Biomarkers for Diabetic Retinopathy - Could Endothelin 2 Be Part of the Answer?

PURPOSE: The endothelins are a family of three highly conserved and homologous vasoactive peptides that are expressed across all organ systems. Endothelin (Edn) dysregulation has been implicated in a number of pathophysiologies, including diabetes and diabetes-related complications. Here we examined Edn2 and endothelin receptor B (Endrb) expression in retinae of diabetic mouse models and measured serum Edn2 to assess its biomarker potential. MATERIALS AND METHODS: Edn2 and Ednrb mRNA and Edn2 protein expression were assessed in young (8wk) and mature (24wk) C57Bl/6 (wild type; wt), Kimba (model of retinal neovascularisation, RNV), Akita (Type 1 diabetes; T1D) and Akimba mice (T1D plus RNV) by qRT-PCR and immunohistochemistry. Edn2 protein concentration in serum was measured using ELISA. RESULTS: Fold-changes in Edn2 and Ednrb mRNA were seen only in young Kimba (Edn2: 5.3; Ednrb: 6.0) and young Akimba (Edn2: 7.9, Ednrb: 8.8) and in mature Kimba (Edn2:9.2, Ednrb:11.2) and mature Akimba (Edn2:14.0, Ednrb:17.5) mice. Co-localisation of Edn2 with Müller-cell-specific glutamine synthetase demonstrated Müller cells and photoreceptors as the major cell types for Edn2 expression in all animal models. Edn2 serum concentrations in young Kimba, Akita and Akimba mice were not elevated compared to wt. However, in mature mice, Edn2 serum concentration was increased in Akimba (6.9pg/mg total serum protein) compared to wt, Kimba and Akita mice (3.9, 4.6, and 3.8pg/mg total serum protein, respectively; p<0.05). CONCLUSIONS: These results demonstrated that long-term hyperglycaemia in conjunction with VEGF-driven RNV increased Edn2 serum concentration suggesting Edn2 might be a candidate biomarker for vascular changes in diabetic retinopathy.

Increased plasma levels of big-endothelin-2 and big-endothelin-3 in patients with end-stage renal disease.

AIMS: Big endothelins (pro-endothelin; inactive-precursor) are converted to biologically active endothelins (ETs). Mammals and humans produce three ET family members: ET-1, ET-2 and ET-3, from three different genes. Although ET-1 is produced by vascular endothelial cells, these cells do not produce ET-3, which is produced by neuronal cells and organs such as the thyroid, salivary gland and the kidney. In patients with end-stage renal disease, abnormal vascular endothelial cell function and elevated plasma ET-1 and big ET-1 levels have been reported. It is unknown whether big ET-2 and big ET-3 plasma levels are altered in these patients. The purpose of the present study was to determine whether endogenous ET-1, ET-2, and ET-3 systems including big ETs are altered in patients with end-stage renal disease. MAIN METHODS: We measured plasma levels of ET-1, ET-3 and big ET-1, big ET-2, and big ET-3 in patients on chronic hemodialysis (n=23) and age-matched healthy subjects (n=17). KEY FINDINGS: In patients on hemodialysis, plasma levels (measured just before hemodialysis) of both ET-1 and ET-3 and big ET-1, big ET-2, and big ET-3 were markedly elevated, and the increase was higher for big ETs (Big ET-1, 4-fold; big ET-2, 6-fold; big ET-3: 5-fold) than for ETs (ET-1, 1.7-fold; ET-3, 2-fold). SIGNIFICANCE: In hemodialysis patients, plasma levels of the inactive precursors big ET-1, big ET-2, and big ET-3 levels are markedly increased, yet there is only a moderate increase in plasma levels of the active products, ET-1 and ET-3. This suggests that the activity of endothelin converting enzyme contributing to circulating levels of ET-1 and ET-3 may be decreased in patients on chronic hemodialysis.

Portopulmonary hypertension and serum endothelin levels in hospitalized patients with cirrhosis.

