Increase In Plasma Levels Of Endothelin-1 Research Articles

Endothelial ERK1/2 signaling maintains integrity of the quiescent endothelium.

To define the role of ERK1/2 signaling in the quiescent endothelium, we induced endothelial Erk2 knockout in adult Erk1-/- mice. This resulted in a rapid onset of hypertension, a decrease in eNOS expression, and an increase in endothelin-1 plasma levels, with all mice dying within 5 wk. Immunostaining and endothelial fate mapping showed a robust increase in TGFβ signaling leading to widespread endothelial-to-mesenchymal transition (EndMT). Fibrosis affecting the cardiac conduction system was responsible for the universal lethality in these mice. Other findings included renal endotheliosis, loss of fenestrated endothelia in endocrine organs, and hemorrhages. An ensemble computational intelligence strategy, comprising deep learning and probabilistic programing of RNA-seq data, causally linked the loss of ERK1/2 in HUVECs in vitro to activation of TGFβ signaling, EndMT, suppression of eNOS, and induction of endothelin-1 expression. All in silico predictions were verified in vitro and in vivo. In summary, these data establish the key role played by ERK1/2 signaling in the maintenance of vascular normalcy.

Endothelin-1 in hypertensive patients with ischemic heart disease.

This study was aimed at evaluating whether transient dipyridamole-induced myocardial ischemia in hypertensive patients reflects on endothelin-1 plasma levels by comparing normotensives and hypertensives with or without stable angina. Endothelin-1 plasma levels were assessed in baseline conditions and after provocative stress test by dipyridamole. Four groups of ten age- and sex-matched subjects were retrospectively considered among patients referred for chest pain evaluation and submitted to high-dose Dipyridamole Echocardiographic-Scintigraphic combined test (DES). On the basis of DES results we considered: (1) control normotensives subjects; (2) essential hypertensives (for both groups negative result of DES); (3) essential hypertensives with stable angina; and (4) normotensives with stable angina (for both groups concordant DES detection of myocardial ischemia). Our data showed a marked post-DES increase of endothelin-1 plasma levels in hypertensives with stable angina (mean levels = 16.50 ± 4.19pg/ml p < 0.001 vs. baseline = 9.05 ± 1.37pg/ml) and a minor increase in stable angina pts (mean levels = 8.3 ± 1.75pg/ml p < 0.01 vs. baseline = 6.74 ± 0.61pg/ml) whereas non significant increase was observed both in control (mean levels = 5.09 ± 0.83pg/ml p = n.s. vs. baseline = 4.91 ± 1.04pg/ml) and hypertensives groups (mean levels = 6.34 ± 1.72pg/ml p = n.s. vs. baseline = 5.95 ± 1.04pg/ml). ET-1 involvement in hypertension-related ischemic heart disease patho-physiology appears to be considered.

ET-1 Plasma Levels, Aqueous Flare, and Choroidal Thickness in Patients with Retinitis Pigmentosa.

Purpose. To assess endothelin-1 (ET-1) plasma levels, choroidal thickness, and aqueous flare in patients with early stage retinitis pigmentosa (RP) and to search for possible correlations. Methods. We compared 24 RP patients with 24 healthy controls. Choroidal thickness and aqueous flare were measured, respectively, by using a spectral domain optical coherence tomography and a laser flare-cell meter, whereas plasma samples were obtained from each patient to evaluate ET-1 plasma levels. Results. Notably, RP subjects showed significantly increased ET-1 plasma levels and reduced choroidal thickness compared with controls: 2.143 ± 0.258 versus 1.219 ± 0.236 pg/mL, P < 0.002, and 226.75 ± 76.37 versus 303.9 ± 39.87 μm, P < 0.03, respectively. Higher aqueous flare values were also demonstrated in RP compared to controls: in detail, 10.51 ± 3.97 versus 5.66 ± 1.29 photon counts/ms, P < 0.0001. Spearman's correlation test highlighted that the increase of ET-1 plasma levels was related with the decrease of choroidal thickness (r = −0.702; P < 0.023) and the increase of aqueous flare (r = 0.580; P < 0.007). Conclusions. Early stage RP patients show a breakdown of blood-ocular barrier and increased ET-1 plasma levels and these findings may contribute to the reduction of choroidal thickness.

