Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042373 (vascular disease)
 17,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increased activity of the sodium transporter, sodium-lithium countertransport (SLC), is reported in hypertensive white patients with evidence of cardiac and renal injury. The purpose of this study was to determine whether increased SLC activity detects risk for nephropathy or vascular disease in nondiabetic, young adult African-Americans. We examined 85 African-Americans aged 25 to 33 years with measurement of blood pressure, an oral glucose tolerance test to measure insulin response to glucose challenge, and an insulin clamp for insulin sensitivity (M). Fasting plasma lipids were measured, and the Vmax and Km for Na+ were assayed on red blood cells. Urinary albumin excretion (UAE) was measured on timed collections. There was a statistically significant correlation of the Vmax for SLC with M (r = -0.26, P = 0.02) and with UAE (r = 0.25, P = 0.02). The Km for Na+ to activate SLC was also elevated in the subgroup of subjects with elevated Vmax of SLC. There was no significant correlation of SLC with blood pressure in bivariate analysis. Step-wise multiple linear regression analysis of all variables on the Vmax SLC demonstrated that plasma triglyceride, UAE, body mass index, systolic blood pressure, M, and fasting insulin were step-wise selected into the linear regression model (F-ratio = 3.2, df = 77, R = 0.46, P < 0.009). In this young adult African-American population, elevated SLC activity is detected in association with metabolic and lipid alterations typical of insulin resistance. Elevated SLC activity is also associated with higher rates of UAE, suggesting possible evidence of early renal injury.
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PMID:Sodium-lithium countertransport is associated with insulin resistance and urinary albumin excretion in young African-Americans. 900 29

Growth of vascular smooth muscle cells (VSMC) plays an important role in the pathogenesis of atherosclerosis and hypertension. Lysophosphatidic acid (LPA), a natural phospholipid is thought to be an important VSMC mitogen and has recently been suggested to play an important role in the development of vascular disease. In the present study, we describe the effects of LPA on intracellular signalling pathways in VSMC. LPA (5 micrograms/ml) induced an increase of cytosolic free calcium concentration ([Ca2+]i) in the presence and absence of extracellular Ca2+ and markedly stimulated the Na+/H+ exchanger. LPA dose-dependently caused a stimulation of the 42-kDa mitogen-activated protein kinase (MAP kinase) isoform with a maximum at 5 min. Also, LPA induced a 5-fold increase in [3H]thymidine incorporation into cell DNA above the basal value, as well as a 42% increase in cell number. Pretreatment of VSMC with pertussis toxin (PTX) (100 ng/ml) for 24 h markedly blunted the LPA-dependent intracellular signalling transduction including the increase in [Ca2+]i, activation of the Na+/H+ exchanger, activation of MAP kinase and the increase in cell DNA synthesis. These findings demonstrate that the effects of LPA on intracellular signalling transduction pathway as well as on VSMC growth are mediated by PTX-sensitive guanosine triphosphate (GTP) binding protein (Gi protein).
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PMID:Lysophosphatidic acid and intracellular signalling in vascular smooth muscle cells. 912 56

Apart from the initially described vasoconstriction, endothelins have been shown to cause a variety of biological activities in non-vascular tissues. A rapidly growing body of data supports the concept of endothelin as a paracrine acting hormone. In this review, we will discuss the impact of this local endothelin system for various cardiovascular pathophysiological states, especially atherosclerotic vascular disease, restenosis, myocardial infarction, congestive heart failure, and arterial hypertension. In addition, the endothelin system is a modulator of renal function via its binding to abundant receptors in renal tissue and by the ability of renal endothelial and epithelial cells to synthesize and release endothelin. In the kidney, endothelin may function as a paracrine/autocrine factor in the regulation of renal blood flow, glomerular haemodynamics, and sodium and water homeostasis. The renal endothelin system is involved in kidney diseases such as impaired renal function in liver cirrhosis, cyclosporin toxicity, acute renal failure and renal glomerular and interstitial fibrosis. Therapeutic approaches with new orally active endothelin receptor antagonists are also discussed.
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PMID:The paracrine endothelin system: pathophysiology and implications in clinical medicine. 929 57