BACKGROUND: Cirrhosis is associated with several extrahepatic manifestations including portopulmonary hypertension (PPHT). Recent data suggest that endothelins (ETs) are related to the pathophysiology of PPHT. The study aimed to measure serum ET levels in hospitalized cirrhotic patients and to determine their association with PPHT and patient outcome. METHODS: Fifty-seven cirrhotic patients [43 males; median age 58 (28-87) years] underwent Doppler echocardiography. Patients with systolic pulmonary arterial pressure ≥40 mmHg and pulmonary acceleration time <100 ms were deemed to have PPHT. ET-1, 2, and 3 serum levels were measured with an ELISA assay. All-cause mortality was recorded over a median period of 24 months. RESULTS: Nine out of 57 patients (15.8%) had PPHT. Among various clinical variables, only autoimmune hepatitis was associated with PPHT (OR=11.5; 95% CI, 1.58-83.4; P=0.01). ET-1 levels [9.1 (1.6-20.7) vs 2.5 (1.4-9.2) pg/mL, P=0.02] and the ET-1/ET-3 ratio [4.73 (0.9-22.4) vs 1.6 (0.3-10.7), P=0.02] were significantly higher in patients with PPHT than in those without. ET-2 and ET-3 levels did not differ between the two groups. There was no difference in survival between the two groups, although ET-1 levels were associated with an adverse outcome in Cox regression analysis (HR=1.11; 95% CI, 1.02-1.22; P=0.02 per unit increase in ET-1). CONCLUSION: Our data suggest that ET-1 and the ET-1/ET-3 ratio are elevated in patients with PPHT and that ET-1 is associated with a poor outcome irrespective of PPHT.

Endothelin-1 is not predictive of ventricular ectopy or ventricular fibrillation during acute myocardial ischemia.

Endothelin(ET)-1 (ET-1) increases after myocardial infarction and may have effects on myocardial function. ET-1 has also been shown to affect the action potential (AP) which may be arrhythmogenic and predispose to ventricular fibrillation (VF). The effects of ET-2 and ET-3 are uncertain. We hypothesized that the ETs increase during acute ischemia and that plasma levels are predictive of ischemically induced VF. Thirty-four domestic swine underwent balloon occlusion of the proximal LAD coronary artery. Occlusion was confirmed angiographically. Venous samples were collected from the right atrium at baseline and at 5 min intervals for 30 min or until VF induction. ET-1, ET-2, and ET-3 were measured using ELISA. Changes in plasma concentrations were assessed using repeated measures ANOVA with Dunnett's. A p < 0.05 was considered statistically significant. All animals had angiographic evidence of successful proximal LAD occlusion. ET-1 levels were significantly increased from a baseline at 20 min and remained elevated during 30 min of occlusion. ET-2 and ET-3 levels did not change from baseline values (figure, mean +/- SE). VF occurred in 60% of animals. Peak ET-1 values were not significantly different between VF and non-VF animals (6.2 +/- 2.2 vs. 4.8 +/- 2.3 pg/mL). No single ET-1 value had a VF predictive value >50%. There is a significant increase in ET-1 level within 20 min of acute myocardial ischemia. Despite known effects of ET-1 on the AP, this increase did not correlate with the occurrence of VF.

Ursodeoxycholic acid reduces increased circulating endothelin 2 in primary biliary cirrhosis.

