Endothelial Vasomotor Dysfunction Research Articles

Pharmacological concentrations of ascorbic acid are required for the beneficial effect on endothelial vasomotor function in hypertension.

Increased production of superoxide anion may contribute to impaired bioactivity of endothelium-derived nitric oxide in hypertension. Ascorbic acid is capable of scavenging superoxide anion; however, experimental studies have shown that high physiological concentrations (>1 mmol/L) of ascorbic acid are required to prevent superoxide-mediated vascular dysfunction. To seek kinetic evidence that superoxide anion contributes to endothelial vasomotor dysfunction in human hypertension, we examined the effects of 2.4 or 24 mg/min ascorbic acid intra-arterial infusions on forearm blood flow responses to methacholine or sodium nitroprusside in 30 patients with hypertension and 22 age-matched controls. Endothelium-dependent vasodilation to methacholine was significantly impaired in the hypertensive patients, with a response to the highest dose of methacholine (10 microg/min) of 12.3+/-6.7 compared with 16.1+/-5.8 mL. min(-1). dL tissue(-1) in the controls (P<0.001). The response to sodium nitroprusside was equivalent in the 2 groups. Ascorbic acid at 24 mg/min significantly improved the forearm blood flow response to methacholine in hypertensive patients with a peak response of 16.1+/-7.1 mL. min(-1). dL tissue(-1) (P=0.001). This dose produced a cephalic vein ascorbic acid concentration of 3.2+/-1. 4 mmol/L. In contrast, ascorbic acid at 2.4 mg/min had no effect on the methacholine response. Ascorbic acid at both doses had no effect on the vasodilator response to sodium nitroprusside in hypertensive patients or the methacholine response in the controls. These results agree with the predicted kinetics for superoxide anion-mediated impairment of endothelium-derived nitric oxide action. Thus, superoxide anion may contribute to impaired endothelium-dependent vasodilation in patients with hypertension.

Modulation of coronary vasomotor tone by cytokines in cardiac transplant recipients.

Upon exposure to cytokines, endothelial cells may undergo profound alterations of vasomotor function. In this study, we characterized the relationship between coronary epicardial and microvascular vasomotor function and expression of specific cytokine patterns in human heart transplant recipients. We studied 49 cardiac transplant recipients, without acute rejection or infection at an average of 6+/-3 months after transplantation. Coronary resistance vessel function was measured in an endothelium-dependent manner with acetylcholine (5 and 150 microg/5 min; intracoronary injection) and in an endothelium-independent manner with adenosine (400 and 800 microg/5 min; intracoronary injection) using an intracoronary Doppler flow wire. Simultaneous epicardial diameter changes were measured using quantitative coronary angiography. Coronary sinus and aortic serum levels of soluble interleukin (IL)-2 receptor and soluble tumor necrosis factor-a receptors (sTNF-R1 and sTNF-R2), TNF-alpha, and IL-6 were determined. Transcardiac cytokine release (coronary sinus minus aortic levels) was correlated with coronary vasomotor function. The highest amounts of cardiac cytokine release were observed for IL-6 (32+/-14% increase) and sTNF-R1 (26+/-13% increase). A significant inverse correlation between microvascular endothelial function and cardiac release of soluble IL-2 receptor (P=0.04) and IL-6 (P=0.03) was detected, whereas a positive correlation was observed to sTNF-R1 (P=0.004). Distal epicardial endothelial vasomotion was inversely correlated to transcardiac sTNF-R2 release (P=0.03). Cytokine production and activation, a common phenomenon early after heart transplantation, is related at least in part to endothelial vasomotor dysfunction of the epicardial and microvascular compartment. These results support the hypothesis that coronary endothelial dysfunction after cardiac transplantation is an immunologic phenomenon. Since endothelial dysfunction seems to be a crucial step in the pathogenesis of cardiac allograft vasculopathy, coronary cytokine suppression should be a therapeutic target of improved future immunosuppressive regimens.

