endothelin-1 and Coronary-Disease

Factor involved in the pathogenesis of cardiovascular diseases, especially coronary heart disease is the endothelium. The balance between endothelial substances originating from the action, and narrowed the extension is the essence of vascular hemostasis. The main dish is shrinking substances endothelin-1 (ET-1). The aim of the study was to determine the role of signs ET-1 levels in the diagnosis of cardiovascular diseases, especially coronary heart disease. In numerous reports described the impact of increased blood pressure, caused by the press on blood vessels. Most authors reported higher concentrations of ET-1 in serum of patients with ischemic heart disease, particularly its unstable character. High values were observed in patients with myocardial infarction. ET-1 level in the blood is markedly increased in patients with heart failure, correlating with NYHA functional class. High concentrations of ET-1 in many disease entities, and thus its low specificity makes the need for further research on the importance of this substance in the diagnosis of cardiovascular diseases.

Topics: Biomarkers; Cardiovascular Diseases; Coronary Disease; Endothelin-1; Humans; Myocardial Infarction; Sensitivity and Specificity

Unlike the rare and severe genetic defects that cause monogenic diseases, the genetic factors that modulate the individual susceptibility to multifactorial diseases (cardiovascular diseases, cancers, diabetes, etc.) are common, functionally different, forms of genes (polymorphisms), which generally have a modest effect at an individual level but, because of their high frequency in the population, can be associated with a high attributable risk. Environmental factors can reveal or facilitate the phenotypic expression of such susceptibility genes. Indeed, in common diseases genetic effects can be considerably amplified in the presence of triggering factors. There is now accumulating evidence that most of the susceptibility genes for common diseases do not have a primary aetiological role in predisposition to disease, but rather act as response modifiers to exogenous factors such as stress, environment, disease, drug intake. A better characterisation of the interactions between environmental and genetic factors constitute a key issue in the understanding of the pathogenesis of multifactorial diseases. The present paper will review three examples of gene-environment interactions in the field of CHD.

Topics: Alcohol Drinking; Blood Pressure; Body Mass Index; Carrier Proteins; Cholesterol Ester Transfer Proteins; Coronary Disease; Endothelin-1; Environment; Genetic Predisposition to Disease; Glycoproteins; Humans; Life Style; Lipoprotein Lipase; Myocardial Infarction; Triglycerides

Endothelial health is a key factor in normal cardiovascular homeostasis, and recent studies have revealed several important functions of the vascular endothelium that protect against atherothrombosis. These include control over arterial tone, coagulation, fibrinolysis, and vascular growth. Consequently, endothelial dysfunction has been implicated as an important event in the pathogenesis of atherosclerosis, coronary vasoconstriction, hypertension, and myocardial ischaemia. Therefore, there has been considerable research interest in diagnostic assays for the assessment of endothelium. This review outlines the current status of markers of endothelial dysfunction, particularly those related to vasomotor control, as well as circulating markers of vascular health.

Topics: Adult; Aged; Arteriosclerosis; Biomarkers; Child; Confidence Intervals; Coronary Disease; Endothelin-1; Endothelium, Vascular; Humans; Hypercholesterolemia; Hypertension; Nitric Oxide; Plethysmography; Prognosis; Risk; Risk Factors; Tissue Plasminogen Activator; Tomography, Emission-Computed; Vasodilation; Vasomotor System; von Willebrand Factor

The endothelins comprise a family of three isopeptides ET-1, ET-2 and ET-3, whereby ET-1 appears to be the most relevant in humans. They act in a paracrine manner on ETA and ETB receptors. ET-1 plays an important role in the cardiovascular system. In addition, it modulates vasomotion and growth processes, and it participates in thrombogenesis and neutrophil adhesion. This review summarizes some of the current literature pertaining to the physiological and pathophysiological significance of ET-1, focusing the assets and drawbacks of elevated ET-1 levels. In this regard, modulation of the endothelin system by either receptor blockade or by inhibition of endothelin converting enzyme is expected to provide novel therapeutic drug strategies.

Topics: Animals; Calcium Channels, L-Type; Coronary Disease; Endothelin Receptor Antagonists; Endothelin-1; Humans; Hypertension; Receptor, Endothelin A; Receptor, Endothelin B

Endothelin-1 (ET-1), the member of a newly discovered family of vasoactive peptides is the most aggressive endogenous vasoconstrictor agent known to science. This paper summarizes the recent work of a Hungarian research group related to the regulatory role of ET-1 in the mammalian heart. The results highlighted the unique pathophysiological and clinical features of the ET-1 action in the coronary vascular bed suggesting the potential role of the peptide in precipitating coronary spasm as well as its outstanding capacity for inducing cardiac arrhythmias. Contrary to the classical tenets of homeostasis, such effects do not reduce but increase variability and inhomogeneity (both in myocardial blood flow distribution and generation of electrical impulses), indicating the involvement of new types of regulatory principles in the cardiovascular system.

Topics: Arrhythmias, Cardiac; Coronary Disease; Endothelin-1; Heart; Humans

Topics: Coronary Disease; Endothelin-1; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Hypertension; Kidney Diseases; Postoperative Period; Time Factors

The endothelium participates in the control of coronary vascular tone and growth through the release of vasodilating and growth-inhibiting factors such as nitric oxide (NO) and C-type natriuretic peptide (CNP), and vasoconstricting and growth-promoting substances such as endothelin-1 (ET-1). Abnormalities in NO and/or CNP generation or actions have been demonstrated in various cardiovascular pathophysiological states, specifically atherosclerosis, congestive heart failure, hypertension and hypercholesterolaemia. Moreover, an increase in plasma ET-1 levels has also been reported in these disease states. When these observations are considered together, these states may be characterised by an attenuated release or action of NO and/or CNP, together with an augmented release of ET-1. Thus, an imbalance between these opposing factors may contribute to the alteration in vascular tone and the vascular remodelling characteristics of cardiovascular disease. The following article summarises the present knowledge of endothelial control of the coronary circulation and derangements associated with coronary endothelial dysfunction.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Calcium Channel Blockers; Coronary Circulation; Coronary Disease; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide

An increasing body of evidence indicates that the endothelium is crucially involved in the regulation of coronary blood flow and cardiac function. Injury to the endothelium precipitates atherosclerosis by leading to smooth-muscle-cell migration and proliferation, induction of expression of growth factors and impairment in the plasmatic coagulation and endogenous fibrinolysis system. Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and trafficking blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by endothelial vasoconstrictors, such as angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. Modern therapeutic strategies in coronary artery disease focus on preserving or restoring endothelial integrity. Whereas nitrates partly substitute deficient endogenous nitric oxide, calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing Ca2+ inflow and facilitating the vasodilator effects of nitric oxide. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. Furthermore, newly developed specific endothelin antagonists will provide us with greater insight into the beneficial effects of restoring endothelial dysfunction in cardiovascular disease. Thus, drugs can directly affect endothelial function, prevent the action of endothelial mediators, substitute for deficient endothelial factors or indirectly exert protective effects by interfering with cardiovascular risk factors.

Topics: Animals; Coronary Disease; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Humans; Muscle, Smooth, Vascular; Nitric Oxide

The endothelin family of peptides are extremely potent endogenous vasoconstrictor and pressor agents. Of the 3 isoforms, endothelin-1 is the major isoform produced by the vascular endothelium and is, therefore, likely to be of most importance for regulation of vascular function. Two endothelin receptor subtypes have so far been cloned in mammalian species; ET A, and ET B. Both receptor subtypes are found on smooth muscle cells and mediate the vasoconstrictor and pressor actions of endothelin. The ET B receptor is also found on vascular endothelial cells and mediates endothelin-dependent vasodilatation through release of nitric oxide and prostacyclin. Since their discovery in 1988, the endothelins have been the subject of intense research on their physiological function and potential pathophysiological role in cardiovascular disease. There is now good evidence that endothelin regulates vascular tone and blood pressure, and studies to support the development of endothelin receptor antagonists in conditions associated with chronic vasoconstriction, such as hypertension and heart failure, as well as in vasospastic disorders, such as subarachnoid haemorrhage and Raynaud's disease. There are now a number of selective ET A and combined ET A/B receptor antagonists available for preclinical studies. However, it is still not clear which of these will prove to be of most therapeutic value. Some of these agents are currently being assessed in early phase clinical trials. Endothelin receptor antagonists represent a novel therapeutic approach to a fundamental and newly discovered endogenous vasoconstrictor mechanism. The results of the current clinical trials are awaited with considerable interest.

Topics: Amino Acid Sequence; Animals; Cardiovascular Diseases; Coronary Disease; Endothelin Receptor Antagonists; Endothelin-1; Heart Failure; Humans; Hypertension; Migraine Disorders; Raynaud Disease; Subarachnoid Hemorrhage

Myocardial infarction is the major cause of death in the Western world. Men are more prone to develop coronary artery disease than women, who rarely develop coronary disease before menopause. Although epidemiological data has long been available showing a protective effect of estrogen on the vascular system, the underlying mechanisms have been investigated more thoroughly only in recent years. Meta-analysis studies have revealed that only half of the protective effect on estrogen replacement therapy is due to its positive effects on the lipid profile and that a large part of this protection is caused by mechanisms distinct from lipid metabolism. It is now known that estrogens also exert effects on vascular function and structure of the vessel wall involving numerous cellular and molecular mechanisms. Here we review actions of natural estrogens on human vascular cells and arteries. Estrogens can modulate vascular function by increasing nitric oxide production via stimulation of endothelial nitric oxide synthase (eNOS) and decreasing endothelin-1 levels in vivo. Furthermore, 17 beta-estradiol is an inhibitor of vascular smooth muscle cell proliferation and migration, phenomena that play a major role in atherosclerotic vascular disease and in the remodelling process. 17 beta-estradiol can also acutely affect vascular tone in human arteries and attenuates constriction induced by contractile agonists. Finally, clinical studies have shown that 17 beta-estradiol can acutely and chronically ameliorate vascular function in women with and without vascular disease. In conclusion, results from clinical and in vitro studies confirm the positive effects of natural estrogens on vascular function and protection from coronary heart disease. Thus, primary prevention of coronary heart disease by estrogen replacement therapy after the menopause appears to be a new and straightforward approach by which cardiovascular mortality in women can be reduced.

Topics: Adult; Aged; Arteriosclerosis; Coronary Disease; Endothelin-1; Endothelium; Estradiol; Estrogen Replacement Therapy; Estrogens; Female; Humans; Male; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide Synthase

To observe the effects of Liandouqingmai Recipe on life quality and vascular endothelial injury in patients with coronary heart disease.. Capitalized 101 patients with coronary heart disease were randomly divided into a treatment group (n = 45) treated with Liandouqingmai Recipe and a standard treatment group (control group, n = 56). A normal group of 16 healthy persons was additionally set up. Changes in ET-1 and NO levels were measured and Seatle Angina Questionnaire (SAQ) was adopted in studying life quality before and after treatment for two weeks. The data were analyzed with SPSS 16.0 statistic software.. The average level of ET-1 in the normal group was lower and NO higher than that of patients with coronary heart disease. There was no significant difference in the average level of ET-1 and NO and in the scores of SAQ [physical limitation (PL), apngina stability (AS), apngina frequency (AF), treatment satisfaction (TS) and disease perception (DP)] between the two groups before treatment (P > 0.05). But after treatment, the scores of SAQ (PL, AS, AF, TS, DP) and NO level were higher than those in the control group, and ET-1 average level in the treatment group was lower than that in the control group. The negative relations between PL and ET-1 and between AF and ET-1 were found in this study.. Liandouqingmai Recipe can raise scores of SAQ and NO level and decline ET level in patients with coronary heart disease on the basis of convertional standard treatment, thus improving vascular endothelial function and life quality. Life quality is related to vascular endothelial function.

Topics: Aged; Aged, 80 and over; Coronary Disease; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Male; Middle Aged; Quality of Life; Surveys and Questionnaires

Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy.. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012).. In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.

Topics: Adrenomedullin; Aged; Angiotensin-Converting Enzyme Inhibitors; Atrial Natriuretic Factor; Biomarkers; Cardiovascular Diseases; Coronary Disease; Death; Endothelin-1; Female; Glycopeptides; Heart Failure; Humans; Indoles; Male; Middle Aged; Peptide Fragments; Prognosis; Protein Precursors; Risk; Stress, Physiological; Stroke Volume

To observe effects of Liandou Qingmai Recipe (see text) on endothelin-1 (ET-1), nitric oxide (NO), interleukin-6 (IL-6) and IL-10 levels in patients with coronary heart disease.. Total 101 cases with coronary heart disease were randomly divided into a treatment group (n = 45) treated by Liandou Qingmai Recipe and a standard treatment group (control group, n = 56), with a normal group of 16 health persons set up. Changes of ET-1, NO, IL-6 and IL-10 levels were measured before treatment and after treatment for two weeks. And the data were analyzed by SPSS 16.0 statistic software.. Before treatment, the levels of ET-1, IL-6 and IL-10 levels were significantly higher and NO was significantly lower in the patients with coronary heart disease than those in the normal group (90.7 +/- 12.7 ng/L vs 41.8 +/- 13.5 ng/L, 9.17 +/- 0.18 ng/L vs 1.10 +/- 0.08 ng/L, 1.94 +/- 0.26 ng/L vs 1.09 +/- 0.06 ng/L, and 92.2 +/- 17.7 micromol/L vs 124.5 +/- 27.2 micromol/L; all P < 0.05), with no significant differences in the levels of ET-1, NO, IL-6 and IL-10 between the treatment group and the control group (P > 0.05); After treatment, ET-1 and IL-6 significantly decreased in the treatment group and the control group, and NO increased in the treatment group; And IL-6 level was significantly lower and NO level was higher in the treatment group than those in the control group (4.48 +/- 1.22 ng/L vs 5.13 +/- 1.85 ng/L, 117.4 +/- 22.3 micromol/L vs 92.4 +/- 17.1 micromol/L; both P < 0.05); There was a positive correlation between IL-6 and IL-10, and a negative correlation between NO and IL-10 (r = 0.142, r = -0.152; both P < 0.05).. Liandou Qingmai Recipe can decline IL-6, IL-10 and ET-1 levels, and raise NO level in patients with coronary heart disease on the basis of standard treatment, so as to inhibit endothelial inflammatory response, improve vascular endothelial function, with stronger anti-AS action; And vascular endothelial lesion is related with inflammatory response.

Topics: Aged; Aged, 80 and over; Coronary Disease; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Interleukin-10; Interleukin-6; Male; Middle Aged; Nitric Oxide

We sought to examine the effect of trimetazidine (TMZ) on heart rate variability (HRV), endothelin-1 (ET-1), NO, and anginal symptoms in patients with slow coronary artery flow (SCAF).. The 48 patients with SCAF (29 women and 19 men; mean age, 52 +/- 9 years) were included in the study. Twenty milligrams TMZ 3 times a day or matched placebo were given randomly in a double-blinded fashion for 4 weeks. Patients were divided into 4 groups as follows: exercise-positive, TMZ-given group (group A, n = 12); exercise-positive, placebo-given group (group B, n = 12); exercise-negative, TMZ-given group (group C, n = 12); and exercise-negative, placebo-given group (group D, n = 12).. After TMZ treatment, HRV parameters, including SD of the all R-R intervals, SD of the averages of R-R intervals in all 5-minute segments of the entire recording, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, significantly improved both in exercise-positive and exercise-negative groups when compared with baseline. After TMZ treatment, ET-1 and NO levels significantly altered both in exercise-positive and exercise-negative groups when compared with baseline (17.7 +/- 2.7 vs 13.9 +/- 2.8 pg/mL [P = .01] and 18.1 +/- 3.8 vs 14.2 +/- 2.6 pg/mL [P = .01], respectively). After TMZ treatment, NO levels significantly increased in both exercise-positive and exercise-negative groups when compared with baseline (36.4 +/- 5.4 vs 43.3 +/- 6.8 micromol/L [P = .01] and 36.8 +/- 7.8 vs 43.3 +/- 4.8 micromol/L [P = .01], respectively). However, in placebo group, neither HRV parameters nor ET-1 and NO levels altered when compared with baseline. Also, after treatment, a significant correlation was detected between HRV parameters, including SD of the averages of R-R intervals in all 5-minute segments of the entire recording, SD of the all R-R intervals, percentage of R-R intervals with more than 50-millisecond variation, and the square root of the mean of the sum of the squares of differences between adjacent R-R intervals, and NO and ET-1 levels in TMZ group but not placebo.. Short-term TMZ therapy improved HRV parameters and endothelial products such as ET-1 and NO as well as anginal symptom in patients with SCAF. Improvement in HRV parameters was correlated with ET-1 and NO levels.