ET-1 plasma levels, choroidal thickness and multifocal electroretinogram in retinitis pigmentosa

AimTo assess the relationship between both photoreceptor function and choroidal thickness and endothelin-1 (ET-1) plasma levels in patients with early stage retinitis pigmentosa (RP). Main methodsWe compared 24 RP patients (14 males and 10 females), 25 to 42years of age (mean age: 34±7years) with 24 healthy controls (12 males and 12 females) aged between 28 and 45years (mean 36±6.8years). All patients underwent visual field test, electroretinogram and multifocal-electroretinogram and choroidal thickness measurement by using spectral domain optical coherence tomography. Key findingsRP patients had a visual acuity of 0.95, a mean defect of the visual field of −7.90±1.75dB, a pattern standard deviation index of 6.09±4.22dB and a b-wave ERG amplitude of 45.08±8.24μV. Notably RP subjects showed significantly increased ET-1 plasma levels and reduced choroidal thickness compared with controls: respectively, 2.143±0.258pg/ml vs. 1.219±0.236pg/ml; p<0.002 and 226.75±76.37μm vs. 303.9±39.87μm; p<0.03. Spearman's correlation test highlighted that the increase of ET-1 plasma levels was related with the decrease of choroidal thickness (r=−0.702; p<0.023) and the increase of implicit time in both ring 2 (r=−0.669; p<0.034) and ring 3 (r=−0.883; p<0.007) of mfERG. SignificanceIncreased ET-1 plasma levels may play a key role in the impairment of retinal and choroidal blood flow due to the vasoconstriction induced by ET-1. This could lead to worsening of the abiotrophic process of the macular photoreceptors.

A signature of circulating microRNAs differentiates takotsubo cardiomyopathy from acute myocardial infarction

AimsTakotsubo cardiomyopathy (TTC) remains a potentially life-threatening disease, which is clinically indistinguishable from acute myocardial infarction (MI). Today, no established biomarkers are available for the early diagnosis of TTC and differentiation from MI. MicroRNAs (miRNAs/miRs) emerge as promising sensitive and specific biomarkers for cardiovascular disease. Thus, we sought to identify circulating miRNAs suitable for diagnosis of acute TTC and for distinguishing TTC from acute MI.Methods and resultsAfter miRNA profiling, eight miRNAs were selected for verification by real-time quantitative reverse transcription polymerase chain reaction in patients with TTC (n = 36), ST-segment elevation acute myocardial infarction (STEMI, n = 27), and healthy controls (n = 28). We quantitatively confirmed up-regulation of miR-16 and miR-26a in patients with TTC compared with healthy subjects (both, P < 0.001), and up-regulation of miR-16, miR-26a, and let-7f compared with STEMI patients (P < 0.0001, P < 0.05, and P < 0.05, respectively). Consistent with previous publications, cardiac specific miR-1 and miR-133a were up-regulated in STEMI patients compared with healthy controls (both, P < 0.0001). Moreover, miR-133a was substantially increased in patients with STEMI compared with TTC (P < 0.05). A unique signature comprising miR-1, miR-16, miR-26a, and miR-133a differentiated TTC from healthy subjects [area under the curve (AUC) 0.835, 95% CI 0.733–0.937, P < 0.0001] and from STEMI patients (AUC 0.881, 95% CI 0.793–0.968, P < 0.0001). This signature yielded a sensitivity of 74.19% and a specificity of 78.57% for TTC vs. healthy subjects, and a sensitivity of 96.77% and a specificity of 70.37% for TTC vs. STEMI patients. Additionally, we noticed a decrease of the endothelin-1 (ET-1)-regulating miRNA-125a-5p in parallel with a robust increase of ET-1 plasma levels in TTC compared with healthy subjects (P < 0.05).ConclusionThe present study for the first time describes a signature of four circulating miRNAs as a robust biomarker to distinguish TTC from STEMI patients. The significant up-regulation of these stress- and depression-related miRNAs suggests a close connection of TTC with neuropsychiatric disorders. Moreover, decreased levels of miRNA125a-5p as well as increased plasma levels of its target ET-1 are in line with the microvascular spasm hypothesis of the TTC pathomechanism.