BACKGROUND: Endothelins and nitric oxide regulate sinusoidal blood flow and the perfusion of the peribiliary vascular plexus. AIMS: To study the serum and hepatic vein concentration of ET-1, ET-2, ET-3 and nitric oxide in patients with primary biliary cirrhosis and the effect of ursodeoxycholic acid treatment. METHODS: Endothelins and nitrites/nitrates were measured in serum and hepatic vein blood in primary biliary cirrhosis and viral cirrhotic patients prior and after ursodeoxycholic acid therapy and in serum in controls. Endothelins were measured with commercial enzyme-linked immunosorbent assays and nitrites/nitrates with a modification of Griess reaction. RESULTS: The ET-1 and ET-3 levels were similar in patients and controls. Primary biliary cirrhosis patients had the highest serum ET-2 (P < 0.001) compared with other groups. Nitrites/nitrates was increased in primary biliary cirrhosis (P < 0.05) compared with normal. ET-2 and nitric oxide were similar in all primary biliary cirrhosis stages. Ursodeoxycholic acid significantly decreased ET-2 in all stages (I and II: P < 0.05 and III and IV: P < 0.01) and increased nitric oxide (P < 0.05) in early primary biliary cirrhosis. Hepatic vein ET-1 and ET-3 were higher in viral cirrhosis patients, but only in primary biliary cirrhosis a significant difference for ET-1 and ET-3 between hepatic and peripheral veins was found. CONCLUSIONS: Increased ET-2 is an early defect in primary biliary cirrhosis that is significantly reduced by the ursodeoxycholic acid treatment. The possibility of a more generalized endothelial cell dysfunction in primary biliary cirrhosis requires further investigation.

On-road exposure to highway aerosols. 2. Exposures of aged, compromised rats.

Ambient particulate pollution is associated with adverse health effects in epidemiological studies of the elderly with cardiopulmonary diseases. We hypothesize that ultrafine particles (UFP) contribute to these effects, especially when they are freshly generated and occur at high number concentrations. Studies to determine adverse effects have been performed using laboratory-generated surrogates, diluted exhaust from stationary engines, or concentrated ambient UFPs. Methodological difficulties exist with such experiments, and questions remain about how well these particles model those found in ambient air. Freshly generated UFPs are present at high concentrations on highways and vehicle passengers are directly exposed to them. We wished to expose rats to these UFPs to test their potential to cause effects. Since such exposures have not been done before, one objective of our study was to demonstrate the feasibility of an on-road exposure study. Secondly, we wished to determine if there are significant exposure-related effects in aged, compromised rats. Old rats (21-mo F-344) were exposed directly on highways to either the aerosol (<1 microm)/gas phase, gas phase only, or filtered air using an on-road exposure system. Some rats were pretreated with a low dose of inhaled endotoxin or with instilled influenza virus to induce lung inflammation. The exposures in compartmentalized whole-body chambers consisted of 6-h driving periods on I-90 between Rochester and Buffalo once or 3 days in a row. Endpoints related to lung inflammation, inflammatory cell activation, and acute-phase responses were measured after exposure. The on-road exposure system did not affect measured endpoints in filtered air-exposed rats, indicating that it was well tolerated by them. We observed the expected increases in response (inflammation, inflammatory cell activation) to the priming agents. We also found a significant particle-associated increase in plasma endothelin-2, suggesting alterations in vascular endothelial cell activation. In addition, we observed main effects of particles related to the acute-phase response and inflammatory-cell activation. Interactions between on-road particles and the priming agents were also found. These results suggest that exposures to on-road particle mixtures have effects on the pulmonary and cardiovascular system in compromised, old rats. Furthermore, they demonstrate that on-road exposures are feasible and could be performed in future studies with more continuous particle exposures.

[Gestational arterial hypertension. Mechanisms of formation. Treatment with normodipin]. / Gestatsionnaia arterial'naia gipertoniia. Mekhanizmy formirovaniia. Lechenie normodipinom.