We investigated 24-hour ambulatory blood pressure and arterial distensibility, a marker of biophysical vessel wall properties, in 32 normoalbuminuric type I diabetic patients and 32 healthy control subjects on diets containing 50 mmol and 200 mmol sodium per day. The increase in daytime diastolic blood pressure from 50 to 200 mmol sodium was significantly higher in the diabetic patients than in the control subjects (2.3+/-4.9 versus 0.2+/-3.7 mm Hg, P<.05). On a high sodium regimen, femoral artery distensibility was decreased in the diabetic patients compared with the control subjects (19.2+/-7.6 versus 24.1+/-9.3 10[-3]/kPa, P<.05). Angiotensin-converting enzyme inhibition in the diabetic patients on a high sodium diet decreased daytime diastolic blood pressure and increased femoral artery distensibility. The blood pressure decrease in response to angiotensin-converting enzyme inhibition correlated significantly with the blood pressure increase to sodium (for 24-hour systolic and diastolic blood pressure, r=.72, P<.001 and r=.76, P<.001). In addition, we found that in the diabetic patients on a high sodium diet, the renal blood flow response to exogenous angiotensin II was not bimodally distributed, as is the case in essential hypertension, in which a subgroup of the patients are characterized by sodium sensitivity of the blood pressure and an abnormal renal blood flow response to exogenous angiotensin II ("nonmodulator phenotype"). These results show that blood pressure in insulindependent diabetes mellitus is sodium sensitive, but that this is not related to the nonmodulator phenotype, and suggest that in IDDM a relatively high sodium intake may be a factor that predisposes to the development of diabetic vascular disease.
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PMID:Sodium, blood pressure, and arterial distensibility in insulin-dependent diabetes mellitus. 936 71

We previously reported that administration of NO donors ameliorates the severity of myocardial injury in cholesterol-fed rabbits. We now evaluated the effects of probucol, a lipid-lowering antioxidant that can preserve endothelium-dependent relaxation (EDR), in the aortas of cholesterol-fed rabbits. We examined the effects of short-term (7 days) or long-term (24 weeks) administration of 1% probucol on the size of infarcts resulting from 30 minutes of coronary occlusion followed by reperfusion (for 48 hours) in Watanabe heritable hyperlipidemic (WHHL) rabbits. Infarcts in untreated WHHL rabbits were significantly larger than those in the rabbits receiving the long-term but not the short-term treatment with probucol (72.2 +/- 5.4%, 37.6 +/- 6.4%, and 66.7 +/- 3.5%, respectively). Long-term probucol treatment also significantly reduced myeloperoxidase activity in both ischemic and nonischemic myocardium and suppressed P-selectin expression in the coronary vasculature. No significant differences were observed in hemodynamic parameters during myocardial ischemia/reperfusion. Long-term probucol treatment significantly reduced the surface area of atherosclerotic plaque lesions in the aorta (24.4 +/- 3.8% vs 46.3 +/- 6.3, P < .05). Moreover, long-term probucol treatment restored acetylcholine-induced EDR in aortic rings but did not affect sodium nitroprusside-induced relaxation. Finally, long-term probucol treatment resulted in significantly elevated cGMP levels in the aorta. These results indicate that long-term probucol treatment significantly ameliorates myocardial injury in heritable atherosclerotic rabbits, perhaps by reducing the accumulation of leukocytes in the myocardium and atherosclerotic vascular lesions. Thus, long-term administration appears to suppress the progression of atherosclerotic vascular disease in this animal model.
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PMID:Long-term probucol treatment reverses the severity of myocardial injury in watanabe heritable hyperlipidemic rabbits. 940 58

