting insulin in NIDDM patients with CAOD of the lower limbs. Increased plasma ET-1 could reflect a major and/or more diffuse endothelial cell damage or dysfunction in NIDDM than in nondiabetic patients with comparable CAOD of the lower limbs. Augmented mitogenic ET-1 levels could also have a role both in diabetic and nondiabetic angiopathy.. The positive correlation between ET-1 plasma levels and fasting insulin levels in NIDDM patients with CAOD of the lower limbs suggests that the increased ET-1 release could be related to the augmented insulin secretion in these patients. Insulin-related overproduction of ET-1 could promote the atherogenic process and enhance the vascular tone to a greater extent in NIDDM than in nondiabetic patients with CAOD of the lower limbs.

Topics: Arterial Occlusive Diseases; Case-Control Studies; Diabetes Mellitus, Type 2; Diabetic Angiopathies; Endothelin-1; Female; Humans; Insulin; Male; Middle Aged

The existence of a hyperactive hypothalamic pituitary adrenal (HPA) axis in diabetics and its relevance to diabetic complications has been controversial. In this study we determined the 24 hour urinary excretion of free cortisol (UFC), its nyctohemeral variation and its relation to indices of diabetic angiopathy. In 130 subjects with IDDM, aged 15.2+/-4.8 years and diabetes duration 7.3+/-5 years, and in 48 controls of comparable age, UFC, urinary endothelin (UET1), urinary albumin, HbA1c, and plasma renin were determined. The total 24-hour UFC excretion was greater in diabetics than in controls (p=0.002) and also greater in diabetic males than in females (p=0.006), while no sex difference was detected in the controls. Day UFC excretion was greater than night UFC excretion (p<0.001) in all subjects. UFC correlated to carotid intimal plus medial thickness (r=0.48, p=0.002), urinary albumin (r=0.50, p<0.001), UET1 (r=0.56, p<0.001), diastolic, systolic and mean blood pressure (r=0.27, p=0.003; r=0.41, p<0.001; r=0.34, p<0.001), BMI (r=0.50, p<0.001), serum creatinine (r=0.35, p<0.001), total cholesterol (r= -0.19, p=0.036), HDL (r= -0.22, p=0.038), LDL (r= -0.23, p=0.032), age (r=0.61, p<0.001) and diabetes duration (r=0.37, p<0.001). These results suggest that hyperactivity of the HPA axis or of the adrenals, due to chronic stress, hypoglycemic episodes or other factors, possibly contributes to the establishment or progression of diabetic micro- or macroangiopathy.

Topics: Adolescent; Adult; Carotid Arteries; Child; Child, Preschool; Circadian Rhythm; Diabetes Mellitus, Type 1; Diabetic Angiopathies; Endothelin-1; Female; Humans; Hydrocortisone; Male; Reference Values; Sex Characteristics; Tunica Intima; Tunica Media; Ultrasonography

To examine endothelin-1 (ET-1) concentrations longitudinally throughout pregnancy in healthy and insulin-dependent diabetic women and to evaluate the relationship between ET-1 and big ET-1 in normal pregnancy.. Venous blood samples were obtained consecutively in gestational weeks 18, 28, and 38 from 40 healthy women with uneventful pregnancies and 24 pregnant women with IDDM. By radioimmunoassay, plasma ET-1 and big ET-1 were analyzed in the healthy women and plasma ET-1 in the diabetic women.. In the diabetic pregnant women, plasma ET-1 levels were significantly higher than in healthy pregnant women during the entire observation period (P < 0.001), but did not change with advancing gestational age. Five of the diabetic, but none of the healthy pregnant women, developed preeclampsia. ET-1 levels did not differ between the diabetic women who developed preeclampsia and those who did not. Plasma ET-1 levels in healthy pregnant women were within the range of those in healthy nonpregnant women and did not change during pregnancy. The big ET-1 levels increased and the ET-1/big ET-1 ratio decreased significantly during the observation period.. Plasma ET-1 levels do not change with advancing gestational length. During normal pregnancy, the ET-1/big ET-1 ratio decrease, indicating a suppressed converting enzyme activity or altered clearance of ET-1. Pregnant women with IDDM have markedly elevated ET-1 levels. Although diabetic women with and without preeclampsia did not differ with respect to endothelial dysfunction, as reflected by elevated ET-1 concentration, we cannot exclude that altered endothelial function may be of importance for the increased frequency of preeclampsia in pregnant IDDM patients.

Topics: Adult; Analysis of Variance; Diabetic Angiopathies; Endothelin-1; Endothelins; Female; Gestational Age; Humans; Pre-Eclampsia; Pregnancy; Pregnancy in Diabetics; Pregnancy Trimester, Second; Pregnancy Trimester, Third; Protein Precursors; Radioimmunoassay; Reference Values