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Hypercholesterolemia inhibits L-type calcium current in coronary macro-, not microcirculation

¹Department of Biomedical Sciences and ²Dalton 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 20–24 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_v1.2) 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

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