Topics: Blood Flow Velocity; Chi-Square Distribution; Coronary Angiography; Coronary Disease; Coronary Vessels; Double-Blind Method; Electrocardiography, Ambulatory; Endothelin-1; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Regional Blood Flow; Statistics, Nonparametric; Trimetazidine; Vasodilator Agents

To study the association between the indices of endothelial function in obstruction sleep apnea-hypopnea syndrome (OSAHS) and coronary heart disease (CHD) and the effect of nasal continuous positive airway pressure (nCPAP) on the combination of OSAHS and CHD.. A total of 80 subjects were prospectively recruited into four groups including control, OSAHS, CHD, OSAHS with CHD groups, with 20 subjects each. The indices of sleep apnea, serum nitric oxide (NO), and plasma endothelial-1 (ET-1) were measured. The changes of concentration of ET-1 and NO were compared before and after nCPAP therapy. The associations between ET-1 and NO and MSpO2, CT90 were analyzed.. (1) Multi-variable logistic analysis showed that OSAHS was one of the risk factors for CHD (OR = 0.511). (2) Compared with the control subjects and CHD group, there were significantly higher values of CT90, concentrations of ET-1 and lower values of MSpO2, concentrations of NO in both OSAHS and OSAHS with CHD groups (P < 0.01). There were no significant difference in sleep apnea indices between OSAHS and OSAHS with CHD groups (P > 0.05). However, in the group of OSAHS with CHD, the plasma ET-1 was significantly higher, whereas the serum NO was significantly lower than that in the group of OSAHS alone (P < 0.01). (3) The concentration of serum NO in the group of OSAHS was positively correlated with MSpO2 (r = 0.519, P < 0.05) and inversely correlated with CT90 (r = -0.529, P < 0.05). In addition, the concentration of plasma ET-1 was inversely correlated with MSpO2 (r = -0.457, P < 0.05) and positively correlated with CT90 (r = 0.476, P < 0.05). (4) In the groups of OSAHS and OSAHS with CHD, MSpO2, NO and NO/ET-1 after nCPAP therapy were higher than those before therapy, while CT90 and ET-1 were lower than those before therapy (P < 0.01).. OSAHS is one of the risk factors for CHD. Endothelial function was significantly impaired in OSAHS patients, and more severe in patients with OSAHS with CHD. The impairment of endothelial function may be one of the main mechanisms for the development or deterioration of CHD in OSAHS patients. The vascular endothelial dysfunction can be ameliorated by nCPAP treatment, which is correlated with improvement of nocturnal hypoxemia.

Topics: Adult; Body Weight; Continuous Positive Airway Pressure; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Logistic Models; Male; Middle Aged; Nitric Oxide; Sleep Apnea, Obstructive

To explore the effects of Xuezhikang Capsules (ZXKC) and probucol on blood lipids, vascular endothelial functions and redox status in patients with coronary heart disease.. One hundred and twelve patients with coronary heart disease were randomly divided into XZKC-treated group and probucol-treated group, 56 in each. Before and after 8-week treatment, the blood levels of total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), nitric oxide (NO), endothelin-1 (ET-1), reduced glutathione (GSH) and oxidized glutathione (GSSG) were all measured in both groups. The GSH/GSSG redox potential (Eh) was calculated according to the Nernst equation.. In the XZKC-treated group, the blood levels of TC, LDL-C and TG were significantly decreased after 8-week treatment as compared with those before treatment. The blood levels of TC and LDL-C were also significantly decreased in the probucol-treated group as compared with those before treatment. In the XZKC-treated group, the blood levels of ET-1 and GSSG and the GSH/GSSG Eh after treatment were all significantly lower than those before treatment, whereas the blood levels of GSH and NO, the NO/ET-1 ratio, and the GSH/GSSG ratio after treatment were all significantly higher than those before treatment.. The XZKC or probucol treatment can yield a significant decrease in blood lipids in patients with coronary heart disease. Furthermore, XZKC exerts effective protection on vascular endothelial function, and can make GSH/GSSG redox status shift towards deoxidation.

Topics: Aged; Capsules; Cholesterol; Cholesterol, LDL; Coronary Disease; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Female; Glutathione; Humans; Male; Middle Aged; Nitric Oxide; Oxidation-Reduction; Phytotherapy; Triglycerides

Soya isoflavones are thought to be cardioprotective due to their structural similarity to oestrogen. In order to investigate the effect of soya isoflavones on markers of endothelial function we conducted a randomised, double-blind, placebo-controlled, cross-over study with thirty healthy postmenopausal women. The women consumed cereal bars, with or without soya isoflavones (50 mg/d), for 8 weeks, separated by an 8-week washout period. Systemic arterial compliance (SAC), isobaric arterial compliance (IAC), flow-mediated endothelium-dependent vasodilation (FMD) and nitroglycerine-mediated endothelium-independent vasodilation (NMD) were measured at the beginning of the study and after each intervention period. Blood pressure (BP) and plasma concentrations of nitrite and nitrate (NOx) and endothelin-1 (ET-1) were measured at the beginning and end of each intervention period. NMD was 13.4 (SEM 2.0)% at baseline and 15.5 (SEM 1.1) % after isoflavone treatment compared with 12.4 (SEM 1.0)% after placebo treatment (P=0.03). NOx increased from 27.7 (SEM 2.7) to 31.1 (SEM 3.2) microM after isoflavones treatment compared with 25.4 (SEM 1.5) to 20.4 (SEM 1.1) microM after placebo treatment (P=0.003) and a significant increase in the NOx:ET-1 ratio (P=0.005) was observed after the isoflavone treatment compared with placebo. A significant difference in SAC after the isoflavone and placebo treatment was observed (P=0.04). No significant difference was found in FMD, IAC, BP and ET-1. In conclusion, 8 weeks' consumption of cereals bars enriched with 50 mg soya isoflavones/d increased plasma NOx concentrations and improved endothelium-independent vasodilation in healthy postmenopausal women.

Topics: Biomarkers; Brachial Artery; Coronary Disease; Denmark; Endothelin-1; Endothelium, Vascular; Epidemiologic Methods; Female; Food, Fortified; Germany; Glycine max; Humans; Isoflavones; Italy; Middle Aged; Muscle, Smooth, Vascular; Nitric Oxide; Phytotherapy; Postmenopause; United Kingdom; Vascular Resistance; Vasodilation

Patients with heart disease are frequently treated with supplemental oxygen. Although oxygen can exhibit vasoactive properties in many vascular beds, its effects on the coronary circulation have not been fully characterized. To examine whether supplemental oxygen administration affects coronary blood flow (CBF) in a clinical setting, we measured in 18 patients with stable coronary heart disease the effects of breathing 100% oxygen by face mask for 15 min on CBF (via coronary Doppler flow wire), conduit coronary diameter, CBF response to intracoronary infusion of the endothelium-dependent dilator ACh and to the endothelium-independent dilator adenosine, as well as arterial and coronary venous concentrations of the nitric oxide (NO) metabolites nitrotyrosine, NO(2)(-), and NO(3)(-). Relative to breathing room air, breathing of 100% oxygen increased coronary resistance by approximately 40%, decreased CBF by approximately 30%, increased the appearance of nitrotyrosine in coronary venous plasma, and significantly blunted the CBF response to ACh. Oxygen breathing elicited these changes without affecting the diameter of large-conduit coronary arteries, coronary venous concentrations of NO(2)(-) and NO(3)(-), or the coronary vasodilator response to adenosine. Administering supplemental oxygen to patients undergoing cardiac catheterization substantially increases coronary vascular resistance by a mechanism that may involve oxidative quenching of NO within the coronary microcirculation.

Topics: Acetylcholine; Adenosine; Adult; Aged; Cardiac Catheterization; Coronary Circulation; Coronary Disease; Drug Interactions; Endothelin-1; Female; Humans; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Oxygen; Tyrosine; Vasodilator Agents

To investigate the effect and mechanism of Compound Salvia injection (CSI) on nitrate ester tolerance.. Eighty-four patients with coronary heart disease (CHD) were randomly divided into three groups, Group A treated with isosorbide dinitrate (ISD, 15 mg, 4 times per day) alone, Group B with ISD plus CSI and Group C with ISD plus vitamin C. The therapeutic course for all groups was 10 days. The tolerance to nitrate ester and blood pressure were monitored. Before and after treatment, the color Doppler ultrasonic apparatus was used to detect the baseline value of humeral arterial internal diameters (D0), the humeral arterial dilatory response under compression [D1, that is, the flow-mediated vasodilation (FMD)] and the vasodilatory response after sucking of nitroglycerin (D2). And the blood levels of endothelin-1 (ET-1), endothelial nitric oxide synthase (eNOS) mRNA expression were determined. The endothelial-dependent vasodilation (EDD) was expressed by (D1 - D0)/D0 x 100%, and the endothelial-independent vasodilation (EID) was expressed by (D2 - D0)/D0 x 100%.. (1) The occurrence rate of nitrate tolerance in Group B and C (28.57% and 35.7%) was lower than that in Group A (64.29%), but insignificant difference was found between the former two. (2) After treatment, blood pressure increased in Group A to the level of pre-treatment, that in Group C also increased but still lower than that of pre-treatment, while insignificant increase was observed in Group B, comparison between Group B and C showed significant difference (P < 0.05). (3) After treatment, EID lowered in Group A, EDD increased in Group B and C (P < 0.05), EDD and EID in Group B and C were higher than those in Group A (P < 0.05), and EDD was higher in Group B than in Group C (P < 0.05). (4) After treatment, ET-1 mRNA expression lowered in Group B, eNOS mRNA expression increased in Group B and C, with significant difference as compared with those before treatment and those in Group A (P < 0.05), and eNOS mRNA expression in Group C was lower than that in Group B (P < 0.05).. CSI could partially prevent the occurrence of tolerance to nitrate ester, with the effect better than vitamin C, the mechanism might be related with its regulation on eNOS, ET-1 mRNA expression and protection on vascular endothelial function.

Topics: Adult; Aged; Coronary Disease; Drug Resistance; Drugs, Chinese Herbal; Endothelin-1; Female; Humans; Injections, Intravenous; Isosorbide Dinitrate; Male; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Phytotherapy; RNA, Messenger; Salvia miltiorrhiza; Vasodilator Agents

To evaluate the effect of Xiangdan Injection on mRNA expression of the endothelial vaso-active factors of patients with coronary heart disease and blood stasis.. Fifty-six patients were randomly divided into two groups:twenty-eight patients were treated according to the therapeutic guide for coronary heart disease as the control group and 28 were given the same treatment plus Xiangdan Injection as the treated group. The expressions of ET-1 and eNOS mRNA were examined with RT-PCR before experiment and ten days later.. The positive rate of eNOS mRNA of the treated group increased, while the positive rate of ET-1 mRNA of the treated group decreased after ten day's treatment, with significant differences as compared with that before the experiment. Xiangdan Injection up-regulated the eNOS mRNA expression and suppressed the ET-1 mRNA expression. Changes of expression were not observed in the control group.. Xiangdan Injection improves the endothelial function of patients with coronary heart disease and blood stasis by regulating the expressions of ET-1 and eNOS mRNA.

Topics: Aged; Aged, 80 and over; Coronary Disease; Coronary Thrombosis; Endothelin-1; Female; Humans; Injections; Male; Medicine, Chinese Traditional; Middle Aged; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; RNA, Messenger

We have demonstrated that estrogen can reduce myocardial injury in ischemia-reperfusion via activation of ATP-sensitive potassium (K(ATP)) channels. We sought to determine whether the protective effect of estrogen extends to epicardial coronary artery with attenuated vasoconstriction in patients after angioplasty by activation of such channels.. The study was designed to prospectively investigate 41 consecutive patients scheduled for elective coronary angioplasty. Pretreatment with estrogen limited myocardial ischemia during coronary occlusion and attenuated postangioplasty coronary vasoconstriction at the dilated and distal segments. An inhibitor of K(ATP) channels, glibenclamide, did not affect coronary vasomotor response, although it abolished the beneficial effect of estrogen on myocardial ischemia. Patients to whom estrogen was administered after the second balloon deflation experienced a similar magnitude of myocardial ischemia as controls but showed significantly attenuated vasoconstriction compared with controls (P=0.0001). Endothelin-1 levels from the great cardiac vein rose significantly from 1.9+/-0.4 to 3.1+/-0.6 pg/mL (P=0.001) 15 minutes after angioplasty in the control group; this was attenuated after estrogen was administered. Significant correlation was found between the changes in coronary vasomotion of the dilated segment and endothelin-1 levels (r=0.65, P<0.0001).. These results demonstrate that estrogen is protective against both myocardial ischemia and coronary vasoconstriction through different mechanisms. The myocardial effect of estrogen was abolished by glibenclamide, which suggests that the cardioprotective effect of estrogen may result from activation of K(ATP) channels. In contrast, estrogen-induced attenuated vasoconstriction is associated with an attenuated release of endothelin-1, independent of K(ATP) activation.

Topics: Adenosine Triphosphate; Angioplasty, Balloon, Coronary; Cardiotonic Agents; Chest Pain; Coronary Disease; Electrocardiography; Endothelin-1; Estrogens, Conjugated (USP); Female; Glyburide; Heart; Hemodynamics; Humans; Lactic Acid; Male; Middle Aged; Myocardial Ischemia; Myocardium; Potassium Channel Blockers; Potassium Channels; Vasoconstriction

To investigate the relationship between sex hormone levels and blood calcitonin gene-related peptide/endothelin-1, and to evaluate the therapeutic effects of nylestriol.. Forty perimenopausal women without coronary heart disease (CHD) and 30 postmenopausal women with CHD were studied, and 30 postmenopausal women were divided into two groups and treated randomly with either 2 mg nylestriol or placebo. Serum 17 beta-estradiol (E2), testosterone (T), plasma calcitonin gene-related peptide (CGRP) and endothelin-1 (ET-1) were measured.. In postmenopausal women, serum levels of E2 and plasma concentrations of CGRP decreased, while serum levels of T and plasma concentrations of ET-1 increased; E2 was positively related to CGRP, and negatively related to ET-1; T was negatively related to CGRP or ET-1. In the nylestriol group, compared with the parameters before treatment, plasma CGRP increased and ET-1 decreased after treatment.. Estradiol possesses certain effects on endothelial cell, which may be an important aspect of its protective effects.

Topics: Calcitonin Gene-Related Peptide; Coronary Disease; Endothelin-1; Estradiol; Estradiol Congeners; Female; Humans; Middle Aged; Postmenopause; Quinestrol

The goal of this study was to determine the long-term effects of estrogen replacement therapy on the response to endothelin-1 (ET-1) in postmenopausal women with coronary heart disease.. It is thought that the vasoconstrictor ET-1 is involved in the development and progression of atherosclerosis. Estrogen replacement may slow the development of atherosclerosis in postmenopausal women.. Nineteen of 20 postmenopausal women randomized to either three months of 2 mg oral estradiol or placebo completed the double-blind placebo-controlled protocol. Change in forearm blood flow (FBF) in response to a 60 min brachial arterial infusion of ET-1 (5 pmol/min) was measured before randomization, after one month of randomized therapy and after three months of therapy using venous occlusion plethysmography.. Estrogen treatment had no effect on baseline FBF. Systolic and diastolic blood pressure and heart rate did not change in response to estrogen therapy or ET-1. Before randomization, in response to ET-1, FBF was reduced by -21.9% (mean response over 60 min) in the placebo group and -19.0% in the estradiol group (p = 0.67). After one month of therapy, the response was attenuated in the estrogen group, -10.0%, compared with the placebo group, -23.6 (difference in means 13.6%, 95% confidence interval [0.7%, 26.6%], p = 0.041). After three months of therapy, there was no difference in response between the placebo group, -27.0%, and estrogen group, -30.2% (p = 0.65).. In postmenopausal women with coronary heart disease, estrogen therapy inhibits the vasoconstrictor response to ET-1 after one month of therapy. This effect is lost after three months of therapy, suggesting that tachyphylaxis to one potentially beneficial action of estradiol develops during chronic treatment.

