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Altered functional coupling of coronary K⁺ channels in diabetic dyslipidemic pigs is prevented by exercise

¹Departments of Medical Pharmacology and Physiology and ²Department of Internal Medicine, ³The Center for Diabetes & Cardiovascular Health, University of Missouri, Columbia, Missouri 65212; and ⁴Division of Molecular Medicine, ⁵Department of Anesthesiology, ⁶Department of Molecular & Medical Pharmacology, and ⁷Brain Research Institute, David Geffen School of Medicine, University of California, Los Angeles, California 90095

Submitted 22 October 2002 ; accepted in final form 30 April 2003

Chronic hyperglycemia and hypercholesterolemia have been shown to alter ionic currents in vascular smooth muscle. We tested the hypothesis that the combined effect of hyperglycemia and hyperlipidemia (diabetic dyslipidemia) would increase the Ca²⁺-sensitive K⁺ (K_Ca) current as a compensatory response to an increase in intracellular Ca²⁺ concentration. We also hypothesized that exercise training would prevent this elevation in K_Ca current. Miniature Yucatan swine were randomly assigned to five groups: control, standard pig chow (C, n = 6); hyperlipidemic, high-fat pig chow (H, n = 5); diabetic, standard pig chow (D, n = 7); diabetic, high-fat pig chow ("diabetic dyslipidemic," DD, n = 12); and exercise-trained DD (DDX, n = 9). High-fat chow consisted of standard minipig chow supplemented with cholesterol (2%) and coconut oil. Increased coronary vasoconstriction assessed in vivo and in vitro in DD was prevented by exercise. Patch-clamp experiments performed on right coronary artery smooth muscle cells resulted in greater K⁺ current densities in the H, D, and DD groups vs. the DDX group between -10 and 40 mV. In fura 2-loaded cells, current activated by caffeine-induced Ca²⁺ release was greater in H, D, and DD compared with C and DDX (P < 0.05), whereas intracellular Ca²⁺ concentration was not different across groups. Finally, there were no differences in the K_Ca or K_v channel protein content between groups. These data indicate that hyperglycemia, hyperlipidemia, and diabetic dyslipidemia lead to elevated whole cell K⁺ current and increased functional coupling of K_Ca and Ca²⁺ release. Endurance exercise prevented increased coupling of Ca²⁺ release to K_Ca channel activation in diabetic dyslipidemia.

Ca²⁺-dependent K⁺ channel; sarcoplasmic reticulum; Ca²⁺ release; dyslipidemia; voltage clamp; porcine; vascular smooth muscle

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