Atherosclerosis

1988

DOI: 10.1016/0021-9150(88)90009-3

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Antiatherosclerotic and antihyperlipidemic effects of octimibate sodium in rabbits

Andrea M. Hüther³

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Cited by 24 publications

(9 citation statements)

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“…The degree of lesion formation in our hypercholesterolemic rabbits was less than in other reports concerning the effects of ath erosclerosis on endothelium-dependent re laxation [2,5], One reason might be a differ ence in the species of rabbit used, because the extent of atherosclerosis reported in Japanese white rabbits seems to be less than in New Zealand white rabbits after the same length of time on a cholesterol-rich diet [2,[16][17][18], We used four pharmacological agents: acetylcholine, ATP, A23187, and ni troglycerin. Acetylcholine and ATP stimu late the release of EDRF by receptor-me diated mechanisms, A23187 stimulates the release of EDRF by nonreceptor-mediated mechanisms, and nitroglycerin is an endo thelium-independent vasodilator.…”

Section: Discussioncontrasting

confidence: 47%

β-Migrating Very Low Density Lipoprotein Attenuates Endothelium-Dependent Relaxation in Rabbit Atherosclerotic Aortas

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et al. 1989

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We studied the effects of β-migrating very low density lipoprotein (β-VLDL) on the vascular responses of isolated thoracic aortic preparations taken from normal and hypercholesterolemic rabbits. The endothelium-dependent relaxation induced by acetylcholine or adenosine triphosphate (ATP) was attenuated in the arteries from hypercholesterolemic rabbits that were fed a cholesterol-rich diet for 12 weeks. In these aortas, the lesional circumference of the atherosclerotic plaques (fatty streaks) was only 12.18 ± 1.98 %. The relaxation induced by the Ca²⁺ ionophore A23187 or nitroglycerin was not altered. Preincubation with β-VLDL significantly inhibited the relaxation due to acetylcholine, ATP, or A23187, especially in the aortas of hypercholesterolemic rabbits. However, β-VLDL did not alter the response to nitroglycerin. Preincubation with high density lipoprotein had no significant effect on vessel relaxation. These results indicated that endothelium-dependent relaxation was already inhibited in the early stages of atherosclerosis, and that the atherogenic lipoprotein, β -VLDL, further inhibited endothelium-dependent relaxation in atherosclerotic aortas. It may be that β -VLDL also plays a role in determining the level of vascular tonus in atherosclerosis.

“…The degree of lesion formation in our hypercholesterolemic rabbits was less than in other reports concerning the effects of ath erosclerosis on endothelium-dependent re laxation [2,5], One reason might be a differ ence in the species of rabbit used, because the extent of atherosclerosis reported in Japanese white rabbits seems to be less than in New Zealand white rabbits after the same length of time on a cholesterol-rich diet [2,[16][17][18], We used four pharmacological agents: acetylcholine, ATP, A23187, and ni troglycerin. Acetylcholine and ATP stimu late the release of EDRF by receptor-me diated mechanisms, A23187 stimulates the release of EDRF by nonreceptor-mediated mechanisms, and nitroglycerin is an endo thelium-independent vasodilator.…”

Section: Discussioncontrasting

confidence: 47%

β-Migrating Very Low Density Lipoprotein Attenuates Endothelium-Dependent Relaxation in Rabbit Atherosclerotic Aortas

¹

,

et al. 1989

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We studied the effects of β-migrating very low density lipoprotein (β-VLDL) on the vascular responses of isolated thoracic aortic preparations taken from normal and hypercholesterolemic rabbits. The endothelium-dependent relaxation induced by acetylcholine or adenosine triphosphate (ATP) was attenuated in the arteries from hypercholesterolemic rabbits that were fed a cholesterol-rich diet for 12 weeks. In these aortas, the lesional circumference of the atherosclerotic plaques (fatty streaks) was only 12.18 ± 1.98 %. The relaxation induced by the Ca²⁺ ionophore A23187 or nitroglycerin was not altered. Preincubation with β-VLDL significantly inhibited the relaxation due to acetylcholine, ATP, or A23187, especially in the aortas of hypercholesterolemic rabbits. However, β-VLDL did not alter the response to nitroglycerin. Preincubation with high density lipoprotein had no significant effect on vessel relaxation. These results indicated that endothelium-dependent relaxation was already inhibited in the early stages of atherosclerosis, and that the atherogenic lipoprotein, β -VLDL, further inhibited endothelium-dependent relaxation in atherosclerotic aortas. It may be that β -VLDL also plays a role in determining the level of vascular tonus in atherosclerosis.

