Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits

Osborne, John A.; Siegman, Marion J.; Sedar, Albert W.; Mooers, Susan U.; Lefer, Allan M.

doi:10.1152/ajpcell.1989.256.3.c591

Cited by 153 publications

(46 citation statements)

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“…35 In contrast to the effect on PCs, SNP relaxed the DC segments of hypercholesterolemic rabbits similar to control segments, in agreement with other studies of the response to nitrovasodilators in small coronary arteries from cholesterol-fed animals. 26 - 27 Endothelial removal in segments of treated animals enhanced the relaxation to SNP as it did in control animals ( Figure 5), thus indicating that the basalfy released EDRF inhibiting the relaxation of the small coronary arteries to SNP was not affected by the hypercholesterolemia.…”

Section: Impaired Release From the Endothelium Of A Factor Inhibitingmentioning

confidence: 77%

“…21 - 23 In direct contrast, others have reported unaltered endothelium-dependent vasodilation of the hind limb vasculature of the hypercholesterolemic rabbit 24 and unaltered cholinergic vasodilation of perfused kidneys of cholesterol-fed rabbits. 25 Third, although in vitro studies of isolated small coronary arteries from the hypercholesterolemic rabbit indicate impaired relaxation to ACh 26 as in atherosclerotic primates, 27 the findings are ambiguous. Angus and colleagues 28 found that the response to ACh of isolated, small coronary arteries from hypercholesterolemic rabbits was unaltered.…”

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“…- 13 First, Osborne and colleagues 26 showed with electron microscopy that some small coronary arteries with impaired relaxation to ACh from hypercholesterolemic rabbits did not show intimal proliferation, although fatty streaks were present at bifurcation points and occasionally in the linear unbranched segments of the coronary arteries. Furthermore, transmission electron microscopy of primate small coronary arteries with impaired endothelium-dependent response showed foam cells and vacuoles, representing lipid droplets within the endothelium.…”

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Effect of induced hypercholesterolemia in rabbits on functional responses of isolated large proximal and small distal coronary arteries.

Simonsen

Prieto

Mulvany

et al. 1992

Arterioscler Thromb

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We studied the effects of hypercholesterolemia on the vascular responses of proximal and distal parts of the rabbit coronary circulation in two consecutive studies. For 12 weeks, New Zealand White rabbits were fed a control diet or a diet with 1% cholesterol dissolved in either 3% coconut oil (study A) or ether (study B). Isolated proximal epicardial and distal intramyocardial coronary arteries from control and hypercholesterolemic rabbits were mounted for isometric tension recording in a double myograph. In study A for hypercholesterolemic rabbits (A=12), the maximal relaxation and sensitivity to acetylcholine (ACh) were significantly decreased in proximal coronary segments contracted with 30 mmol/1 potassium solution compared with segments from control rabbits (it=13). The only change observed in distal coronary segments was a slight decrease in relaxation in response to low ACh concentrations (10~* and 3 x 10~* mol/1). However, in study B for proximal coronary and distal coronary segments from hypercholesterolemic rabbits (n=13), the area under the ACh relaxation curve was increased compared with that of control r abbits (n = 12). Other parameters that were similarly affected in studies A and B include the following: 1) proximal coronary segments from hypercholesterolemic rabbits were more sensitive to sodium nitroprusside (SNP) than were those from control rabbits, but this was not true for distal coronary segments; 2) endothelial removal from arterial segments of control rabbits induced a significant increase in sensitivity and maximal relaxation to SNP of proximal coronary and distal coronary arteries; 3) in segments from hypercholesterolemic rabbits, the absence of endothelium did not alter the response of proximal coronary segments to SNP but did augment the relaxation of distal coronary segments to SNP; 4) the maximal response to 5-hydroxvtrvptamine in proximal coronary arteries from hypercholesterolemic rabbits was increased compared with those from control rabbits, whereas such changes were not observed in distal coronary arteries; and 5) histological examination showed the presence of atheromatous plaques in proximal coronary but not in distal coronary segments from treated animals. In conclusion, the present investigation demonstrates that induced hypercholesterolemia alters both the structure and function of proximal parts of the coronary circulation. In distal coronary arteries of hypercholesterolemic rabbits, the only change observed was an impaired endothelium-dependent cholinergie relaxation, but even this change appeared to be dependent on the manner in which cholesterol was added to the diet, although parallel studies are required to confirm this. (

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Section: Impaired Release From the Endothelium Of A Factor Inhibitingmentioning

confidence: 77%

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confidence: 99%

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confidence: 99%

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Effect of induced hypercholesterolemia in rabbits on functional responses of isolated large proximal and small distal coronary arteries.

Simonsen

Prieto

Mulvany

et al. 1992

Arterioscler Thromb

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“…Received October 29, 1992 revision accepted February 16, 1993. plaque-lined coronary arteries. 13 However, no data are available on leukocyte adherence to the coronary endothelium over the course of the hypercholesterolemic preplaque period. Moreover, the relation of adherence to EDRF production would also be of considerable interest.…”

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Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium.