AIM: To study endothelium-dependent vasodilatation (EDVD), plasma endothelin 1,2 (ET-1,2) contents and urinary NO metabolites in normal pregnancy and various kinds of gestoses with evaluation of normodipine effects on blood pressure and EDVD. MATERIAL AND METHODS: 59 primigravidas 18-32 years of age (pregnancy terms 34-39 weeks) were divided into three groups. Group 1 consisted of 23 women with arterial hypertension treated with normodipine in 11 of them. In group 2 sixteen pregnant women had edema and group 3 consisted of 20 women with physiological pregnancy. 12 non-pregnant women comprised a control group. RESULTS: In normal pregnancy ET-1,2 content was low while urine NO metabolites levels were high. This contributes to maintaining adequate reaction of the brachial artery in response to the "shiftstress". In women with edema the brachial artery response to short-term occlusion was decreased. In women with both high blood pressure and edema had vascular response paradoxically spastic with a two-fold decrease in blood flow rate, high plasma ET-1.2 contents and low urine NO metabolites levels. Normodipine in gestational arterial hypertension normalizes both blood pressure and EDVD. CONCLUSION: Endothelial dysfunction is an important factor predisposing to development of arterial hypertension. Monotherapy with normodipine (5 mg/day in a single daily dose) during 3 weeks is effective in controlling gestational hypertension.

Endothelin-1 plasma levels in cluster headache.

BACKGROUND AND OBJECTIVE: A role for endothelin-1, a potent vasoconstrictor peptide, in some cerebrovascular diseases has been proposed. To obtain preliminary data about peripheral concentrations of endothelin-1 in acute cluster headache, we measured the plasma endothelin-1 secretory pattern in 10 men with cluster during and independent of a headache attack. METHODS: We collected blood samples for plasma endothelin-1 determinations at 0, 15, 30, 45, 60, 90, and 120 minutes during a cluster attack and closely monitored blood pressures. We repeated the same sampling during an asymptomatic period. RESULTS: The mean values of plasma endothelin-1 (before a cluster headache, 3.3 +/- 0.3 pg/mL) significantly increased (F = 2.578, P < .05) during an attack, reaching their peak at 30 minutes (5.0 +/- 0.5 pg/mL, P < .05). We found no significant variations in mean arterial pressure. CONCLUSION: Endothelin-1 may play a role in the pathophysiology of cluster attacks. The increase in plasma observed during cluster attacks may be linked to alterations in systemic hemodynamics and vascular tone.

Plasma endothelin in patients with acute aortic disease.

PURPOSE AND BACKGROUND: We investigated the plasma levels of endothelin 1/2 in patients with acute symptoms relating to a known or newly diagnosed aortic aneurysm in order to investigate the possible role of peptides in the development of the disease. METHODS: Endothelin 1/2 plasma levels were determined in patients admitted to the emergency unit with suspected acute aortic disease. The history, type of aneurysm, outcome and laboratory findings were determined and compared to endothelin 1/2 levels collected on admission. RESULTS: In patients with ruptured aneurysm (n=27) or acute aortic dissection (n=18) the endothelin 1/2 median levels were higher 1.1 (25th and 75th quartile 0.7, 1.7) fmol/ml than in patients (n=20) with pre-existing aneurysm 0.7 (0.4, 1.1) fmol/ml (P=0.013). Patients who died had significantly higher endothelin levels 1.3 (0.8, 1.9) fmol/ml than the survivors 0.8 (0.5, 1.4) fmol/ml (P=0.04). In a logistic regression analysis, only a higher blood pressure on admission was an independent predictor of survival. CONCLUSION: Endothelin 1/2 levels are elevated in patients with acute dissection or ruptured aneurysm, but they are not an independent predictor of survival.

Nitric oxide and endothelin-1,2 in actinic keratosis and basal cell carcinoma: changes in nitric oxide/endothelin ratio.