Topics: Aged; Blood Flow Velocity; Coronary Disease; Double-Blind Method; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Female; Follow-Up Studies; Forearm; Humans; Middle Aged; Plethysmography; Postmenopause; Tachyphylaxis; Vasoconstriction

Coronary artery bypass operations are associated with increased circulating levels of the powerful vasoconstrictor endothelin 1. The pulmonary circulation is an important site for both production and clearance of endothelin 1. Lung endothelial injury resulting from cardiopulmonary bypass could modify pulmonary endothelin 1 metabolism through an increase in production, a reduction in removal, or a combination of both.. Pulmonary endothelin 1 kinetics were quantified by using the indicator-dilution technique in patients undergoing coronary artery bypass grafting with (n = 11) or without cardiopulmonary bypass (ie, beating heart; n = 10). Mixed venous endothelin 1 levels were also measured in samples from the pulmonary artery, and systemic levels were obtained from the radial artery.. Pulmonary artery endothelin 1 levels were similar before and after cardiopulmonary bypass, with means of 1.59 +/- 0.37 pg/mL and 1.33 +/- 0.15 pg/mL (P =.45), respectively. Systemic endothelin 1 levels, however, increased after bypass from 1.64 +/- 0.22 pg/mL to 2.07 +/- 0.16 pg/mL (P =.01). In the beating heart group, endothelin 1 levels before and after the operation were similar in the pulmonary artery (1.25 +/- 0.27 pg/mL and 1.45 +/- 0.31 pg/mL, respectively; P =.38), as well as in the radial artery (1.70 +/- 0.26 pg/mL and 1.73 +/- 0.35 pg/mL, respectively; P =.92). The capacity to clear endothelin 1 from the pulmonary circulation, as computed from the permeability-surface area product for endothelin 1, was not affected by cardiopulmonary bypass before and after the operation (25.19 +/- 2.67 mL/s and 23.12 +/- 4.39 mL/s, respectively; P =.49). It was similar and also unaffected in the beating heart group.. Coronary artery bypass grafting with cardiopulmonary bypass is associated with an increase in systemic endothelin 1 levels. The mechanism involved is not related to a decreased pulmonary clearance of endothelin 1 from the systemic circulation but rather to an increased endothelin 1 release by the lungs.

Topics: Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Female; Follow-Up Studies; Humans; Lung; Male; Middle Aged; Postoperative Period; Preoperative Care; Pulmonary Artery; Radial Artery; Sensitivity and Specificity; Stroke Volume; Treatment Outcome

To examine the contribution of endothelin type A (ET(A)) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans.. Controlled clinical study.. Tertiary cardiovascular referral centre.. 14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years.. After diagnostic coronary arteriography, BQ-123 (a selective ET(A) receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone.. Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments.. The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p < 0.05 v baseline). Coronary blood flow increased from 75 (10) to 92 (10) ml/min and coronary vascular resistance decreased from 1.99 (0.36) to 1.44 (0. 22) mm Hg/ml/min after BQ-123 (both p < 0.05 v baseline). The response to BQ-123 of patients with and without coronary artery disease was similar. There was no effect of saline in the controls.. Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans by ET(A) receptor stimulation. The role of ET(B) receptors remains to be defined.

Topics: Blood Flow Velocity; Case-Control Studies; Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; Male; Middle Aged; Receptors, Endothelin; Vascular Resistance

Estrogen reverses acetylcholine-induced coronary vasoconstriction via the possible facilitation of endothelium-derived NO. Estrogen also affects endothelium-derived constrictor factors. We therefore investigated the effects of 17beta-estradiol on coronary vasomotor responses to substance P (SP), and coronary sinus endothelin-1 and NO metabolite levels in postmenopausal women with coronary heart disease.. We studied 20 women; 14 received estrogen (mean age 65+/-2 years) and 6 served as ethanol control subjects (age 63+/-3 years). Intracoronary infusions of papaverine (8 mg) and SP were administered before and 20 minutes after 50 pg/min 17beta-estradiol or 0.2 microL/min control. Coronary blood flow was calculated from the diameter, as measured with quantitative coronary angiography, and flow velocity, as measured with intracoronary Doppler. Coronary sinus plasma endothelin-1 and nitrite/nitrate (NO(2)/NO(3)) were measured at baseline, at peak velocity response to each infusion, and every 5 minutes during the estradiol infusion. Endothelin-1 levels were decreased after 20 minutes of estradiol (1.12+/-0.18 versus 0.86+/-0.17 pmol/L baseline2 versus estradiol, P:=0.05). Endothelin-1 levels to SP decreased after 17beta-estradiol (1.29+/-0. 18 versus 1.04+/-0.15 and 1.3+/-0.16 versus 0.99+/-0.17 pmol/L for before versus after estradiol, 10 and 25 pmol/min SP; both P:<0.05). NO(2)/NO(3) levels did not change. There was no change in vasomotor responses to estradiol alone or to papaverine or SP before versus after estradiol.. Short-term intracoronary 17beta-estradiol administration decreases coronary endothelin-1 levels. There was no enhancement of vasomotor responses to SP after the administration of estrogen, suggesting that the effects of estrogen on coronary acetylcholine responses may be a specific and not a generalized effect on coronary vasoreactivity.

Topics: Arteries; Blood Pressure; Coronary Circulation; Coronary Disease; Endothelin-1; Estradiol; Female; Heart Rate; Humans; Isosorbide Dinitrate; Middle Aged; Nitric Oxide; Papaverine; Postmenopause; Substance P; Vasodilator Agents; Women's Health

Immunosuppression may have an important impact on early graft coronary endothelial injury. We investigated functional and morphologic coronary alterations, myocardial expression, and cardiac release of possible mediators of allograft vasculopathy within 6 months after cardiac transplantation with respect to different immunosuppressive regimens. Epicardial and microvascular endothelium-dependent and endothelium-independent vasomotor function and epicardial intimal thickening were measured in 8 transplant recipients treated with cyclosporin A (CyA), azathioprine, and prednisone (group 1), 9 transplant recipients treated with tacrolimus (TKL), azathioprine, and prednisone (group 2), and 14 patients treated with TKL, mycophenolate mofetil (MMF), and prednisone (group 3). The gene expressions of inducible and endothelial nitric oxide synthase (iNOS and eNOS), endothelin-1, prostacyclinsynthase, and thromboxansynthase were analyzed in endomyocardial biopsy specimens using semiquantitative reverse transcription polymerase chain reaction. Transcardiac cytokine release, endothelin-1, and nitrate-release were determined from plasma samples. Epicardial endothelial dysfunction (vasoconstriction to acetylcholine > 10%) and microvascular smooth muscle cell dysfunction (flow velocity increase to adenosine and nifedipine < 2.0) were enhanced in heart transplant recipients immunosuppressed with TKL, azathioprine, and prednisone. The prevalence of epicardial dysfunction was 78% in group 2 versus 44% and 46% in group 1 and 3 (p < 0.05), respectively. The prevalence of microvascular dysfunction was 56% in group 2 versus 13% and 7% in group 1 and 3 (p < 0.02), respectively. Coronary vasomotor dysfunction was associated with increased myocardial iNOS expression (p < 0.05), decreased eNOS expression (p < 0.05), and enhanced cardiac immunoreactive interleukin-6 (p < 0.01). Coronary intimal thickening was not different between the groups. The combination of TKL and MMF appears to be superior to TKL and azathioprine (and comparable to CyA and azathioprine) concerning preservation of early coronary vasomotor function, eNOS expression, iNOS suppression as well as cardiac interleukin-6 release. This may have an important impact on subsequent development of transplant coronary atherosclerosis.

Topics: Adult; Cardiac Catheterization; Coronary Disease; Cytokines; DNA Primers; DNA, Complementary; Endothelin-1; Endothelium, Vascular; Female; Gene Expression Regulation; Heart Transplantation; Humans; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Nitrates; Radioimmunoassay; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Ultrasonography, Doppler

To investigate whether ECC may produce regional liberation of inflammatory mediators capable of inducing vascular effects and organ damage.. Comparative study [corrected].. Cardiac surgery department in a University hospital.. Fifteen patients undergoing coronary artery bypass grafting (CABG, group A) and ten patients operated for infrarenal abdominal aortic aneurysm (controls, group B) have been studied.. Levels of Interleukin 1beta (IL1), Tumor Necrosis Factor alpha (TNF), Interleukin 6 (IL6), and Endothelin 1 (ET1) were measured in pulmonary capillary, arterial, and venous blood and in bronchoalveolar lavages (BAL) before, during and after extracorporeal circulation (ECC) or surgical intervention.. TNF-alpha (never >35 pg/ml) and IL1beta (range 20-300 pg/ml) values did not change over time for both groups. IL6 concentrations in all samples of group A increased between five and twenty fold, during and after ECC (from 3-5 pg/ml up to 240 pg/ml, p<0.001). This trend was similar in controls after surgical stress. Endothelin 1 was always undetectable in the BAL fluid, with a modest, but significant increase in pulmonary capillary blood of group A, after ECC, (from 11+/-4 pg/ml to 18+/-5 pg/ml, p<0.001). This increment correlated well with the PVR increase, but was transient and after 24 hours, ET1 values returned to baseline levels. Mean values of ET1 increased also in controls, but not significantly.. ECC may induce ET1 liberation in pulmonary circulation with transient pulmonary vasoconstriction, but wihout intra-alveolar release, or lung damage. Augmented concentrations of IL6 probably express a response to surgical procedure rather than an effect exclusively related to ECC.

Topics: Adult; Aged; Aged, 80 and over; Aortic Aneurysm, Abdominal; Bronchoalveolar Lavage Fluid; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Endothelium, Vascular; Extracorporeal Circulation; Female; Humans; Interleukin-1; Male; Middle Aged; Pulmonary Alveoli; Pulmonary Circulation; Reference Values; Tumor Necrosis Factor-alpha

To explore the effect of composite salviae dropping pill (CSDP) on endothelin (ET-1) gene expression in circulating endothelial cells.. Seventy cases of stable angina pectoris were randomly divided into 2 groups, the CSDP group and the isosorbide dinitrate (ID) group. They were treated with CSDP and ID respectively, their ET-1 gene expression in endothelial cells of peripheral circulation was measured before and after treatment by reverse transcriptase-Polymerase Chain Reaction and compared between the two groups as well as with that of 30 healthy subjects.. Electrophoresis banding of 546 bp cDNA procured from 69 cases of 70 patients was positive, while no positive banding was obtained from healthy subjects. Six cases from the 29 patients treated with CSDP had their banding turned to negative, while in the ID group, no one had turned to negative after treatment. And ET-1 PCR product (absorbed optic density) in the CSDP group was markedly lower than that in the ID group, P < 0.05.. DSP could inhibit ET-1 gene expression in endothelial cells of peripheral circulation directly.

Topics: Aged; Aged, 80 and over; Coronary Disease; Drugs, Chinese Herbal; Endothelin-1; Endothelium, Vascular; Female; Gene Expression; Humans; Male; Middle Aged; Plant Extracts; RNA, Messenger; Salvia miltiorrhiza

A variety of vascular effects have been ascribed to 17 beta-oestradiol. These effects may partially explain the reduced incidence of cardiovascular disease found in post-menopausal women on oestrogen replacement therapy.. To evaluate the effects of 2 mg sublingual 17 beta-oestradiol on exercise capacity, exercise-induced myocardial ischaemia and circulating levels of endothelin-1 in post-menopausal women with stable coronary artery disease.. Twelve post-menopausal women, mean age 61 (range 52-72) years, with angiographically verified significant coronary artery disease, were randomly assigned to 2 mg of sublingual 17 beta-oestradiol, 2.5 mg of buccal nitroglycerine and to placebo in a double-blind cross-over study design with at least 2 days between each of the study arms. Antianginal medications, with the exception of beta-blockers, were discontinued before investigation. All study patients underwent a maximal bicycle exercise test 30 min after drug intake. Blood was withdrawn immediately before and up to 8 h after medication for analyses of circulating levels of oestradiol and endothelin-1.. The mean serum levels of oestradiol increased from a control level of 72 +/- 28 pmol.l-1 to 3557 +/- 1731 pmol.l-1 after 30 min and to 5028 +/- 3971 pmol.l-1 after 60 min with a gradual decline thereafter. Sublingual 17 beta-oestradiol did not induce any improvement in exercise duration when compared with nitroglycerin and placebo (500 +/- 112 s, 505 +/- 107 s, 498 +/- 157 s), and did not influence time to onset of ST-segment depression (358 +/- 89 s, 436 +/- 93 s, 384 +/- 116 s). The plasma levels of endothelin-1 did not change after administration of 17 beta-oestradiol, nitroglycerin or placebo.. No effects of exercise capacity, exercise-induced acute ischaemia, or plasma levels of endothelin-1 were found after a single dose of 2 mg 17 beta-oestradiol in post-menopausal women with documented coronary artery disease.

Topics: Administration, Sublingual; Coronary Disease; Cross-Over Studies; Double-Blind Method; Electrocardiography; Endothelin-1; Estradiol; Estrogen Replacement Therapy; Exercise Test; Female; Humans; Middle Aged; Myocardial Ischemia; Nitroglycerin; Postmenopause; Treatment Outcome

There is a growing body of evidence that perfusion temperature during cardiopulmonary bypass (CPB) influences postoperative systemic vascular resistance (SVR). The reason for this is not clear. Extracorporeal circulation can provoke raised plasma levels of endothelin-1 (ET-1), a very potent vasoconstrictor peptide produced by endothelial cells. We therefore analysed the effect of CPB temperature on postoperative vascular resistance and plasma concentrations of ET-1.. Thirty four patients undergoing elective coronary artery bypass grafting procedures were randomly assigned for either normothermic (37 degrees C, n = 17) or hypothermic CPB (28 degrees C, n = 17). Serial measurements of SVR and plasma ET-1 concentrations were performed before, during, and until 9 h after CPB measured.. As a consequence of CPB, plasma ET-1 levels increased slightly in both groups. In normothermic patients, ET-1 reached maximal levels at the end of CPB whereas ET-1 levels in patients after hypothermic CPB had a tendency to further increase during the stay in the intensive care unit. Plasma ET-1 levels were significantly higher in patients 9 h postoperatively after hypothermic CPB (1.94 +/- 0.28 vs. 1.30 +/- 0.12 pg/ml, P = 0.033), which was associated with significantly higher systemic vascular resistance index (SVRI) in these patients (area under the curve; 1978 +/- 76 vs. 1626 +/- 69 dyne s/cm5 per m2, P = 0.003). Plasma ET-1 levels showed a positive correlation with postoperative SVRI (P = 0.008, r = 0.51) and a negative correlation with minimal rectal temperature during CPB (P = 0.006, r = 0.55).. These results suggests that the hemodynamic differences after normothermic and hypothermic CPB might be mediated, at least in part, by temperature dependent changes in ET-1 plasma levels.

Topics: Adult; Aged; Cardiopulmonary Bypass; Coronary Disease; Critical Care; Endothelin-1; Female; Hemodynamics; Humans; Hypothermia, Induced; Male; Middle Aged; Postoperative Complications; Treatment Outcome; Vascular Resistance

This study was to observe the effect of Sodium TanshinoneⅡA Sulfonate (ST-ⅡAS) on blood uric acid (UA), human Soluble Intercellular Adhesion Molecule-1 (sICAM-1), Endothelin-1 (ET-1) and percentage of brachial artery Flow-Mediated Dilatation (FMD) in individuals with Hyperuricemia Complicated Coronary Heart Disease (HC-CHD). The study's participants were 108 patients with HC-CHD who attended our hospital between January 2020 and June 2022. In the trial, the patients were split into two groups with 54 instances each: the general group and the observation group. The observation group received ST-IIAS therapy, while the general group received standard care. The experiment chose to observe and compare the difference of uric acid, sICAM-1, ET-1, FMD, therapeutic effectiveness and negative effects between the two groups at various times. Results showed that on the 14th day, the observation group's amounts of UA, sICAM-1, and ET-1 were inferior to the general group (P<0.05); On the 7th and 14th days, the observation group's amount of ET-1 was lower than that of the general group (P<0.05); The observation group's FMD of patients on the 14th day was inferior to the general group after treatment (P<0.05); The observation group's overall effective rate was 94.44% higher than the general group's (P<0.05); The observation group experienced fewer negative responses than the general group did (P<0.05). In conclusion, ST-ⅡAS can be used for uric acid, vascular endothelial systolic and diastolic function in patients with HC-CHD, and has better clinical efficacy and lower risk of adverse reactions.

Topics: Alkanesulfonates; Coronary Disease; Dilatation; Endothelin-1; Humans; Hyperuricemia; Uric Acid

Endothelin 1 (ET-1) has been shown to have a key role in homeostasis and function of endothelium and maybe fundamental in the relationship between coronary heart disease (CHD) and periodontitis. In this trial, we assessed the influence on serum and salivary ET-1 levels of gingival health, CHD, periodontitis, or a combination of periodontitis-CHD. Clinical and periodontal parameters, were collected from periodontitis patients (n = 34), CHD patients (n = 34), periodontitis + CHD patients (n = 34), and from healthy patients (n = 34) together with saliva and serum samples. The median concentrations of salivary and serum ET-1 were significantly higher in the CHD patients [serum: 1.4(1.1-1.6) pg/ml; saliva 1.2 (0.9-1.6) µmol/g, p < 0.01] and in the periodontitis + CHD patients [serum: 1.7 (1.2-21.8) pg/ml; salivary 1.4(1-1.6) µmol/g, p < 0.001] respect to periodontitis and control patients. Through a univariate regression analysis, c-reactive protein (CRP) and CHD (both p < 0.001) and periodontitis (p = 0.029) were statistically correlated with ET-1 in serum. The multivariate regression analysis demonstrated that only CRP was the statistically predictor of ET-1 in serum(p < 0.001). The multivariate regression analysis in saliva demonstrated that, regarding ET-1 levels the only predictor were CRP (p < 0.001) and total cholesterol (p = 0.042). The present study evidenced that subjects with CHD and periodontitis plus CHD had higher serum and salivary levels of ET-1 compared to subjects with periodontitis and healthy controls. Moreover, only CRP remained a major predictor of increased ET-1 concentrations in both serum and saliva.

