Raised Plasma Concentrations of Endothelin-1 and -3 in Marmosets with Acute Aortic Stenosis: No Relation to the Renin-angiotensin System

Plasma levels of endothelin (ET), plasma renin activity (PRA) and angiotensin II (Ang II) were measured in anaesthetized marmosets exposed to acute aortic stenosis proximal to the renal arteries. In vehicle experiments, ET rose from 5 ± 2 to 38 ± 4 pg ml^-1, PRA from 5 ± 2 to 99 ± 21 ng ml^-1 h^-1 and Ang II from 21 ± 4 to 213 ± 76 pg ml^-1. Administration of renin inhibitor and angiotensin converting enzyme inhibitor reduced PRA and Ang II to control levels, while the plasma levels of ET increased further (51 ± 10 and 71 ± 16 pg ml^-1, respectively). During aortic stenosis the two isoforms ET-1 and ET-3 appeared in the circulation, while in conscious control animals only ET-1 was found. It is concluded that the increased plasma levels of ET in our primate model could not be ascribed to the increased circulating levels of PRA and Ang II.     

Hypertension in cyclosporin A-treated patients is independent of circulating endothelin levels

Abstract. Objectives. To measure blood pressure (BP), plasma endothelin-1 (ET-1), atrial natriuretic peptide (ANP), antidiuretic hormone (ADH) and aldosterone (ALDO) concentration, and plasma renin activity (PRA) in patients treated with a low-dose cyclosporin A (CyA). Design. An open study of patients with rheumatoid arthritis (RA) or palmoplantar pustulosis (PPP). Setting. Out-patient clinics at the Central Hospital of Jyväskylä and Helsinki University Central Hospital. Subjects. CyA was given to 25 patients with RA and to 10 patients with PPP. Intervention. RA patients were given CyA at a dose of 2.5±0.13 mg kg^?1 body weight (BW) to 3.47±0.79 mg kg^?1 BW (mean values±SD) at the start of the study and after 6 months, respectively, and the CyA dose was 2.67±0.13 mg kg^?1 BW decreasing to 2.07±0.96 mg kg^?1 (P < 0.001) after 4 months in PPP subjects. Results. Systolic (sBP) and diastolic blood pressure (dBP) increased from 127.8±13.6/79.7±8.4 mmHg to 140.0±19.8/83.8±9.7 mmHg during the study (P < 0.03). Plasma ET-1, ANP, ALDO and ADH concentration and PRA did not change during 4 to 6 months of CyA treatment. The plasma ANP concentration was constantly higher in CyA-treated RA patients (112±87 ng l^?1) to 118±78 ng l^?1) than in PPP patients (37.3±26 ng l^?1 to 47.7±39.9 ng l^?1; P < 0.02). The serum creatinine concentration remained within the normal range, but increased from baseline (76.7±11.9 μmol l^?1), to 90±15.4 μmol l^?1 (P < 0.001). The serum magnesium concentration decreased significantly (P < 0.005) after 6 months of CyA treatment in RA patients. No correlation was found between serum creatinine and plasma ET-1 concentration. Conclusions. Increased blood pressure during CyA treatment was independent of circulating ET-1 levels. A low dose of CyA did not induce increased ET-1 synthesis as judged from plasma samples. The high plasma ANP level observed in RA patients could be due to fluid retention caused by concomitant treatment with non-steroid anti-inflammatory drugs. Fluid retention and decreased magnesium levels could also be involved in the development of hypertension in CyA-treated subjects.     

Handgrip Increases Endothelin-1 Secretion in Normotensive Young Male Offspring of Hypertensive Parents

