Loss Of Endothelium-dependent Vasodilation Research Articles

Loss of endothelium-dependent vasodilation in the pulmonary vessels of sheep after prolonged endotoxin.

We examined the hemodynamic response of awake sheep to prolonged endotoxin infusion (10 ng.kg-1 x min-1 for 12 h) and the in vitro endothelium-dependent relaxation of pulmonary arterial vessels excised 12 h after the end of endotoxin infusion to determine whether the development of pulmonary hypertension after endotoxin is associated with loss of endothelium-dependent relaxation. In seven of nine sheep, there was a maintained increase (4-68% of baseline) in pulmonary arterial pressure 24 h after the beginning of endotoxin infusion. The greater the increase in pulmonary arterial pressure in vivo, the greater was the in vitro deficit in endothelium-dependent relaxation of the pulmonary vessels. The maximum in vitro vessel dilation was 59% for pulmonary artery rings isolated from sheep without a sustained increase in pulmonary arterial pressure 24 h after endotoxin. Prolonged endotoxin infusion did not alter the in vitro response of pulmonary arterial vessels to KCl or 10(-5) M norepinephrine. Force development, response to 10(-5) M norepinephrine, and vasodilation in response to acetylcholine were also not altered in pulmonary vessels taken from control sheep and exposed in vitro to tumor necrosis factor-alpha (400 U/ml). Our results suggest that loss of endothelium-dependent relaxation in pulmonary vessels supports the sustained pulmonary hypertension that develops after prolonged exposure to endotoxin.

Influence of serum cholesterol and other coronary risk factors on vasomotion of angiographically normal coronary arteries.

It has been shown that there is impairment of the vasodilatory response to acetylcholine in patients with hypercholesterolemia and angiographically normal coronary arteries. Moreover, in patients with angiographically smooth coronary arteries, the number of coronary risk factors is associated with a loss of endothelium-dependent vasodilation. The purpose of the present analysis was to evaluate in patients with and without coronary artery disease coronary vasomotor response to dynamic exercise in angiographically normal and stenosed coronary arteries and to relate the response to serum cholesterol levels as well as to other coronary risk factors. Luminal area change during exercise (delta-ex, percent change compared with rest = 100%) was determined by biplane quantitative coronary arteriography in three groups: Group 1 consisted of 14 patients with normal total serum cholesterol of < 200 mg/100 mL; mean, 173 mg/100 mL (mean age, 51 years). Group 2 comprised 23 patients with a slightly elevated cholesterol of 200 to 250 mg/100 mL; mean, 223 mg/100 mL (mean age, 53 years). Group 3 had 24 patients with markedly elevated cholesterol of > 250 mg/100 mL; mean, 288 mg/100 mL (mean age, 54 years). Serum cholesterol levels and categorical risk factors such as positive family history, history of hypertension, smoking, obesity, and diabetes were related to exercise-induced vasomotor response. The three groups did not differ with regard to clinical characteristics, exercise work load, and hemodynamic data measured during exercise. However, delta-ex in normal vessels was significantly different between all three groups (ANOVA, P < .01): +31% (group 1), +18% (group 2), and +4% (group 3). Delta-ex in stenotic vessels did not differ between the groups: -5% (group 1), -13% (group 2), and -12% (group 3). Delta-ex of the nonstenosed vessel correlated significantly and inversely with total cholesterol, with low-density lipoprotein cholesterol, with the ratio of total to high-density lipoprotein cholesterol, and with the number of coronary risk factors present in a patient. High total cholesterol and a history of hypertension were independent risk factors for impaired coronary vasomotion. In patients with and without coronary artery disease, hypercholesterolemia and a history of hypertension independently impair exercise-induced coronary vasodilation in angiographically normal coronary arteries. In the stenotic vessel, vasomotion during exercise does not appear to be influenced by the actual serum cholesterol. The precise mechanism by which the impaired vasomotion of the angiographically normal coronary arteries is mediated is unknown, but a direct negative effect of hypercholesterolemia on endothelial function or early undetected atherosclerosis appears to be the most likely explanation.