Endothelin-1 plasma levels and vascular endothelial dysfunction in primary open angle glaucoma

AimsTo assess the relationship between endothelial dysfunction, endothelin 1 (ET-1) plasma levels and subclinical inflammation in primary open angle glaucoma (POAG) patients. Main methodsWe enrolled 40 POAG patients with progressive visual field damage, although well controlled intraocular pressure (IOP) and compared to age and sex matched healthxy subjects. Each patient underwent an ophthalmological examination, a standard achromatic perimetry (SAP), blood sampling to assess ET-1 plasma levels, an objective assessment of cellularity within the anterior chamber (FLARE) and measurement of flow mediated dilation (FMD) with high resolution 2-dimensional ultrasonographic imaging of the brachial artery. Key findingsAt baseline, POAG patients, compared to healthy controls, showed an increase of ET-1 plasma levels: 2.83±0.28pg/ml vs. 1.75±0.25pg/ml (p<0.001), lower FMD values 4.46±1.28% vs. 13.18±2.80% (p<0.001) and increased FLARE values 9.98±0.97 photons/ms vs. 5.87±0.64 photons/ms (p<0.001). A follow up after 1year revealed a further increase of ET-1 plasma levels (to 3.68±0.60; p<0.001) and decrease of FMD (3.52±1.28; p>0.001). SignificanceThe increase of ET-1 in POAG patients is related to vascular dysfunction (r=0.942; p=0.001) and vascular dysfunction is related to sub-clinical intraocular inflammation (r=0.968; p=0.001). Thus ET-1 and vascular dysfunction related to sub-clinical inflammation may play a key role in determining a progressive visual field damage in POAG patients who present a well-controlled IOP.

ET-1 plasma levels and ocular blood flow in retinitis pigmentosaThis article is one of a selection of papers published in the two-part special issue entitled 20 Years of Endothelin Research.

Retinitis pigmentosa (RP) is an inherited retinal disorder clinically characterized by a pale, waxy optic nerve head, attenuated retinal blood vessels, and bone spicule pigment in the retina. Hemodynamic studies have demonstrated that RP is associated with a reduction in the retinal and choroidal blood flow. Retinal hemodynamic impairment is also present in early stages of RP, and various hypotheses have been advanced as to the cause. The authors studied 20 patients, 12 males and 8 females, aged 26-42 years (mean 35.1 years) and affected by simplex RP. The patients had a visual acuity of 0.9 +/- 0.1, visual field mean defect of -6.52 +/- 3.58 dB, and b-wave electroretinogram amplitude of 260.08 +/- 8.24 microV. An increase in plasma levels of endothelin-1 (ET-1) was found: 1.910 +/- 0.317 pg/mL versus 1.180 +/- 0.210 pg/mL in non-RP controls (p < 0.02). Moreover both an ocular and systemic vascular impairment was detected by means of color Doppler imaging and laser Doppler flowmetry performed during a cold pressor test. We found a correlation between the increase of ET-1 plasma levels in RP and the decrease of peak systolic velocity in the ophthalmic artery (p < 0.03) and in the posterior ciliary arteries (p < 0.006). It is thought that an increase of ET-1 and retinal oxygen levels in RP could lead to vasoconstriction and a decrease of the retinal blood flow, worsening the abiotrophic process.

Endothelin-1 (1-31) Is an Intermediate in the Production of Endothelin-1 After Big Endothelin-1 Administration In Vivo

The precursor of endothelin-1, big endothelin-1, can be hydrolyzed by chymase to generate endothelin-1 (1-31) in vitro. In the present study, we explored the processes involved in the production of endothelin-1 (1-31) as well as its pharmacodynamic characteristics in the rabbit in vivo. Endothelin-1 (1-31) (1 nmol/kg, injected into the left cardiac ventricle) induced a monophasic increase of mean arterial blood pressure similarly to big endothelin-1 (1-38), whereas endothelin-1 induces a biphasic response. Phosphoramidon, a dual neutral endopeptidase and endothelin-converting enzyme inhibitor, blocked both pressor responses to endothelin-1 (1-31) and big endothelin-1 but not those afforded by endothelin-1. Thiorphan, a neutral endopeptidase inhibitor, markedly inhibited the response to endothelin-1 (1-31) but only weakly reduced that of big endothelin-1. In contrast, CGS 35066, an endothelin-converting enzyme inhibitor, was significantly more efficient against the pressor response to big endothelin-1 than to endothelin-1 (1-31). Furthermore, injection of big endothelin-1 concomitantly with phosphoramidon induced an increase in endothelin-1 (1-31) plasma levels. Finally, intracardiac-administered endothelin-1 (1-31) induced an increase of endothelin-1 plasma levels, which are markedly reduced by phosphoramidon and thiorphan but not by CGS 35066. Our results thus demonstrate that endothelin-1 (1-31) is an alternate intermediate in the production of endothelin-1 after big endothelin-1 administration in the rabbit in vivo.

