Abnormal Endothelial Function Research Articles

Effect of glycosylated hemoglobin on endothelium-dependent relaxation of omental arteries from pregnant women

Objective: This study was intended to test the hypothesis that glycosylated hemoglobin adversely affects endothelium-dependent vascular relaxation during pregnancy. Study Design: Omental artery rings (3 mm) obtained from patients undergoing cesarean delivery at term were suspended in organ chambers for isometric tension recording in Krebs bicarbonate solution. They were bubbled with 5% carbon dioxide in air (37°C, pH 7.4). After equilibration at 1-g passive tension and contraction with endothelin 1, concentration-relaxation curves in response to bradykinin were determined in the presence or absence of oxyhemoglobin, glycosylated hemoglobin, or nitric oxide synthase inhibitors (N ω-nitro-l -arginine methyl ester or N ω-nitro-l -arginine). Results: Oxyhemoglobin and glycosylated hemoglobin attenuated the endothelium-dependent relaxation induced by bradykinin. The inhibition did not differ significantly between the 2 nitric oxide scavengers and was of the same magnitude as that noted with the nitric oxide synthase inhibitors. Conclusion: Glycosylation of hemoglobin does not change its effect on endothelium-dependent relaxation in human omental vessels during pregnancy. These data do not support the hypothesis that glycosylated hemoglobin may be the reason for abnormal endothelial function in diabetes. (Am J Obstet Gynecol 1998;179:1047-50.)

Different patterns of endothelial cell activation in renal and pulmonary vascular disease in scleroderma.

Abnormal endothelial cell function is implicated in the development of scleroderma, and in major life-threatening complications of the disease. The nature of the stimulus leading to abnormal endothelial cell function in scleroderma, scleroderma renal crisis, and scleroderma-associated pulmonary hypertension was investigated by measurement of soluble adhesion molecules, shed by activated endothelial cells, in sera from patients with these conditions. In scleroderma renal crisis, mean levels of soluble E-selectin (p < 0.05 limited scleroderma, p < 0.0001 diffuse scleroderma), sVCAM-1 (soluble vascular cell adhesion molecule-1) (p < 0.05 limited scleroderma, p < 0.05 diffuse scleroderma), and sICAM-1 (soluble intercellular adhesion molecule-1) (p < 0.0001 limited scleroderma, p < 0.0001 diffuse scleroderma) were raised, supporting a model of endothelial cell activation in this complication. Evidence for endothelial cell activation in scleroderma-associated pulmonary hypertension was inconsistent, with normal sE-selectin and normal sVCAM-1 in sera from patients with limited scleroderma and pulmonary hypertension. The endothelial cell phenotype in scleroderma-associated pulmonary hypertension may resemble that of unstimulated cells. The pulmonary vascular and renal vascular lesions associated with scleroderma may arise by distinct pathogenic mechanisms.

Insulin-Mediated Venodilation Is Impaired in Patients With High Cholesterol

Recently we have reported that insulin attenuates norepinephrine (NE)-induced vasoconstriction via a cyclic GMP-NO synthase pathway. Because hypercholesterolemia has been associated with abnormal endothelial function, we investigated whether insulin-mediated vasodilation is impaired in hypercholesterolemia. To assess vasoreactivity, NE (12.5, 25, 50, and 100 ng/min), NE (100 ng/min) combined with insulin (8, 16, 24, and 32 microU/min), and NE (100 ng/min) combined with sodium nitroprusside (0.01, 0.1, 1, 10, and 100 ng/min) were infused into dorsal hand veins. Changes in venous diameter were measured by ultrasonography, using a 7.5-MHz transducer. Twenty-two healthy, normotensive hypercholesterolemic subjects (HC; mean total cholesterol 6.93 mmol/L, HDL 1.45 mmol/L, LDL 4.81 mmol/L) and 18 age-matched normal control subjects (NC; mean total cholesterol 4.81 mmol/L, HDL 1.16 mmol/L, LDL 3.18 mmol/L) were studied. All HC had normal glucose tolerance test results. Baseline vein diameters were similar between groups, and the vasoconstrictor response to NE was not significantly different between HC and NC. Insulin significantly attenuated NE-induced vasoconstriction in NC but not in HC (P<0.01). Both groups were able to venodilate with sodium nitroprusside. To investigate the effects of cholesterol reduction on vascular reactivity, venoreactivity studies were repeated in 12 HC after treatment with 20 to 40 mg/d lovastatin for 6 weeks. There were no significant venoreactivity changes with the treatment. Plasma LDL cholesterol concentration was inversely correlated to venodilator effect of insulin (r=-0.42, P<0.02). In conclusion, insulin-mediated vasodilation is impaired in patients with high cholesterol. Absence of normal insulin-mediated but not sodium nitroprusside-induced venodilation in hypercholesterolemia suggests that insulin-mediated vasodilation is endothelium dependent.

