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

Hypercholesterolemia (HC) is a primary 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 (similar to200 mum), and large arterioles (similar to100 mum). I-Ca was determined by whole cell voltage clamp. L-type I-Ca was reduced similar to30% 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-beta-cyclodextrin and mimicked in control CASM by incubation with the cholesterol donor cholesterol: methyl-beta-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.