Endothelin in coronary endothelial dysfunction early after human heart transplantation

Background Cytokines and growth factors released as part of the immune response to alloantigenic stimuli are capable of regulating endothelin-1 expression in the allograft. Endothelin plays a significant role as a modulator of coronary vascular reactivity in the early stages of atherosclerosis and may be important as a participant in and marker for cardiac allograft vasculopathy. Methods We characterized a possible relationship between morphological and functional coronary changes, transcardiac plasma endothelin level and myocardial endothelin–mRNA expression in 33 cardiac transplant recipients in the early, stable phase 5 ± 3 months after orthotopic heart transplantation. Coronary microvascular function was determined as endothelium-dependent with acetylcholine and endothelium-independent with adenosine using intracoronary Doppler-FloWire. The percentage of the epicardial diameter changes was measured using quantitative coronary angiography. Intravascular ultrasound was performed to quantify intimal hyperplasia. Cardiac endothelin uptake or release was determined by measuring plasma endothelin levels in the coronary sinus and aorta. Myocardial endothelin-gene expression was determined using semiquantitative RT-PCR. Results The aortic endothelin levels were significantly increased in transplant recipients compared to nontransplanted patients (11.8 ± 2.2 vs 7.2 ± 0.9 fmol/mL; P < 0.001). Endothelin uptake was noticed in the majority of patients, and the amount of endothelin uptake was correlated to microvascular ( r = 0.37; P < 0.05) and epicardial ( r = 0.41; P < 0.03) endothelium-dependent vasodilatation. High mRNA signal intensity was associated with significantly reduced coronary flow response to acetylcholine compared to patients with low myocardial gene expression (coronary flow reserve 2.4 ± 0.9 vs 3.4 ± 0.8, respectively; P < 0.005). Morphological coronary changes early after transplantation were not correlated to endothelin plasma levels or myocardial gene expression. Conclusion Coronary endothelial vasomotor dysfunction after cardiac transplantation is associated with an increased myocardial endothelin mRNA expression and decreased endothelin-uptake by the heart. We postulate that early activation in the endothelin system may have a pivotal role in the acceleration of the atherosclerotic process in transplant patients.

Enhanced angiotensin-converting enzyme activity and impaired endothelium-dependent vasodilation in aortae from hypertensive rats: evidence for a causal link

Endothelial vasomotor function is impaired in a variety of disorders representing both early and late stages of atherosclerosis. There is experimental evidence for enhanced vascular angiotensin-converting enzyme (ACE) activity in these disorders. We explored whether enhanced vascular ACE activity accounts for endothelial dysfunction in experimental hypertension. Hypertension was induced in rats by coarctation of the aorta. At 2 weeks post-operation, the animals were randomly divided into groups receiving the ACE inhibitor quinapril (2.0 mg.kg(-1).day(-1)), the angiotensin type-1 receptor antagonist losartan (3.0 mg.kg(-1).day(-1)), the B(2) kinin receptor antagonist icatibant (0.4 mg.kg(-1).day(-1)), quinapril plus icatibant, losartan plus icatibant, or no drug. Analyses were performed 4 weeks post-operation. None of the drug treatments had any significant effect on blood pressure. ACE activity was nearly doubled in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril reduced ACE activity in aortae from hypertensive rats by 75%, losartan caused a 40% decrease, and icatibant had no effect. Endothelium-dependent, nitric oxide-mediated vasodilator responses studied in vitro were impaired by 40% in aortae from untreated hypertensive rats as compared with sham-operated rats. Both quinapril and losartan restored endothelial vasomotor function in aortae from hypertensive rats. Co-applied icatibant negated the effects of quinapril, but not those of losartan. The level of endothelial NO synthase (eNOS) mRNA determined by competitive RNA PCR was decreased by half in aortae from untreated hypertensive rats as compared with sham-operated rats. Quinapril induced an increase in the eNOS mRNA level of 350% in aortae from hypertensive rats, which was negated by co-applied icatibant. Losartan restored eNOS mRNA expression in aortae from hypertensive rats to normal levels, and this effect was not modified by co-applied icatibant. These findings suggest that enhanced vascular ACE activity accounts for endothelial vasomotor dysfunction by impairing the bioavailability of endothelium-derived NO. Both enhanced formation of angiotensin II and enhanced metabolism of bradykinin might account for a vascular deficiency of bioactive NO.