A morphological and functional study of Congenital Hereditary Endothelial Dystrophy.

To contribute to the basic understanding of Congenital Hereditary Endothelial Dystrophy (CHED) by clinical, functional, and histopathological examinations of three cases. Prior to grafting, corneas were evaluated by slit lamp examination and by assessment of endothelial permeability to fluorescein. Following penetrating keratoplasty, corneal buttons were evaluated by light- and electron microscopy and by assessment of stromal swelling pressure. Patients with CHED had a markedly increased corneal thickness (0.93-0.98 mm) with epithelial oedema and a stromal swelling pressure close to zero; suggesting that the stroma was maximally swollen in vivo. Corneal endothelium showed an increased permeability to fluorescein; suggesting a functional barrier defect. Histopathological evaluation revealed: 1) a normal endothelial cell density; 2) an abnormal endothelial morphology with irregular and multi-nucleated cells containing abnormal cell organelles; and 3) a profound thickening of Descemet's membrane, 16-18 microm, with multiple focal areas of abnormal fibrillar deposits in the posterior half. This study suggests that the primary defect in patients with CHED is a degenerated and dysfunctional corneal endothelium, characterized by an increased permeability and an abnormal and accelerated Descemet's membrane secretion. The underlying pathophysiological mechanism(s) may be related to an abnormal endothelial barrier function, leading to secondary swelling of the stroma and epithelium. Further studies are needed to identify the specific functional defect(s) and the embryological origin of the abnormal corneal endothelium in CHED.

Biology of endothelium.

Endothelial cells form a multifunctional cell lining that covers all of the inner surface of blood vessels and regulates several important physiological and pathological reactions. These include inflammation/immune reaction, blood vessel tonus, hemostasis/thrombosis, angiogenesis and so on. Thus, abnormalities of endothelial function may play crucial roles in the development of angitis syndrome, thrombosis/embolism, bleeding disseminated intravascular coagulation (DIC), and neovascularization in some pathological states including tumor growth and diabetic retinopathy. Research on endothelial cells now forms a new frontier termed 'Endotheliology'. Recent advances of the functional and structural aspects of endothelial cells are reviewed here mainly from the viewpoint of endothelial regulation of coagulation and the fibrinolytic system. First we show that the natural endothelial membrane protein thrombomodulin is localized not only on apical endothelial surface but also in caveolae. Since it has been reported that such factors involved in coagulation/fibrinolysis as tissue factor, tissue factor pathway inhibitor (TFPI), thrombin receptor and urokinase receptor are also localized in the caveolae, this membrane structure may act as a special component to regulate coagulation/fibrinolysis on the endothelial membrane surface. Next we demonstrate the signaling pathway of the thrombin receptor. Thrombin cleaves the N-terminus of the receptor as a substrate, exposing a new N-terminus. This newly exposed N-terminus acts as a ligand and activates platelets, endothelial cells and vascular smooth-muscle cells. We have identified that the signal from the thrombin receptor activates NF-kappaB through the activation of protein C kinase, tyrosine kinase and MAP kinase, and results in proliferation of the cells. We have also shown that the receptor is over-expressed on platelets from diabetes patients.

