Mechanism of Differential Cardiovascular Response to Propofol in Dahl Salt-Sensitive, Brown Norway, and Chromosome 13-Substituted Consomic Rat Strains: Role of Large Conductance Ca2+ and Voltage-Activated Potassium Channels

  1. Anna Stadnicka,
  2. Stephen J. Contney,
  3. Carol Moreno,
  4. Dorothee Weihrauch,
  5. Zeljko J. Bosnjak,
  6. Richard J. Roman and
  7. Thomas A. Stekiel
  1. Departments of Anesthesiology (A.S., S.J.C., D.W., Z.J.B., T.A.S.) and Physiology (C.M., R.J.R., Z.J.B.) and Human and Molecular Genetics Center (C.M.), Medical College of Wisconsin, Milwaukee, Wisconsin; and Clement J. Zablocki VA Medical Center, Milwaukee, Wisconsin (T.A.S.)
  1. Address correspondence to:
    Dr. Anna Stadnicka, Anesthesia Research, MEB 4280, Medical College of Wisconsin, 8701 Watertown Plank Rd., Milwaukee, WI 53226. E-mail: astadnic{at}mcw.edu

Abstract

Cardiovascular sensitivity to general anesthetics is highly variable among individuals in both human and animal models, but little is known about the genetic determinants of drug response to anesthetics. Recently, we reported that propofol (2,6-diisopropylphenol) causes circulatory instability in Dahl salt-sensitive SS/JRHsdMcwi (SS) rats but not in Brown Norway BN/NHsdMcwi (BN) rats and that these effects are related to genes on chromosome 13. Based on the hypothesis that propofol does target mesenteric circulation, we investigated propofol modulation of mesenteric arterial smooth muscle cells (MASMC) in SS and BN rats. The role of chromosome 13 was tested using SS-13BN/Mcwi and BN-13SS/Mcwi consomic strains with chromosome 13 substitution. Propofol (5 μM) produced a greater in situ hyperpolarization of MASMC membrane potential in SS than BN rats, and this effect was abrogated by iberiotoxin, a voltage-activated potassium (BK) channel blocker. In inside-out patches, the BK channel number, Po, and apparent Ca2+ sensitivity, and propofol sensitivity all were significantly greater in MASMC of SS rats. The density of whole-cell BK current was increased by propofol more in SS than BN myocytes. Immunolabeling confirmed higher expression of BK α subunit in MASMC of SS rats. Furthermore, the hyperpolarization produced by propofol, the BK channel properties, and propofol sensitivity were modified in MASMC of SS-13BN/Mcwi and BN-13SS/Mcwi strains toward the values observed in the background SS and BN strains. We conclude that differential function and expression of BK channels, resulting from genetic variation within chromosome 13, contribute to the enhanced propofol sensitivity in SS and BN-13SS/Mcwi versus BN and SS-13BN/Mcwi strains.

Footnotes

  • This work was supported in part by the National Institutes of Health General Medicine Institute [Grant GM 068725] (to T.A.S.); the National Institutes of Health National Heart, Lung and Blood Institute [Grant HL036279] (to R.J.R.); and the National Institutes of Health National Heart, Lung and Blood Institute [Grant HL082798] (SCOR grant to A. W. Cowley, support for the chromosome 13-substituted consomic rats).

  • Part of this work was previously presented: Stadnicka A, Contney SJ, Bosnjak ZJ, Stekiel WJ, Stekiel TA (2006) Propofol effects on maxiKCa channels in mesenteric artery myocytes of Dahl SS, BN and SS13BN rats. Anesthesiology A1612 and Abstracts2View on CD-ROM; 59th Annual Meeting of the American Society of Anesthesiologists; 2006 October 14–18; Chicago, IL; American Society of Anesthesiologists, Park Ridge, IL.

  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

  • doi:10.1124/jpet.109.154104.

  • ABBREVIATIONS: SS, salt sensitive; BN, Brown Norway; BK, large conductance calcium and voltage-activated potassium channels; RGD, Rat Genome Database; Em, membrane potential; NS1619 (1,3-dihydro-1-[2-hydroxy-5-(trifluoromethyl)phenyl]-5-(trifluoromethyl)-2H-benzimidazol-2-one; IbTX, iberiotoxin; MASMC, mesenteric arterial smooth muscle cell(s); Vh, holding potential(s); PBS, phosphate-buffered saline; IBK, whole-cell BK outward current; Ang II, angiotensin II.

    • Received March 24, 2009.
    • Accepted June 17, 2009.
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  1. Published online before print June 18, 2009, doi: 10.1124/jpet.109.154104 JPET September 2009 vol. 330 no. 3 727-735
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