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

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-13 BN /Mcwi and BN-13 SS /Mcwi consomic strains with chromosome 13 substitution. Propofol (5 M) 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 2ϩ sensitivity, and propofol sensitivity all were significantly greater in MASMC of SS rats. The density of wholecell BK current was increased by propofol more in SS than BN myocytes. Immunolabeling confirmed higher expression of BK ␣ 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.The sensitivity to general anesthetics is highly variable among strains of rats and individual patients. This is thought to be due in part to genetic differences, but little is known about the pharmacogenetics of the response to anesthetics or the mechanisms involved. We recently identified a major strain difference in the cardiovascular sensitivity to anesthetics whereby Dahl salt-sensitive SS/JRHsdMcwi (SS) rats exhibited a much higher cardiovascular sensitivity to general anesthetic agents than control salt-resistant Brown Norway BN/NHsdMcwi (BN) rats. This was evidenced by the cardiovascular collapse that occurred at lower concentrations of infused pentobarbital (Stekiel et al

Strain Differences in Cortical Electroencephalogram Associated with Isoflurane-induced Loss of Consciousness

“…We have recently observed that two rat strains (SS/JrHsdMcwi, abbreviated as SS and BN/NhsdMcwi abbreviated as BN), which are parental strains for a larger chromosome substitution model, exhibit marked differences in cardiovascular sensitivity 4 and movement response 5 to anesthetics, with SS being considerably more sensitive than BN. Additional (preliminary) studies suggested that there also were strain differences in anesthetic sensitivity related to loss of consciousness.…”

Perivascular adipose tissue-derived adiponectin activates BKCa channels to induce anticontractile responses

“…This channel is known to be involved in the development of hypertension (44), downregulated in diabetes (35), and impaired in metabolic syndrome (2) and insulin resistance (6) and therefore may be involved in mediating PVAT anticontractility. It is a transmembrane channel composed of four ␣-and four ␤-subunits.…”

Pharmacogenomic Strain Differences in Cardiovascular Sensitivity to Propofol

“…Concomitant enhancement in in situ arterial vascular smooth muscle (VSM) hyperpolarization, reflects a greater reduction in VSM tone in small resistance-regulating arteries. The basis for this hyperpolarization difference appears to be a genetic alteration in normal vascular control mechanisms, particularly calcium-sensitive potassium channel function and expression 7 . Such greater VSM sensitivity to anesthetics predisposes the animal to exaggerated depressor responses during anesthetic exposure.…”