Plasmakonzentrationen von Endothelin-1 nach myokutaner Latissimus dorsi-Transplantation - Bedeutung für den Reperfusionsschaden

The success of a free flap transplantation is based on a sufficient microanastomosis which meets the following requirements: a pedicle placed without kinking or twisting, a good drainage, a well defined recipient vessel and integrity of the endothelium. The aim of this study was to determine whether operation-related ischaemia through flap transplantation and tourniquet induces an increase of Endothelin-1 plasma levels as one cause of vasospasm during microvascular procedures. We focused our attention in particular on the reperfusion period which is often limited to an irreversible perfusion failure of microcirculation due to free radicals, interleukin and Endothelin-1. Twenty-one patients with tissue injury of the lower leg were included in our study, fourteen underwent a latissimus dorsi muscle transplantation with a combined ischaemia, seven patients had a tourniquet ischaemia for tumour resection, debridement and local flap transfer. The duration of ischaemia varied due to the course of operation. The withdrawal of venous blood via central vein catheter, flap vein and wound bed followed a fixed time table pre- and post-reperfusion (T1: preoperative day via cubital vein, T2: 6th postoperative day, T3: 5 min, T4: 10 min, T5: 15 min, T6: 1 h post-declamping and after tourniquet ischaemia via central vein catheter and T7: within 5 min from the flap vein immediate after recharging the flap). The vessel anastomosis determined the withdrawal from the local wound bed. ET-1 in venous blood samples were measured with ELISA. The duration of ischaemia in the tourniquet group ranged from 22 min up to 210 min with a mean of 76.58 min and in the latissimus group from 87 min up to 203 min with a mean of 139.21 min. The mean ET-1 plasma concentration measured systemically before operation in the 21 patients was 0.51 +/- 0.08 pg/ml (Mean +/- SD). This result corresponds with data published in literature. The locally measured plasma levels of ET-1 after tourniquet and flap ischaemia were increased with 0.34 up to 3.90 pg/ml (0.95 +/- 0.79 pg/ml [Mean +/- SD]) for the tourniquet group and with 0.34 up to 14.87 pg/ml (1.85 +/- 3.64 pg/ml [Mean +/- SD]) for the latissimus group. This is an increase compared to systemically measured values as 0.75 +/- 0.06 pg/ml (Mean +/- SD) for the tourniquet group and 0.58 +/- 0.21 pg/ml (Mean +/- SD) for the latissimus group. We conclude that Endothelin-1 is increased locally in the early reperfusion period after free latissimus dorsi-transplantation.