Objectives. We tested the hypothesis that an abnormal response of plasma endothelin-1 (ET-1) is elicited by handgrip exercise (HG) in young normotensive offspring of hypertensive parents.Background. It has been hypothesized that ET-1 is involved in blood pressure control and plays a pathophysiologic role in the development of clinical hypertension.Methods. Two groups of healthy male subjects, 11 with hypertensive parents (group A) and 10 without a family history of hypertension (group B), underwent 4 min of HG at 50% maximal capacity. Heart rate and blood pressure and plasma levels of ET-1, epinephrine and norepinephrine were measured at baseline, peak HG, and after 2 (R2) and 10 (R10) min of recovery.Results. Group A had higher norepinephrine levels than group B throughout the test (baseline 181 ± 32 [SEM] vs. 96 ± 12 pg/ml, p < 0.05; peak HG 467 ± 45 vs. 158 ± 12 pg/ml, p < 0.000001; R2 293 ± 46 vs. 134 ± 8 pg/ml, p < 0.01; R10 214 ± 27 vs. 129 ± 10 pg/ml, p < 0.0005); no significant difference in epinephrine levels was detected. Compared with group B subjects, group A had higher baseline ET-1 levels (1.07 ± 0.14 vs. 0.59 ± 0.11 pg/ml, p < 0.02), which increased to a greater extent at peak HG (1.88 ± 0.31 vs. 0.76 ± 0.09 pg/ml, p < 0.005) and R2 (2.46 ± 0.57 vs. 1.31 ± 0.23 pg/ml, p < 0.05) and remained elevated at R10 (3.16 ± 0.78 vs. 0.52 ± 0.09 pg/ml, p < 0.002). Multivariate analysis demonstrated that only a family history of hypertension (chi-square = 7.59, p = 0.0059) and ET-1 changes during HG (chi-square = 4.23, p = 0.0398) were predictive of blood pressure response to HG and that epinephrine and norepinephrine were not.Conclusions. The response to HG in offspring of hypertensive parents produced increased ET-1 plasma levels and resulted in a sustained ET-1 release into the bloodstream during recovery compared with offspring of normotensive parents. This may be an important marker for future clinical hypertension.     

Endothelin-1 and -3 plasma concentrations in patients with cirrhosis: Role of splanchnic and renal passage and liver function

Increased as well as decreased plasma concentrations of the endothelins, endogenous vasoactive peptides, have been reported in cirrhosis. This might be caused by alterations of hepatic or renal clearance or release. Therefore, the aim of the current study was to investigate the influence of splanchnic and renal passage and of liver function on plasma concentrations of endothelin-1 (ET-1) and endothelin-3 (ET-3) in patients with cirrhosis compared with controls. Eighteen patients with cirrhosis and 8 normotensive controls of similar age were investigated. Arterial and venous plasma samples were obtained simultaneously, and ET-1 and ET-3 concentrations were determined in extracted plasma by two separate radioimmunoassays. Arterial as well as hepatic and renal venous concentrations of ET-1 in cirrhosis (17.8 ± 0.8 pg/mL, 19.1 ± 0.9 pg/mL, and 16.8 ± 0.8 pg/mL) were significantly (P < .001) higher than in controls (9.2 ± 1.7 pg/mL, 9.0 ± 2.0 pg/mL, and 8.4 ± 1.9 pg/mL, respectively). The same held true for the corresponding ET-3 plasma concentrations in cirrhosis (19.3 ± 1.6 pg/mL, 20.5 ± 1.5 pg/mL, and 18.4 ± 1.5 pg/mL, respectively) compared with controls (11.1 ± 1.8 pg/mL, 11.3 ± 1.5 pg/mL, and 10.1 ± 1.7 pg/mL, respectively; P < .01). There was a significant (P < .05) renal net extraction of ET-1 and ET-3 in cirrhosis. In contrast, a significant (P < .05) net release of ET-1 and ET-3 (2.40 ± 0.80 ng/min and 1.75 ± 1.16 ng/ min) during splanchnic passage was observed in cirrhosis, but not in controls (−0.24 ± 0.51 ng/min, and −0.46 ± 0.64 ng/min). Plasma concentrations of ET-3 in cirrhosis were correlated to the Child-Turcotte score (r = .66, P < .01) and inversely to the functional liver cell mass, determined by the galactose elimination capacity (r = −.72, P < .01). Hepatic venous ET-1 concentrations correlated to the hepatic blood flow assessed by the indocyanine green clearance (r = .48; P < .05). Net splanchnic release may contribute to elevated ET-1 and ET-3 plasma concentrations in patients with cirrhosis. Splanchnic ET-1 and ET-3 handling in cirrhosis may be influenced by different mechanisms.     

Plasma endothelin levels in patients with cirrhosis and their relationships to the severity of cirrhosis and renal function

Background/Aims: Increased plasma endothelin levels have been reported in patients with cirrhosis. However, the relationship between plasma endothelin concentrations and hyperdynamic circulation or renal functions has not been documented.Methods: We measured the plasma endothelin-1 and endothelin-3 concentrations using radioimmunoassay in 96 patients with cirrhosis (Pugh's A in 26, Pugh's B in 45 and Pugh's C in 25) and compared these values to 56 age- and sex-matched healthy subjects. Systemic and portal hemodynamic measurements, effective renal plasma flow, creatinine clearance, plasma aldosterone concentration and plasma renin activity were recorded for each patient.Results: Plasma endothelin-1 and endothelin-3 levels were significantly increased in patients with cirrhosis compared to healthy subjects. Additionally, plasma endothelin-1 and endothelin-3 values were higher in patients with cirrhosis and ascites than in those without ascites. Moreover, plasma endothelin-1 levels increased in relation to the severity of cirrhosis. On the other hand, modest negative correlations were found betwen endothelin-1 and creatinine clearance or effective renal plasma flow.Conclusions: Plasma endothelin-1 and endothelin-3 levels are increased in patients with cirrhosis compared to healthy subjects. The increase in plasma endothelin-1 levels is related at least in part to the severity of cirrhosis. Increased endothelin-1 levels may possibly contribute to renal dysfunction in patients with cirrhosis.     

