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Contribution of electromechanical coupling between KV and CaV1.2 channels to coronary dysfunction in obesity

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Abstract

Previous investigations indicate that diminished functional expression of voltage-dependent K+ (KV) channels impairs control of coronary blood flow in obesity/metabolic syndrome. The goal of this investigation was to test the hypothesis that KV channels are electromechanically coupled to CaV1.2 channels and that coronary microvascular dysfunction in obesity is related to subsequent increases in CaV1.2 channel activity. Initial studies revealed that inhibition of KV channels with 4-aminopyridine (4AP, 0.3 mM) increased intracellular [Ca2+], contracted isolated coronary arterioles and decreased coronary reactive hyperemia. These effects were reversed by blockade of CaV1.2 channels. Further studies in chronically instrumented Ossabaw swine showed that inhibition of CaV1.2 channels with nifedipine (10 μg/kg, iv) had no effect on coronary blood flow at rest or during exercise in lean swine. However, inhibition of CaV1.2 channels significantly increased coronary blood flow, conductance, and the balance between coronary flow and metabolism in obese swine (P < 0.05). These changes were associated with a ~50 % increase in inward CaV1.2 current and elevations in expression of the pore-forming subunit (α1c) of CaV1.2 channels in coronary smooth muscle cells from obese swine. Taken together, these findings indicate that electromechanical coupling between KV and CaV1.2 channels is involved in the regulation of coronary vasomotor tone and that increases in CaV1.2 channel activity contribute to coronary microvascular dysfunction in the setting of obesity.

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Acknowledgments

This work was supported by AHA grants 10PRE4230035 (ZCB) and NIH grants HL092245 (JDT), HL115140 (JDT and AGO), T32DK007519; O’Leary (HB), T32HL079995; Goodwill (KM), and T32DK064466; Owen (PR).

Conflict of interest

The authors have no conflicts to disclose.

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Authors and Affiliations

  1. Department of Cellular and Integrative Physiology, Indiana University School of Medicine, 635 Barnhill Drive, Indianapolis, IN, 46202, USA

    Zachary C. Berwick, Adam G. Goodwill, Steven P. Moberly, Meredith Kohr Owen, Steven J. Miller, Alexander G. Obukhov & Johnathan D. Tune

  2. Department of Surgery, Indiana University School of Medicine, Indianapolis, USA

    Steven J. Miller

  3. Department of Exercise Physiology, West Virginia University School of Medicine, Morgantown, USA

    Gregory M. Dick

  4. Center for Cardiovascular and Respiratory Sciences, West Virginia University School of Medicine, Morgantown, USA

    Gregory M. Dick

  5. Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, USA

    Heather A. O’Leary

  6. Department of Internal Medicine, University of Missouri School of Medicine, Columbia, MO, USA

    Shawn B. Bender

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  1. Zachary C. Berwick
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Berwick, Z.C., Dick, G.M., O’Leary, H.A. et al. Contribution of electromechanical coupling between KV and CaV1.2 channels to coronary dysfunction in obesity. Basic Res Cardiol 108, 370 (2013). https://doi.org/10.1007/s00395-013-0370-0

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