Effect of lipid-lowering therapy on myocardial ischemia.

Myocardial blood flow in patients with coronary artery disease depends on the severity of the coronary narrowings and the functional status of the coronary vessels. Coronary atherosclerotic plaques, which contain high concentrations of lipids, are more sensitive to change in coronary tone. The increased tendency of these active plaques for vasoconstriction is caused by abnormal endothelial function. Because regression of significant coronary plaques is highly unlikely, effort is made to improve endothelial function, thereby improving myocardial blood flow. Reduction of the cholesterol level by lipid-lowering drugs is associated with restoration of the vasodilatory response of the coronary arteries, thereby reducing the likelihood of plaque rupture and its consequences: myocardial infarction and death. Myocardial ischemia during daily life is induced by increased demand and increased coronary tone; therefore, it was not surprising that recent studies have indicated that cholesterol lowering reduced the frequency of daily ischemic episodes. Because improvement in endothelial function is already observed within a few weeks/months of lipid lowering, it is hoped that this therapy will rapidly reduce the frequency and severity of myocardial ischemia and its clinical expression, angina pectoris. At a later phase (1-2 years), cholesterol lowering will also reduce major cardiac events.

Cigarette Smoking Is Associated With Increased Human Monocyte Adhesion to Endothelial Cells: Reversibility With Oral l-Arginine but Not Vitamin C

Objectives. This study sought to assess the effect of cigarette smoking on adhesion of human monocytes to human endothelial cells and to measure the effect of l-arginine and vitamin C supplementation on this interaction.Background. Cigarette smoking has been associated with abnormal endothelial function and increased leukocyte adhesion to endothelium, both key early events in atherogenesis. Supplementation with both oral l-arginine (the physiologic substrate for nitric oxide) and vitamin C (an aqueous phase antioxidant) may improve endothelial function; however, their benefit in cigarette smokers is not known.Methods. Serum was collected from eight smokers (mean [±SD] age 33 ± 5 years) with no other coronary risk factors and eight age- and gender-matched lifelong nonsmokers. The serum was added to confluent monolayers of human umbilical vein endothelial cells and incubated for 24 h. Human monocytes obtained by counterflow centrifugation elutriation were then added to these monolayers for 1 h, and adhesion then was measured by light microscopy. To assess reversibility, monocyte/endothelial cell adhesion was then measured for each subject 2 h after 2 g of oral vitamin C and 2 h after 7 g of oral l-arginine.Results. In smokers compared with control subjects, monocyte/endothelial cell adhesion was increased (46.4 ± 4.5% vs. 27.0 ± 5.2%, p < 0.001), endothelial expression of intercellular adhesion molecule (ICAM)-1 was increased (0.31 ± 0.02 vs. 0.22 ± 0.03, p = 0.004), and vitamin C levels were reduced (33.7 ± 24.1 vs. 53.4 ± 11.5 μmol/liter, p = 0.028). After oral l-arginine, monocyte/endothelial cell adhesion was reduced in smokers (from 46.4 ± 4.5% to 35.1 ± 4.0%, p = 0.002), as was endothelial cell expression of ICAM-1 (from 0.31 ± 0.02 to 0.27 ± 0.01, p = 0.001). After vitamin C, there was no significant change in monocyte/endothelial cell adhesion or ICAM-1 expression from baseline in the smokers despite an increase in vitamin C levels (to 115 ± 7 μmol/liter).Conclusions. Cigarette smoking is associated with increased monocyte–endothelial cell adhesion when endothelial cells are exposed to serum from healthy young adults. This abnormality is acutely reversible by oral l-arginine but not by vitamin C.(J Am Coll Cardiol 1997;29:491–7)

Bradykinin-mediated cardiovascular protective actions of ACE inhibitors. A new dimension in anti-ischaemic therapy?