Safety and efficacy of nesiritide in pediatric heart failure

BackgroundWe hypothesized that recombinant B-type natriuretic peptide (BNP) (nesiritide) could improve urine output and neurohormonal markers of heart failure without worsening renal function in pediatric patients.Methods and ResultsWe analyzed our experience involving 140 nesiritide infusions in 63 consecutive children. Serum levels of BNP and electrolytes were measured before and after therapy. Dosing was begun at 0.01 mcg·kg·min without a bolus and titrated to a maximum of 0.03 mcg·kg·min, in 0.005-mcg·kg·min increments. Blood pressure, heart rate, and heart rhythm were monitored. In a substudy, 20 patients with decompensated cardiomyopathy-related heart failure received 72 hours of nesiritide with prospective assessment of aldosterone, norepinephrine, plasma renin, and endothelin-1 levels before and after therapy. The heart rate decreased significantly (P = .001). Urine output increased significantly on Days 1 and 3 (P ≤ .001 and .004, respectively). The mean serum creatinine level decreased from 1.135 to 1.007 mg/dL (P ≤ .001). In the substudy, aldosterone levels decreased from 37.5 ± 57.1 to 20.5 ± 41.9 ng/dL (P = .005). Plasma renin, norepinephrine, and endothelin-1 levels decreased nonsignificantly. Two infusions were discontinued because of hypotension.ConclusionsNesiritide safely treated decompensated heart failure in children. Increased urine output reflected improving renal function. Improved neurohormonal markers were seen after 72 hours of therapy, and complications were uncommon.     

The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus

We have recently reported a combination of renal features that suggests independent angiotensin-mediated control of the renal circulation in the majority of hypertensive patients with type II diabetes. To ascertain whether other tissue elements of the renin-angiotensin-aldosterone system (RAAS) also were activated, we examined the adrenal response to angiotensin II (AngII) infusion on a low salt diet. We assessed also the renin response to the upright position in patients on a low salt diet and renin suppression in patients on a high salt diet. We compared responses in 42 hypertensive patients with type II diabetes (53.1 ± 1.4 years, mean ± SEM), 25 healthy controls (52.6 ± 4.4 years); and 137 essential hypertensives without diabetes (43.3 ± 1.2 years). A low renin state, defined as a plasma renin activity (PRA) <2.5 ng angiotensin I (AI)/mL/h after 5 to 7 days on a 10-mmol Na diet and 2 h of upright posture, was found in 21% of the essential hypertensives, but in only 14% of patients with type II diabetes. On this diet, PRA increased from 2.7 ± 0.4 supine to 10.1 ± 1.3 ng AI/mL/h upon standing in healthy subjects. In patients with type II diabetes, PRA was 3.6 ± 0.4 and increased to 9.1 ± 1.0 ng AI/mL/h. On a high salt (200 mmol) diet, healthy subjects showed the expected PRA suppression (0.3 ± 0.1), but in patients with type II diabetes the PRA was less suppressed (1.2 ± 0.3 ng AI/mL/ h; P = .003). Thus, in most hypertensive patients with type II diabetes the RAAS shows normal activation, but is poorly suppressible. AngII infused intravenously to assess adrenal responsiveness in patients on a low salt diet caused an essentially identical increase in aldosterone concentration in patients with type II diabetes (21.1 ± 1.7 to 44.0 ± 5.9 ng/dL) and in essential hypertension (20.6 ± 1.4 to 43.7 ± 2.8 ng/dL). The frequency of nonmodulation assessed as a blunted adrenal response to AngII infusion was identical in type II diabetes (47%) and in essential hypertension (46%) after exclusion of the low renin patients. Thus, at the level of one tissue renin system, the adrenal glomerulosa, responses were unaltered in patients with type II diabetes. The relative unresponsiveness of the renal blood supply to infused AngII in type II diabetes in association with an enhanced renal vasodilator response to angiotensin converting enzyme inhibition probably reflects local, intrarenal actions secondary to the diabetic state. The infrequency of a low renin state, and the inappropriately high renin levels on a high salt intake, provide a rational basis for pharmacologic interruption of the renin system to treat patients with type II diabetes.     