Topics: Adult; Biomarkers; C-Reactive Protein; Case-Control Studies; Coronary Disease; Endothelin-1; Female; Humans; Inflammation Mediators; Male; Middle Aged; Multivariate Analysis; Periodontitis; Saliva

Endothelin-1 (ET-1) has been implicated in the development of post-heart transplantation (HT) cardiac allograft vasculopathy (CAV), but has not been well studied in humans.. In 90 HT patients, plasma ET-1 was measured within 8 weeks after HT (baseline) via a competitive enzyme-linked immunosorbent assay. Three-dimensional volumetric intravascular ultrasound of the left anterior descending artery was performed at baseline and at 1 year. Accelerated CAV (lumen volume loss) was defined with the 75th percentile as a cutoff. Patients were followed beyond the first year after HT for late death or retransplantation. A receiver operating characteristic (ROC) curve demonstrated that a baseline ET-1 concentration of 1.75 pg/mL provided the best accuracy for diagnosis of accelerated CAV at 1 year (area under the ROC curve 0.69, 95% confidence interval [CI] 0.57-0.82; P = .007). In multivariate logistic regression, a higher baseline ET-1 concentration was independently associated with accelerated CAV (odds ratio [OR] 2.13, 95% CI 1.15-3.94; P = .01); this relationship persisted when ET-1 was dichotomized at 1.75 pg/mL (OR 4.88, 95% CI 1.69-14.10; P = .003). Eighteen deaths occurred during a median follow-up period of 3.99 (interquartile range 2.51-9.95) years. Treated as a continuous variable, baseline ET-1 was not associated with late mortality in multivariate Cox regression (hazard ratio [HR] 1.22, 95% CI 0.72-2.05; P = .44). However, ET-1 >1.75 pg/mL conferred a significantly lower cumulative event-free survival on Kaplan-Meier analysis (P = .047) and was independently associated with late mortality (HR 2.94, 95% CI 1.12-7.72; P = .02).. Elevated ET-1 early after HT is an independent predictor of accelerated CAV and late mortality, suggesting that ET-1 has durable prognostic value in the HT arena.

Topics: Allografts; Biomarkers; California; Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Male; Middle Aged; Postoperative Complications; Predictive Value of Tests; Prognosis; Prospective Studies; Risk Factors; ROC Curve; Survival Rate; Ultrasonography, Interventional

The vasoconstricting peptide endothelin-1 has been proposed to be a marker of cardiovascular disease. Our aim was to investigate whether circulating endothelin-1 levels predict coronary heart disease (CHD) in Sweden.. In 2002-2005, 2816 adult participants (30-74 years) were randomly selected from two municipalities in south-western Sweden. Cardiovascular risk factors and endothelin-1 levels were assessed at baseline, and incident CHD was followed-up in all participants through 2011. After exclusion of 50 participants due to known CHD at baseline and 21 participants because of unsuccessful analysis of endothelin-1, 2745 participants were included in the study. In total, 72 CHD events (52 in men and 20 in women) were registered during the follow-up time.. We showed that baseline circulating endothelin-1 levels were higher in women with incident CHD than in women without CHD (3.2 pg/ml, SE: 0.36 vs 2.4 pg/ml, SE: 0.03, p = 0.003) whereas this difference was not observed in men (2.3 pg/ml, SE: 0.16 vs 2.3 pg/ml, SE: 0.04, p = 0.828). An age-adjusted Cox proportional regression analysis showed an enhanced risk of CHD with increasing baseline endothelin-1 levels in women (hazard ratio (HR) = 1.51, 95 % CI = 1.1-2.1, p = 0.015) but not in men (HR = 0.98, 95 % CI = 0.8-1.2, p = 0.854). Furthermore, the predictive value of endothelin-1 for incident CHD in women was still significant after adjustments for age, HOMA-IR, apolipoprotein (apo)B/apoA1 and smoking (HR = 1.53, CI = 1.1-1.2, p = 0.024).. Circulating endothelin-1 levels may predict CHD in women.

Topics: Adult; Aged; Biomarkers; Coronary Disease; Endothelin-1; Female; Humans; Incidence; Kaplan-Meier Estimate; Longitudinal Studies; Male; Middle Aged; Multivariate Analysis; Predictive Value of Tests; Prognosis; Proportional Hazards Models; Prospective Studies; Risk Assessment; Risk Factors; Sex Factors; Sweden; Up-Regulation

The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans.

Topics: Animals; Atherosclerosis; Biomarkers; Biopterins; Body Temperature; Body Weight; Coronary Disease; Drug Evaluation, Preclinical; Endothelin-1; Extreme Heat; Infrared Rays; Male; Mice; Mice, Knockout; Nitric Oxide; Random Allocation; Superoxide Dismutase

To evaluate the vascular endothelium in patients with cardiopulmonary disease, by studying the levels of endothelin-1 (ET-1) and C-type natriuretic peptide (CNP).. Examinations were conducted in 212 dwellers of the Astrakhan Region, including 40 patients with chronic obstructive pulmonary disease (COPD) concurrent with hypertensive disease (HD), 40 patients with COPD concurrent with coronary heart disease (CHD), 27 somatically healthy individuals, 35 patients with Stage II HD, 35 patients with Functional Classes II and III CHD, and 35 patients with moderate and severe COPD.. The patients with COPD concurrent with HD and CHD were found to have endothelial dysfunction manifesting itself in the overproduction of ET-1 and CNP. The level of CNP was statistically significantly higher in the COPD + HD group than in the HD and COPD groups whereas in the COPD + HD group the level of ET-1 remained comparable to that in the COPD and HD groups. This indicates that CNP is a more sensitive indirect marker of endothelial dysfunction and that nitric oxide deficiency is aggravated in the concurrence of COPD and HD as compared to a mononosological entity (HD, COPD).. The concurrence of COPD and CHD is more unfavorable for the development and severity of endothelial dysfunction, which may lead to mutual aggravation syndrome, the rapider progression of the diseases, and the increased frequency of complications.

Topics: Comorbidity; Coronary Disease; Disease Progression; Endothelin-1; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Natriuretic Peptide, C-Type; Predictive Value of Tests; Prognosis; Pulmonary Disease, Chronic Obstructive

Coronary heart disease is a major cause of mortality in women and persons with diabetes. Mental stress and major depressive disorder have both been associated with coronary heart disease. Endothelial functioning is a clinically meaningful manifestation of CHD that is detectable in its earliest stages.. This study aims to determine whether acute stress and lifetime history of major depressive disorder are associated with functional and biochemical markers of endothelial function and whether this relationship varies by diabetes status.. Resting endothelial function was assessed for n = 215 postmenopausal women with no known or suspected coronary artery disease participated. Of these, 108 had a positive lifetime major depressive disorder (L-MDD; assessed through structured clinical interview) and had been free of major depressive disorder for >6 months; 103 had type 2 diabetes. Endothelial reactivity to acute mental stress was assessed for n = 114 of the participants. Endothelial function was assessed by flow-mediated dilation of the brachial artery (FMD) by total plasma nitrite, the cumulative molecule from nitric oxide (NO) generation, and by plasma endothelin-1 (ET-1).. Participants with L-MDD had lower NO and lower FMD compared to never-depressed controls. Secondary analyses suggest that among participants with L-MDD, antidepressant medications are associated with higher NO. Participants with diabetes had higher NO but lower FMD than nondiabetic controls. Mental stress affected FMD in the entire sample. Diabetes moderated the effect of mental stress on NO and L-MDD moderated the effect of mental stress on ET-1.. History of depression, even in full remission, is associated with impaired endothelial functioning regardless of diabetes status. Acute mental alters FMD, NO, and ET-1 differentially among subgroups.

Topics: Aged; Brachial Artery; Coronary Disease; Depressive Disorder, Major; Diabetes Mellitus, Type 2; Endothelin-1; Endothelium, Vascular; Female; Humans; Middle Aged; Postmenopause; Stress, Psychological

Topics: Biomarkers; Capillaries; Coronary Disease; Endothelin-1; Humans; Magnetic Resonance Imaging; Monitoring, Physiologic; Myocardial Infarction; Myocardium; Prognosis; Radiography; Stroke Volume

Coronary vascular dysfunction has been observed in several models of heart failure (HF). Recent evidence indicates that exercise training is beneficial for patients with HF, but the precise intensity and underlying mechanisms are unknown. Left ventricular (LV) hypertrophy can play a significant role in the development of HF; therefore, the purpose of this study was to assess the effects of low-intensity interval exercise training on coronary vascular function in sedentary (HF) and exercise trained (HF-TR) aortic-banded miniature swine displaying LV hypertrophy. Six months postsurgery, in vivo coronary vascular responses to endothelin-1 (ET-1) and adenosine were measured in the left anterior descending coronary artery. Baseline and maximal coronary vascular conductance were similar between all groups. ET-1-induced reductions in coronary vascular conductance (P < 0.05) were greater in HF vs. sedentary control and HF-TR groups. Pretreatment with the ET type A (ET(A)) receptor blocker BQ-123 prevented ET-1 hypersensitivity in HF animals. Whole cell voltage clamp was used to characterize composite K(+) currents (I(K(+))) in coronary smooth muscle cells. Raising internal Ca(2+) from 200 to 500 nM increased Ca(2+)-sensitive K(+) current in HF-TR and control, but not HF animals. In conclusion, an ET(A)-receptor-mediated hypersensitivity to ET-1, elevated resting LV wall tension, and decreased coronary smooth muscle cell Ca(2+)-sensitive I(K(+)) was found in sedentary animals with LV hypertrophy. Low-intensity interval exercise training preserved normal coronary vascular function and smooth muscle cell Ca(2+)-sensitive I(K(+)), illustrating a potential mechanism underlying coronary vascular dysfunction in a large-animal model of LV hypertrophy. Our results demonstrate the potential clinical impact of exercise on coronary vascular function in HF patients displaying pathological LV hypertrophy.

Topics: Animals; Blood Pressure; Capillaries; Cardiotonic Agents; Coronary Circulation; Coronary Disease; Coronary Vessels; Dobutamine; Endothelin A Receptor Antagonists; Endothelin-1; Heart Rate; Hypertrophy, Left Ventricular; In Vitro Techniques; Male; Muscle, Smooth, Vascular; Myocardial Contraction; Peptides, Cyclic; Physical Conditioning, Animal; Potassium Channels, Calcium-Activated; Receptor, Endothelin A; Swine; Swine, Miniature

Research has identified the vasoconstrictors endothelin-1 (ET-1) and urotensin-II (U-II) as having a role in the development of atherosclerotic cardiovascular disease. We aimed to observe alterations in plasma levels of both ET-1 and U-II in patients with coronary heart disease (CHD) undergoing percutaneous transluminal coronary angioplasty (PTCA) and stent therapy from November 2006 through May 2007. We examined plasma levels of ET-1 and U-II in 40 patients with CHD and 40 age-matched healthy subjects by radioimmunoassay (RIA). Chi-square test, Student's t-test, and one-way analysis of variance were used for statistical analyses. Correlations between variables were tested by simple linear regression analysis. Coronary heart disease patients had significantly higher ET-1 and UII levels than healthy controls (20.05 +/- 4.65 vs 8.16 +/- 3.38 and 71.90 +/- 11.61 vs 20.89 +/- 7.00 pg/ml, respectively, all P < 0.01). Importantly, plasma levels of U-II and ET-1 were correlated in patients with CHD (r = 0.64, P = 0.01). On day 1 after PTCA and stent therapy, plasma levels of ET-1 and U-II were significantly higher, by 99% and 25%, respectively, than those before therapy (all P < 0.01). On day 3 after therapy, ET-1 levels were higher by 25% (P < 0.01) than before therapy, and U-II levels decreased rapidly and were close to baseline levels (P > 0.05). On day 7 after therapy, CHD patients had significantly lower ET-1 and U-II levels than before therapy (all P < 0.01). Since ET-1 and U-II levels may be increased in plasma of patients with CHD, their activation might have clinical significance in terms of early intervention in patients with CHD, especially after PTCA and stent therapy.

Topics: Adult; Aged; Angioplasty, Balloon, Coronary; Case-Control Studies; Chi-Square Distribution; Coronary Disease; Endothelin-1; Female; Humans; Linear Models; Male; Middle Aged; Radioimmunoassay; Stents; Time Factors; Treatment Outcome; Up-Regulation; Urotensins

To determine whether a tendency to angry rumination predicts anger recall (AR) stress-provoked increase in endothelin (ET)-1 among patients with coronary heart disease (CHD).. Patients with chronic stable CHD (n = 105) completed a five-item measure of tendency to angry rumination (DAB-VR) and underwent a laboratory AR stress protocol (15-minute resting baseline [BL], 8-minute AR). Blood samples drawn at end of BL and AR were assayed for ET-1. Change in ET-1 from BL to AR (increase versus decrease/no change) was treated dichotomously in multivariate logistic regression models, including DAB-VR score and potential confounders, to evaluate the contribution of DAB-VR to the prediction of change in ET-1.. In the multivariate model, DAB-VR score significantly predicted ET-1 increase (odds ratio, 1.34; 95% confidence interval, 1.10-1.1.63; p = .004), controlling for age, history of diabetes, hypercholesterolemia, rate pressure product, use of beta blockers, and statins.. A tendency to angry rumination independently predicted AR stress-provoked ET-1 increase among patients with CHD. Given the involvement of ET-1 in plaque rupture, anger rumination tendency may identify vulnerability to anger-triggered acute coronary syndrome through prolongation of initial anger mobilization. The contribution of ruminative thinking to sustained poststress ET-1 elevation and the synergistic relationship of ET-1 during emotional stress with norepinephrine and nitric oxide remain to be explored.

Topics: Aged; Anger; Coronary Disease; Data Collection; Electrocardiography; Endothelin-1; Female; Health Status; Humans; Male; Mental Recall; Middle Aged; Norepinephrine; Risk Assessment; Risk Factors; Stress, Psychological; Thinking; Ventricular Dysfunction, Left

Endothelin-1 has been implicated in atherosclerotic and ischemic heart disease. No population-based studies have examined the association of endothelin-1 with coronary heart disease (CHD). We performed a cross-sectional analysis of 961 older women and men. CHD was defined as a history of myocardial infarction, coronary surgery, angina, or major Q-wave abnormality on electrocardiography. We examined the association of endothelin-1 with CHD after adjusting for known risk factors and atherosclerosis measures. A total of 248 women and 156 men had CHD. Median endothelin-1 levels were similar by gender and higher among those with versus those without CHD (3.3 vs 3.1 pg/ml, p <0.001). After adjusting for age, smoking, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, hypertension, diabetes, alcohol use, exercise, aspirin, cholesterol-lowering medication, and hormone therapy use, endothelin-1 had a stronger association with CHD in women (odds ratio [OR] 3.02, (95% confidence interval 1.43 to 6.37) than in men (OR 1.82, 95% confidence interval 0.74 to 4.51). Age modified the effect of endothelin-1 with CHD in men (OR 0.47 for age <75 years vs 3.84 in men >or=75 years, p = 0.05 for interaction). Further adjustment for ankle-brachial index and carotid intima media thickness did not alter these results. In conclusion, higher endothelin-1 levels are independently associated with CHD in women of all ages and among older men only.

