ifetroban and Hypercholesterolemia

We compared the impact of hypercholesterolaemia and mixed dyslipidaemia on vascular function, vascular structure and fibrinolytic balance in rabbits. To this end, vascular reactivity was studied in aortic rings from rabbits fed a control diet, a diet containing 0.5% cholesterol+14% coconut oil (mixed dyslipidaemia) or a diet containing 1% cholesterol (hypercholesterolaemia) for 12-14 weeks. Morphometric analysis of aorta was also performed and plasminogen activator inhibitor-1 (PAI-1) as well as tissue-type plasminogen activator (t-PA) plasma activities were measured. Both diets induced a similar increase in cholesterol plasma levels, although triacylglycerols (triglycerides) were increased in animals with mixed dyslipidaemia. Hypercholesterolaemia was associated with intimal thickening, reduction in acetylcholine-induced relaxation ( P <0.05) and increased vasoconstriction induced by acetylcholine+ N (G)-nitro-L-arginine methyl ester (L-NAME) when compared with controls ( P <0.05). These effects were more marked ( P <0.05) in animals with mixed dyslipidaemia. Incubation with ifetroban, a thromboxane A(2)/prostaglandin H(2) receptor antagonist, increased acetylcholine-induced relaxation ( P <0.05) and reduced acetylcholine+L-NAME contraction ( P <0.05) in both diet groups. In contrast, the presence of PD 145, an endothelin (ET)(A)/ET(B) receptor antagonist, exerted these effects only in rabbits with mixed dyslipidaemia. Both hypercholesterolaemia and mixed dyslipidaemia induced a similar increase in PAI-1 and a similar decrease in t-PA plasma activities. These data suggest that hypertriglyceridaemia can increase the deleterious effects of hypercholesterolaemia on endothelial function and vascular structure. This additional harmful effect exerted by triacylglycerols on endothelial function could, in part, be mediated by ET.

Topics: Acetylcholine; Animals; Aorta; Arteriosclerosis; Bridged Bicyclo Compounds, Heterocyclic; Diet; Endothelium, Vascular; Enzyme Inhibitors; Fibrinolysis; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; In Vitro Techniques; Male; Models, Animal; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Oxazoles; Plasminogen Activator Inhibitor 1; Rabbits; Thromboxane A2; Tissue Plasminogen Activator; Vasoconstrictor Agents

Numerous studies have shown that elevated plasma cholesterol can exacerbate renal disease. However, the effect of lipids on renal structure and vascular function in normal kidneys is less well established. Therefore, the aim of this study was to evaluate the impact of hypercholesterolaemia on glomerular structure and vascular reactivity of segmental arteries in rabbits. In addition, we also studied whether or not atorvastatin can prevent these structural and vascular alterations in hypercholesterolaemic rabbits.. Male New Zealand rabbits were fed either a normal rabbit chow or a diet containing 1% cholesterol and treated or not with atorvastatin (1 mg/kg/day) for 12 weeks. Dose-response curves to acetylcholine (10(-9)-10(-4) mol/l) and sodium nitroprusside (10(-9)-10(-4) mol/l) were studied in segmental arteries in the presence or absence of the thromboxane A2/PGH2 receptor antagonist ifetroban (10(-5) mol/l). Glomerular size and structure were also evaluated.. Compared with control animals, hypercholesterolaemic rabbits presented glomerular hypertrophy and several types of injuries (capillary collapse, hyalinosis and alterations of Bowman's capsule), suggesting diffuse glomerulosclerosis. Segmental arteries also showed relaxing responses to acetylcholine and sodium nitroprusside which were lower than and similar to, respectively, those of control animals. The presence of ifetroban improved the acetylcholine response only in hypercholesterolaemic rabbits. Atorvastatin treatment prevented vascular and most glomerular changes associated with hypercholesterolaemia even in the presence of very high cholesterol levels.. Atorvastatin exerts a protective effect on renal damage associated with hypercholesterolaemia even in the presence of deleterious levels of plasma cholesterol.

Topics: Acetylcholine; Animals; Anticholesteremic Agents; Atorvastatin; Bridged Bicyclo Compounds, Heterocyclic; Cholesterol, Dietary; Disease Models, Animal; Endothelium, Vascular; Glomerulosclerosis, Focal Segmental; Heptanoic Acids; Hypercholesterolemia; Kidney; Male; Nitroprusside; Oxazoles; Phenylephrine; Platelet Aggregation Inhibitors; Pyrroles; Rabbits; Renal Circulation; Vasodilation