Plasma endothelin levels in cirrhotic subjects.

Endothelin-1, a potent vasoconstrictor peptide with 21 amino acid residues, is released by the vascular endothelium. Plasma immunoreactive endothelin levels were measured in 23 patients with cirrhosis and in 20 healthy subjects. Concentrations were significantly lower in patients with non-uraemic cirrhosis than in normal subjects (19.4 +/- 8.9 pmol/l vs. 48.8 +/- 24.8 pmol/l, p less than 0.002). Plasma renin, aldosterone, atrial natriuretic peptide, arginine-vasopressin and catecholamines did not show significant correlations with plasma endothelin-1 levels. Furthermore, there were no significant differences in plasma endothelin levels for etiology of cirrhosis, presence of ascites or varices. These data suggest that low circulating endothelin may be involved in the development or maintenance of systemic vasodilatation in cirrhosis.     

Value of cardiopulmonary exercise testing and big endothelin plasma levels to predict short-term prognosis of patients with chronic heart failure

Objectives. We tested the hypothesis that, in patients with stable heart failure, measuring big endothelin-1 (ET-1) plasma level at rest predicts short-term prognosis better than peak oxygen consumption (Vo₂max) at exercise.Background. Cardiopulmonary exercise testing and evaluation of neurohumoral plasma factors are established tools to estimate survival in patients with heart failure. No data, however, exist comparing the prognostic value of both marker categories simultaneously.Methods. Two hundred twenty-six heart failure patients were studied in regard to a combined end point of death and prioritization for urgent cardiac transplantation within 1 year follow-up.Results. During the study period 149 patients were without cardiac events (group A), 69 patients died or were urgently transplanted (group B) and 8 patients were alive after a nonurgent heart transplant operation. Norepinephrine (p < 0.0001), atrial natriuretic peptide (p < 0.001), big endothelin plasma levels (p < 0.0001 as well as workload, Vo₂max and achieved percentage of predicted peak oxygen consumption (pVo₂max) (all p < 0.0001) differed significantly between groups A and B. In multivariate stepwise regression analysis, however, only big ET-1 plasma concentration (×2 = 74.4, p < 0.0001), New York Heart Association function class (×2 = 33.9, p < 0.0001), maximal workload (×2 = 7.2, p < 0.01, and plasma atrial natriuretic peptide (ANP) concentration (×2 = 4.6, p < 0.05) were independently related to outcome. Peak oxygen consumption or pVo₂max did not reach statistical significance in this model. Event-free survival rates were significantly lower in patients with a big ET-1 level of 4.3 fmol/ml or more than with lower big ET-1 levels (p < 0.0001).Conclusion. We conclude that in patients with chronic heart failure who are stable on oral therapy measuring big ET-1 and ANP plasma levels may be a valuable noninvasive adjunct to improve the prognostic accuracy of detecting high risk patients compared with exercise testing alone.     

Regulation of plasma endothelin by salt in salt-sensitive hypertension

BACKGROUND: Salt dependency of blood pressure (BP) characterizes most models of experimental hypertension in which endothelins play a significant vasoconstrictor role. Despite this, there are no data on the regulation of plasma endothelin by salt balance in human hypertension. METHODS AND RESULTS: Plasma endothelin was measured in 47 patients with essential hypertension. Endothelin, catecholamine, and plasma renin activity (PRA) responses to 24-hour sodium deprivation (decreasing Na) were assessed in 29 of these patients. Endothelin was higher in hypertensive patients (4.6+/-0.2 fmol/mL) than in 20 control subjects (3.3+/-0.3 fmol/mL, P:<0.002), was correlated with BP, and was negatively associated with PRA (P:<0.04). Salt-sensitive, salt-resistant, and indeterminate groups were defined by the tertiles of the t statistic for the difference in BP before and after decreasing Na. Systolic BP falls were -15+/-1, -2+/-2, and -9+/-1 mm Hg, respectively. PRA, its response to decreasing Na, and its level after decreasing Na were lowest (albeit nonsignificant) in salt-sensitive patients. Baseline catecholamine and endothelin levels did not differ among the groups. In response to decreasing Na, catecholamines increased more significantly in salt-sensitive patients (+2.4+/-0.9 nmol/L) than in the other groups (0.4+/-0.2 and 0.7+/-0.2 nmol/L for indeterminate and salt-resistant groups, respectively; P:<0.03), whereas endothelin increased in the salt-sensitive group (0.8+/-0.3 fmol/mL), decreased in the salt-resistant group (-0.4+/-0.3 fmol/mL), and sustained minimal change in the indeterminate group (0.2+/-0.3 fmol/mL) (P:<0.04). Thus, endothelin levels in the salt-depleted state were highest in salt-sensitive patients (5.2+/-0.4 fmol/mL) versus the other groups (3.4+/-0.4 and 4.4+/-0.4 fmol/mL for salt-resistant and indeterminate groups, respectively) (P:<0.02). Changes in endothelin during decreasing Na and levels after decreasing Na were correlated with changes in catecholamines (P:<0.02). CONCLUSIONS:-Our data suggest that salt-depleted salt-sensitive hypertensives with blunted renin responses exhibit enhanced catecholamine-stimulated endothelin levels and may therefore respond better than unselected patients with essential hypertension to endothelin receptor blockers.     