Sodium-lithium countertransport activity has been proposed as a marker for hypertension and is lower in black compared to Caucasian subjects both with and without vascular disease. The question arises of what is the primary kinetic locus of the altered behaviour of the countertransporter in black subjects and whether this is also seen in normotensive subjects from other non-Caucasian ethnic groups. We studied the sodium-lithium countertransporter in four ethnic groups (black [n = 45], Caucasian [n = 45], Chinese [n = 40], and South Asian [n = 39]) of age-matched normotensive males (age range 18-35 y) with no first-degree family history of hypertension or diabetes. The clinical and laboratory characteristics of the subjects were similar in all four ethnic groups. Minor differences noted were: significantly higher mean height, weight and serum creatinine concentration (P < 0.001) and significantly lower plasma triglyceride concentration (P = 0.02) in the black compared to the other study groups. Sodium-lithium countertransport activity (mmol Li/l RBC h) was significantly lower in the black subjects (0.113 [0.013-0.265]) compared with the other groups (Caucasian, 0.247 [0.037-0.614]; Chinese, 0.210 [0.100-0.707]; South Asian, 0.211 [0.037-0.617]; P < 0.001). No differences were noted between the four study groups in respect of kNa. Mean (s.d.) Vmax values (mmol Li/l RBC h) were also reduced in the black subjects (0.152 [0.088]) compared to the other ethnic groups (Caucasian, 0.376 [0.159]; Chinese, 0.364 [0.182]; South Asian, 0.329 [0.155]; P < 0.001) and there was a strong relationship between countertransport activity and Vmax (r > 0.52; P < 0.001; for each of the study groups). The differences in mean Vmax noted between the Caucasian, South Asian and Chinese subjects were not significant. These results show that, when compared with three other selected ethnic groups, black subjects demonstrate an altered behaviour with respect to Vmax of the sodium-lithium countertransporter, which occurs in the absence of demonstrable vascular pathology.
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PMID:Kinetic characteristics of the erythrocyte sodium-lithium countertransporter in black normotensive subjects compared with three other ethnic groups. 1146 63

Dynamic changes in the reduction-oxidation (redox) state of the tissue lead to the pathophysiological condition. Reduced homocysteine causes dysfunctions in endothelium. The proliferation of smooth muscle cells may lead to occlusive vascular disease, ischemia, and heart failure, but whether fibrosis and hypertension are a consequence of smooth muscle proliferation is unclear. Redox changes during hyper-homocyst(e)inemia may be one of the causes of premature atherosclerotic heart disease. To examine the effect of homocystine on human vascular smooth muscle cells (HVSMC), we isolated HVSMC from idiopathic dilated cardiomyopathic hearts. Coronaries in these hearts were apparently normal. HVSMC numbers in culture were measured by hemocytometer in the presence and absence of homocystine. Results show that homocystine induced cellular proliferation. This proliferation was reversed by the addition of the antioxidant N-acetylcysteine (NAC). Homocystine induces collagen expression in a dose- and time-dependent manner, as measured by Northern blot (mRNA) analysis. The 50% inhibitory concentration of 5 microM for collagen was estimated. The induction of collagen was reversed by the addition of NAC and reduced glutathione. To localize the receptor for homocystine on HVSMC, we synthesized fluorescamine-labeled homocystine conjugate. Incubation of labeled homocystine with HVSMC demonstrated membrane and cytosol localization of homocystine binding. The receptor-ligand binding was disrupted by NAC. Based on sodium dodecyl sulfate-polyacrylamide gel electrophoresis fluorography, we observed a 40- to 25-kDa homocystine redox receptor in HVSMC. Our results suggested that the redox homocysteine induces HVSMC proliferation by binding to the redox receptor and may exacerbate atherosclerotic lesion formation by inducing collagen expression.
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PMID:Homocysteine redox receptor and regulation of extracellular matrix components in vascular cells. 948 29

Chronic arsenic exposure is associated with alterations in peripheral circulation and vascular disease. Toxicity to the vasculature is documented, but the effect of arsenic on the erythrocyte has not been evaluated. To determine if arsenic was toxic to human erythrocytes and whether this could contribute to vascular disease, human erythrocytes were incubated in vitro with sodium arsenate, As(V), or sodium arsenite, As(III), and assessed for damage. After 5 h of incubation with 10 mM As(V) or As(III), significant cell death (hemolysis) only occurred in the As(V) treated cells. Morphologic changes were assessed by scanning electron microscopy and light microscopy. As(V) induced a classic discocyte-echinocyte transformation extending to the formation of sphero-echinocytes; these changes were concentration dependent. As(III) treatment also resulted in echinocyte formation but less extensive than in As(V) treated cells, and no sphero-echinocytes were formed. The observed damage was consistent with reported changes induced by ATP depletion, and measurement of ATP in these samples confirmed this as a mechanism of damage. As(V) treatment at concentrations as low as 0.01 mM for 5 h significantly depleted ATP, and As(III) was relatively ineffective in causing ATP depletion. Based on these three parameters, the erythrocyte was estimated to be as much as 1000 times more susceptible to As(V) than As(III). ATP is required for the cell to maintain membrane integrity and deform efficiently in circulation. The changes described here could contribute to vascular occlusion, ischemia, and tissue death associated with arsenic circulatory disorders.
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PMID:Arsenate toxicity in human erythrocytes: characterization of morphologic changes and determination of the mechanism of damage. 951 38