Lefer

1993

Arterioscler Thromb

135

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Hypercholesterolemia, before atherosclerosis, is known to reduce agonist-(e.g., acetylcholine) mediated nitric oxide (NO) production within 2 weeks of a cholesterol-enriched diet. However, no data exist on the effect of hypercholesterolemia on the basal release of NO from blood vessels. We studied the basal release of NO in rabbit coronary arteries by addition of the NO synthase blocker yV G -nltro-L-arginine-methyl ester (L-NAME). Basal release of NO was markedly attenuated 2 weeks after introduction of a 0.5% cholesterol addition to the diet One week later, the adherence of neutrophils to the coronary endothelium was significantly enhanced (i.e., threefold; p<0.01 different from control). The increased adhesiveness could be attributed to enhanced endothelial adhesion rather than to changes in the properties of the leukocytes. Both phenomena could be reversed by addition of L-arginine to isolated coronary arteries. Administration of 10 mg/day lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, markedly attenuated both the reduced basal NO production and the increased adhesiveness of the endothelium. These results support the concept that NO is an important protective agent produced by the endothelium to preserve the integrity of the endothelium and may protect it against atherogenesis. (Arteriosclerosis and Thrombosis 1993;13:771-776) KEY WORDS • endothelium-derived relaxing factor • nitric oxide • lovastatin • leukocyte adherence A therosclerosis is thought to be induced by injury / \ or pathophysiological changes to the vascular J. \ . endothelium.1 One of the earliest alterations to the endothelium after exposure to high cholesterol levels is the loss of endothelium-derived relaxing factor (EDRF), now identified as nitric oxide (NO).W EDRF has been shown to exert a variety of physiological actions in addition to its well-known relaxation of vascular smooth muscle, 4 including inhibition of platelet aggregation, 5 attenuation of leukocyte adherence to the endothelium, 6 -7 and the quenching of superoxide radicals. -9Many investigators have shown a reduction in agonistmediated EDRF production or release in atherosclerotic vessels. 1011 Recently, however, a significant endothelial dysfunction characterized by reduced EDRF release was shown within 2 weeks after initiation of a 0.5% cholesterol supplement to the diet, before any coronary artery plaque occurred.12 This is consistent with other reports of endothelial dysfunction in rabbit coronary arteries without plaque that are adjacent to Supported by research grant GM-45434 from the National Institutes of Health.Address for correspondence: Dr. Allan M. Lefer, Department of Physiology, Jefferson Medical College, 1020 Locust Street, Philadelphia, PA 19107-6799. Received October 29, 1992 revision accepted February 16, 1993. plaque-lined coronary arteries. 13 However, no data are available on leukocyte adherence to the coronary endothelium over the course of the hypercholesterolemic preplaque period. Moreover, the relation of adherence t...

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“…2,9 In more advanced stages, the endothelium-independent relaxation, as assessed by the direct action of nitrovasodilators on arterial smooth muscle cells, can also be affected. [3][4][5][6][7][8][9][10][11]12 In addition, hyperlipidemia and atherosclerosis can be associated with abnormal vasoconstrictor responses. [13][14][15][16][17] Reduced ␣-adrenergic contractile responses but increased serotonergic contractile responses were reported in hyperlipidemic rabbits.…”

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Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice

et al. 1999

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Background-Atherogenic lipoproteins can impair the endothelium-dependent arterial relaxation, and circumstantial evidence suggests a beneficial role of plasma high density lipoproteins and apolipoprotein (apo) A-I in counteracting the endothelium dysfunction. In the present study, vascular reactivity was determined in control, apoE-deficient mice (apoE-KO mice), and apoE-deficient mice expressing human apoA-I (apoE-KO/HuAITg mice). Methods and Results-In the first part of the study, control and apoE-KO mice were fed a low-fat or a high-fat diet for 23 weeks, and the vasoactive responses of isolated thoracic aortic segments to norepinephrine, sodium nitroprusside, and acetylcholine (ACh) were determined. Whereas norepinephrine, sodium nitroprusside, and ACh evoked similar vascular responses in control and apoE-KO mice fed the low-fat diet, high-fat feeding in apoE-KO mice produced a significant 3-fold increase in the mean concentration required to produce a half-maximal relaxing effect (EC 50 ) of ACh as compared with control mice. This reflects a weaker sensitivity to ACh of the aortic segments from the apoE-deficient animals. In the second part of the study, the mean EC 50 for ACh after high-fat feeding was found to be 4.4-fold lower in apoE-KO/HuAITg mice than in apoE-KO mice, indicating that the reduced sensitivity to ACh of the thoracic aorta from the apoE-KO mice fed the high-fat diet is improved by the expression of human apoA-I. Conclusions-The present study demonstrates that the endothelium-dependent arterial relaxation is impaired in apoE-KO mice fed the high-fat diet. The endothelium dysfunction tends to be normalized by human apoA-I expression.

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Lack of endothelium-dependent relaxation in coronary resistance arteries of cholesterol-fed rabbits

Cited by 153 publications

References 20 publications

Effect of induced hypercholesterolemia in rabbits on functional responses of isolated large proximal and small distal coronary arteries.

Effect of induced hypercholesterolemia in rabbits on functional responses of isolated large proximal and small distal coronary arteries.

Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium.

Impairment of Endothelium-Dependent Arterial Relaxation By High-Fat Feeding in ApoE-Deficient Mice

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