cicaprost and Hypercholesterolemia

The efficacy of the oral prostacyclin mimetic cicaprost in preventing atheromatous plaque formation was studied in an in vivo model of experimental hypercholesterolemia. New Zealand white rabbits were fed either standard chow or a cholesterol-enriched (1%) diet for 12 weeks. Cicaprost was added to the drinking water in a non-hypotensive dose (5 micrograms/kg/day) and withdrawn 3 days prior to studying platelet, leukocyte and endothelial function. In cholesterol-fed rabbits, oral cicaprost reduced the aortic intimal surface covered by atheromatous lesions from 84 to 63% (P < 0.05). There was no major difference in serum lipid composition between cicaprost- and vehicle-treated animals. In hyper-cholesterolemic rabbits there was a significant impairment of endothelium-dependent relaxations. Cicaprost treatment considerably improved this endothelial function but had no effect in rabbits receiving standard diet. In addition, platelet and leukocyte hyperreactivity, as seen in hypercholesterolemic rabbits, were largely reduced by cicaprost treatment. These data are the first to demonstrate marked antiatherosclerotic effects of long-term oral prostacyclin treatment. The mechanism may be related to improved endothelial function and subsequent prevention of secondary platelet and neutrophil hyperreactivity.

Topics: Acetylcholine; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Aorta; Arteriosclerosis; Blood Platelets; Endothelium, Vascular; Epoprostenol; Hypercholesterolemia; Male; Muscle Relaxation; Neutrophils; Prostaglandins, Synthetic; Rabbits

The effects of the orally active prostacyclin mimetic cicaprost on morphologic and functional alterations of rabbit aorta was investigated in experimental hypercholesterolemia. Oral cicaprost resulted in a significantly reduced aortic atheromatous plaque formation and partially prevented hypercholesterolemia-induced impairment of endothelium-dependent relaxations. It is concluded that long-term substitution with PGI2 may beneficially influence the progression of atherosclerosis.

Topics: Administration, Oral; Animals; Aorta, Thoracic; Arteriosclerosis; Blood Vessels; Epoprostenol; Hypercholesterolemia; Lipids; Muscle Relaxation; Muscle, Smooth, Vascular; Rabbits

Isolated Langendorff-hearts prepared from cholesterol fed rabbits (1% cholesterol for 3 months) showed a significant impairment in endothelium-dependent relaxation after short-term infusion of bradykinin (0.05 mumol/l) and carbamoylcholine (0.1 mumol/l). Generation of the endothelial mediators nitric oxide and prostacyclin by bradykinin was enhanced in hypercholesterolemia. Cicaprost treatment (5 micrograms/kg x d) largely prevented the hypercholesterolemia-related impairment of coronary vasodilation and nitric oxide release. It is concluded that (i) impairment of endothelium-dependent relaxation in the coronary microcirculation of hypercholesterolemic rabbits is not due to diminished endothelium-dependent mediator release but rather to accelerated inactivation or reduced activity of the released mediators and that (ii) oral cicaprost beneficially influence these alterations.

Topics: 6-Ketoprostaglandin F1 alpha; Administration, Oral; Animals; Blood Pressure; Coronary Circulation; Coronary Disease; Epoprostenol; Hypercholesterolemia; In Vitro Techniques; Nitric Oxide; Rabbits; Vasodilation

Oral treatment of cholesterol-fed rabbits with the PGI2 mimetic cicaprost largely reduces hypercholesterolemia-induced platelet and neutrophil hyperreactivity. In addition, cicaprost prevents atherosclerosis-induced platelet desensitization for PGI2. These effects persist after cicaprost treatment is withdrawn. Since platelets and leukocytes are supposed to contribute to atherogenesis, this suggests a favourable effect of long-term oral PGI2 substitution in hypercholesterolemia.

Topics: Adenosine Diphosphate; Administration, Oral; Animals; Cholesterol; Collagen; Epoprostenol; Hypercholesterolemia; Lymphocyte Activation; Male; Neutrophils; Platelet Activation; Platelet Aggregation; Platelet Aggregation Inhibitors; Rabbits