We studied endothelial-mediated microvascular blood flow in neuropathic diabetic patients to determine the association between endothelial regulation of the microcirculation and the expression of endothelial constitutive nitric oxide synthetase (ecNOS) in the skin. Vasodilation on the dorsal foot in response to heating and iontophoresis of acetylcholine (endothelium-dependent) and sodium nitroprusside (endothelium-independent) were measured using single-point laser Doppler and laser Doppler imaging in diabetic patients with neuropathy (DN), with neuropathy and vascular disease (DI), with Charcot arthropathy (DA), and without complications (D), and in healthy control subjects (C). The response to heat was reduced in the DN (321 [21-629] percentage of increase over the baseline, median [interquartile range]) and DI (225 [122-470]) groups but was preserved in the DA (895 [359-1,229]), D (699 [466-1,029]), and C (810 [440-1,064], P < 0.0001) groups. The endothelial-mediated response to acetylcholine was reduced in the DN (17 [11-25]), DA (22 [2-34]), and DI (13 [2-30]) groups compared with the D (47 [24-58]) and C (44 [31-70], P < 0.001) groups. The non-endothelial-mediated response to sodium nitroprusside was also reduced in the DI (4 [0-18]), DN (17 [9-26]), and DA (21 [11-31]) groups compared with the D (37 [19-41]) and C (44 [26-67], P < 0.0001) groups. There was a significant reduction in vasodilation in the DI group compared with all other groups (P < 0.0001). Full thickness skin biopsies from the dorsum of the foot of 15 DN, 10 DI, and 11 C study subjects were immunostained with antiserum to human ecNOS, the functional endothelial marker GLUT1, and the anatomical endothelial marker von Willebrand factor. The staining intensity of ecNOS was reduced in both diabetic groups. No differences were found among the three groups in the staining intensity of von Willebrand factor and GLUT1. We conclude that the endothelium-dependent and endothelium-independent vasodilations are impaired in diabetic patients predisposed to foot ulceration and that neuropathy is the main factor associated with this abnormality. Reduced expression of ecNOS may be a major contributing factor for endothelial dysfunction. These data provide support for a close association of neuropathy and microcirculation in the pathogenesis of foot ulceration.
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PMID:Endothelial dysfunction and the expression of endothelial nitric oxide synthetase in diabetic neuropathy, vascular disease, and foot ulceration. 951 54

Abnormal biosynthesis of thromboxane and prostacyclin has been implicated in patients with primary pulmonary hypertension and secondary pulmonary hypertension associated with congenital heart disease, and could be involved in the pathogenesis of pulmonary vascular disease. The chronic effects of an oral prostacyclin analogue, beraprost sodium, on thromboxane and prostacyclin biosynthesis and on pulmonary circulation were investigated in 15 children with pulmonary hypertension. The plasma concentrations of thromboxane B2 and 6-keto-prostaglandin F1 alpha were measured, as was the urinary excretion of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, which are stable metabolites of thromboxane A2 and prostacyclin, respectively. In patients with pulmonary hypertension, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were greater than in healthy controls: 210 +/- 49 versus 28 +/- 4 pg/mL (P < 0.05) and 32.6 +/- 8.9 versus 5.7 +/- 1.8 (P < 0.01), respectively. After 3 months of administration of beraprost, the plasma concentration of thromboxane B2 and the ratio of thromboxane B2 to 6-keto-prostaglandin F1 alpha were reduced significantly: 210 +/- 49 to 98 +/- 26 pg/mL (P < 0.01) and 32.6 +/- 8.9 to 18.0 +/- 6.7 (P < 0.05), respectively. In contrast, the plasma concentrations of 6-keto-prostaglandin F1 alpha in patients were slightly but not significantly higher than in controls, and did not change significantly after administration of beraprost. The concentrations of 11-dehydro-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in urine correlated significantly with thromboxane B2 and 6-keto-prostaglandin F1 alpha, respectively, in plasma. Beraprost improved the imbalance of thromboxane and prostacyclin biosynthesis and has a potential efficacy for preventing the progressive development of pathological changes in pulmonary vasculature.
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PMID:Chronic effects of oral prostacyclin analogue on thromboxane A2 and prostacyclin metabolites in pulmonary hypertension. 958 94


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