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1 Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA; Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA
2 Department of Biomedical Sciences, University of Missouri, Columbia, MO, USA
* To whom correspondence should be addressed. E-mail: bowlesd{at}missouri.edu.
Hypercholesterolemia is a primary risk factor for the development of coronary heart disease (CHD). Coronary ion regulation, especially calcium, is thought to be important in CHD development; however, the influence of high dietary fat/cholesterol on coronary arterial smooth muscle (CASM) ion channels is unknown. The purpose of this study was to determine the effect of diet-induced hypercholesterolemia (HC) on CASM voltage-gated calcium current (ICa). Male, miniature swine were fed a high fat/cholesterol diet (40% kcal fat, 2% wt cholesterol) for 20-24 weeks, resulting in elevated serum total and LDL-cholesterol. Histochemistry indicated early atherosclerosis in large coronary arteries. CASM were isolated from the right coronary artery (RCA, > 1.0 mm ID), small arteries (~200 µm) and large arterioles (~100 µm). ICa was determined using whole cell voltage clamp. L-type ICa was reduced ~30% by HC compared to controls in the RCA (-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 (Cav1.2) mRNA and membrane protein levels were unaffected by HC. Inhibition of ICa 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 ICa is decreased in large coronary arteries in early stages of atherosclerosis, while ICa 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.
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