“…The decrease in arterial macrophage-foam cell number, size, and fatty streak area in hamsters receiving octimibate and BMY 42393 confirms the reduction of atherosclerosis in cholesterol-fed rabbits that were treated with either octimibate 41 or the prostacyclin agonist cicaprost. 42 several possible mechanisms through which prostacyclin agonists affect the development of the fatty streak.…”

Section: Controlmentioning

confidence: 60%

Prostacyclin agonists reduce early atherosclerosis in hyperlipidemic hamsters. Octimibate and BMY 42393 suppress monocyte chemotaxis, macrophage cholesteryl ester accumulation, scavenger receptor activity, and tumor necrosis factor production.

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et al. 1993

Arterioscler Thromb

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We determined the effects of two prostacyclin agonists (octimibate and BMY 42393) on the progression of the fatty streak in vivo and on macrophage function in vitro. Hamsters were fed chow plus 0.05% cholesterol and 10% coconut oil. Control hamsters were compared with animals receiving either octimibate (10 or 30 nig/kg per day) or BMY 42393 (30 mg/kg per day). After 10 weeks of treatment, octimibate decreased plasma total cholesterol and triglycerides by 43% and 32%, respectively. Neither agonist affected blood pressure or heart rate. Lesion-prone aortic arches were stained with hematoxylin and oil red O and examined en face. Compared with controls, octimibate and BMY 42393 on average decreased mononuclear cells attached to the luminal surface by 44% and reduced subendothelial macrophage-foam cell number by 56%, foam cell size by 38%, and fatty streak area by 63%. Since octimibate is a putative inhibitor of acyl coenzyme A cholesterol acyltransferase, we studied the effect of both agents on cholesteryl ester metabolism in murine macrophages. At 10 yu.M, octimibate and BMY 42393 decreased cholesteryl ester accumulation in macrophages by 90% and 41%, respectively. Octimibate inhibited cholesteryl ester synthesis by 96% and increased the rate of cholesteryl ester degradation by 52%. Both prostacyclin agonists reduced macrophage scavenger receptor-mediated uptake of acetylated low density lipoprotein by 24-66% and increased cyclic adenosine monophosphate levels. Octimibate and BMY 42393 inhibited the secretion of tumor necrosis factor by 80-88% when macrophages were activated with lipopolysaccharide. At 10 juM, both agents decreased human monocyte chemotaxis to /V-formylmethionyl-leucyl-phenylalanine by 64-79%. The in vitro results with octimibate and BMY 42393 are consistent with the low number of small foam cells quantified in vivo. We suggest that octimibate and BMY 42393 suppress monocyte-macrophage atherogenic activity and cytokine production and thus inhibit the development of early atherosclerosis.

“…Therefore, F-1394 may have a hypocholesterolemic potential for postprandial hyperlipidemic patients by oral administration immediately after a meal. Although there have been numerous reports on the hypocholesterolemic action by other ACAT inhibitors in cholesterol diet-fed animals (17,18,20,21,(24)(25)(26)(27), the immediate effect after single oral administration of these compounds has not been demonstrated. In this study, we demonstrated the immediate effect of F-1394 on hypercholesterolemia induced by dietary cholesterol feeding.…”

Section: Discussionmentioning

confidence: 99%

Hypocholesterolemic Action and Prevention of Cholesterol Absorption via the Gut by F-1394, a Potent Acyl-CoA:Cholesterol Acyltransferase (ACAT) Inhibitor, in Cholesterol Diet-Fed Rats

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et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-In the present study, we investigated the hypocholesterolemic effect of F-1394 ((ls,2s)-2-[3-(2,2-dimethylpropyl)-3-nonylureido]aminocyclohexane-1-yl 3-[N-(2,2, 5, 5-tetramethyl-1, 3-dioxane-4-carbonyl)amino]propionate), a potent and selective inhibitor of acyl-CoA:cholesterol acyltransferase (ACAT), and the effect on cholesterol absorption via the gut in rats fed a 1 % cholesterol diet. Single administration of F-1394 to the cholesterol diet-fed rats at the doses of 3-30 mg/kg, p.o. decreased the serum cholesterol levels by 16 -54% 3 hr after the administration. The ACAT activity in the small intestinal mucosa of the rats given orally F-1394 (30 mg/kg) was significantly inhibited 3 hr after the administration. The hypocholesterolemic action of F-1394 had a faster onset than that of DL-melinamide or CL-277,082. The study by the dual isotope ratio method showed that F-1394 (30 mg/kg, p.o.) significantly suppressed the dietary cholesterol absorption. Furthermore, in the determination of cholesterol absorption by using 14C-cholesterol as the oral tracer, the administration of F-1394 (30 mg/kg, p.o.) 1 or 2 hr before or immediately after the application of the oral tracer significantly prevented the appearance of the radioactivity in the circulation by around 90%. These results indicate that oral administration of F-1394 inhibits the ACAT activity in the small intestinal mucosa and subsequently contributes much to the prevention of cholesterol absorption via the gut, resulting in the decrease in serum cholesterol levels in the cholesterol diet-fed rats. Furthermore, the effect of F-1394 appears immediately after its administration in contrast to that of DL-melinamide or CL-277,082.

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