Usefulness of the supine-rest maneuver before neurohormonal sampling

In congestive heart failure (CHF), several endocrine systems are progressively activated in an attempt to maintain a working hemodynamic. 1 Francis G.S Benedict C Johnstone D.E Kirlin P.C Nicklas J Liang C.S Kubo S.H Rudin-Toretsky E Yusuf S the SOLVD InvestigatorsComparison of neuroendocrine activation in patients with left ventricular dysfunction with and without congestive heart failure. Circulation. 1990; 82: 1724-1729 Crossref PubMed Scopus (1276) Google Scholar Measurements of various neurohormones, such as atrial natriuretic factor (ANF), the N-terminal part of its precursor (N-proANF), or the brain natriuretic peptide (BNP), as well as measurements of vasoactive paracrine peptides, such as endothelin-1 (ET-1), are increasingly advocated to evaluate the disease severity or to predict the adverse clinical outcomes. 2 McDonagh T.A Robb S.D Murdoch D.R Morton J.J Ford I Morrison C.E Tunstall-Pedoe H McMurray J.J.V Biochemical detection of left ventricular systolic dysfunction. Lancet. 1998; 351: 9-13 Abstract Full Text Full Text PDF PubMed Scopus (908) Google Scholar , 3 Selvais P.L Donckier J.E Robert A Laloux O Van Linden F Ahn S Ketelslegers J.M Rousseau M.F Cardiac natriuretic peptides for diagnosis and risk stratification in heart failure influences of left ventricular dysfunction and coronary artery disease on cardiac hormonal activation. Eur J Clin Invest. 1998; 28: 636-642 Crossref PubMed Scopus (84) Google Scholar By analogy with norepinephrine assays, it is common practice to use the so-called “30-minute supine rest” maneuver before sampling of these neurohormones. This procedure is supposed to blunt any stress-related changes in catecholamine levels. 4 Benedict C.R Shelton B Johnstone D.E Francis G Greenberg B Konstam M Probstfield J.L Yusuf S the SOLVD InvestigatorsPrognostic significance of plasma norepinephrine in patients with asymptomatic left ventricular dysfunction. Circulation. 1996; 94: 690-697 Crossref PubMed Scopus (288) Google Scholar This time-consuming procedure is certainly a major restriction when considering the implementation of neurohormone measurement as a standard tool in the evaluation or follow-up of large numbers of patients with CHF. Furthermore, it is also often believed that the plasma levels of natriuretic peptides will increase in the supine position and that the plasma levels of ET-1 will decrease. However, this is only an indirect inference from the observed decrease of natriuretic peptide plasma levels and of the increase in ET-1 plasma levels when assuming the upright position. 5 Nicholls D.P Riley M Elborn J.S Stanford C.F Shax C McKillop J.M Buchanan K.D Regulatory peptides in the plasma of patients with chronic cardiac failure at rest and during exercise. Eur Heart J. 1992; 13: 1399-1404 PubMed Google Scholar , 6 Solomon L.R Atherton J.C Bobinski H Green R Effect of posture on plasma immunoreactive atrial natriuretic peptide concentration in man. Clin Sci. 1986; 71: 299-305 Crossref PubMed Scopus (55) Google Scholar , 7 Westendorp R.G.J Roos A.N Riley L.C.M Walma S Frölich M Meinders A.E Chronic stimulation of atrial natriuretic peptide attenuates the secretory response to postural changes. Am J Med Sci. 1993; 306: 371-375 Crossref PubMed Scopus (5) Google Scholar , 8 La Villa G Vena S Conti A Fronzaroli C Brat A Lazzeri C Tosti Guerra C Madiai S Marra N Frachi F Plasma levels of brain natriuretic peptide in healthy subjects and patients with essential hypertension:response to posture. Clin Sci. 1993; 85: 411-416 PubMed Google Scholar , 9 Kaufman H Oribe E Oliver J.A Plasma endothelin during upright tilt relevance for orthostatic hypotension?. Lancet. 1991; 338: 1542-1545 Abstract PubMed Scopus (139) Google Scholar Surprisingly, there is no systematic and comparative study of the effects of this maneuver on the plasma levels of natriuretic or vasoactive peptides. The aim of the present study was to evaluate the real relevance of the supine-rest position in a healthy and cardiac population.

Pseudoexfoliatio capsulae and endothelin-1 plasma levels.

The authors found an increase of endothelin-1 (ET-1) plasma levels in patients with pseudoexfoliatio syndrome (PXS): 2.730 +/- 0.224 pg/ml vs 1.420 +/- 0.30S pg/ml. With Color Doppler Imaging (CDI) they found in PXS patients a decrease of peak systolic velocity values in the posterior ciliary arteries that were 12.725 +/- 2.536 cm/sec vs 15.450 +/- 3.173 cm/sec (p < 0.049) while the resistance values were increased 0.640 +/- 0.051 vs 0.548 +/- 0.058 (p < 0.001). The increase of ET-1 plasma levels may assess the vasospasm and uveal tissue hypoxia.