In addition to being accepted therapy in hypertension and heart failure, ACE inhibitors may well offer a new dimension in anti-ischaemic therapy. Currently, anti-ischaemic properties have been demonstrated by ACE inhibitors in selected patient groups, including patients with left ventricular dysfunction with or without a direct temporal relationship with myocardial infarction. Anti-ischaemic effects of ACE inhibitors become apparent late after initiation of treatment and suggest a structural rather than a functional effect. Underlying mechanisms may include a reduction in ventricular dilatation and (abnormal) cardiac hypertrophy, leading to less myocardial oxygen demand and, possibly, improved subendocardial blood supply, and vasculoprotective effects, i.e. anti-atherosclerotic and antiremodelling properties, a beneficial effect on the fibrinolytic system and an improvement in abnormal endothelial vasodilator function. The latter aspect is most probably the pivotal mode of action where the anti-ischaemic profile of ACE inhibition is concerned. An improvement in endothelial dysfunction has been shown in patients with mild to moderate coronary artery disease [Trial on Reversing ENdothelial Dysfunction (TREND)]. It is of importance that, in both clinical experiments and human studies, the role of bradykinin appears central in the structural and functional cardiovascular effects of ACE inhibition. This is particularly true for the improvement of impaired endothelial function. Myocardial ischaemia evokes vasoconstrictor neurohormonal activation, which may lead to coronary vasoconstriction in diseased coronary segments. The subsequent abnormal endothelial function leads to diminished coronary flow and also increases systemic vasotone and afterload, thus unfavourably altering the myocardial oxygen supply/demand ratio. Under laboratory conditions, acute ACE inhibition counteracts this activation in humans. However, it is speculated that this anti-ischaemic mechanism may become operative and clinically important during long term oral ACE inhibitor therapy when endothelial function improves, and may subsequently protect against the vasoconstrictor effect of neurohormonal activation. As it is unlikely that the mechanisms mentioned above are only relevant in patients with ventricular dysfunction or heart failure, several large controlled trials are currently examining the long term anti-ischaemic and cardiovascular protective effects of ACE inhibition in patients at risk of a cardiovascular event [Heart Outcomes Prevention Evaluation study (HOPE)], with a normal cardiac function [Prevention of Events with ACE inhibition study (PEACE)] or in all patients with coronary artery disease irrespective of cardiac function [EUropean trial of Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA)].

Vascular endothelial dysfunction

Injury or activation of the endothelium changes its regulatory functions and results in abnormal endothelial cell function. Dysfunction of the endothelium has been defined as an imbalance between relaxing and contracting factors, between procoagulant and anticoagulant mediators or between growth-inhibiting and growth-promoting substances. The first part of this review describes endothelial dysfunction in hypercholesterolemia, and atherosclerosis in intimal thickening induced by perivascular and intravascular techniques. We focus on the implications of endothelial dysfunction in these conditions and the role of nitric oxide, endothelium-dependent hyperpolarization, endothelin, cytokines, adhesion molecules, growth factors, and thrombosis. In the second part, the endothial dysfunction in other diseases including hypertension, syndrome X, and diabetes is discussed. Finally, a short overview of therapeutic approaches of the dysfunctional endothelium is given.

Effect of Short-Term Treatment of SHR With the Novel Calcium Channel Antagonist Mibefradil on Function of Small Arteries

Treatment of spontaneously hypertensive rats (SHR) and Wistar-Kyoto control rats (WKY) for at least 12 weeks with calcium channel antagonists is associated with regression of structural hypertensive changes in the heart and in conduit and small arteries. To establish whether structural or functional changes of small arteries could be corrected with shorter periods of specific antihypertensive treatment, SHR and WKY were treated for 4 weeks with the novel calcium channel blocker mibefradil. Blood pressure rise was significantly reduced by mibefradil treatment in SHR to 165 ± 1 mm Hg compared to a systolic blood pressure of 183 ± 2 mm Hg in untreated SHR ( P < .01). Aortic hypertrophy in SHR was slightly reduced by treatment, but small artery hypertrophy in 4 vascular beds (mesenteric, renal, coronary, and femoral) was unaffected by administration of mibefradil for 4 weeks. Mibefradil treatment resulted in normalization of endothelium-dependent relaxation in mesenteric small arteries, with disappearance of acetylcholine-induced contractions, although hypertrophy and remodeling of these small arteries were not significantly affected by treatment. In WKY rats, treatment had no effect on either structure or function of small arteries. These results demonstrate that treatment with the calcium antagonist mibefradil may induce an improvement in altered endothelial function even before regression of cardiovascular hypertrophy and remodeling takes place under treatment, indicating that normalization of abnormal small artery endothelial function in SHR under antihypertensive therapy may be independent of correction of altered small artery structure.

