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

• Published in: Journal of applied physiology (1985) Vol. 96; no. 6; pp. 2240 - 2248
• Main Authors: Bowles, D. K, Heaps, C. L, Turk, J. R, Maddali, K. K, Price, E. M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Am Physiological Soc 01.06.2004; American Physiological Society
• Subjects: Animals; Biological and medical sciences; Calcium; Calcium Channels, L-Type - drug effects; Calcium Channels, L-Type - genetics; Calcium Channels, L-Type - physiology; Cardiovascular disease; Cholesterol; Cholesterol, Dietary; Circulation; Coronary Circulation - physiology; Disorders of blood lipids. Hyperlipoproteinemia; Gene Expression Regulation - physiology; Health risk assessment; Hypercholesterolemia - physiopathology; Male; Medical sciences; Metabolic diseases; Microcirculation - physiopathology; Patch-Clamp Techniques; RNA, Messenger - genetics; Swine; Swine, Miniature; Animal model; Calcium; cyclodextrin; Electrophysiology; Lipids; Smooth muscle; Hyperlipoproteinemia; Ionic channel; Ionic current; Lipoprotein; Inorganic element; Microcirculation; voltage-gated calcium channels; Minipig; Dyslipemia; Ungulata; vascular smooth muscle; Coronary artery; porcine; Metabolic diseases; Cholesterol; Vertebrata; Mammalia; Hypercholesterolemia; Animal; Artiodactyla
• ISSN: 8750-7587; 1522-1601
• DOI: 10.1152/japplphysiol.01229.2003

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 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 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 ).