BACKGROUND: Nitric oxide (NO) is an inorganic free radical gas which has cytostatic/cytotoxic actions in tumoral tissues, including gynecologic, breast, and colon cancer. Nitric oxide is also a multifunctional signaling molecule active in many cells of the body, including endothelial cells, macrophages, monocytes, hepatocytes, mast cells, osteoblasts, and astrocytes. Endothelin-1 (ET-1) is a 21-amino acid peptide that stimulates the proliferation of vascular smooth muscle cells, fibroblasts, and keratinocytes, and plays a role in the expression of proto-oncogenes (c-myc, c-fos), which precedes cell proliferation. Similar to NO, ET is secreted by different cell types, including macrophages, monocytes, hepatocytes, endothelial cells, vascular smooth muscle cells, and various tumor cells. Elevated ET-1 levels are observed in pulmonary, hepatocellular, and prostate cancers. Actinic keratosis (AK) and basal cell carcinoma (BCC) are common skin tumors with accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation. AIM: To investigate plasma NOx (nitrite/nitrate -- the end products of NO metabolism), ET, and the NOx/ET ratio in patients with AK and BCC in comparison with healthy controls. METHODS: NOx, ET, and the NOx/ET ratio were measured in 13 patients with AK, 12 patients with BCC, and in 16 healthy controls. RESULTS: Data analysis indicated a significant increase in plasma NOx, ET, and NOx/ET values in BCC patients in comparison with controls (P < 0.001, P < 0.05 and P < 0.001, respectively). Plasma ET levels in AK were also increased in comparison with controls (P < 0.001). When the two study groups (AK and BCC) were compared, a significant increase (P < 0.001) in the NOx/ET ratio in BCC was found. CONCLUSIONS: The increased plasma ET and NOx levels in AK and, especially, BCC are probably the result of and/or reason for the accentuated hyperkeratinization, hyperpigmentation, and keratinocyte proliferation. The increased production of ET and NO by keratinocytes may function as growth and cytotoxic factors and potential mitogens, and may accelerate further proliferation of these skin tumors. In addition, the increased NOx/ET ratio probably reflects a disturbed equilibrium between these two substances, leading to cell damage and tumor promotion and proliferation.

ET(B) receptor blockade potentiates the pressor response to big endothelin-1 but not big endothelin-2 in the anesthetized rabbit.

The precursor of endothelin-1, big endothelin-1, is considered to be a more reliable marker of systemic production of vasoactive peptide. However, it is largely unclear whether ET(B) receptor-dependent clearance and endothelium-derived relaxing factors affect the precursor in a similar manner to mature ET-1. These ET(B)-dependent modulations of big ET-1 and big ET-2 pressor properties were therefore studied in the anesthetized rabbit. When injected into the left cardiac ventricle, ET-1 and ET-2 (0.01 to 1 nmol/kg) each induced biphasic responses (a depressor followed by a pressor response), whereas big ET-1 and big ET-2 (0.1 to 3 nmol/kg) caused only protracted pressor responses. The highest dose of big ET-1 caused significantly greater responses than ET-1, ET-2, or big ET-2. A selective ET(A) receptor antagonist, BQ-123 (1 mg/kg), markedly reduced pressor responses to all 4 peptides, whereas blockade of ET(B) receptors with BQ-788 (0.25 mg/kg) sharply potentiated the responses to ET-1, ET-2, and big ET-1, but not to big ET-2. Indomethacin (10 mg/kg) sharply potentiated the pressor response to ET-1 (1 nmol/kg), but not big ET-1, at all time points. In control animals, ET-1, but not big ET-1, also triggered an indomethacin-sensitive increase in circulating prostacyclin. Finally, systemically administered big ET-1, but not big ET-2, induced a phosphoramidon-sensitive increase in plasma IR-ET. Our results suggest a significant limiting role of ET(B) receptors on pressor responses to big ET-1. In contrast, the same receptor entities do not modulate the hemodynamic properties of the ET-2 precursor, given that, unlike big ET-1, it is poorly converted in the pulmonary or systemic circulation in anesthetized rabbits.

[Plasma concentrations of endothelin-1 and endothelin-2 in patients with pulmonary hypertension]. / Stezenie endoteliny-1,2 w surowicy chorych na nadcisnienie plucne.

