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.
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.
Stadnicka
Anna
A
Department of Anesthesiology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA. astadnic@mcw.edu
Contney
Stephen J
SJ
Moreno
Carol
C
Weihrauch
Dorothee
D
Bosnjak
Zeljko J
ZJ
Roman
Richard J
RJ
Stekiel
Thomas A
TA
D000818:Animals; D030801:Animals, Genetically Modified; D001562:Benzimidazoles / Q000494:pharmacology; D002875:Chromosomes / Q000235:genetics*; D006439:Hemodynamics / Q000187:drug effects*; D006801:Humans; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D008564:Membrane Potentials / Q000187:drug effects; D032389:Myocytes, Smooth Muscle / Q000187:drug effects; D018408:Patch-Clamp Techniques; D010455:Peptides / Q000494:pharmacology; D024642:Potassium Channels, Voltage-Gated / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D015742:Propofol / Q000494:pharmacology*; D051381:Rats; D011914:Rats, Inbred BN; D020303:Rats, Inbred Dahl; D013045:Species Specificity; D013152:Splanchnic Circulation / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D001562:Benzimidazoles; D006993:Hypnotics and Sedatives; D051036:Large-Conductance Calcium-Activated Potassium Channels; D010455:Peptides; D024642:Potassium Channels, Voltage-Gated; C086491:NS 1619; C064719:iberiotoxin; D015742:Propofol