Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation
1 Department of Biomedical Sciences and 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211 Submitted 17 November 2003 ; accepted in final form 27 January 2004 Hypercholesterolemia (HC) is a mary risk factor for the development of coronary heart disease. Coronar...
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Published in | Journal of applied physiology (1985) Vol. 96; no. 6; pp. 2240 - 2248 |
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Main Authors | , , , , |
Format | Journal Article |
Language | English |
Published |
Bethesda, MD
Am Physiological Soc
01.06.2004
American Physiological Society |
Subjects | |
Online Access | Get full text |
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Summary: | 1 Department of Biomedical Sciences and 2 Dalton Cardiovascular Research Center, University of Missouri, Columbia, Missouri 65211
Submitted 17 November 2003
; accepted in final form 27 January 2004
Hypercholesterolemia (HC) is a mary risk factor for the development of coronary heart disease. Coronary ion regulation, especially calcium, is thought to be important in coronary heart disease development; however, the influence of high dietary fat and cholesterol on coronary arterial smooth muscle (CASM) ion channels is unknown. The purpose of this study was to determine the effect of diet-induced HC on CASM voltage-gated calcium current ( I Ca ). Male miniature swine were fed a high-fat, high-cholesterol diet (40% kcal fat, 2% wt cholesterol) for 2024 wk, resulting in elevated serum total and low-density lipoprotein cholesterol. Histochemistry indicated early atherosclerosis in large coronary arteries. CASM were isolated from the right coronary artery (>1.0 mm ID), small arteries ( 200 µm), and large arterioles ( 100 µm). I Ca was determined by whole cell voltage clamp. L-type I Ca was reduced 30% by HC compared with controls in the right coronary artery (-5.29 ± 0.42 vs. -7.59 ± 0.41 pA/pF) but not the microcirculation (small artery, -8.39 ± 0.80 vs. -10.13 ± 0.60; arterioles, -10.78 ± 0.93 vs. -11.31 ± 0.95 pA/pF). Voltage-dependent activation was unaffected by HC in both the macro- and microcirculation. L-type voltage-gated calcium channel (Ca v 1.2) mRNA and membrane protein levels were unaffected by HC. Inhibition of I Ca by HC was reversed in vitro by the cholesterol scavenger methyl- -cyclodextrin and mimicked in control CASM by incubation with the cholesterol donor cholesterol:methyl- -cyclodextrin. These data indicate that CASM L-type I Ca is decreased in large coronary arteries in early stages of atherosclerosis, whereas I Ca in the microcirculation is unaffected. The inhibition of calcium channel activity in CASM of large coronary arteries is likely due to increases in membrane free cholesterol.
cholesterol; vascular smooth muscle; cyclodextrin; voltage-gated calcium channels; porcine
Address for reprint requests and other correspondence: D. K. Bowles, E102 Veterinary Medicine, Univ. of Missouri, Columbia, MO 65211 (E-mail: bowlesd{at}missouri.edu ). |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 8750-7587 1522-1601 |
DOI: | 10.1152/japplphysiol.01229.2003 |