Improvement of endothelial vasomotor dysfunction by treatment with alpha-tocopherol in patients with high remnant lipoproteins levels

OBJECTIVESThis study sought to examine whether oral intake of alpha-tocopherol, an antioxidant, could improve endothelium-dependent vasorelaxation in patients with high remnant lipoproteins levels.BACKGROUNDRemnant lipoproteins are known to be atherogenic and impair endothelium-dependent arterial relaxation, but the underlying mechanisms remain unclear. Oxidative stress is a common feature of various risk factors for atherosclerosis.METHODSFlow-mediated vasodilation of the brachial artery during reactive hyperemia was examined by high resolution ultrasound technique before and at the end of 4 weeks treatment with oral administration of alpha-tocopherol acetate (300 IU/day) or placebo, which was randomly assigned, in 40 patients with high serum levels of remnants and in 30 patients with low remnants levels in the fasting state (>75th percentile and <25th percentile, respectively, of the distribution of remnants levels in 150 consecutive hospitalized patients).RESULTSBefore treatment, flow-mediated vasodilation was lower in patients with high remnants levels than in those with low levels (4.1 ± 0.3% vs. 6.0 ± 0.5%, p < 0.01). Treatment with alpha-tocopherol but not with placebo significantly increased flow-mediated dilation in patients with high remnants levels (7.5 ± 0.4% after alpha-tocopherol vs. 4.2 ± 0.4% after placebo, p < 0.01). In patients with low remnants levels, alpha-tocopherol was not effective. The beneficial effect with alpha-tocopherol in high remnants patients was associated with decrease in plasma levels of thiobarbituric acid reactive substances, an indicator of lipid peroxidation (6.6 ± 0.3 nmol/ml before alpha-tocopherol vs. 4.6 ± 0.3 after alpha-tocopherol, p < 0.05).CONCLUSIONSAlpha-tocopherol improved impairment of endothelium-dependent vasodilation in patients with high remnants levels. The increase in oxidative stress may at least partly contribute to endothelial vasomotor dysfunction in patients with high remnants levels.

Effect of insulin resistance on the endothelial vasomotor function of the coronary artery of nondiabetic patients.

Attention has been paid to the relationship between insulin resistance and coronary artery disease. The present study investigated the relationship between insulin resistance and the endothelial vasomotor function of the coronary artery of nondiabetic patients with chest pain and a positive exercise tolerance test. Twenty-five nondiabetic patients with chest pain were included. Patients with a steady state plasma glucose (SSPG) level of greater than or equal to 135 mg/dl were placed in the insulin resistant (IR) group, and those with a SSPG level less than 135 mg/dl were placed in the noninsulin resistant (NIR) group. The effect of acetylcholine, papaverine, and isosorbide dinitrate on the vasomotor response of the coronary endothelium was studied. The percent change in diameter of the coronary artery after injection of acetylcholine (20 microg ml(-1) min(-1)) was 84+/-17% in the IR group, and 109+/-18% in the NIR group. The difference in the degree of the vasodilative response is statistically significant (p<0.01). The percent change in coronary flow velocity after injection of acetylcholine (20 microg ml(-1) min(-1)) in the IR group was 120+/-67%, whereas that in the NIR group was 256+/-58%; the increase in coronary artery flow velocity of the IR group was significantly smaller than that of the NIR group (p<0.01). Nondiabetic patients with insulin resistance have endothelial vasomotor dysfunction, which raises an important question as to whether nondiabetic patients with insulin resistance should be treated to prevent the development of coronary heart disease.

Endothelial vasomotor dysfunction in offsprings of patients with essential hypertension

Endothelial vasomotor dysfunction in offsprings of patients with essential hypertension

Role of Endothelial Dysfunction in Coronary Artery Disease and Implications for Therapy