Topics: Aged; California; Coronary Disease; Cross-Sectional Studies; Electrocardiography; Endothelin-1; Female; Humans; Logistic Models; Male; Middle Aged; Prevalence; Risk Factors; Statistics, Nonparametric

We investigated the mechanism by which C-reactive protein (CRP) affects pro-inflammatory activities of vascular smooth muscle cells (VSMCs).. RT-PCR, flow cytometry, and immunoblotting assays consistently showed the expression of FcgammaRIIa by cultured VSMCs isolated from human coronary arteries. Immunofluorescence staining of human coronary artery plaque showed the co-localization of FcgammaRIIa with alpha-actin(+) VSMCs in atheromatous regions. Confocal microscopic image analysis of H(2)DCFDA-labeled cells showed that CRP induced intracellular reactive oxygen species (ROS) generation by FcgammaRIIa(+) HEK293T cells. Moreover, CRP time- and dose-dependently generated ROS in VSMCs through FcgammaRIIa activation. VSMCs mainly express NADPH oxidase 4 isoform (Nox4), the suppression of which using a specific siRNA completely abolished CRP-induced ROS generation by VSMCs. The downregulation of p22(phox), a component of the active Nox4 complex, by transfecting with specific decoy oligomers and functional blocking of FcgammaRIIa not only inhibited the CRP-induced ROS generation but also reduced the degree of AP-1 and NF-kappaB activation, the production of MCP-1, IL-6, and ET-1, and the apoptotic changes of VSMCs in response to CRP.. CRP-induced ROS generation by VSMCs, which requires functional activation of FcgammaRIIa and NADPH oxidase 4, orchestrates pro-inflammatory activities of VSMCs and may eventually promote atherogenesis and plaque rupture.

Topics: Aged; Antigens, CD; Apoptosis; C-Reactive Protein; Cell Line; Cells, Cultured; Chemokine CCL2; Coronary Disease; Coronary Vessels; Endothelin-1; Enzyme Activation; Flow Cytometry; Gene Expression; Humans; Interleukin-6; Male; Membrane Glycoproteins; Microscopy, Confocal; Myocytes, Smooth Muscle; NADPH Oxidase 1; NADPH Oxidase 2; NADPH Oxidase 4; NADPH Oxidases; NF-kappa B; Reactive Oxygen Species; Receptors, IgG; Recombinant Proteins; Reverse Transcriptase Polymerase Chain Reaction; Transcription Factor AP-1; Transcription Factor CHOP; Transfection

Increased endothelin-1-mediated vasoconstrictor tone has been linked to the etiology of a number of pathologies associated with human aging, including hypertension, congestive heart failure, and coronary artery disease. However, it is currently unclear whether aging, per se, is associated with enhanced endothelin-1 system activity. We hypothesized that endothelin-1 vasoconstrictor activity is greater in healthy older compared with young men and that regular aerobic exercise is an effective intervention for reducing endothelin-1 vasoconstrictor tone in older previously sedentary men. Forearm blood flow (plethysmography) responses to intra-arterial infusion of endothelin-1 (5 pmol/min; for 20 minutes) and selective (BQ-123; 100 nmol/min; for 60 minutes) and nonselective (BQ-123+BQ-788; 100 nmol/min; for 60 minutes) endothelin-1 receptor blockade were determined in 28 healthy, sedentary men: 13 younger (age: 27+/-1 years) and 15 older (age: 62+/-2 years). The vasoconstrictor response to endothelin-1 was significantly blunted ( approximately 65%) in the older versus younger men. In response to BQ-123, resting forearm blood flow increased ( approximately 20%; P<0.05) in the older but not in the younger men. The addition of BQ-788 to BQ-123 did not significantly affect the blood flow responses to BQ-123 in either group. Eight of the 15 older sedentary men completed a 3-month aerobic exercise intervention. After the intervention, the vasoconstrictor response to endothelin-1 was markedly increased (225%; P<0.05), whereas BQ-123 resulted in modest vasoconstriction in the previously sedentary older men. These results demonstrate that endothelin-1-mediated vasoconstrictor tone increases with age in healthy men but can be alleviated with regular aerobic exercise.

Topics: Adult; Age Factors; Aged; Aging; Analysis of Variance; Body Composition; Cohort Studies; Coronary Circulation; Coronary Disease; Endothelin-1; Endothelium, Vascular; Exercise; Humans; Male; Middle Aged; Oxygen Consumption; Probability; Prognosis; Risk Factors; Sensitivity and Specificity; Vasoconstriction

Inflammation is relatively common in individuals with a sleep disorder and is associated with quality of sleep. The purpose of this study was to examine whether inflammation is associated with quality of sleep in healthy individuals.. Observational study in a General Clinical Research Center.. This study characterized inflammation and polysomno-graphically verified sleep in 124 African American and Caucasian American women and men without a sleep disorder.. Circulating levels of 3 markers and/or mediators of inflammation known to be elevated in sleep disorders and in cardiovascular disease were determined (interleukin-6 [IL-6] endothelin-1 [ET-1], soluble intercellular adhesion molecule-1 [sICAM-1]). Sleep was characterized by polysomnography. Multiple linear regression analyses showed that increasing age, male sex, and African American ethnicity were independently associated with poorer sleep. After controlling for these variables, higher levels of ET-1 were independently associated with greater sleep latency (P < or = 0.01), greater rapid eye movement (REM) latency (P < or = 0.01), more slow wave sleep (P < or = 0.05), and less stage 1 sleep (P < or = 0.01). Higher IL-6 levels were independently associated with greater REM latency (P < or = 0.05).. The findings suggest that, in individuals without a known sleep disorder, ET-1, a potent vasoconstrictor and mediator of inflammation, is associated with more deep sleep, whereas both ET-1 and IL-6 are associated with increased latency of sleep and of REM. The findings underscore the complex relationships between peripheral markers of inflammation and sleep.

Topics: Adult; Biomarkers; Coronary Disease; Endothelin-1; Female; Health Status; Humans; Intercellular Adhesion Molecule-1; Interleukin-6; Male; Middle Aged; Sleep

Myocardium undergoes functional changes in the infarcted region primarily due to ischemia. Following myocyte functional alterations of the noninfarcted myocardium are caused by remodelling and hypertrophy. We have monitored and compared changes in the electrocardiographical (ECG) image after coronary artery occlusion (CAO, n=5) and intracoronary endothelin-1 (ET-1, n=3) administration during a 6-month period. In 3 dogs, the CAO was repeated 6 months after the first occlusion. Signal-averaged ECG (SA ECG) was recorded before the operation and 10 days, 1 month, 3 months and 6 months after myocardial infarction (MI). The modified Wigner distribution was used for spectrotemporal analysis of the SA ECG. Eight-hour Holter monitoring was performed in each dog before and after experimental MI. Spectrotemporal representations of the QRS complex were stabilized after the first 1-month period in the group of dogs after CAO. The same results were also observed after the repeated CAO. No arrhythmias were recorded 9 days after CAO. The spectrotemporal representations of the QRS complex after intracoronary ET-1 administration were not stabilized during the whole observed period. Very few arrhythmic events were recorded by Holter monitoring already 3 days after intracoronary ET-1 injection. Experimental MI induced by CAO caused a changed ECG image, which was stable from 1 month after MI induction till the end of the monitoring. However, the ECG image after ET-1 administration was not stable during the whole observed period. No arrhythmic events were recorded in either group 3 months postoperatively that could be caused by healthy myocardial status before the experimental MI induction. In clinical practice, however, ischemic heart disease usually precedes the MI. Arrhythmogenic substrate could thus be a consequence of combination of healthy status of the myocardium before MI and MI itself.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Disease Models, Animal; Dogs; Electrocardiography, Ambulatory; Endothelin-1; Heart; Myocardial Infarction; Risk Factors; Signal Processing, Computer-Assisted; Time Factors

Fresh vehicular emissions potentially represent a ubiquitous environmental concern for cardiovascular health. We compared electrocardiographic effects of fresh gasoline engine emissions with resuspended paved road dust in a mouse model of coronary insufficiency. Apolipoprotein E (ApoE)-/- mice on a high fat diet were exposed by whole-body inhalation to either gasoline emissions at 60 microg/m3 particulate matter (PM), an equivalent atmosphere with particles filtered out of the whole exhaust, or paved road dust at 0.5 and 3.5 mg /m3 for 6 h/d for 3 d. Radiotelemetry recordings of electrocardiogram (ECG) were analyzed for changes in T-wave morphology (QT interval, T-wave amplitude, and T-wave Area). Following exposures, lung lavage and blood samples were obtained to assay for markers of pulmonary and systemic inflammation. No exposure induced significant changes in heart rate and only the high concentration of road dust induced signs of pulmonary inflammation. T-wave area exhibited significant deviation from baseline values during exposure to gasoline exhaust particulates, but not to either concentration of road dust or gasoline emissions sans particulates. Gasoline-exposed mice demonstrated elevated plasma endothelin-1, but did not cause systemic inflammation. These data support the hypothesis that freshly-generated engine emissions, as opposed to resuspended paved road dust, may drive cardiac effects that have been observed at road-sides in the environment. The absence of ECG effects for both very high concentrations of road dust PM and equivalent concentrations of the vapor/gas phase of gasoline engine exhaust further indicate the specific risk conferred by fresh vehicular PM.

Topics: Animals; Apolipoproteins E; Biomarkers; Bronchoalveolar Lavage Fluid; Coronary Disease; Dust; Electrocardiography; Electrophysiology; Endothelin-1; Gasoline; Heart; Inflammation; Male; Mice; Mice, Knockout; Particulate Matter; Pneumonia; Vehicle Emissions

The bioactive peptide endothelin modulates left ventricular function by changing afterload, coronary vascular tone, and myocardial contractility. However, whether increased plasma endothelin levels observed in patients during and after coronary revascularization and cardiopulmonary bypass reflect actual myocardial interstitial levels are unknown.. A microdialysis probe (outer diameter: 0.77 mm; length: 4 mm) was placed in the left ventricular apical midmyocardium in 20 patients and myocardial interstitial fluid was collected (2.5 microL/min) at baseline and up to 30 minutes after cardiopulmonary bypass. Myocardial interstitial and systemic arterial endothelin were measured by radioimmunoassay.. Baseline myocardial interstitial endothelin was over 6-fold higher than plasma (20.11 +/- 2.07 vs 3.19 +/- 0.25 fmol/mL, P < .05). Plasma endothelin increased by 23% +/- 12% at 60 minutes of cardiopulmonary bypass whereas myocardial interstitial endothelin increased by 105% +/- 24%, P < .05), and this change was higher than in the plasma ( P < .05). Although no further change in plasma endothelin occurred during cardiopulmonary bypass, myocardial interstitial levels increased further after crossclamp removal (400% +/- 75%) and remained significantly higher than plasma at separation from cardiopulmonary bypass.. The unique findings of this study were 2-fold: First, significant compartmentalization of endothelin exists within the human myocardium. Second, a significantly higher and temporally disparate change in myocardial interstitial endothelin occurs during and after cardiopulmonary bypass when compared with systemic levels. These dynamic changes in myocardial endothelin likely influence coronary vascular tone and contractility.

Topics: Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Female; Humans; Male; Microdialysis; Middle Aged; Myocardial Contraction; Myocardium; Postoperative Period; Ventricular Dysfunction, Left

Plasma levels of endothelin-1 (ET-1) increase after coronary angioplasty (PTCA) due to endothelial injury during the procedure. ET-1 has been found in human endocardial and myocardial cells. It is not known whether ET-1 increases after thermal injury induced by radiofrequency catheter ablation (RFA).. We determined plasma ET-1 levels at baseline, immediately after, and at 2 and 6 h post-procedure in 31 patients undergoing PTCA and 16 patients undergoing RFA. Patients subjected to diagnostic coronary angiography (n=15) or electrophysiology study (n=13) served as controls.. Compared to baseline, ET-1 levels increased significantly immediately post-PTCA (55.1+/-20.1 vs. 42.7+/-14.9 pg/ml, p<0.01) and at 2 h post-RFA (98.0+/-11.7 vs. 53.0+/-17.4 pg/ml, p<0.01) and returned to baseline measurements at 2 h post-PTCA and 6 h post-RFA. There was no change of ET-1 levels in the control groups. ET-1 kinetics curve was significantly higher post-RFA compared to post-PTCA (p<0.001). ET-1 immediately post-PTCA correlated with total pressure-time product applied for balloon inflation during the procedure (r=0.56, p<0.01). There was no correlation between ET-1 levels and the number of RFA applications. No patient developed ischemia post-PTCA. There were no complications or arrhythmia recurrences post-RFA.. Endocardial thermal injury incurred during RFA is another mechanism of endothelin increase apart from mechanical injury of the coronary endothelium during PTCA and represents further evidence for the existence of the peptide in human endocardial endothelial and myocardial cells. ET-1 increase is delayed and more pronounced post-RFA compared to post-PTCA. Despite that, it does not seem to have any clinical impact in the immediate post-RFA period.

Topics: Arrhythmias, Cardiac; Biomarkers; Catheter Ablation; Coronary Angiography; Coronary Disease; Electrocardiography; Endocardium; Endothelin-1; Female; Follow-Up Studies; Humans; Male; Middle Aged; Postoperative Period; Severity of Illness Index; Treatment Outcome

We performed a cohort study of 392 postmenopausal women who had coronary disease to assess whether baseline serum endothelin-1 level predicts angiographic disease progression, nonfatal myocardial infarction, or death. Angiographic progression was defined as the annualized change in minimal lumen diameter of all qualifying lesions for each patient. Twenty-nine patients died or had a myocardial infarction during follow-up. Each picogram per milliliter increase in endothelin-1 was associated with a 1.8-fold increased risk of death or myocardial infarction. After adjustment for potential confounders, endothelin-1 remained a predictor of clinical events but was not correlated with angiographic progression.

Topics: Aged; Biomarkers; Coronary Angiography; Coronary Disease; Disease Progression; Endothelin-1; Female; Humans; Middle Aged; Myocardial Infarction; Postmenopause; Predictive Value of Tests; Randomized Controlled Trials as Topic

Endothelial dysfunction, which is more often observed in conduit arteries such as the aorta, carotid, femoral, and brachial arteries, is largely due to alterations in cellular signal transduction initiated by an escalating cycle of damage triggered by oxidative stress. This phenomenon is exacerbated in the elderly, where a progressive loss of vascular endothelial function and concurrent loss of vasomotor control is frequent. In a previous study, we demonstrated that the wild artichoke (Cynara cardunculus) is able to increase the production of the vasorelaxant factor nitric oxide by cultured aortic endothelial cells. We now extended that study to verify (1) the vasorelaxant potential of C. cardunculus on isolated rat aortic rings and (2) whether the vasomodulating properties of C. cardunculus are maintained in vivo, after administration to aged rats. The results demonstrate that the wild artichoke and its main components, namely, luteolin and apigenin, improve aortic relaxation when added to the incubation bath. Moreover, the feeding of wild artichoke [10 mg (kg of polyphenols)(-1) day(-1)] to aged rats significantly restores proper vasomotion, to a degree similar to that observed in young animals. This study provides further justification to the advice to consume wild greens as part of a balanced diet and suggests that close attention should be paid to the diet of the elderly, because it can effectively modulate important parameters of cardiovascular risk.

Topics: Aging; Animals; Aorta, Thoracic; Biomarkers; Chromatography, High Pressure Liquid; Coronary Disease; Cynara; Dinoprost; Endothelin-1; Flavonoids; In Vitro Techniques; Male; Muscle Relaxation; Muscle, Smooth, Vascular; Oxidative Stress; Phenols; Plant Extracts; Polyphenols; Rats; Rats, Inbred BN; Rats, Inbred F344; Rats, Sprague-Dawley

Coronary slow flow (CSF) is characterized by delayed opacification of coronary arteries in the absence of epicardial occlusive disease. In this study, we aimed to determine endothelin-1 (ET-1), nitric oxide (NOx) levels and time domain heart rate variability (HRV) parameters in patients with CSF and relationship among these parameters.. Thirty-three patients with CSF detected in the coronary angiography (17 females; mean age 55 +/- 7) and 19 patients with normal coronary flow (10 females; mean age 54 +/- 11) as a control group were enrolled in the study. Patients were divided into two groups according to exercise testing as if positive (group A, n = 8) or negative (group B, n = 25).. Plasma ET-1 levels were higher in the group A patients (28.7 +/- 17.4 pg/ml) than that of group B (15.9 +/- 10.6 pg/ml) and control group (6.0 +/- 5.7 pg/ml); and higher in group B patients than that of control group (P < 0.05). Although groups A and B did not differ according to plasma NOx levels (23.4 +/- 13.5 micromol/L vs. 32.8 +/- 22.7 micromol/L, P > 0.05), NOx levels in group A were lower than the control group (23.4 +/- 13.5 micromol/L versus 42.5 +/- 15.9 micromol/L, P < 0.05). Time domain HRV parameters were decreased in all patient groups. This was more prominent in group A. Additionally, HRV parameters were negatively correlated with ET-1 and TIMI frame counts. TIMI frame count was also significantly correlated with ET-1 and NOx levels (r = 0.61, P < 0.0001, r =-0.30, P < 0.05). Upon intravascular ultrasonography investigation, the common finding was longitudinally extended massive calcification throughout the epicardial arteries. Mean intimal thickness was 0.50 +/- 0.13 mm (group A; 0.58 +/- 0.11 mm, group B 0.47 +/- 0.12 mm, P = 0.029).. The present study demonstrated that in patients with CSF, both increased plasma ET-1, decreased plasma NOx and diffuse atherosclerosis may cause the decrease in HRV by effecting myocardial blood flow.