Endothelium-dependent vasorelaxation is impaired in cocaine arteriopathy

This study sought to assess endothelium-dependent vasorelaxation in long-term users of cocaine. Cocaine use has been associated with myocardial infarction, stroke and intestinal infarction. Previously demonstrated effects of the drug, including increased heart rate and blood pressure and increased vascular tone, do not explain the sporadic nature of these vascular events or the occurrence of ischemia remote from acute administration. Abnormal endothelial function could contribute to focal vasospasm and thrombosis and predispose to premature atherosclerosis, all of which have been demonstrated in cocaine users with myocardial infarction. Using plethysmography, we studied the change in forearm blood flow in response to intraarterial acetylcholine and nitroprusside in 10 long-term cocaine users and 13 control subjects of similar age who had not used cocaine; sample size was based on a 70% power to detect a 20% reduction in flow with acetylcholine between subjects and control subjects. Using graded doses of intracoronary acetylcholine (from 10(-9) to 10(-6) mol/liter), we studied a second group of 10 cocaine users with angiographically normal or near-normal arteries. Mean forearm blood flow during acetylcholine infusion was significantly lower in cocaine users than in control subjects (p = 0.02). During nitroprusside infusion, there was no difference (p = 0.2) between cocaine users and control subjects. Cigarette smoking did not explain the differences between cocaine users and control subjects. Acetylcholine elicited coronary vasoconstriction in 8 of 10 subjects. We conclude that endothelium-dependent vasorelaxation is impaired in long-term users of cocaine.

Altered coronary endothelial function in a patient with asymptomatic left ventricular dysfunction

Coronary endothelial dysfunction has been demonstrated in patients with symptomatic heart failure. Furthermore the endothelium has been implicated in the pathogensis of cardiomyopathy in patients with normal coronary angiograms and no other known causes of heart failure. Herein we describe an asymptomatic patient with an early cardiomyopathy and abnormal coronary endothelial function. There was no evidence for coronary disease by both angiography and intravascular ultrasound. Epicardial coronary artery vasoconstriction and a decrease in coronary blood flow was noted during the intracoronary infusion of graded concentrations of acetylcholine. This case demonstrates that endothelial dysfunction occurs in the setting of asymptomatic left ventricular dysfunction and highlights the potential importance of the endothelium in the early development of heart failure.

The role of endothelium-derived vasoactive substances in the pathophysiology of exercise intolerance in patients with congestive heart failure

The vascular endothelium releases vasoactive substances that appear to play an important role in the normal regulation of peripheral vasomotor tone. Nitric oxide, endothelins, prostaglandins, and other endothelium-derived vasodilating and vasoconstricting factors are released by the vascular endothelium in response to a diverse array of hormonal, pharmacologic, chemical, and physical stimuli. Shear stress, produced by pulsatile blood flow at the endothelial cell luminal surface, alters endothelial production of several endothelium-derived vasoactive substances, which may contribute to regional regulation of skeletal muscle blood flow during exercise. Abnormal vascular endothelium function has been shown in both experimental and clinical heart failure. Preliminary data suggest that abnormalities of endothelial function may contribute to increased peripheral vasomotor tone during exercise in patients with congestive heart failure.