Atherosclerosis is a complex process that is characterized by the accumulation of modified low-density lipoprotein (LDL), local inflammatory and immune responses, and reduced nitric oxide bioavailability within the arterial wall. These cellular changes lead to endothelial vasomotor dysfunction, plaque instability, and the development of clinical events such as stable angina and the acute coronary syndromes. The vascular endothelium plays a critical role in modulating both the inflammatory response and vasomotor abnormalities that occur in those with coronary artery disease or risk factors for disease. In these conditions, endothelial cells are activated by cytokines to express cellular adhesion molecules that facilitate the adhesion of leukocytes to the endothelium, and their migration into the subintimal space. Cytokines stimulate inflammatory and smooth muscle cells in the intima to produce degradative enzymes, including metalloproteinases that can weaken the fibrous cap of atherosclerotic lesions and make them vulnerable to rupture. Endothelial cells also regulate vascular tone by the synthesis of nitric oxide. Atherosclerosis and other conventional risk factors for coronary artery disease are associated with endothelial vasodilator dysfunction in the coronary epicardial and resistance vessels, which likely contributes to myocardial ischemia. Several studies have demonstrated that lowering serum total and LDL cholesterol reverses endothelial vasomotor dysfunction, reduces myocardial ischemia, and lowers the risk of the acute coronary syndromes or need for revascularization. Improving endothelial function, for example, by lowering blood cholesterol should now be regarded as a goal of therapy in the treatment of coronary artery disease.

CAPILLARY DYSFUNCTION IN STRIATED MUSCLE ISCHEMIA/REPERFUSION

The major dysfunction of capillaries after prolonged periods of ischemia is the lack of re-establishment of nutritive blood flow upon onset of reperfusion, i.e., capillary no-reflow. Several mechanisms have been proposed to cause capillary no-reflow, including intravascular hemoconcentration and thrombosis, leukocyte plugging, endothelial cell swelling, vasomotor dysfunction, and interstitial edema formation. Electron microscopic studies suggest that thrombus formation and intravascular clotting are not significant mechanisms. Moreover, intravital microscopic studies have demonstrated that plugging of capillaries by leukocytes is not a primary cause for the manifestation of no-reflow in postischemic striated muscle. In contrast, both in vivo studies and histological examinations support the concept that ischemia/reperfusion induces the disruption of the endothelial integrity with loss of fluid to endothelial cells and the interstitial space. As a consequence, these pathological sequelae are associated with intravascular hemoconcentration, endothelial cell swelling and interstitial edema formation, which contribute to capillary lumenal narrowing, increase of hydraulic resistance, and, thus, impairment of perfusion. Whether the postischemic diameter response with dilation of reperfused capillaries and lumenal narrowing of no-reflow capillaries involves endothelin/nitric oxide-triggered capillary pericyte function remains to be determined.

Biological mechanisms for the clinical success of lipid-lowering in coronary artery disease and the use of surrogate end-points.

The small changes in luminal narrowing observed with lowering total cholesterol are unlikely to be the principal mechanism by which lipid-lowering achieves a reduction in clinical events and revascularization rates. Endothelium dependent vasomotor function, and the cellular characteristics of plaques that seem to be intimately related to rupture and thrombosis, are factors that may explain the clinical success from correcting the dyslipidemias. Dyslipidemias cause endothelial dysfunction that predisposes to vasoconstriction of the epicardial coronary arteries and the resistance vessels relative to metabolic demand. Dysfunctional endothelium also promotes the recruitment of inflammatory cells into the vessel wall which contributes to the activation of vascular smooth muscle cells and sets up an environment within the plaque that predisposes to rupture and a prothrombotic state. Aggressive lowering of total cholesterol, and especially LDL and oxidized LDL, improves coronary endothelial function both of the epicardial and resistance vessels, and leads to a reduction in myocardial ischemia. Lipid-lowering may promote plaque stability in part by reducing the recruitment of inflammatory cells, and possibly by changing the size or consistency of the lipid-rich core of plaques. A thicker fibrous cap and stiffer plaque that is less likely to rupture may result, and in the event that rupture does occur, cholesterol lowering may reduce the formation of overlying thrombus. Testing coronary or peripheral artery endothelial vasomotor dysfunction may be a surrogate measure for assessing the effectiveness of interventions to prevent coronary heart disease. These tests are likely to be used increasingly to identify interventions that deserve greater attention in larger clinical trials, as well as providing mechanisms for any observed clinical benefits.

Angiotensin converting enzyme inhibition, with quinapril, improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND study (trial on reversing endothelial dysfunction)

Angiotensin converting enzyme inhibition, with quinapril, improves endothelial vasomotor dysfunction in patients with coronary artery disease: The TREND study (trial on reversing endothelial dysfunction)