Topics: Analysis of Variance; Blood Flow Velocity; Case-Control Studies; Chi-Square Distribution; Coronary Angiography; Coronary Circulation; Coronary Disease; Echocardiography; Electrocardiography; Endothelin-1; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Regional Blood Flow

Mitral annulus calcification (MAC) is a chronic degenerative noninflammatory process. The goal of this study was to determine endothelin-1 (ET-1) and nitric oxide (NOx) levels in patients with MAC and compare them with those in normal subjects. The study group included 39 patients [26 females (66%), age, 63 +/- 8 years] with MAC and 20 [11 females (55%), age, 61 +/- 7 years] healthy subjects. The patients were divided into two subgroups, group A with severe MAC and group B with mild MAC, according to the severity of the MAC. Plasma ET-1 levels were higher and NOx levels were lower in patients than controls [(6.5 +/- 5.6 pg/mL vs 3.7 +/- 2.9 pg/mL for ET-1 and 35.0 +/- 10.6 micromol/L vs 42.3 +/- 9.9 micromol/L for NOx; P < 0.05 for both)]. In the subgroups, ET-1 levels were higher in group A than group B (8.65 +/- 6.84 pg/mL vs 4.74 +/- 3.45 pg/mL, P < 0.05) and the control group (8.65 +/- 6.84 pg/mL vs 3.70 +/- 2.88 pg/mL, P < 0.05). There was no difference between group B and the control group. Plasma NOx levels were significantly decreased in group A compared to controls (32.22 +/- 11.88 micromol/L vs 42.25 +/- 9.99 micromol/L, P < 0.05). However, no significant difference was observed between group B (37.38 +/- 9.06 micromol/L) and the other groups. Diabetes mellitus, coronary artery disease, and dyslipidemia were significantly associated with ET-1 levels. However, this association was not observed for NOx. In conclusion, patients with MAC have increased ET-1 and decreased NOx levels. This seems to be more prominent in patients with severe MAC.

Topics: Aged; Calcinosis; Coronary Disease; Diabetes Mellitus; Echocardiography; Echocardiography, Doppler, Color; Endothelin-1; Female; Heart Valve Diseases; Humans; Male; Middle Aged; Mitral Valve; Nitrates; Nitric Oxide; Nitrites

To determine the tissue content and endothelin-receptor characteristics of endothelin-1 in the radial artery in relation to the internal mammary artery.. Endothelin-1 content was quantified in the radial artery and the internal mammary artery. Both arteries were exposed to endothelin-1 and agonists of the endothelin A and B receptors.. The highest level of endothelin-1 was found in the radial artery. Endothelin-1 contracted both arteries. The contraction was sensitive to endothelinA-receptor agonism and enhanced in both arteries by inhibition of prostacyclin and nitric oxide formation. In the internal mammary artery the endothelinB-receptor agonist caused an endothelinA-receptor sensitive contraction augmented by inhibition of nitric oxide and prostacyclin. However, in the radial artery this contraction was only observed in the presence of inhibition of nitric oxide and prostaglandin.. The highest endothelin-1 content was found in the radial artery. The functional effects of endothelin-1 in the radial artery were similar to that in the internal mammary artery, mediated by predominantly endothelinA-receptor activation causing vasoconstriction. Selective endothelinA-receptor blockade may prove beneficial in preventing graft spasm in the radial as well as the internal mammary artery.

Topics: Biomarkers; Coronary Artery Bypass; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Indomethacin; Male; Mammary Arteries; Radial Artery; Receptor, Endothelin A; Receptor, Endothelin B; Sensitivity and Specificity; Tissue Culture Techniques; Ultrasonography

Topics: Adult; Biomarkers; C-Reactive Protein; Cell Adhesion Molecules; Coronary Disease; Endothelin-1; Endothelium, Vascular; Humans; Hypertriglyceridemia; Inflammation; Interleukin-6; Male; Risk Factors; von Willebrand Factor

In this study, the endothelin-1 (ET-1) and nitric oxide (NO) concentrations in slow coronary flow (SCF) patients were assessed before and at the peak of the exercise stress test and compared with the values from healthy controls. The study population was 25 patients who underwent coronary angiography and were diagnosed as SCF (11 females (44%), aged 56.7+/-9.8 years), and 20 normal subjects (9 females (45%), aged 54.3+/-9.2 years). Mean TIMI frame count in the patients was 54.1+/-13.4. Blood samples were drawn at rest and immediately at the end of exercise testing. The baseline ET-1 concentrations of the control subjects were lower than those of the patients (7.0+/-4.5 pg/ml vs 11.1+/-5.9 pg/ml p<0.0001) and this difference increased after exercise (6.2+/-4.3 pg/ml vs 20.1 +/-10.4 pg/ml, p<0.0001). Post-exercise ET-1 concentrations were significantly higher than baseline in patients with SCF (p<0.0001) and a reduction in the ET-1 concentrations was observed in control subjects (p<0.05). Baseline NO concentrations of the patients were lower than those of the control subjects (27 +/-5.1 micromol/L vs 31.2+/-4.9 micromol/L, p=0.0001). Although the NO concentrations in both groups were significantly increased after exercise (29.4 +/-5.9 micromol/L vs 33.3+/-5.6 micromol/L, p<0.05 for both), the difference was not significant. A significant negative correlation among post-exercise ET-1 concentrations and maximal heart rate, exercise duration and exercise rate - pressure product, and a significant positive correlation among post-exercise NO concentrations and maximal heart rate and exercise duration were observed in both groups. The results of this study show that endothelial function (assessed by ET-1 and NO concentrations) and its response to exercise were abnormal in SCF patients compared with healthy subjects, and this may play some pathophysiologic role.

Topics: Angina Pectoris; Biomarkers; Blood Flow Velocity; Blood Pressure; Coronary Disease; Endothelin-1; Exercise Test; Female; Heart Rate; Humans; Male; Middle Aged; Nitric Oxide; Reference Values; Regression Analysis

Regular consumption of red wine reduces mortality from coronary heart disease. This observation has been attributed to the anti-thrombotic effects of ethanol and to the antioxidant properties of polyphenolic compounds present in red wine. Here we show that an extract of red wine polyphenols causes a concentration-dependent inhibition of endothelin-1 synthesis in cultured bovine aortic endothelial cells. This action was associated with modifications in phosphotyrosine staining, indicating that the active components of red wine cause specific modifications of tyrosine kinase signalling. Thus inhibition of endothelin-1 synthesis by red wine may reduce the development of atherosclerosis, and hence decrease coronary heart disease.

Topics: Animals; Antioxidants; Aorta; Cattle; Cells, Cultured; Coronary Disease; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Plant Extracts; Wine

Novel data is presented from this electron-immunocytochemical study that demonstrates endothelin-containing cerebrovascular nerves in the human middle cerebral artery.

Topics: Axons; Cerebral Arteries; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Microscopy, Immunoelectron; Middle Aged

Endothelin, a peptide with strong vasoconstrictive and mitogenic properties, has been found to increase after cardiac transplantation. We therefore assessed the association between its precursor peptide, big endothelin-1, and intimal hyperplasia and coronary flow reserve after heart transplantation.. Thirty-five patients without hemodynamically significant coronary artery disease after heart transplantation were investigated: Average peak flow velocity in the left anterior descending artery (LAD) was assessed by intracoronary Doppler at baseline as well as after injection of adenosine; coronary flow reserve was calculated as a ratio of both and was corrected for patient age and baseline average peak flow velocity. Lumen, intima + media and total vessel area were measured by intracoronary ultrasound. The plasma concentration of big endothelin-1 in venous blood was determined by radioimmunoassay.. Patients with elevated big endothelin-1 levels (>2 fmol/ml) tended to have a decreased corrected coronary flow reserve (2.60 +/- 0.9 vs 3.21 +/- 1.0, p = 0.078). They also had a significantly larger intima + media area (5.82 +/- 2.9 vs 2.37 +/- 2.9 mm(2), p = 0.004) and total vessel area (18.36 +/- 5.8 vs 12.81 +/- 4.8 mm(2), p = 0.012) than those with normal plasma concentrations.. Our study suggests an association between elevated big endothelin-1 plasma levels and the development of intimal hyperplasia and reduction of coronary flow reserve after cardiac transplantation.

Topics: Adult; Aged; Biomarkers; Cohort Studies; Coronary Angiography; Coronary Circulation; Coronary Disease; Endothelin-1; Female; Heart Transplantation; Hemodynamics; Humans; Hyperplasia; Male; Middle Aged; Predictive Value of Tests; Prevalence; Probability; Radioimmunoassay; Risk Assessment; Sensitivity and Specificity; Severity of Illness Index; Tunica Intima; Ultrasonography, Doppler; Ultrasonography, Interventional

Endothelin-1 (ET-1), a potent vasoconstrictor, is released in response to several inflammatory cytokines after heart transplantation. The present study correlated patterns of myocardial ET-1 expression in heart biopsies with acute rejection, post-transplantation ischemic injury, and subsequent development of coronary vasculopathy.. Patterns of myocardial ET-1 expression were evaluated in 47 heart transplant recipients at 3 months after transplant. Transplant vasculopathy was documented by coronary angiography at 2 years after transplant. Expression of ET-1 was tabulated for both blood vessels and the interstitium. Vascular ET-1 expression was positive in 7/17 (41%) of patients with greater than grade 2 (International Society Heart Lung Transplant) rejection compared with 3/30 (10%) of patients with grade 0 and grade 1A rejection (P=0.02). Compared with patients with negative interstitial ET-1 expression (n=22), patients with positive interstitial ET-1 expression (n=25) had higher incidence of post-transplantation ischemic injury (52% versus 9%, P=0.002), lower mean episodes of acute rejection (> or = grade 2) during the first 3 months of transplant (1.09+/-0.66 versus 1.86+/-1.6, P=0.048), and more common vasculopathy at 2 years (50% versus 15%, P=0.02), and they tended to have worse survival (83.2% versus 100%, P=0.058).. Vascular ET-1 expression is likely to be associated with acute rejection. Interstitial ET-1 expression, however, is more likely to be associated with post-transplantation ischemic injury and subsequent development of coronary vasculopathy.

Topics: Coronary Angiography; Coronary Disease; Coronary Vessels; Endothelin-1; Graft Rejection; Heart Transplantation; Humans; Middle Aged; Myocardial Ischemia; Myocardium; Survival Rate; Treatment Outcome

Previous studies in animal models of angioplasty have suggested a role in neointimal hyperplasia for endothelins (ETs), potent vasoconstricting peptides that also exert growth-promoting effects. The present studies were undertaken to test the hypothesis that endothelin receptor blockade can reduce neointimal thickening in injured porcine coronary arteries.. An ET(A)/ET(B) antagonist, L-749,329, was evaluated as an inhibitor of intimal thickening in a porcine balloon/stent model of coronary artery injury. L-749,329 competitively inhibited [(125)I]ET-1 binding to porcine ET(A) (IC(50) approximately 0.3 nmol/L) or ET(B) (IC(50) approximately 20 nmol/L) receptors and inhibited ET-1-stimulated signaling in cell culture. In anesthetized pigs, big ET-1-stimulated increases in systemic blood pressure were totally inhibited after intravenous infusion of L-749,329 (>/=0.2 mg. kg(-1). h(-1)). In vascular injury studies, pigs were treated with vehicle or L-749,329 (1 mg. kg(-1). h(-1)) beginning 2 days before and continuing 28 days after experimental angioplasty. Left anterior descending, left circumflex, and/or right coronary arteries were injured by inflation of an angioplasty balloon wrapped with a coiled metallic stent. After 28 days, mean neointimal thickness in the L-749,329-treated group was reduced by 9.0% compared with vehicle-treated controls, but this effect was not statistically significant (P=0.13).. Blockade of endothelin receptors for 28 days with only a mixed ET(A)/ET(B) receptor antagonist is insufficient to substantially inhibit intimal hyperplasia after balloon/stent coronary artery injury in the pig, in contrast to results with a selective ET(A) antagonist. The effects of selective or mixed ET(A)/ET(B) antagonists in diseased vessels remain to be determined in this model.

Topics: Acetamides; Animals; Binding, Competitive; Blood Pressure; Cell Line; Cells, Cultured; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin Receptor Antagonists; Endothelin-1; Female; Iodine Radioisotopes; Male; Muscle, Smooth, Vascular; Peptides, Cyclic; Receptor, Endothelin A; Receptor, Endothelin B; Receptors, Endothelin; Signal Transduction; Swine; Tunica Intima

Endothelin-1 (ET-1) and adrenomedullin (ADM) are both produced in the arterial wall, but have opposing biological actions. Evidence from experimental animals suggests a functional interaction between ET-1 and ADM. We have tested this in humans. Small resistance arteries were obtained from gluteal biopsies taken from patients with chronic heart failure (CHF) due to coronary heart disease (CHD), or with CHD and preserved ventricular function. The contractile responses to big ET-1 and to ET-1 in both sets of vessels were studied in the absence (control) and presence of ADM at 20 pmol/l (low ADM) or 200 pmol/l (high ADM), using wire myography. ADM did not affect the conversion of big ET-1 into ET-1 in vessels from patients with either CHD or CHF. Low ADM did not alter the contractile response to ET-1 in vessels from patients with CHF. Low ADM was not tested in vessels from patients with CHD, but high ADM did not affect this response in arteries from these patients. High ADM did, however, significantly reduce the vasoconstrictor effect of ET-1 in vessels from patients with CHF. The maximum response, as a percentage of the response to high potassium, was 199% (S.E.M. 25%) in the control experiments (n=14), 205% (27%) in the low-ADM (n=7) studies and 150% (17%) in the high-ADM (n=6) experiments (P<0.001). Furthermore, the Hill coefficient increased from 0.57+/-0.05 in the absence of ADM to 1.16+/-0.15 in the high-ADM experiments, indicating that ADM at 200 pmol/l specifically antagonized one receptor type in vessels from patients with CHF. We conclude that there is a one-site receptor interaction between ADM and ET-1 that is specific for vessels from patients with CHF. This functional interaction between ADM and ET-1 in resistance arteries may be of pathophysiological importance in CHF.

Topics: Adrenomedullin; Analysis of Variance; Cardiac Output, Low; Case-Control Studies; Coronary Disease; Dose-Response Relationship, Drug; Endothelin-1; Female; Humans; Male; Myography; Peptides; Receptors, Endothelin; Vascular Resistance; Vasoconstriction; Vasodilator Agents

Endothelin-converting enzyme (ECE)-1 activates endothelin-1 (ET-1) and may thus contribute to the regulation of vascular tone and cell growth during atherosclerosis.. To evaluate ECE-1 immunoreactivity concerning big ET-1/ET-1, we performed qualitative and quantitative immunohistochemistry in normal internal mammary arteries (n=10), in coronary arteries with adaptive intimal fibrosis (n=10), in aortic fatty streaks (n=10), and in distinct regions of advanced carotid plaques (n=15). Furthermore, we determined ECE-1 activity in the control specimens and in the inflammatory intimal regions of carotid plaques. Double immunolabeling showed that ECE-1 was present in endothelial cells, vascular smooth muscle cells, and macrophages. All ET-1(+) cells were simultaneously ECE-1(+). Most importantly, there were significantly more ET-1(+) cells in the intima and media when atherosclerosis was in an inflammatory stage than when it was in a noninflammatory stage. Moreover, ECE-1 activity was upregulated in the intima of carotid plaques, although immunohistochemically, there were no significant differences between the number of ECE(+) cells in the different compartments of the arterial wall.. Together with ET-1, ECE-1 is abundantly present in human arteries and at different stages of atherosclerotic plaque evolution. The upregulation of the ECE-1/ET-1 system is closely linked to the presence of chronic inflammation and is present in very early stages of plaque evolution. Therefore, enhanced production of active ET-1 may substantially contribute to cell growth and the regulation of vascular tone in advanced atherosclerotic lesions and in the very early stages of plaque evolution, when a plaque is still imperceptible clinically.