762-5 Late Endothelial Dysfunction Following Kawasaki Disease

Kawasaki disease (KD) is a multi-system vasculitis which often involves the coronary arteries in the acute stage. Long-term complications such as myocardial infarction and sudden death are recognised, but the incidence and determinants of vascular damage which may predispose to late events are unknown. We used external high resolution ultrasound to study endothelial function in the systemic arteries of 10 patients, a median of 11 (5–17) years after acute KD, and in 10 age and sex matched controls. The median age of the patients was 13 (11–18) years. Only one patient had coronary artery abnormalities detected during the acute illness and none had current clinical or hematological evidence of acute inflammation. All subjects were normotensive, non-smokers and on no vasoactive medication. Brachial artery diameter was measured at rest, in response to reactive hyperemia (RH) (with flow increase leading to endothelium-dependent dilation) and after sublingual nitroglycerin (GTN, an endothelium-independent dilator). Vessel size, baseline flow, degree of RH (Doppler estimated) and total cholesterol were similar in both groups. Flow mediated dilation was impaired in the KD patients (5 ± 1% versus controls 11 ± 1%, p &lt; 0.0005). In contrast, GTN caused dilation in all subjects (KD patients 25 ± 4% versus controls 23 ± 2%, P = NS). Thus, KD patients have abnormal endothelial function which is present in the systemic arteries late after the acute disease in the absence of coronary artery abnormalities. This may be an important factor in the genesis of late vascular complications

775-6 Vascular Remodling and Endothelial Dysfunction in Coronary Disease

Early coronary atherosclerosis (CA) is characterized by endothelial dysfunction which is manifested by coronary vasoconstriction in response to the endothelial-dependent vasodilator acetylcholine. The endothelium may be involved in the adaptive process of vascular remodeling (VR). While vascular remodeling has been demonstrated in advanced CA, it is not known if this process occurs early in the course of CA. Thus, this study was designed to test the hypothesis that VR characterized by proximal coronary artery enlargement occurs in patients with angiographically normal or mild CA and abnormal coronary endothelial function. To test this hypothesis, 20 patients found to have normal coronary angiograms or mild CA were studied. Acetylcholine was infused in incremental doses into the left anterior descending (LAD) with angiographic measurement of lumen diameter. Patients were divided into two groups based on their coronary endothelial function. Group 1 demonstrated coronary vasoconstriction in response to acetylcholine and Group 2 had a normal vasodilatory response. Intravascular ultrasound measurements of the proximal LAD diameter and area were made following nitroglycerin. Vessel diameter and area were measured at the internal elastic membrane and indexed to body surface area (BSA). Comparison between the two groups is outlined below:Empty CellGroup 1 (n = 14)Group 2 (n = 6)Vessel Diameter (mm)5.1 ± 0.2*39 ± 0.2Vessel Area (mm2)19.1 ± 1.5*12.4 ± 1.3Vessel Diameter Index (mm/m2)2.6 ± 0.1*2.1 ± 0.1Vessel Area Index (mm2/m2)10.0 ± 0.7*6.6 ± 0.6Data are mean ± SEM*p &lt; 0.02 vs. Group 2 Data are mean ± SEM p &lt; 0.02 vs. Group 2 Five patients in Group 1 and one in Group 2 had ultrasound evidence of mild atherosclerosis. This study demonstrates in vivo that vascular remodeling characterized by enlargement of the proximal coronary arteries occurs early in the course of coronary disease in the presence of endothelial dysfunction.

Oxidized LDL and Reduction of the Antiaggregating Activity of Nitric Oxide Derived from Endothelial Cells