Increased pressure in pulmonary artery is connected among other things with increased endothelin plasma concentration. The aim of the study was to assess plasma endothelin concentration in patients with pulmonary hypertension. The analysis comprised 22 patients with increased pressure in pulmonary artery in the course of pulmonary thromboembolism or chronic exacerbated left ventricular failure and 10 patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration was measured in pulmonary artery and capillary wedge pressure were evaluated with Swan-Ganz catheter and also peripheral and pulmonary vascular resistance were calculated. Endothelin plasma concentration in peripheral vein was compared between patients and healthy volunteers. Plasma endothelin concentration in pulmonary artery, peripheral artery and vein was higher in patients with pulmonary hypertension than in patients with chronic exacerbated left ventricular failure without pulmonary hypertension. Plasma endothelin concentration in patients with chronic exacerbated left ventricular failure without pulmonary hypertension was higher in pulmonary artery than in peripheral artery and vein. At these patients plasma endothelin concentration in the peripheral vein didn't differ significantly from the healthy volunteers.

Plasma endothelin levels in patients with abdominal aortic aneurysms.

OBJECTIVES: endothelin 1,2 plays a significant role in the process of atherogenesis and vascular wall injury. The aim of this study was to assess whether plasma endothelin 1,2 levels were elevated in patients with large or symptomatic abdominal aortic aneurysms (AAAs). DESIGN: a prospective open study. MATERIALS AND METHODS: plasma endothelin 1,2 levels were measured in 65 consecutive patients with infrarenal aortic aneurysms and compared with the levels in 44 healthy volunteer controls. The data for abdominal aneurysm patients was analysed in four subgroups: (i) small aneurysms (<5 cm), (ii) large aneurysms (>/=5 cm), (iii) asymptomatic aneurysms and (iv) symptomatic aneurysms. Comparisons were made between endothelin 1,2 levels in aneurysm patients and controls and between the different aneurysm subgroups. RESULTS: a highly significant difference (p<0.0001) was found between aneurysm patients and controls. Patients with large aneurysms had significantly higher levels than patients with small aneurysms (p<0.01). There was no statistical difference in endothelin 1,2 levels between symptomatic and asymptomatic patients; however, the highest levels were found in large, symptomatic aneurysms and the lowest in small, asymptomatic aneurysms. CONCLUSIONS: plasma endothelin 1,2 is an endogenous marker of aneurysm diameter. Further studies are required to determine whether it relates to the rate of growth of aneurysms.

Comparison between plasma concentrations of testosterone, nitric oxide and endothelin 1-2 in penile and brachial venous blood: preliminary results in men with psychogenic impotence.

In the present study venous plasma concentrations of testosterone (T), nitric oxide (NO) and endothelin 1-2 (ET1-2) in the flaccid penis and brachial blood were measured in men with psychogenic impotence. T and NO were significantly lower in the penile venous blood, while ET1-2 showed no statistical difference. These data support the hypothesis of testosterone dependence of penile nitric oxide synthesis (NOS).

[Levels of adrenomedullin in plasma of patients with chronic congestive heart failure]. / Stezenie adrenomedulliny w surowicy chorych na przewlekla zastoinowa niewydolnosc krazenia.

Adrenomedullin is a potent vasodilator and natriuretic peptide that may an important role in cardiovascular disease. To investigate the role of adrenomedullin in the pathophysiology of congestive heart disease, plasma levels of adrenomedullin were measured in patients with congestive heart failure. Venous blood samples at rest were obtained before and after treatment from patients with congestive heart failure in New York Heart Association functional class II (n-23), III (n-26) and IV (n-14) and from normal subjects (n-30). Plasma adrenomedullin, endothelin-1,2, and atrial natriuretic peptide were determined by radioimmunoassay, plasma noradrenaline by radioenzymatic assay. Left ventricular ejection fraction was measured by echocardiography. The mean plasma level of adrenomedullin in normal subjects was 8.2 pmol/l, tended to be increased in patients with congestive heart failure those in class II (12.9 pmol/l) and were significantly increased in classes III and IV (21.3 and 29.9 respectively). Plasma adrenomedullin was correlated strongly with endothelin-1,2, atrial natriuretic peptide, and noradrenaline, and relatively weakly with left ventricular ejection fraction. Plasma adrenomedullin levels significantly decreased after treatment. These findings indicate that plasma levels of adrenomedullin are elevated in congestive heart failure and may be involved in the defense mechanism against further peripheral vascular resistance elevation in congestive heart failure.

