Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.

Osborne, John A.; Lento, Paul; Siegfried, Martin R.; Stahl, Gregory L.; Fusman, B; Lefer, Allan M.

doi:10.1172/jci113905

Cited by 148 publications

(51 citation statements)

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“…- 55 Our results give some evidence that even small diet modifications might influence the effect on endothelium-dependent relaxation in hypercholesterolemic rabbits and might explain the contrasting results between studies that have reported either unaltered 25128 or impaired 20 -26 endothelium-dependent relaxation of DCs. However, it should be emphasized that studies A and B were performed consecutively, and examination of the tables shows some differences in the control values obtained in each study.…”

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confidence: 74%

“…19 Second, the endotheliumdependent vasodilator effect of ACh in the perfused Langendorff heart preparation of hypercholesterolemic rabbits is converted to vasoconstriction, 20 and impaired vasodilation to ACh in the perfused hind limb and cremaster preparation of hypercholesterolemic rabbits is found. 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.…”

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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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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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confidence: 74%

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confidence: 99%

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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“…The HMG-CoA reductase blockers known as statins prevent the synthesis of cholesterol at the mevalonate and provide significant protection against coronary artery disease (Shepherd et al, 1995;Treasure et al, 1995) stroke (Delanty and Vaughan, 1997) and ischemic injury (Lefer et al, 1999). In addition to the effects of statins on cholesterol, statins also preserve endothelial function in animal models (Osborne et al, 1989) and in humans (Levine et al, 1995;Treasure et al, 1995;Kinlay et al, 1996).…”

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confidence: 99%

The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis

Sasaki

Bharwani²,

Jordan³

et al. 2003

J Pharmacol Exp Ther

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The dextran sulfate (DSS) model of colitis causes intestinal injury sharing many characteristics with inflammatory bowel disease, e.g., leukocyte infiltration, loss of gut epithelial barrier, and cachexia. These symptoms are partly mediated by entrapped leukocytes binding to multiple endothelial adhesion molecules (MAdCAM-1, VCAM-1, ICAM-1, and E-selectin). Pravastatin, an 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitor, has anti-inflammatory potency in certain inflammation models; therefore, in this study, we measured the effects of pravastatin in DSS-induced colitis. The administration of pravastatin (1 mg/kg) relieved DSS-induced cachexia, hematochezia, and intestinal epithelial permeability, with no effect on serum cholesterol. Histopathologically, pravastatin prevented leukocyte infiltration and gut injury. Pravastatin also blocked the mucosal expression of MAdCAM-1. DSS treatment promoted mucosal endothelial nitric-oxide synthase (eNOS) mRNA degradation, an effect that was blocked by pravastatin. Importantly, the protective effects of pravastatin in DSS-induced colitis were not found in eNOS-deficient mice. Our results demonstrate that HMG-CoA reductase inhibitors preserve intestinal integrity in colitis, most likely via increased eNOS expression and activity, independent of cholesterol metabolism.Inflammatory bowel disease (IBD) (Crohn's colitis and ulcerative colitis) is characterized by tissue edema, increased gut epithelial permeability, and extensive infiltration of the gut by leukocytes. The general morbidity and weight loss in individuals with IBD can be attributed to leukocyte sequestration in the gut in this condition (Perkal and Seashore, 1989;Shanahan, 2002). The current literature suggests that multiple immune, genetic, and environmental factors influence both the initiation and progression of colitis (Farrell and Peppercorn, 2002). Despite the fact that the normal intestinal mucosa maintains a high density of leukocytes compared with most tissues, it is not typically inflamed or edematous. However, during active periods of colitis, the colon is even more extensively colonized by lymphocytes and neutrophils that promote extensive oxidant and protease-dependent injury to the gut. Therefore, it is assumed that the intestine has several specialized mechanisms that normally contain these immune responses and that the impairment of these immune-limiting processes causes the entrapment and activation of leukocytes seen in IBD injury. Among the several endogenous agents that control inflammation, nitric oxide has received a great deal of interest as a factor that can limit forms of inflammation. Endothelial cells release nitric oxide (NO) through both by the "constitutive" (eNOS and NOS3) and inducible nitric oxide synthases (iNOS and NOS1). NO released by microvascular endothelial cells reduces several indices of inflammation in vivo and in vitro. NO is a potent reactive oxygen species scavenger and can block many oxidant-mediated inflammatory responses including leukocyte and platel...

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“…33 This was confirmed in isolated rabbit hearts after a 0.5% cholesterol diet for 2-3 weeks. 34 In this regard, Osborne et al 12 related the ischemic injury in hypercholesterolemic rabbits (i.e., 0.5% cholesterol for 2-3 weeks) to endothelial dysfunction. Both the endothelial dysfunction and the myocardial injury were attenuated by lovastatin treatment over the 2-3-week period.…”

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confidence: 99%

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

Lefer

1993

Arterioscler Thromb

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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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Cardiovascular effects of acute hypercholesterolemia in rabbits. Reversal with lovastatin treatment.

Cited by 148 publications

References 28 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.

The 3-Hydroxy-3-methylglutaryl-CoA Reductase Inhibitor Pravastatin Reduces Disease Activity and Inflammation in Dextran-Sulfate Induced Colitis

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

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