Renal endothelin in heart failure and its relation to sodium excretion

Background Recent studies have shown that endothelin-1 (ET-1) antagonists increase sodium excretion and improve renal blood flow in experimental heart failure (HF). However, despite a number of investigations that have reported a significant increase in ET-1 plasma levels in patients with HF, it is still not known whether increased renal synthesis and urinary excretion of ET-1 occur. Our aim was to investigate renal ET-1 formation and its relation to sodium excretion in patients with HF. Methods One hundred forty-seven patients with HF, subdivided according to New York Heart Association (NYHA) functional classes, and 28 healthy controls were studied. ET-1 and big ET-1 were measured in plasma and in 24-hour urine by radioimmunoassay. Atrial and brain natriuretic peptide, arginine vasopressin, plasma renin activity, and hemodynamic variables were also investigated. Results Urinary ET-1 excretion was already increased in NYHA class II patients (P < .001 vs controls), whereas plasma ET-1 increased only in NYHA class III and IV patients (P < .001). In the 71 subjects who were not receiving diuretic treatment, urinary ET-1 was selected as the strongest predictor of sodium excretion by multivariate stepwise analysis. Conclusions Urinary ET-1 excretion increases in an earlier phase of HF than plasma ET-1 and appears to be closely correlated with sodium excretion, indicating renal ET-1 is a target for ET-1 antagonists in patients with HF. (Am Heart J 2000;140:617-23.)

ET-1 plasma levels during cold stress test in sclerodermic patients.

Endothelial cell injury in blood vessels of small arteries and capillaries is considered the primary event in the pathogenesis of systemic sclerosis (SSc). Because endothelin-1 (ET-1) is mainly released in the site of endothelial cell damage, thereby inducing a potent vasoconstriction, it was our intention to study ET-1 release in a group of SSc patients during a cold pressor test (CPT). Twelve SSc patients and a control group of 10 healthy subjects underwent CPT. Blood samples for ET-1 assay were collected at 90 and 180 seconds of exposure to cold stress. Heart rate and blood pressure were recorded at the same intervals. A capillaroscopic examination was performed in both groups before and after CPT. We observed significantly higher levels of plasma ET-1 in SSc patients compared with those of the control group at baseline (P=0.007) and at 90 (P=0.006) and 180 seconds (P=0.03) of CPT. During the test, the capillaroscopic examination showed a dramatic worsening of the vascular picture that was parallel to the increase in ET-1 plasma levels. This suggests that higher ET-1 plasma levels can have a part in the acute vascular reactivity of SSc patients undergoing CPT.

Exercise Increases Endothelin-1 Plasma Concentrations in Patients with Coronary Artery Disease

Previous studies suggest that ET-1 plays a role in induction of coronary artery disease (CAD). It was shown that secretion of endothelin-1 (ET-1) by the vascular endothelium is enhanced in atherosclerotic alterations and may be antagonized by EDRF. The objective of the present study was to investigate the effects of ergometric exercise on plasma ET-1 concentrations, and the potential modulatory role of LDL cholesterol, and the effects of an orally administered nitrate, PETN, in patients with CAD. Ten men with CAD and 10 healthy men underwent bicycle ergometry according to the WHO-standards. Venous blood samples for determination of ET-1 concentrations were drawn directly before and 5 min after ergometric exercise. Patients were randomized and treated for 72 h in a crossover design either with placebo or pentaerithrityltetranitrate (PETN). After 72 h the identical ergometric protocol was repeated. Basal plasma levels of ET-1 were 6.1 +/- 0.7 pg/ml (patients) and 5.5 +/- 0.6 pg/ml (controls) (n.s.). After ergometric exercise ET-1 plasma concentrations rose significantly (7.3 +/- 0.9 pg/ml; p < 0.05) in the patient group under placebo treatment, whereas they remained constant (5.5 +/- 0.7 pg/ml) with PETN treatment. ET-1 levels remained unaffected by ergometric exercise in healthy controls. Mean LDL cholesterol plasma levels in patients with CAD were 156 +/- 8 mg% and 152 +/- 7 mg% in healthy controls. In the patient group there was a significant (p < 0.002) positive correlation between the exercise-induced increase in ET-1 and the LDL cholesterol plasma concentrations (r = 0.85). Blood pressure and heart rate were not modified by PETN treatment. In patients with CAD bicycle ergometry induced an increase in ET-1 plasma concentrations. The positive correlation with the LDL cholesterol plasma levels indicates that LDL cholesterol is involved in regulation of ET-1 secretion in vivo. PETN therapy completely abolished the exercise-induced increase in ET-1 plasma levels. This may result from local hemodynamic effects of the nitrate; hypothetically a nitrate-induced rise in the local NO concentrations can be considered. The clinical implications of these findings remain elusive. However, the findings of the present study are in accordance with the beneficial clinical effects of nitrates in patients with CAD.