Changes in plasma and amniotic fluid endothelin levels during pregnancy: facts or artefacts?

OBJECTIVE: To describe the evolution of immunoreactive endothelins (irETs) in maternal peripheral plasma and in amniotic fluid at different stages of pregnancy using two different radioimmunoassays. STUDY DESIGN: Peripheral blood samples were obtained from ten non-pregnant and eighty-four pregnant patients at different stages of pregnancy, but not in labor. Amniotic fluid samples were obtained in ten patients during the second trimester of pregnancy and in twenty-two patients at term. Endothelin concentrations were assayed using two different kits: by antigenic cross-reactions, the RPA 545 assay allowed the detection of ET-1, ET-2 and big ET-1; the RPA 555 assay allowed the detection of ET-1, ET-2 and ET-3. RESULTS: Using the RPA 555 kit, no differences were observed in irET plasma levels between non-pregnant and pregnant patients whatever the gestational age. With the RPA 545 kit, the irET levels were significantly lower in pregnant patients during the first and second trimesters of pregnancy when compared to non-pregnant patients. Immunoreactive ET levels then increased significantly in the last month of pregnancy when compared to mid-pregnancy levels. In amniotic fluid, irET levels were significantly higher at term than during the early second trimester, without any difference between the two RIA kits. CONCLUSION: Our results are indicative of a differential evolution in ET isoforms during pregnancy in maternal peripheral blood. The increase in irET observed towards the end of pregnancy in maternal plasma and in amniotic fluid suggests that ET could play a role in the onset of parturition.

Serum level of endothelin-1 and -2 in pregnancies complicated by EPH gestosis.

We examined the endothelin (ET)-1 and -2 concentration in peripheral blood serum of 27 pregnant patients with EPH gestosis who underwent cesarean section between the 32nd and 38th week of gestation (group Gc). The control group consisted of 26 healthy pregnant women who underwent cesarean section due to fetal malpositions (group Kc). ET concentration in umbilical venous blood serum in 22 cases of EPH gestosis (group Gp) and 20 cases from the control group (Kp) was measured after delivery. ET concentration was determined with use of a radioimmunoassay method after extraction with column chromatography. The mean ET concentration was 41.55 pg/ml in group Gc and was significantly higher than in group Kc-6.77 pg/ml. The mean ET concentration in umbilical blood serum in group Gp was 50.59 pg/ml and was significantly higher than in Gc and Kp groups-where ET concentration was 17.11 pg/ml. These studies indicate that the high level of ET may play an important role in pathogenesis of EPH gestosis as well as having influence on uteroplacental and umbilicoplacental circulation.

Effects of antiendothelin treatment on the early hemodynamic changes in hyperdynamic endotoxemia.

We have performed a series of experiments to study the effects of a newly developed antisense homology box-derived endothelin (ET) antagonist peptide (ETR-P1/fl) on the early hemodynamic changes in a hyperdynamic endotoxemic dog model. Mean arterial pressure (MAP), cardiac output (CO) and myocardial contractility (MC) were measured in closed-chest animals. Plasma levels of ET-1,2 were determined by radioimmunassay. A hyperdynamic circulatory response was elicited with a 2-hour infusion of 5.3 micrograms/kg of E. coli endotoxin (ETX). Control and ETX-treated animals received an infusion of ETR-P1/fl (0.1 mg/kg) i.v. ETX treatment decreased MAP and MC, increased initially CO, and a long lasting elevation in the plasma ET level was observed. In ETX-treated animals the administration of ETR-P1/fl significantly prolonged the increase in CO and inhibited the depression of MC. Our results suggest that treatment with the ET antagonist ETR-P1/fl may be advantageous in the early phase of endotoxemia.