Role of plasma and urinary endothelin-1 in early diabetic and hypertensive nephropathy

To evaluate the role of circulating and renal endothelin-1 (ET-1) in early diabetic nephropathy, plasma ET-1 levels and urinary ET-1 excretion were evaluated in lean, normotensive patients affected by non–insulin-dependent diabetes (NIDDM) either with (n = 9, NIDDM+) or without microalbuminuria (n = 18, NIDDM−); in never-treated, lean, essential hypertensive patients with (n = 12, EH+) or without microalbuminuria (n = 10, EH−); and in healthy volunteers (n = 12). Results showed higher plasma ET-1 levels in NIDDM+ (1.97 ± 0.58 pg/mL) than in NIDDM− (1.59 ± 0.14 pg/mL, P = .013), EH+ (1.40 ± 0.21 pg/mL, P = .005), EH− (0.91 ± 0.19 pg/mL, P < .0001), and controls (0.60 ± 0.10 pg/mL, P < .0001). The circulating ET-1 concentration was also higher in EH+ than EH− and controls (P < .0001).Urinary ET-1 excretion did not differ (P = .387, NS) between NIDDM+ (48.5 ± 20.1 pg/min) and NIDDM− (40.9 ± 21.6 pg/min), but was significantly reduced (P < .0001) in both groups compared with controls (70.0 ± 15.5 pg/min). Similar findings were observed in hypertensive subgroups. No correlations were found between urinary ET-1 and other variables, including plasma ET-1 levels, in all groups.In conclusion, NIDDM+ is accompanied by a significant increase in plasma ET-1 levels. A significant elevation of circulating ET-1 concentration was evident also in NIDDM−, suggesting that early abnormalities of ET-1 production might precede the microalbuminuric phase of diabetes-related renal damage.     

Alterations in angiotensin II release and vascular reactivity in hypertensive men: a pilot study

Cold- and insulin-mediated release of angiotensin II (AII) and endothelin-1 (ET-1), as well as vascular reactivity to exogenous ET-1 and to insulin, were compared in hypertensive and normotensive subjects.Peripheral vascular release of AII and of ET-1 was investigated in 10 hypertensive (H; 29.2 ± 5.8 years) and 12 normotensive (N; 29.1 ± 4.6 years) men in two separate trials. Net transfemoral balance of AII and of ET-1 was calculated from the respective Arterio-Venous (A-V) differences in plasma concentrations (PC) of the peptides and the regional plasma flow (indocyanine-green dye method), both at baseline conditions and after a cold stimulus (immersion of one hand into ice water) in 7H and 6N, or during short-time hyperinsulinemia (hyperinsulinemic euglycemic clamp: biosynthetic human insulin, 1 mU/kg/min) in 7H and 7N. Moreover, hemodynamic changes to sequential exogenous ET-1 infusion (1, 2.5, 5, 10, 20, 40 ng/min) or during hyperinsulinemic clamp were studied in 7H and 6N and 7H and 7N, respectively.Baseline net-transfemoral balance of ET-1 and of AII were similar in the two subject groups. The cold stimulus provoked a similar increase in transfemoral ET-1 release in H and N (H: 257.0 ± 31.7 to 526.2 ± 393.7 pg/min; N: 280.2 ± 112.7 to 524.0 ± 393.7 pg/min, mean ± SD, P < .05). In contrast, the cold-induced increase in transfemoral AII release was somewhat more pronounced in H than in N (H: 162.2 ± 304.6 to 1081.7 ± 1037.7 pg/ min, P < .05; N: 83.9 ± 166.3 to 317.6 ± 187.8 pg/min, P < .02; maximum value H v N P < .05). During the hyperinsulinemic clamp the PC of insulin increased from 5.8 ± 2.8 to 69.1 ± 15.5 μU/mL in H and from 4.6 ± 1.7 to 67.5 ± 9,5 μU/mL in N; P < .0005. Hyperinsulinemia induced a similar elevation of norepinephrine PC in H and N, but an increase in transfemoral ET-1 release in N only (219.7 ± 161.2 to 512.2 ± 279.0 pg/min, P < .02). In contrast, hyperinsulinemia increased transfemoral AII formation in H (730.4 ± 554.3 to 1088.6 ± 597.9 pg/min, P < .05), but not in N. Insulin-mediated vasodilation was observed only in N, whereas ET-1-induced vasoconstriction was blunted in H.We conclude that the cold-induced increase in peripheral vascular release of AII is more pronounced in H than in N, whereas insulin provokes an increase in AII formation in hypertensives only. Moreover, insulin-mediated vasodilation and ET-1-dependent vasoconstriction are blunted in hypertensive subjects.     

