RGD Reference Report - 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. - Rat Genome Database

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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.

Authors: Stadnicka, A  Contney, SJ  Moreno, C  Weihrauch, D  Bosnjak, ZJ  Roman, RJ  Stekiel, TA 
Citation: Stadnicka A, etal., J Pharmacol Exp Ther. 2009 Sep;330(3):727-35. Epub 2009 Jun 18.
RGD ID: 2312729
Pubmed: PMID:19541907   (View Abstract at PubMed)
PMCID: PMC2729794   (View Article at PubMed Central)
DOI: DOI:10.1124/jpet.109.154104   (Journal Full-text)

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-13(BN)/Mcwi and BN-13(SS)/Mcwi consomic strains with chromosome 13 substitution. Propofol (5 microM) 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, P(o), and apparent Ca(2+) 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 alpha 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-13(BN)/Mcwi and BN-13(SS)/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-13(SS)/Mcwi versus BN and SS-13(BN)/Mcwi strains.

Objects referenced in this article
Strain BN-Chr 13SS Chr 18SS/Mcwi null Rattus norvegicus
Strain BN-Chr 13SS/Mcwi null Rattus norvegicus
Strain BN/NHsdMcwi null Rattus norvegicus
Strain SS-Chr 13BN/Mcwi null Rattus norvegicus
Strain SS/JrHsdMcwi null Rattus norvegicus

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