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1 Departments of Medical Pharmacology & Physiology, University of Missouri, Columbia, MO, USA; The Center for Diabetes & Cardiovascular Health, University of Missouri, Columbia, MO, USA
2 Departments of Medical Pharmacology & Physiology, University of Missouri, Columbia, MO, USA
3 Division of Molecular Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, USA; David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
4 Division of Molecular Medicine, University of California Los Angeles, Los Angeles, CA, USA; Department of Anesthesiology, University of California Los Angeles, Los Angeles, CA, USA; Department of Molecular & Medical Pharmacology, University of California Los Angeles, Los Angeles, CA, USA
5 Departments of Internal Medicine, University of Missouri, Columbia, MO, USA
6 Departments of Medical Pharmacology & Physiology, University of Missouri, Columbia, MO, USA; Departments of Internal Medicine, University of Missouri, Columbia, MO, USA; The Center for Diabetes & Cardiovascular Health, University of Missouri, Columbia, MO, USA
* To whom correspondence should be addressed. E-mail: sturekm{at}missouri.edu.
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 KCa current as a compensatory response to an increase in intracellular [Ca2+]. Further, we hypothesized that endurance exercise training would prevent this elevation in KCa current. Miniature Yucatan swine were randomly assigned to 5 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); exercise trained DD, (DDX, n=9). High fat chow consisted of standard mini-pig chow supplemented with cholesterol (2%) and coconut oil. Increased coronary vasoconstriction assessed in vivo and in vitro in DD was prevented by exercise. Perforated patch clamp experiments were performed on smooth muscle cells from right coronary artery. Whole cell K current densities of the H, D and DD groups were greater than the DDX group at all membrane potentials between -10 and 40 mV. In fura-2 loaded cells, outward current activated by caffeine-induced Ca2+ release from the sarcoplasmic reticulum was significantly greater in H, D, and DD compared to C and DDX, while intracellular [Ca2+] was not different across groups. Finally, there were no differences in the KCa or KV channel protein content between groups. These data indicate that hyperglycemia, hyperlipidemia, and diabetic dyslipidemia all lead to an increase in the whole cell K current and an increase in the functional coupling of KCa and Ca2+ release. Endurance exercise training prevented increased coupling of Ca2+ release to KCa channel activation in diabetic dyslipidemia.
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