Elevated plasma endothelin concentrations in heart failure; an effect of angiotensin II?

Endothelin is a powerful vasoconstrictor that may be partlyresponsible for the increases in venous and arterial tone characteristicof heart failure. The release of endothelin from endothelialcells in culture is stimulated by angiotensin II. We investigated the relationship between plasma concentrationsof immuno reactive endothelin-1 and angiotensin II in 25 patientswith heart failure and eight with ischaemic heart disease butnormal left ventricular function. Plasma concentrations of endothelinand angiotensin II were correlated (Spearman rank correlationcoefficient of 0.72; P<0.0001) in patients with heart disease.Plasma concentrations of angiotensin II and endothelin werehigher in those patients with heart failure. Angiotensin II was infused over a 3 h period in eight healthyvolunteers. Infusion of angiotensin II increased plasma concentrationsof angiotensin II to levels greater than those usually foundin patients with severe heart failure but induced only a modestrise in plasma concentrations of immunoreactive endothelin-1(0.77 ±0.16 to 1.03 ± 0.03 pmol. I^–1, P<0.02). Increased plasma concentrations of angiotensin II and endothelin-1both appear to reflect the presence and severity of heart failure.Although a significant correlation exists between plasma concentrationsof angiotensin II and endothelin in patients with heart failure,the relationship may not be causal.     

Plasma immunoreactive endothelin concentration correlates with severity of coronary artery disease in patients with stable angina pectoris and normal ventricular function

Objectives. The present study tested the hypothesis that plasma immunoreactive endothelin concentration correlates with the severity and extent of coronary atherosclerosis.Background. Plasma endothelin-1 concentration is increased in patients with unstable coronary syndromes and advanced atherosclerosis. This finding, together with other clinicopathologic observations, suggests that endothelins may participate in the atherogenic process. However, the relation between plasma immunoreactive endothelin and coronary artery disease in patients with stable angina pectoris remains controversal.Methods. Ninety consecutive patients undergoing coronary angiography for the investigation of exertional chest pain and 49 normal control subjects were prospectively studied. Eleven patients had normal coronary angiographic findings (group I), 65 had coronary artery stenoses (group II), and 14 had coronary artery disease plus symptoms indicating atheroma in other vascular territories (group III). Computerized angiography was used to determine the extent, severity and morphology of coronary stenoses. Plasma immunoreactive endothelin was measured by radioimmunoassay.Results. Mean (± SD) plasma endothelin concentration (pg/ml) was significantly higher in patients than in control subjects (7.29 ± 4.07 vs. 3.48 ± 1.29, p < 0.0001). Endothelin levels were higher in patients of group III than in those of groups II and I (9.43 ± 5.48, 7.20 ± 3.72 and 4.94 ± 2.89, respectively, p = 0.02). In patients of group II, plasma endothelin correlated with the maximal degree of stenosis in each patient (r = 0.25, p = 0.04) and with the number of stenoses with ≥70% diameter narrowing (r = 0.36, p = 0.002). The highest plasma endothelin levels were found in patients with total occlusions (8.65 ± 3.78 vs. 6.46 ± 3.51, p = 0.02).Conclusions. Plasma immunoreactive endothelin concentration is increased in patients with chronic stable angiuya. The highest levels occur in patients with severe stenoses and total coronary occlusion.     

