Abstract
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.
Footnotes
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This work was supported in part by grants from Center for Biomedical Research and Development (Nonprofit Organization) (Bruxelles, Belgium) and from Grant 1/2286/05 from the Ministry of Education of the Slovak Republic.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.089847.
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ABBREVIATIONS: CCBs, calcium channel blockers; NO, nitric oxide; ApoE-/- KO, apolipoprotein E-deficient knockout; SNAP, S-nitroso-N-acetylpenicillamine; PRA, plasma renin activity; ET-1, endothelin-1; TBARS, thiobarbituric acid-reactive substance(s); WD, Western-type diet; ND, normal diet or standard chow; SBP, systolic blood pressure; Ang, angiotensin; l-NNA, N-omega-nitro-l-arginine; SOD, superoxide dismutase; LDL, low-density lipoprotein; HDL, high-density lipoprotein; VLDL, very low-density lipoprotein; ROS, reactive oxygen species; mN, millinewton; Ach, acetylcholine; ANOVA, analysis of variance; Lac1 and Lac3, lacidipine at 1 and 3 mg/kg/day.
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↵ The online version of this article (available at http://jpet.aspetjournals.org) contains supplemental material.
- Received May 23, 2005.
- Accepted July 12, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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