[Circadian urinary excretion of catecholamine, plasma atrial natriuretic peptide, endothelin and neuropeptide Y in obese patients with hypertension]. / Dobowe wydalanie katecholamin z moczem oraz stezenia w surowicy przedsionkowego peptydu natriuretycznego, endoteliny i neuropeptydu y u osób otylych chorych na nadcisnienie tetnicze.

UNLABELLED: Obesity increases the risk of developing hypertension by two-to fourfold, with more that one third of all cases of hypertension attributable to obesity. The present study tested the role of atrial natriuretic peptide (ANP), endothelin-1,2 (ET-1,2) and neuropeptide Y (NPY) in pathogenesis of obesity hypertension. The plasma concentrations of ANP, ET-1,2 and NPY were determined in the peripheral venous blood by radioimmunoassay in 27 obese hypertensive patients (group I), in 24 obese normotensive patients (group II), and in 35 normal subjects (group III). RESULTS: Mean plasma ANP was significantly higher in obese than in normal subjects. ANP levels were higher in patients group I than in those group II and I. In patients of group I plasma ANP concentrations correlated with III BMI and mean blood pressure. Plasma levels of ET-1,2 and NPY were similar in patients group I, II and III.

[Endothelin and big endothelin in coronary heart disease and acute coronary syndromes]. / Endothelin und Big-Endothelin bei der koronaren Herzerkrankung und akuten Koronarsyndromen.

Endothelin (ET), the most potent endogenous vasoconstrictor with mitogenic potency, is generated from its precursor big-endothelin (BET) in a proteolytic process and discussed as a pathogenetic factor in coronary artery disease and in the acute coronary syndromes. Several studies documented elevated plasma endothelin concentrations in acute myocardial infarction, but conflicting results were reported in patients with stable and unstable angina. Only few studies determined big endothelin, although it half-life and plasma concentrations are higher in comparison to endothelin. ET and BET levels (Radioimmunoassay, Biomedica GmbH, Vienna) were determined in patients with stable angina (SAP, n = 20), unstable angina (IAP, n = 12), acute myocardial infarction (AMI, n = 12) and healthy subjects (NP, n = 11). The concentrations of ET and BET (median (minimum-maximum) in fmol/ml) of the patients with stable angina (SAP: ET 0.7 (0.3-1.1); BET 1.7 (0.7-2.9)), unstable angina (IAP: ET 1.0(0.5-1.7); BET 2.5 (1.3-4.1)) and acute myocardial infarction (AMI: ET 1.2 (0.6-2.3); BET 3.6 (3.2-5.3)) showed a significant difference compared to controls (NP: ET 0.5 (0.4-0.7); BET 1.4 (1.1-1.7)) (SAP vs. NP: ET p < 0.01; BET p < 0.05; IAP and AMI vs. NP: ET and BET p < 0.001). Also, the concentrations of the peptides differed significantly dependent on the clinical severity of coronary artery disease (AMI vs. SAP: ET and BET p < 0.001; AMI vs. IAP: BET p < 0.05; IAP vs. SAP: ET p < 0.05; BET p < 0.01). Twelve of 15 patients with big endothelin concentrations over 3 fmol/ml suffered acute myocardial infarction. Seven of 12 patients with AMI showed elevated ET and BET concentrations before the increase of creatinecinase. There was no correlation between number of risk factors per patient, cholesterin and subfractions, severity of CAD classified in one-two-three-vessel disease or coronary score according to modified criteria of the American Heart Association (AHA). We conclude that in patients with coronary artery disease endothelin and big endothelin levels are elevated and related to the clinical and not to the morphological severity of coronary artery disease. Big endothelin is the more sensitive parameter in comparison to endothelin and indicates a severe course of myocardial ischemia in patients with unstable angina. The development of assays with the possibility of a quick determination of the peptides may be valuable for risk stratification of acute coronary events.