Detection and characterization of endothelin in transformed human osteoblast cell culture medium

Endothelin-1 (ET-1), a 21 amino acid peptide originally purified from conditioned medium of cultures of porcine aortic endothelial cells, is recognized also as a product of many other cells such as epithelial cells, glial cells, and neurons. It is now recognized that at least ET-1 plays an important role in bone metabolism. It has been shown that ET-1 inhibits osteoclast bone resorption by a direct effect on cell motility and it can also activate phospholipase C in the osteoblast. Furthermore, several studies have shown that ET-1 stimulates the formation of inositol phosphates, the synthesis of DNA, the mobilization of calcium from extra- and intracellular pools, the activation of phospholipase D, and the stimulation of tyrosine phosphorylation in osteoblast-like (MC3T3-E1 and UMR-106) cells. The aim of the present study was to detect and characterize the presence of endothelin in transformed human osteoblast cell culture medium (HTb96) by radio-immunoassay and chromatography methods. Immunoreactive endothelin (IR-ET) was undetectable in the medium incubated at 0.5 and 1 h and was 3.2±0.2 fmol/10⁵ cells (mean ± SEM, n=6) at 2 h, 9.5±0.5 fmol/10⁵ cells at 6 h, 19.8 ± 2.1 fmol/10⁵ cells at 24 h, and 23.7 ± 2.0 fmol/10⁵ cells at 48 h, respectively. Sephadex G-25 superfine chromatography and fast protein liquid chromatography studies showed that >90% of IR-ET in the culture medium coeluted with synthetic ET-1. These results show that ET-1 could be formed by transformed human osteoblasts. Further studies should be conducted to elucidate the physiological role of endothelins as possible autocrine, paracrine, or endocrine factors in calcium and bone metabolism.     

产前慢性缺氧对子代大鼠心肌内皮素-1、内皮素转换酶-1mRNA表达的影响

目的研究产前慢性缺氧对子代大鼠心肌内皮素-1(endothelin-1,ET-1)、内皮素转换酶-1(endothelin converting enzyme-1,ECE-1)mRNA表达的影响。方法 25只SD大鼠孕鼠,按电脑随机数字表法均分为4个妊娠期缺氧组(早期缺氧组、中期缺氧组、晚期缺氧组、全期缺氧组)和1个对照组,每组5只。出生子代大鼠分别于1个月龄、3个月龄、6个月龄每组电脑随机数字表法取雌、雄子鼠各5只,选用荧光定量聚合酶链反应法检测子代大鼠心肌ET-1、ECE-1 mRNA表达。结果与对照组比较,缺氧组6个月龄子鼠ET-1、ECE-1 mRNA表达升高,差异有统计学意义(P<0.01),以妊娠中期缺氧雄性子代升高最为显著。结论产前慢性缺氧可引起子代大鼠心肌ET-1、ECE-1 mRNA表达升高,其中妊娠中期缺氧雄性子鼠受的影响最大,这可能与子代成年后高血压的发生有一定关联。     

Discrepant distribution of big endothelin (ET)-1 and ET receptors in the pulmonary artery.

Since pulmonary vasculature is complex in terms of regional difference in structure and function, it is important to understand the site of endothelin (ET) synthesis and the distribution of the ET system along the axial pathways of pulmonary artery. The expression of big ET-1, ET converting enzyme (ECE) and ET(A) receptors were examined in rat pulmonary arteries under normal and hypoxic conditions using an immunohistochemical method and Northern blot analysis. In normal conditions, big ET-1 was expressed in the intima and media of pulmonary arteries with a predominant distribution in the distal segments and a preferential localization in the media, while ETA receptors were dominantly expressed in the proximal segments. ECE was constitutively expressed in the intima and media. Following exposure to hypoxia, messenger ribonucleic acid (mRNA) expression of ET-1 and ET(A) receptors were up-regulated by two-fold and immunoreactivities for big ET-1, ECE, and ET(A) receptors significantly increased by two to five-fold in the distal segments. Smooth muscle cells are an important source of endothelin-1 in the pulmonary artery. The distribution of big endothelin-1 and endothelin A receptors in pulmonary arteries was discrepant in normal conditions while their expression concomitantly increased in the distal segments in hypoxic conditions. This heterogeneity may play an important role in the regulation of pulmonary vascular tone.     