Oxidized LDL has been observed to induce abnormalities in endothelial function which may be relevant for the progression of atherosclerotic lesions. We studied in vitro the possible effects of oxidized LDL on the antiaggregating activity of endothelial cells, which is dependent on release of prostacyclin and nitric oxide. We used an experimental model in which cultured human endothelial cells were placed in the aggregometer in contact with human platelets, after blockade of cyclo-oxygenase by adding acetylsalicylic acid. In this way the antiaggregant effect of endothelial cells was dependent on the release of nitric oxide alone; prevention of antiaggregant activity by preincubation of endothelial cells with 300 microM L-NG-mono-methylarginine confirmed this. When this system was used, endothelial cells (2-7.5 x 10(5)/ml) almost completely inhibited thrombin-induced (0.02-0.08 U/ml) platelet aggregation (2 x 10(8) platelets/ml), measured according to Born (11.1% +/- 8.5 vs 68.6% +/- 12.6, M +/- SD). This antiaggregating activity was reduced when slightly oxidized LDL 100 micrograms/ml (35.2% +/- 14.9, p < 0.001), but not native LDL 100 micrograms/ml (7.5% +/- 7.6), was added immediately before aggregation was induced. Incubation of endothelial cells with oxidized LDL 100 micrograms/ml for 1 h did not affect the antiaggregating capacity, unless oxidized LDL was present during aggregation (18.3% +/- 10.2 vs 35.8% +/- 9.6, p < 0.02). No significant direct effect of either oxidized or native LDL on stimulated platelet aggregation was observed. Our results indicate that slightly oxidized LDL can reduce the antiaggregating properties of the endothelium, probably by interaction with NO rather than through inhibition of its synthesis.

Nitric oxide production by human umbilical vessels in severe pre-eclampsia

Pre-eclampsia is characterized by an increased vascular tone which might be related to an abnormal endothelial cell function. As representatives of the fetal circulation, we compared the nitric oxide (NO)-releasing capacity of human umbilical vessels from normal and pre-eclamptic pregnancies. Normal and pre-eclamptic umbilical vessels were mounted in parallel in an organ chamber with three perfusion lines superfusing the same detector tissue (rubbed rat aortic ring). In this cascade system the capacity of the umbilical vessels to release NO was measured under basal conditions and after stimulation with histamine, bradykinin or calcium ionophore A23187. Relaxations dependent on basal NO release were found to be significantly higher in pre-eclamptic vessels (especially in veins) than in normal vessels. Conversely, stimulated NO release in response to histamine or bradykinin was significantly decreased in pre-eclamptic umbilical arteries, but not in veins, compared with normal vessels. However, there was no significant difference in the release of NO in response to A23187 between normal and pre-eclamptic vessels. The NO-releasing and NO-producing capacity in the vessels from fetal circulation is not diminished in pre-eclampsia. However, in pre-eclamptic umbilical arteries the NO release in response to certain stimuli (histamine or bradykinin) is diminished, probably as a result of alterations in the receptor function.

17 beta-estradiol preserves endothelial vasodilator function and limits low-density lipoprotein oxidation in hypercholesterolemic swine.

Cardiovascular events are less prevalent in premenopausal women and women receiving estrogen replacement than in postmenopausal women or men. Endothelium-derived relaxing factor (EDRF) is an important local modulator of vascular tone, and abnormal endothelial function is related, in part, to the oxidative modification of low-density lipoprotein (LDL). Estrogens possess substantial antioxidant activity and inhibit LDL modification in vitro. We investigated the effects of 17 beta-estradiol (E2) on endothelial vasomotor function in cholesterol-fed miniature swine. Animals underwent ovariectomy or a sham procedure and received E2 or placebo via implant yielding three groups: sham, ovariectomy (E2 placebo), and implant (E2 implant). After 16 weeks, coronary arteries were harvested and endothelial function was examined in vitro. Vessels from the sham and implant groups demonstrated preserved endothelium-dependent relaxation to bradykinin, substance P, and A23187. Vessels from the ovariectomy group exhibited impaired relaxation to bradykinin and substance P (P < .05 versus sham and implant groups) but not to A23187. Plasma E2 levels were strongly correlated with the response to bradykinin (R = .82, P < .001), substance P (R = .64, P < .01), and A23187 (R = .65, P < .01). Compared with the ovariectomy group, LDL derived from the sham and implant groups was markedly resistant to ex vivo oxidation (P < .05), and this effect correlated with preserved endothelium-dependent relaxation to bradykinin (R = .62, P < .03) and substance P (R = .61, P < .03). Thus, E2 preserves endothelial function in cholesterol-fed swine in association with protection of LDL against oxidative modification. These data suggest that E2 may, in part, favorably affect vascular function and coronary artery disease by virtue of its antioxidant properties.