Exercise Increases Endothelin-1 Plasma Concentrations in Patients with Coronary Artery Disease

Summary: Previous studies suggest that ET-1 plays a role in induction of coronary artery disease (CAD). It was shown that secretion of endothelin-1 (ET-1) by the vascular endothelium is enhanced in atherosclerotic alterations and may be antagonized by EDRF. The objective of the present study was to investigate the effects of ergometric exercise on plasma ET-1 concentrations, and the potential modulatory role of LDL cholesterol, and the effects of an orally administered nitrate, PETN, in patients with CAD. Ten men with CAD and 10 healthy men underwent bicycle ergometry according to the WHO-standards. Venous blood samples for determination of ET-1 concentrations were drawn directly before and 5 min after ergometric exercise. Patients were randomized and treated for 72 h in a crossover design either with placebo or pentaerithrityltetranitrate (PETN). After 72 h the identical ergometric protocol was repeated. Basal plasma levels of ET-1 were 6.1 ± 0.7 pg/ml (patients) and 5.5 ± 0.6 pg/ml (controls) (n.s.). After ergometric exercise ET-1 plasma concentrations rose significantly (7.3 ± 0.9 pg/ml; p < 0.05) in the patient group under placebo treatment, whereas they remained constant (5.5 ± 0.7 pg/ml) with PETN treatment. ET-1 levels remained unaffected by ergometric exercise in healthy controls. Mean LDL cholesterol plasma levels in patients with CAD were 156 ± 8 mg% and 152 ± 7 mg% in healthy controls. In the patient group there was a significant (p < 0.002) positive correlation between the exercise-induced increase in ET-1 and the LDL cholesterol plasma concentrations (p= 0.85). Blood pressure and heart rate were not modified by PETN treatment. In patients with CAD bicycle ergometry induced an increase in ET-1 plasma concentrations. The positive correlation with the LDL cholesterol plasma levels indicates that LDL cholesterol is involved in regulation of ET-1 secretion in vivo. PETN therapy completely abolished the exercise-induced increase in ET-1 plasma levels. This may result from local hemodynamic effects of the nitrate; hypothetically a nitrate-induced rise in the local NO concentrations can be considered. The clinical implications of these findings remain elusive. However, the findings of the present study are in accordance with the beneficial clinical effects of nitrates in patients with CAD.

Plasma endothelin-1 levels in stable and unstable angina.

Plasma levels of endothelin-1 are elevated in acute myocardial infarction with higher levels in complicated infarctions. Measurements of levels in unstable angina could help clarify whether the elevation is the consequence of cell necrosis or is in some way related to the pathophysiology of acute coronary syndromes. Plasma endothelin-1 levels were determined by radioimmunoassay in 29 patients with unstable angina and 6 with a myocardial infarction. Blood samples were obtained at admission before drug administration and 6 and 72 h later. Levels were also determined in 27 control subjects and in 29 patients with stable angina. Admission levels were similar in unstable angina, 0.635 +/- 0.052 pg/ml [log(1 + x)], and myocardial infarction, 0.746 +/- 0.122, and significantly higher than in controls, 0.428 +/- 0.047, and stable angina patients, 0.449 +/- 0.052 (p < 0.01). In unstable angina, levels decreased progressively to normal at 6 h, 0.557 +/- 0.049 pg/ml, and 72 h 0.474 +/- 0.054, as opposed to an increase to 0.868 +/- 0.109 (p < 0.05) after 6 h in myocardial infarction followed by a decrease to 0.597 +/- 0.122 at 72 h. The elevation in unstable angina did not correlate with other clinical or laboratory characteristics. Unstable angina is associated with an increase in endothelin-1 plasma levels during the acute phase, suggesting a role of this endothelium-derived vasoactive peptide in the pathophysiology of acute coronary artery syndromes.