Captopril does not acutely modulate plasma endothelin-1 concentration in human congestive heart failure

Summary Congestive heart failure (CHF) is a syndrome characterized by increased levels of angiotensin II (Ang II) and endothelin-1 (ET-1). In vitro, Ang II stimulates ET-1 release. The purpose of this study was to assess the effect of a single dose of an angiotensin-converting enzyme inhibitor (ACEI) captopril versus placebo on plasma endothelin concentration in human congestive heart failure. Captopril (25 mg, given orally) was compared with placebo in a group of 20 patients with systolic dysfunction in a double-blind randomized study. Plasma irET concentration was significantly increased in CHF patients compared with normal subjects (5.59 pg/ml±0.35 vs. 3.58 pg/ml±0.99, p<0.0002). Despite the decrease in systolic blood pressure and the increase in plasma renin activity, suggesting a significant blockade of the renin-angiotensin system, no difference in plasma irET-1 was observed between captopril and placebo. Our results suggest that captopril does not acutely influence irET-1 plasma concentration in human CHF. These data do not support the hypothesis that the acute vasodilator effect of a single dose of 25 mg of captopril given orally involves modulation of the increased plasma concentration of endothelin observed in CHF.     

Concentration of circulating plasma endothelin in patients with angina and normal coronary angiograms.

BACKGROUND--Some patients with angina pectoris and normal coronary arteriograms have reduced coronary flow reserve and abnormal endothelium dependent vasodilator responses. Endothelin-1 (ET-1), a potent vasoconstrictor, is an important modulator of microvascular function and may also have algogenic properties. METHOD--Plasma ET-1 was measured in peripheral venous blood in 40 patients (30 women) (mean (SD) age 56 (8) years) with angina and normal coronary arteriograms and 21 normal controls (17 women) (mean (SD) age 53 (7) years). Patients with systemic hypertension, left ventricular hypertrophy, or coronary spasm were excluded. Plasma ET-1 was measured using radioimmunoassay. RESULTS--Thirty five patients had > or = 1 mm ST segment depression during exercise. Left bundle branch block was present in four patients at rest and in one during exercise. Mean (SD) (range) concentration of ET-1 (pg/ml) was higher in patients than in controls (3.84 (1.25) (1.97-7.42) v 2.88 (0.71) (1.57-4.48) P < 0.0001). In patients with "high" (> control mean (one SD)) ET-1 concentrations (n = 23), the time to onset of chest pain during exercise was significantly shorter (6.21 (3.9) v 9.03 (3.9) min; p = 0.01) than in patients with "low" ET-1 concentrations. Of the five patients with left bundle branch block, four had plasma ET-1 concentration > 4.0 pg/ml. CONCLUSION--Plasma endothelin is raised in patients with angina and normal coronary arteriograms and is consistent with the demonstration of endothelial dysfunction in such patients. The association between "high" plasma ET-1 and an earlier onset of chest pain during exercise suggests that endothelin may also have a role in the genesis of chest pain in patients with normal coronary arteries.     

Atrial natriuretic peptide exerts protective action against angiotensin II-induced cardiac remodeling by attenuating inflammation via endothelin-1/endothelin receptor A cascade

We aimed to investigate whether atrial natriuretic peptide (ANP) attenuates angiotensin II (Ang II)-induced myocardial remodeling and to clarify the possible molecular mechanisms involved. Thirty-five 8-week-old male Wistar–Kyoto rats were divided into control, Ang II, Ang II + ANP, and ANP groups. The Ang II and Ang II + ANP rats received 1 μg/kg/min Ang II for 14 days. The Ang II + ANP and ANP rats also received 0.1 μg/kg/min ANP intravenously. The Ang II and Ang II + ANP rats showed comparable blood pressure. Left ventricular fractional shortening and ejection fraction were lower in the Ang II rats than in controls; these indices were higher (P < 0.001) in the Ang II + ANP rats than in the Ang II rats. In the Ang II rats, the peak velocity of mitral early inflow and its ratio to atrial contraction-related peak flow velocity were lower, and the deceleration time of mitral early inflow was significantly prolonged; these changes were decreased by ANP. Percent fibrosis was higher (P < 0.001) and average myocyte diameters greater (P < 0.01) in the Ang II rats than in controls. ANP decreased both myocardial fibrosis (P < 0.01) and myocyte hypertrophy (P < 0.01). Macrophage infiltration, expression of mRNA levels of collagen types I and III, monocyte chemotactic protein-1, and a profibrotic/proinflammatory molecule, tenascin-C (TN-C) were increased in the Ang II rats; ANP significantly decreased these changes. In vitro, Ang II increased expression of TN-C and endothelin-1 (ET-1) in cardiac fibroblasts, which were reduced by ANP. ET-1 upregulated TN-C expression via endothelin type A receptor. These results suggest that ANP may protect the heart from Ang II-induced remodeling by attenuating inflammation, at least partly through endothelin 1/endothelin receptor A cascade.