Impaired endothelium-dependent vasodilation in patients with insulin-dependent diabetes mellitus.

Endothelium-dependent vasodilation is abnormal in experimental models of diabetes mellitus. We postulated that abnormalities of endothelial function are also present in patients with insulin-dependent diabetes mellitus and may contribute to the pathogenesis of vascular disease in these individuals. Vascular reactivity was measured in the forearm resistance vessels of 15 patients with insulin-dependent diabetes mellitus and 16 age-matched normal subjects. No patient had hypertension or dyslipidemia. Each subject was pretreated with aspirin to inhibit endogenous production of prostanoids. Methacholine chloride (0.3 to 10 micrograms/min) was administered via the brachial artery to assess endothelium-dependent vasodilation. Sodium nitroprusside (0.3 to 10 micrograms/min) and verapamil (10 to 300 micrograms/min) were infused intra-arterially to assess endothelium-independent vasodilation; phenylephrine (0.3 to 3 micrograms/min) was administered to examine vasoconstrictor responsiveness. Forearm blood flow was determined by venous occlusion plethysmography, and dose-response curves were generated for each drug. Basal forearm blood flow in diabetic and normal subjects was comparable (2.6 +/- 0.2 versus 2.1 +/- 0.3 mL x 100 mL-1 x min-1, respectively; P = NS). The forearm vasodilative response to methacholine was less in diabetic than in normal subjects. At the highest dose of methacholine, the forearm blood flow increased 9.5 +/- 1.1 mL x 100 mL-1 x min-1 in diabetic subjects and 15.3 +/- 1.4 mL.100 mL-1 x min-1 in normal subjects (P < .01). The forearm blood flow responses to nitroprusside and verapamil and the forearm vasoconstrictor responses to phenylephrine were similar in diabetic and healthy subjects. In diabetic subjects, endothelium-dependent vasodilation correlated inversely with serum insulin concentration but not with glucose concentration, glycosylated hemoglobin, or duration of diabetes. Endothelium-dependent vasodilation is abnormal in forearm resistance vessels of patients with insulin-dependent diabetes mellitus. This abnormality may be relevant to the high prevalence of vascular disease that occurs in these individuals.

Endothelin‐1 modulates vascular smooth muscle structure and vasomotion: Implications in cardiovascular pathology

AbstractEndothelin‐1 modulates vascular smooth muscle tone by exerting potent vasoconstrictor actions through the ETA receptor subtype located on the membranes of vascular smooth muscle cells. This receptor subtype also mediates the growth‐promoting actions of this peptide in vascular smooth muscle cells. The ETA receptor is distinct, however, from the endothelin receptor subtype located on the endothelium; the anatomically and functionally distinct ETB receptor mediates the release of the endothelium‐derived factor nitric oxide, a labile substance which not only produces potent vasodilation but also possesses anti‐mitogenic activity. This report describes the interaction between these two vasoactive factors in the control of cardiovascular function. Under normal conditions the endothelium serves to modulate the contractile and proliferative actions of endothelin‐1. However, many cardiovascular disorders (e.g., hypertension, atherosclerosis, vascular restenosis, subarachnoid hemorrhage, etc.) are associated with both abnormal endothelial cell function, resulting in an inability to synthesize and/or release nitric oxide, and elevated circulating levels of endothelin‐1. Since the resultant loss/inhibition of nitric oxide will augment both the contractile and proliferative actions of endothelin‐1, this has the potential to promote vasoconstriction and smooth muscle hyperplasia/hypertrophy at the site of any such lesion. Since evidence is accumulating that both endothelin‐1 and nitric oxide play pivotal roles in the control of both vascular smooth muscle tone and growth, any imbalance between these two counter‐regulatory systems is likely to have profound pathological consequences within the cardiovascular system. © 1993 Wiley‐Liss, Inc.