Calcium channel blocker inhibits Western-type diet-evoked atherosclerosis development in ApoE-deficient mice.
Calcium channel blockers slow the progression of atherosclerosis. The purpose of the present experiments was to examine the action of lacidipine in a condition that accelerates the development of atherosclerosis in order to test the hypothesis that the protective action of lacidipine in atherosclerosis is unrelated to the reduction of blood pressure. Male ApoE-deficient mice (6 weeks old) were exposed either to normal chow (ND) or to a Western-type diet (WD, adjusted calorie diet containing 42% from fat) for 8 weeks. Western-type diet induced a reduction of nitric oxide (NO)-mediated endothelium-dependent relaxation to acetylcholine (Max relaxation % = 55.8 +/- 2 for ND and 46.6 +/- 2 for WD, n = 8, p < 0.05). Dose-relaxation curves to S-nitroso-N-acetylpenicillamine (SNAP) NO donor were also significantly rightward-shifted (n = 7, ANOVA, p < 0.01) in WD compared with ND arteries. Chronic treatment of WD mice with lacidipine (1 and 3 mg/kg/day) increased significantly the acetylcholine-evoked relaxation (to 76.6 +/- 3.5%, n = 6, ANOVA, p < 0.001) and prevented the loss of responsiveness to SNAP in mice exposed to WD. Plasma renin activity and endothelin-1 plasma levels as well as thiobarbituric acid-reactive substance levels in kidneys were significantly lower in WD mice treated with lacidipine than in untreated ones. In mice exposed to WD lacidipine reduced extension of atherosclerotic lesions, renal injury and increase in blood pressure. Experimental data indicate that inhibition of Western-type diet-evoked alterations is related to both antioxidant and vasoactive properties of lacidipine.
Kyselovic
Jan
J
Department of Pharmacology, Faculty of Pharmacy, Comenius University, Bratislava, Slovak Republic.
Martinka
Peter
P
Batova
Zuzana
Z
Gazova
Andrea
A
Godfraind
Theophile
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000502:physiology*; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D008076:Cholesterol, HDL / Q000097:blood; D008078:Cholesterol, LDL / Q000097:blood; D004032:Diet; D004095:Dihydropyridines / Q000494:pharmacology*; D007678:Kidney Glomerulus / Q000473:pathology; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology; D010396:Penicillamine / Q000031:analogs & derivatives / Q000494:pharmacology; D017540:Tunica Media / Q000473:pathology; D014661:Vasoconstriction / Q000187:drug effects
D001057:Apolipoproteins E; D002121:Calcium Channel Blockers; D008076:Cholesterol, HDL; D008078:Cholesterol, LDL; D004095:Dihydropyridines; C110881:S-nitro-N-acetylpenicillamine; C060285:lacidipine; D009569:Nitric Oxide; D010396:Penicillamine; D000109:Acetylcholine