Topics: Aorta; Aortic Diseases; Arteriosclerosis; Aspartic Acid Endopeptidases; Carotid Arteries; Carotid Stenosis; Chronic Disease; Coronary Disease; Coronary Vessels; Disease Progression; Endothelin-1; Endothelin-Converting Enzymes; Enzyme Activation; Humans; Immunohistochemistry; Inflammation; Mammary Arteries; Metalloendopeptidases; Tunica Intima; Tunica Media

We have shown previously that a small bolus dose of endothelin-1, given intravenously before coronary occlusion, exerts a marked antiarrhythmic effect in anaesthetised rats. The aim of the current study was to determine whether or not this is due to a direct effect of endothelin-1 on the heart by assessing the antiarrhythmic effect of endothelin-1 against occlusion-induced arrhythmias in rat isolated hearts. Rat isolated hearts were perfused in Langendorff mode (constant flow) and subjected to coronary artery occlusion for 30 min. Coronary perfusion pressure and a surface electrocardiogram (ECG) were monitored throughout the experiment. In the first series of studies, the effects of three 5-min infusions of endothelin-1 (0.1-10 nM), given prior to coronary occlusion, were assessed. A second series of hearts was given a single bolus dose of endothelin-1 (10 pmol) 5 min prior to ischaemia. A third series of experiments was performed using a modified (low K+) Krebs Henseleit solution to increase the incidence of ischaemia-induced ventricular fibrillation (VF). In these hearts, endothelin-1 (0.1 or 2 pmol) was administered as a bolus injection 5 min before ischaemia. Infusion of endothelin-1 prior to ischaemia did not modify the incidence or severity of arrhythmias at any of the concentrations used. Bolus administration of endothelin-1 (10 pmol) in hearts perfused with Kreb's Henseleit solution containing normal K+ (4.4 mM) was found to cause a small rise in coronary perfusion pressure, with no preceding depressor response. Under these conditions, endothelin-1 exerted only a very moderate reduction in arrhythmias, by reducing the arrhythmia count in the 21-30-min post-occlusion period. Furthermore, in hearts perfused with low K+ solution, bolus injection of endothelin-1, in a dose that either had no effect on coronary perfusion pressure (0.1 pmol) or produced a significant vasodilator effect with no significant pressor effect (2 pmol), had no effect on ventricular fibrillation. Thus, in concentrations that are sufficient to exert effects on the coronary vasculature, endothelin-1 fails to modify arrhythmias in an isolated heart preparation. These results suggest that the antiarrhythmic effects of endothelin-1 previously observed in vivo are not due to a direct effect on either the myocardium or the coronary blood vessels.

Topics: Animals; Arrhythmias, Cardiac; Coronary Disease; Dose-Response Relationship, Drug; Endothelin-1; Heart; In Vitro Techniques; Male; Myocardial Ischemia; Perfusion; Potassium; Rats; Rats, Sprague-Dawley; Tachycardia, Ventricular; Time Factors; Ventricular Fibrillation

Topics: Animals; Biopterins; Cholesterol; Coronary Disease; Coronary Vessels; Dose-Response Relationship, Drug; Endothelin-1; Hypercholesterolemia; Superoxides; Swine

Endothelins are potent vasoconstrictors and pressor peptides and are important mediators of cardiac, renal and endocrine functions. Increased ET-1 levels in disease states such as congestive heart failure, pulmonary hypertension, acute myocardial infarction, and renal failure suggest the endothelin system as an attractive target for pharmacotherapy. A non-peptidic, selective, competitive endothelin receptor antagonist with an affinity for the ET(A) receptor in the subnanomolar range was administered by continuous intravenous infusion to beagle dogs, rats, and Goettingen minipigs. It caused mild arteriopathy characterised by segmental degeneration in the media of mid- to large-size coronary arteries in the heart of dog, but not rat or minipig. The lesions only occurred in the atrium and ventricle. Frequency and severity of the vascular lesions was not sex or dose related. No effects were noted in blood vessels in other organs or tissue. Plasma concentrations at steady state, and overall exposure in terms of AUC((0-24h)) were higher in minipig and rat than the dog but did not cause cardiac arteriopathy. These findings concur with those caused by other endothelin anatagonists, vasodilators and positive inotropic/vasodilating drugs such as potassium channel openers, phosphodiesterase inhibitors and peripheral vasodilators, and confirm that dogs appear to be uniquely sensitive to the development of cardiac vascular lesions.

Topics: Animals; Coronary Disease; Dioxoles; Dogs; Endothelin Receptor Antagonists; Endothelin-1; Female; Indans; Male; Rats; Rats, Sprague-Dawley; Receptor, Endothelin A; Species Specificity; Swine; Swine, Miniature

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Randomized Controlled Trials as Topic; Renin-Angiotensin System; Sympathetic Nervous System

Neurohormones may influence vascular tone both during and after exercise. Neuropeptide Y (NPY), which is costored and released with norepinephrine (NE) during sympathetic activity, is a potent vasoconstrictor with a relatively long half-life. We therefore examined its possible association with the ischemic response to exercise in patients with coronary artery disease.. Twenty-nine male patients with effort-induced angina pectoris underwent a symptom-limited exercise test. In addition to conventional ST-segment analysis, we examined ischemia on the basis of heart rate (HR)-adjusted ST-segment changes through calculation of the ST/HR slope during the final 4 minutes of exercise and of the ST/HR recovery loop after exercise. Blood samples were taken before, during, and after exercise for an analysis of several neurohormones. Mean ST-segment depression was -223+/-20.2 microV (P:<0.0001) just before the termination of exercise, followed by a gradual normalization, but it remained significant after 10 minutes (-49+/-8.9 microV, P:<0.0001). At the end of exercise, the ST/HR slope, which reflects myocardial ischemia, was -6.0+/-0.77 microV/HR. In most patients, ST-segment levels at a given HR were lower during recovery than during exercise, here referred to as ST "deficit." Exercise increased the plasma levels of NPY, NE, epinephrine, and N-terminal proatrial natriuretic peptide, but big endothelin remained unchanged. Although NE and epinephrine peaked at maximal exercise, the highest levels of NPY and N-terminal proatrial natriuretic peptide were observed 4 minutes after exercise. The maximal increase in the NPY correlated significantly with ST-segment depression at 3 minutes after exercise (r=-0.61, P:= 0.0005), the ST deficit at the corresponding time point (r=-0.66, P:= 0.0001), and the duration of ST-segment depression after exercise (r= 0.42, P:=0.02). In contrast, no such correlations were found for NE.. The present study has for the first time demonstrated a correlation between plasma NPY levels and the degree and duration of ST-segment depression after exercise in patients with coronary artery disease, which suggests that NPY may contribute to myocardial ischemia in these patients.

Topics: Analysis of Variance; Angina Pectoris; Atrial Natriuretic Factor; Coronary Disease; Electrocardiography; Endothelin-1; Endothelins; Epinephrine; Exercise Test; Heart Rate; Humans; Male; Middle Aged; Neuropeptide Y; Norepinephrine; Protein Precursors; Time Factors

We have determined whether vasoconstrictor endothelin-B- (ET(B)) receptors are altered in human coronary artery disease. Variable responses to the ET(B) agonist sarafotoxin S6c (S6c) were obtained in control [cardiomyopathy (CDM), n = 15] and diseased [ischaemic heart disease (IHD), n = 16] coronary arteries, with 40% and 50% of arteries not responding, respectively. S6c potently contracted the remaining vessels with EC50 values of 0.4 nM (95% CI, 0.05-2.8 nM) in CDM (n = 9/15) and 1.1 nM (95% CI 0.2-9.2 nM) in IHD (n = 8/16) (p > 0.05, Mann Whitney U-test). No difference in maximum response to S6c was observed between the two groups; CDM 18.5 +/- 6.19% (n = 15), IHD 10.5 +/- 3.48% (n = 16). No significant alteration in medial ET(B)-receptor density was observed in diseased vessels compared to control, with endothelin-A- (ET(A)) receptors comprising over 90% of the total endothelin (ET) receptor population in both CDM and IHD arteries. Our data imply that there is no increase in the importance of the constrictor ET(B)-receptor in human coronary artery disease.

Topics: Adult; Azepines; Coronary Disease; Coronary Vessels; Endothelin-1; Female; Humans; Indoles; Male; Middle Aged; Receptor, Endothelin B; Receptors, Endothelin; Vasoconstriction

The aim of this work was to investigate the influence of endothelin on myocardial ischemia and reperfusion in anaesthetized dogs. Animals were submitted to left thoracotomy and 120 min of left anterior descending coronary occlusion, followed by 180 min of reperfusion. Arterial blood pressure and electrocardiogram (ECG) were recorded in order to analyze heart rate (HR)-pressure product and production of ectopic beats. Infarcted areas were identified by a macroscopic staining method and infarct size was expressed as percentage of risk zone. To inhibit the effects of endothelin in a group of animals, we administered intravenously an endothelin synthesis inhibitor (phosphoramidon) and in another group, an endothelin-1 A receptor blocker (BQ-123). Phosphoramidon decreased the HR-pressure product during reperfusion period, and both, phosphoramidon and BQ-123 decreased infarct size by 40% and the number of ventricular ectopic beats by 88% and 68%, respectively, as compared to the saline treated dogs. In conclusion, endothelin seems to play a deleterious role on the myocardium submitted to ischemia and reperfusion.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Coronary Disease; Dogs; Drug Therapy, Combination; Endothelin Receptor Antagonists; Endothelin-1; Glycopeptides; Injections, Intravenous; Myocardial Infarction; Myocardial Reperfusion; Peptides, Cyclic; Receptor, Endothelin A; Receptors, Endothelin; Ventricular Fibrillation; Ventricular Premature Complexes

The participation of endothelin-1 (ET-1) in the control of vascular tone in humans has been questioned, on the basis of the finding of subthreshold immunoreactive (ir) ET-1 plasma levels. However, because most ET-1 is secreted abluminally, it might attain a higher concentration in the tunica media than in plasma. Furthermore, evidence indicates that vascular smooth muscle cells (VSMCs) can synthesize ET-1 on stimulation in vitro. We therefore looked for irET-1 in the different layers of the wall of human arteries, including renal, gastric, and internal thoracic artery wall, obtained ex vivo from consenting patients with coronary artery disease and/or high blood pressure undergoing surgery, as well as from young organ donors.. We performed immunohistochemistry with specific anti-ET-1 and anti-vWF antibodies followed by detection with an avidin-biotin complex ultrasensitive kit. The presence of preproET-1 and human endothelin-converting enzyme-1 (hECE-1) mRNA was also investigated by reverse transcription-polymerase chain reaction in homogenates of vessel wall, including preparations deprived of both endothelium and adventitia, and in isolated VSMCs. We detected irET-1 in the endothelium of all arteries and in the tunica media of internal thoracic artery from most patients with coronary artery disease. PreproET-1 and hECE-1 mRNA was also detected in VSMCs isolated from these vessels. irET-1 and irvWF staining in endothelium and tunica media was measured by use of microscope-coupled computer-assisted technology. Significant correlations between the amount of irET-1 in the tunica media and mean blood pressure (P<0.05), total serum cholesterol (P<0.05), and number of atherosclerotic sites (P<0.001) were found. Thus, in organ donors, irET-1 was detectable almost exclusively in endothelial cells, whereas in patients with coronary artery disease and/or arterial hypertension, sizable amounts of irET-1 were detectable in the tunica media of different types of arteries. In addition, VSMCs isolated from these vessels coexpressed the preproET-1 and hECE-1 genes.. Collectively, these findings are consistent with the contention that endothelial damage occurs in most patients with atherosclerosis and/or hypertension and that ET-1 is synthesized in VSMCs of these patients.

Topics: Adult; Aged; Aged, 80 and over; Arteries; Aspartic Acid Endopeptidases; Child; Coronary Disease; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Endothelium, Vascular; Female; Fluorescent Antibody Technique; Gene Expression; Humans; Hypertension; Immunohistochemistry; Male; Metalloendopeptidases; Middle Aged; Muscle, Smooth, Vascular; Protein Precursors; RNA, Messenger; Tunica Media

Nitric oxide and endothelin-1 (ET-1) are two major endothelium-derived factors with opposing effects on the function and structure of the vessel wall. We investigated the endothelial expression of endothelial nitric oxide synthase (eNOS) and ET-1 in coronary artery disease (CAD) with special reference to the types of underlying lesions. Immunohistochemistry and in situ hybridization were performed in coronary arteries of heart transplant recipients with (n = 16) and without (n = 11) CAD. All coronary arteries from patients with CAD (n = 23) had concentric fibrous or advanced lesions, whereas most of the arteries (25 of 31) from patients with non-CAD showed normal appearance (myointimal thickening only) or eccentric lesions alone. Normal coronary segments consistently showed apparent endothelial immunoreactivity and mRNA signals for both eNOS and ET-1. In atherosclerotic coronary segments, endothelial expression of eNOS and ET-1 was reduced in most lesion sites, particularly in severe subendothelial lesions with dense fibrosis or macrophage accumulation, but not with smooth muscle cells only. Conversely apparent ET-1, compared with weak or focal eNOS signals, were more frequently seen in coronary segments with concentric severe lesions from CAD but not non-CAD patients. Immunoreactivity and mRNA signals for ET-1 were co-localized with those for ET converting enzyme-1 in the endothelium, as well as in the underlying macrophages and smooth muscle cells. These results indicate the presence of differential endothelial expression of eNOS and ET-1 in diseased human coronary arteries with severe concentric atherosclerotic lesions, a finding that was rare in atherosclerotic lesions of coronary arteries of non-CAD patients. Altered expression of endothelium-derived factors may contribute to abnormality of coronary vasomotor tone and the formation of subendothelial lesions in CAD.

Topics: Aspartic Acid Endopeptidases; Coronary Disease; Coronary Vessels; Endothelin-1; Endothelin-Converting Enzymes; Endothelium, Vascular; Female; Hemodynamics; Humans; Immunohistochemistry; Male; Metalloendopeptidases; Middle Aged; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Reference Values; RNA, Messenger

Plasma atrial natriuretic peptide (ANP) concentration increases during ventricular arrhythmias and rapid ventricular pacing but less is known about plasma brain natriuretic peptide (BNP) and endothelin (ET-1). In the present study concentrations of ANP, the amino terminal part of the proANP (NT-proANP), BNP, and ET-1 were measured in the coronary sinus and femoral artery before and at the end of rapid ventricular pacing in 15 patients with coronary arterial disease. The changes were compared with the changes in mean arterial blood pressure, pulmonary capillary wedge pressure (PCWP), transcardiac differences in pH, pCO2, lactate, and norepinephrine. There was an increase in PCWP and a transient decrease in blood pressure after initiation of pacing. Pacing caused a decrease in ST-segment, transcardiac difference of norepinephrine, lactate extraction, pCO2 difference, and an increase in pH difference. Concentration of ANP in the coronary sinus and femoral artery and its transcardiac difference increased during pacing (P < 0.001), whereas changes in NT-proANP were small and BNP and ET-1 levels remained unchanged. The change in transcardiac ANP difference correlated with the change in lactate (r = 0.53, P < 0.05) but not that of norepinephrine, PCWP, or blood pressure. The results show that the plasma concentration of ANP increases more than that of NT-proANP during rapid ventricular pacing. Ischemia-induced release of ANP and its diminished elimination may contribute to the increased plasma ANP level.

Topics: Aged; Angina Pectoris; Atrial Natriuretic Factor; Cardiac Pacing, Artificial; Coronary Disease; Endothelin-1; Energy Metabolism; Female; Heart Rate; Heart Ventricles; Hemodynamics; Humans; Lactic Acid; Male; Middle Aged; Myocardium; Natriuretic Peptide, Brain

The plasma level of endothelin-1 (ET-1) increases in several cardiovascular disorders. The present study examined whether threshold doses of ET-1 affect vascular tone and autoregulatory vasodilation during a reduction in perfusion pressure in the coronary microcirculation in vivo. In anesthetized open-chest dogs, arterial microvessels in the epimyocardium were observed through a microscope equipped with a floating objective. In 6 dogs, ET-1 (10(-13) to 10(-8)mol/L) was superfused onto the epimyocardium in a cumulative fashion. In another set of dogs (n= 16), the perfusion pressure of the observed vascular bed was reduced to 60 mmHg (mild stenosis) and to 40 mmHg (severe stenosis) by a hydraulic occluder, and the microvascular responses were observed in the presence (n=9) or absence (n=7) of ET-1 (10(-12) or 10(-11) mol/L). ET-1 > or =10(-11) mol/L constricted coronary arterioles (< or =100 microm in diameter) and small arteries (>100 microm in diameter) in a dose-dependent fashion. ET-1 of 10(-12) mol/L affected neither the basal diameters nor the dilation of vessels during the pressure reduction. ET-1 of 10(-11) mol/L decreased the diameters of arterioles and small arteries before and during the mild and severe stenosis. However, ET-1 did not attenuate the percentage dilation of arterioles from the baseline in response to the mild and severe stenosis. The data indicates the following: (1) ET-1 at doses > or =10(-11) mol/L similarly constricts coronary arterioles and small arteries; (2) ET-1 at 10(-11) mol/L, which is slightly higher than the pathophysiological plasma level, increases the basal vascular tone, but does not attenuate the autoregulatory vasodilation of the coronary microcirculation.

