Influence of serum cholesterol on atherogenesis and intimal hyperplasia after angioplasty: inhibition by amlodipine.
The objectives of the present study were to determine whether serum hypercholesterolemia (HC) promotes the development of spontaneous and angioplasty-induced lesions and whether amlodipine inhibits these lesions and cellular processes underlying their genesis. Rabbits were fed normal, 0.5%, or 2% cholesterol diets for 9 wk, which resulted in the development of increasing HC. After week one, balloon dilation of the abdominal aorta was performed while the thoracic aorta was not disturbed and monitored for the development of spontaneous lesions. Lesion size increased with the degree of HC and was accompanied by increased collagen synthesis and smooth muscle cell (SMC) proliferation at each site. Amlodipine (5 mg/kg p.o.) inhibited lesion size by 50% (P < 0.01) at both sites in cholesterol-fed animals but not at angioplasty sites in animals on a normal diet. Local collagen synthesis was inhibited at both sites by amlodipine in the diet animals. The increase in HC was accompanied by a 1.7-fold increase in basal Ca2+ uptake in SMCs in the thoracic aorta, which was not altered by amlodipine, nifedipine, Ni2+, or La3+, revealing an uninhibitable calcium leak during atherogenesis. In culture, cholesterol enrichment increased SMC proliferation, collagen synthesis, and the secretion of a soluble SMC mitogen, which were inhibited by amlodipine (10(-9) M). Finally, in SMC membranes, amlodipine uniquely restored the cholesterol-expanded membrane bilayer width without any effect on membrane fluidity. This study establishes a causal role between serum HC and the development of spontaneous and angioplasty-induced lesions and the ability of amlodipine to disrupt this action by a novel remodelling action on the SMC membrane.
Kahn
Mark B
MB
Department of Surgery, Thomas Jefferson University College of Medicine, Philadelphia, Pennsylvania 19107, USA.
Boesze-Battaglia
Kathleen
K
Stepp
David W
DW
Petrov
Artium
A
Huang
Yong
Y
Mason
R Preston
RP
Tulenko
Thomas N
TN
D017311:Amlodipine / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000473:pathology; D001161:Arteriosclerosis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology*; D002791:Cholesterol, Dietary / Q000097:blood*; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D011817:Rabbits; D017539:Tunica Intima / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D002791:Cholesterol, Dietary; D014665:Vasodilator Agents; D017311:Amlodipine