Impaired contraction and relaxation in skin resistance arteries from patients with congestive heart failure

The aim was to determine the pharmacological reactivity of human small resistance arteries in patients with cardiac failure. Small arteries (< 300 microns internal diameter) were removed from gluteal skin biopsy specimens and mounted in a double myograph for isometric force recording. Arteries from six patients with congestive heart failure contracted to only 65% of the maximum response recorded in nine arteries from normal volunteers when activated by potassium chloride (124 mM), noradrenaline (1 microM), or both. The lesser contraction in congestive heart failure vessels with no significant shift in sensitivity (EC50) was also observed in concentration-response studies with noradrenaline, angiotensin I, and angiotensin II. The concentration-contraction curves for serotonin showed only 40% of the maximum contractility to K+ in normal arteries, and this ratio was similar in congestive heart failure arteries. Normal arteries precontracted with noradrenaline (1 microM) relaxed in response to sodium nitroprusside, calcitonin gene related peptide, and the endothelium dependent agonist acetylcholine; in congestive heart failure vessels there was a marked loss of the relaxation response only to acetylcholine. These results suggest that in chronic congestive heart failure skin resistance arteries have impaired contraction responses probably independent of any receptor down regulation. The loss of endothelium dependent vasodilatation to acetylcholine suggests that EDRF release is impaired. These changes may well play an important role in the disturbances of peripheral vascular function associated with heart failure.

New insights into the management of myocardial ischemia

Episodes of ST depression are closely related to transient decreases in regional myocardial perfusion during physical or mental stress. At the on-set of these events, there is transient constriction of atherosclerotic stenoses, with an increase in myocardial demand as reflected by increases in heart rate and blood pressure. Recent research has shown that normal epicardial coronary arteries respond to these provocations and to increasing blood flow with progressive vasodilation. In contrast, atherosclerotic vessels lose this ability to dilate and may show paradoxical constriction. This abnormal constriction parallels the response of the arteries to acetylcholine, which can be used to assess the ability of the coronary endothelium to regulate vasodilation. The loss of endothelium-dependent vasodilation appears to be an important functional manifestation of coronary atherosclerosis and a potential triggering mechanism for transient ischemia. Dysfunctional endothelium may also result in a procoagulant surface, with cell adherence and local thrombus formation. Restoration of normal endothelial function is likely to emerge as an important therapeutic objective in the management of myocardial ischemia and coronary atherosclerosis.

Coronary vasomotor response to acetylcholine relates to risk factors for coronary artery disease.

In animals, acetylcholine dilates normal arteries and produces vasoconstriction in the presence of hypercholesterolemia, hypertension, or atherosclerosis, reflecting endothelial cell dysfunction. In patients with angiographically smooth coronary arteries, acetylcholine has been reported to produce both vasodilation and constriction. To test the hypothesis that the acetylcholine response relates to risk factors for coronary artery disease, acetylcholine 10(-8) to 10(-6) M was infused into the left anterior descending or circumflex coronary artery, and diameter changes were assessed with quantitative angiography in 34 patients with angiographically smooth coronary arteries. The acetylcholine response ranged from +37% (dilation) to -53% (constriction) at the peak acetylcholine dose. All coronary arteries dilated in response to nitroglycerin (26 +/- 17%), suggesting an abnormality of endothelial function in the patients with a constrictor response to acetylcholine. By multiple stepwise regression analysis, serum cholesterol (p less than 0.01), male gender (p less than 0.001), family history (p less than 0.05), age (p less than 0.05), cholesterol level (p less than 0.01), and total number of risk factors (p less than 0.0001) were independently associated with the acetylcholine response. Thus, coronary risk factors are associated with loss of endothelium-dependent vasodilation. The development of vasoconstriction is likely to be an abnormality of endothelial function that precedes atherosclerosis or an early marker of atherosclerosis not detectable by angiography.

Contrary effects of acetylcholine on coronary arteries and aortocoronary venous grafts in man

The endothelium-dependent vasomotor responses differ in arteries and veins, and the transfer of veins into the arterial circulation by venous grafting may change their endothelial function. The purpose of this study was to examine the responses to acetylcholine in aortocoronary venous grafts of coronary arteries in man which may indicate differences in the endothelial function of these vessels. Five patients with venous grafts (12 to 72 months after implantation) and five patients without any angiographic evidence for coronary artery disease (controls) were examined. The effect of local infusions of acetylcholine (7-70 nmol min-1) on the vessel diameters was assessed by quantitative angiography. In controls, acetylcholine caused no consistent reaction, but in patients with venous grafts the arterial segments distal to the bypass anastomoses were contracted (7 nmol min-1: 82 +/- 2%; P greater than 0.01). We observed that aortocoronary venous grafts reacted differently to acetylcholine compared with the coronary arteries (P less than 0.05): a slight but not significant dilatation of the venous graft occurred (7 nmol min-1: 103 +/- 1%). The contraction of atherosclerotic coronary arteries of patients with aortocoronary venous grafts is in accord with the assumption of a loss of endothelium-dependent vasodilatation in coronary artery disease. The cholinergic influence on the vasomotor control of venous grafts seems to be either of little importance or less affected by atherosclerotic endothelial lesions than in coronary arteries.