Topics: Animals; Arteries; Arterioles; Blood Gas Analysis; Capillaries; Cerebral Veins; Coronary Circulation; Coronary Disease; Coronary Vessels; Dogs; Dose-Response Relationship, Drug; Endothelin-1; Female; Hemodynamics; Homeostasis; Hydrogen-Ion Concentration; Male; Microcirculation; Vasoconstriction; Vasodilation

Endothelin has both vasoconstrictor and mitogenic properties and might, therefore, play a role in the pathogenesis of acute coronary syndromes and coronary atherosclerosis. The aim of the study was to characterize the mechanisms and kinetics of cardiac endothelin-1 (ET-1) release following a local endothelial injury during PTCA (group A) and after sustained myocardial ischemia (group B). Additionally, the precision of agreement between measurements in coronary sinus and peripheral venous samples should be analyzed. In group A, elective PTCA was performed in 20 patients with stable angina pectoris and a > 70% type A stenosis. Simultaneous determinations of ET-1 from coronary venous and peripheral venous blood were done before balloon inflation and during the several hours following the last dilatation procedure. A coronary sinus study with high rate atrial pacing was performed in 20 group B patients with coronary multivessel disease. ET-1 was determined from coronary sinus and peripheral venous blood samples prior to stimulation and during several hours after cessation of pacing. Control groups were provided for both groups. The control group consisted of 10 patients with coronary angiography without PTCA for group A and 10 patients with angiographic normal coronary arteries for group B.PTCA induced an instantaneous increase of coronary sinus ET levels from 4.1 +/- 1.1 pg/ml to 13.7 +/- 2.3 pg/ml (peripheral venous 7.9 +/- 2.5 pg/ml), which was more pronounced if the target vessel was the left anterior descending artery. This peak was followed by a gradual decrease of ET-1 to the limit of normal within 6 hours. The concentrations of ET, furthermore, remained higher in the coronary sinus compared with the peripheral vein indicating a persisting cardiac release of ET. In group B, incremental atrial pacing resulted in myocardial ischemia, and a significant increase in ET-1 from 4.6 +/- 0.6 pg/ml to 13.1 +/- 2.8 pg/ml was detected in the coronary sinus samples. A persistent cardiac release of ET-1, as reflected by sustained elevated coronary sinus concentrations, was observed for up to one hour after cessation of pacing. The analysis of measurement agreement between coronary venous and peripheral venous samples revealed considerable variations of the differences between the two sampling sites indicating wide limits of agreement. Despite a significant positive correlation, our date reflecting a remarkable lack of agreement.. 1) An enhanced release of ET-1 following PTCA is mainly due to the localized endothelial injury, and the ET-1 levels remain elevated for up to hours after the mechanical stimulus. 2) A short-lasting myocardial ischemia is associated with a significant ET-1 increase. 3) For refined evaluations of release kinetics of cardiac ET-1, blood sampling from the coronary sinus seems to be essential.

Topics: Aged; Angina Pectoris; Angioplasty, Balloon, Coronary; Cardiac Pacing, Artificial; Coronary Disease; Endothelin-1; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Myocardial Ischemia; Reference Values; Sensitivity and Specificity

Since raised levels of endothelin-1 (ET-1) have been detected in the human coronary sinus following percutaneous transluminal angioplasty (PTCA) we investigated the role of ET-1 in the etiology of vascular restenosis.. Balloon angioplasty of coronary arteries was performed in pigs and the animals were treated with placebo or the endothelin (ETA) receptor antagonist LU 135252 (30 mg/kg/day). After 4 weeks vascular stenosis and the distribution of endothelin and its receptors was evaluated.. The pronounced neointima formation in the control group (neointima:media ratio = 0.87 +/- 0.36) was significantly reduced by LU 135252 (0.43 +/- 0.30, P < 0.001). Angioplasty caused a significant increase in medial ETA (approximately 275%, P < 0.026) and ETB (approximately 250%, P < 0.001) binding to injured, compared with non-injured segments, an effect that was also reduced by LU 135252 (ETA = 11.5% increase; ETB = 14% increase). The neointima of control animals exhibited ET-1 like immunoreactivity as well as ETA and ETB binding sites.. These data indicate that endothelin is locally-released from endothelial and vascular smooth muscle cells following angioplasty which binds to ETA and ETB receptor sites in the neointima and media. Since administration of the ETA antagonist LU 135252 markedly reduces neointima formation and medial ET binding, we conclude that vascular smooth muscle cell proliferation and subsequent neointima formation is mediated predominantly via ETA receptors. These data underscore the therapeutic potential of ETA antagonists in reducing the degree of restenosis following vascular injury.

Topics: Angioplasty, Balloon, Coronary; Animals; Autoradiography; Coronary Disease; Coronary Vessels; Endothelin Receptor Antagonists; Endothelin-1; Immunohistochemistry; Phenylpropionates; Protein Binding; Pyrimidines; Random Allocation; Recurrence; Swine

Endothelin, a potent vasoconstrictor, mitogen, and stimulant of collagen synthesis, is reported to be increased after vascular injury. We tested the hypothesis that tissue endothelin levels and its receptor expression are increased following double balloon injury in a porcine coronary artery model of restenosis. Male miniature swine maintained on a hyperlipidemic diet underwent oversized balloon injury to both the proximal right coronary artery and left circumflex coronary artery. Two weeks following the initial injury, the arteries were repeat injured at the same site and subsequently harvested four weeks later. Proximal balloon injured (BI) and distal non-balloon-injured (NBI) segments from the same artery were collected. Tissue endothelin-1 (ET-1) levels were measured by ELISA. Endothelin receptors were assayed by radioligand binding using 125I-ET-1 and also immunolabeling. Tissue endothelin levels were 4-5 fold greater in BI arteries as compared to NBI. There was a significant increase in tissue ET-1 levels and endothelin receptor binding following double balloon injury relative to NBI control arteries. Western blots showed an increased expression of ET(A) receptor protein in injured vessels compared to non-injured arteries. Immunohistochemistry using an ET(A) receptor specific antibody confirmed increased receptor density following balloon injury. Thus, in an in vivo double balloon injury model for coronary artery restenosis, the response to vascular injury is increased tissue ET-1 content and upregulation of ET(A) receptor density associated with increased receptor protein.

Topics: Animals; Catheterization; Coronary Disease; Coronary Vessels; Endothelin-1; Enzyme-Linked Immunosorbent Assay; Male; Swine; Up-Regulation

The objective of this study was to examine the endothelial function of internal mammary artery in patients with coronary artery disease and in heart transplant recipients. Therefore the response of this artery to increasing concentrations of acetylcholine (1, 10, 20 microg/min for 2.5 minutes each) was assessed in 6 patients in a control group, 16 patients with coronary artery disease (CAD group) matched for risk factors with 16 heart graft recipients (who underwent transplantation for nonischemic heart failure), and 12 patients with coronary artery disease and peripheral vascular disease (PVD group). Diameters of proximal and middle segments of internal mammary artery were measured by quantitative angiography. The responses to the first concentration of acetylcholine were attenuated in these three groups compared with the control group. At the highest concentration of acetylcholine the diameter increase was similar in the control and CAD groups, whereas the responses remained significantly impaired in the transplant and PVD groups. However, after selective infusion of L-arginine (30 mg/min for 11 minutes), the precursor of endothelium-derived nitric oxide, was performed, the responses to acetylcholine were restored in these two latter groups. Endothelin plasma levels were significantly enhanced in the PVD group, which exhibited the most severe impairment in acetylcholine-induced vasodilation. Thus some patients with CAD, mainly those with advanced atherosclerosis, and cardiac transplant recipients exhibit internal mammary artery endothelial dysfunction, and this abnormality seems reversible.

Topics: Acetylcholine; Adult; Coronary Angiography; Coronary Disease; Endothelin-1; Endothelium, Vascular; Heart Transplantation; Hemodynamics; Humans; Mammary Arteries; Middle Aged; Peripheral Vascular Diseases

We have determined the ability of the endothelin A (ETA)-selective antagonist PD156707 to block constrictor ET-1 responses in blood vessels from the diseased human heart. ET-1 potently contracted nonatherosclerotic coronary arteries from patients with cardiomyopathy (pD2 = 7.96 +/- 0.15; n = 6), atherosclerotic coronary arteries from patients with ischemic heart disease (pD2 = 8.26 +/- 0.20; n = 4), and saphenous vein grafts that had developed "atherosclerotic" disease after coronary artery bypass (pD2 = 8.41 +/- 0.09; n = 6). PD156707 (100 nM) antagonized the vasoconstrictor response to ET-1 in each of the three preparations, with estimated pA2 values of 7.91 +/- 0.20, 8.05 +/- 0.14, and 8.07 +/- 0.02, respectively. These data suggest that the upregulation of ETB receptors that has been reported in human atherosclerotic coronary arteries does not contribute significantly to the ET-1-mediated constrictor response in these vessels in vitro.

Topics: Adult; Arteries; Arteriosclerosis; Coronary Artery Bypass; Coronary Disease; Coronary Vessels; Dioxoles; Endothelin Receptor Antagonists; Endothelin-1; Female; Humans; In Vitro Techniques; Male; Middle Aged; Receptor, Endothelin A; Saphenous Vein

The endothelium plays a fundamental role in the regulation of the vascular tone. It produces EDRF-NO that dilates the vessels. In endothelial dysfunction, the reduction of EDRF-NO production increases the vasoconstrive effects of endothelin-1 and angiotensin-II. The endothelial dysfunction is part of the coronary artery disease. It can be minimized by angiotensin-converting enzyme inhibitors that block the deleterious effects of angiotensin-II.

Topics: Angiotensin II; Angiotensin-Converting Enzyme Inhibitors; Coronary Disease; Endothelin-1; Endothelium, Vascular; Humans; Nitric Oxide; Vasoconstrictor Agents; Vasodilator Agents

Endothelin-1 (ET-1) is an endothelium-derived mediator with vasoconstrictive and mitogenic activity which stimulates vascular smooth muscle cell proliferation. The aim of this study was to evaluate ET-1 production during percutaneous transluminal coronary angioplasty (PTCA) and elective stent implantation. We hypothesized that the additional vessel wall trauma induced by stent deployment might be associated with a greater production of ET-1. To this end, ET-1 levels were measured in 18 patients undergoing PTCA and stenting (12 with left anterior descending coronary artery stenosis and 6 with circumflex artery lesion). The sampling sites were the coronary ostium and coronary sinus in basal conditions (before the procedure), during first balloon inflation, and 5, 20, 60 min after the end of first balloon inflation. At baseline, ET-1 levels were higher in the coronary sinus than in coronary ostium (1.58 +/- 0.22 vs 1.29 +/- 0.20 pg/ml, p < 0.001). During first balloon inflation, ET-1 coronary sinus levels significantly diminished with respect to the basal levels (1.08 +/- 0.32 vs 1.58 +/- 0.22 pg/ml, p < 0.001). Further significant variations of ET-1 levels were not detected neither following the first balloon inflation nor after stent deployment. In conclusion, the culprit lesion seems to produce most of ET-1 circulating in the coronary tree. This is demonstrated by higher ET-1 levels in the coronary sinus compared to coronary ostium at baseline, and even more by the significant ET-1 reduction in the coronary sinus during first balloon inflation. Despite our expectations, we did not detect any significant ET-1 increase during stent deployment.

Topics: Aged; Angioplasty, Balloon, Coronary; Coronary Circulation; Coronary Disease; Endothelin-1; Humans; Male; Middle Aged; Myocardial Ischemia; Stents

Endothelin-1 (ET-1) with its well-known vasoconstrictive and mitogenic action and through its interaction with insulin, blood glucose, and lipids might play an important role in the accelerated atherogenic process in diabetes mellitus.. To determine whether ET-1 levels are indicative of macrovascular disease in diabetes mellitus.. In the present cross-sectional study, plasma ET-1 concentrations were measured in members of three groups. The first group consisted of 20 patients (15 men and five women; aged 56.3 +/- 12.5 years) with non-insulin-dependent diabetes mellitus and coronary artery disease, the second group of 20 patients (16 men and four women, aged 56.9 +/- 11.2 years) with coronary artery disease only, and the third group of 10 healthy subjects who served as controls. ET-1 levels were determined by a radioimmunoassay.. The mean plasma ET-1 levels for the three groups were 3.59 +/- 1.88, 4.31 +/- 1.32, and 4.42 +/- 1.01 pmol/l respectively, and there was no statistically significant difference among the groups (P = 0.23). There was also no correlation between the plasma ET-1 concentration and age, sex, body mass index, triglyceride, total cholesterol, high-, low- and very-low density lipoprotein levels, for all groups, and, for the first group, hemoglobin A1c (HbA1c), the duration of diabetes mellitus.. The plasma ET-1 concentration is not elevated in non-insulin-dependent diabetes mellitus patients with macrovascular disease, which might reflect the fact that its action occurs in a paracrine or an autocrine rather than an endocrine fashion and suggests that ET-1 levels are not necessarily indicative of macrovascular disease in diabetes mellitus.

Topics: Aged; Arteriosclerosis; Coronary Disease; Cross-Sectional Studies; Diabetes Mellitus, Type 2; Endothelin-1; Female; Humans; Male; Middle Aged

Topics: Coronary Disease; Endothelin-1; Graft Rejection; Heart Transplantation; Humans; Transplantation, Homologous

Topics: Adult; Coronary Disease; Endothelin-1; Female; Humans; Hypertension; Male; Middle Aged

The pathogenesis of transplant coronary artery disease (TCAD) is unknown, but it is thought to derive from an interaction between immune and nonimmune factors, leading to smooth muscle cell proliferation and accumulation in the expanded neointima. Endothelin-1 (ET-1), a potent vasoconstrictor with mitogenic properties for vascular smooth muscle cells, has recently been demonstrated in native vessel atherosclerosis. The present study used immunohistochemistry to investigate the role of ET-1 in TCAD.. ET-1 immunoreactivity and cellular localization were assessed in human coronary arteries with TCAD (n = 13) and in normal coronary arteries (n = 10) with single- and double-label immunohistochemistry. The intensity of immunostaining was determined by a semiquantitative method. Diffuse and intense ET-1 immunoreactivity was found in 11 of 13 patients with TCAD (85%), mainly in myointimal cells and, in lesser amounts, in macrophages and endothelial cells. In contrast, normal coronary arteries had only faint immunostaining localized to the endothelial layer. Mean semiquantitative grade was significantly higher in TCAD than in normal arteries (1.8 versus 0.7; P < .05). ET-1 was more frequently present in lipid-rich, atheromatous lesions than in lipid-poor, proliferative ones. Intimal neovessels consistently immunostained for ET-1.. Immunoreactivity for ET-1 is significantly increased in TCAD, possibly as a result of stimulatory cytokines and growth factors that are upregulated in the posttransplant state. The results suggest a role for this mitogenic peptide in the pathogenesis of graft arteriosclerosis.

Topics: Adult; Coronary Artery Disease; Coronary Disease; Coronary Vessels; Endothelin-1; Female; Heart Transplantation; Humans; Immunohistochemistry; Male; Middle Aged; Transplantation, Homologous

Despite the significant advances made in the understanding and treatment of coronary artery disease much remains unclear about the pathogenesis of this complex atherothrombotic process. Atherogenesis may reflect a combination of multiple factors interacting with one another leading to coronary artery occlusion. One potential participant may be endothelin-1 (ET-1), a potent mitogenic vasoconstrictor. The presence of endothelin within saphenous veins before insertion and after removal during coronary artery bypass grafting (CABG) because of bypass closure, within internal mammary arteries before and after surgical intervention, and within native coronary artery segments resected during CABG was demonstrated immunocytochemically with an antiendothelin antibody and aminoethyl carbazole as the indicator chromogen. Increased amounts of ET-1 were observed in failed venous grafts, in damaged internal mammary artery grafts, and in vessels of the myocardium. These results suggest that ET-1 may play a significant pathophysiologic role in the evolution of coronary heart disease.

Topics: Adult; Aged; Aged, 80 and over; Coronary Artery Bypass; Coronary Disease; Coronary Vessels; Endothelin-1; Endothelium, Vascular; Female; Humans; Immunohistochemistry; Male; Middle Aged

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.

Topics: Adult; Aged; Aged, 80 and over; Angina Pectoris; Angina, Unstable; Coronary Disease; Endothelin-1; Endothelin-2; Endothelins; Humans; Male; Middle Aged; Myocardial Infarction; Prognosis; Protein Precursors; Radioimmunoassay; Reference Values; Risk Factors