Differences in Cardiovascular Sensitivity to Propofol in a Chromosome Substitution Rat Model

Cilj: Na osnovi prethodnih opažanja o različitoj osjetljivosti štakorskih sojeva na anestetike, uporabili smo novopostavljeni štakorski model da bismo istražili razlike osjetljivosti kardiovaskularnoga sustava na uobičajeni, klinički važan anestetik propofol i povezali te razlike sa specifičnim zamjenama kromosoma. Postupci: Osjetljivost kardiovaskularnoga sustava na propofol uspoređena je u skupinama normotenzivnih visokosrođenih štakora Dahl Salt Sensitive (soja Dahl, osjetljivi na sol, SS) i Brown Norway (BN), kao i na jedinstvenom nizu konzomičnih sojeva izvedenih iz tih SS i BN roditelja. Konzomični su sojevi napravljeni uvođenjem pojedinačnih kromosoma BN u inače nepromijenjeni SS genetički ustroj. Osjetljivost kardiovaskularnog sustava testirana je mjerenjem brzine infuzije propofola potrebne da se srednji arterijski tlak snizi za 50% i uzrokuje kardiovaskularni kolaps u oba parentalna i u konsomičnom soju. Rezultati: U usporedbi sa sojem BN, značajno manja brzina infuzije propofola izazivala je i 50% sniženje srednjega arterijskoga tlaka i krajnji kardiovaskularni kolaps u soju SS. Zamjena kromosoma 13 BN, ali ne i drugih kromosoma BN, smanjila je povećanu osjetljivost na propofol u štakora soja SS na razinu one u štakora soja BN. Zaključak: Razlika osjetljivosti na propofol u štakora soja SS i BN povezana je s 13. kromosomom. To odgovara prijašnjim podatcima i predstavlja prvu potpunu analizu svih štakorskih autosomnih kromosoma s obzirom na njihovu osjetljivost na anestetike. Ovo prvo smještanje rečenoga obrtanja osjetljivosti na 13. kromosom predstavlja osnovicu na koju se mogu nastaviti dodatne, selektivnije genetičke analize. Takva istraživanja mogu poslužiti u otkrivanju specifičnih dijelova genoma koji su odgovorni za razlike u fiziološkim reakcijama na različite anestetike.Aim: Based on previous observations of strain-related alterations in sensitivity to anesthetics, this study used a newly established genetic rat model to identify differences in cardiovascular sensitivity to the commonly used, clinically relevant, anesthetic propofol and to correlate such differences with specific chromosomal substitutions. Methods: Cardiovascular sensitivity to propofol was compared in groups of normotensive Dahl Salt Sensitive (SS) and Brown Norway (BN) inbred rats, as well as in a unique panel of consomic rats based on these SS and BN parentals. The consomics were produced by introgression of individual BN chromosomes into an otherwise unchanged SS genetic background. Cardiovascular sensitivity was assessed by measuring the infusion rate of propofol required to reduce mean arterial blood pressure by 50% and cause cardiovascular collapse in each parental and consomic strain. Results: Significantly lower propofol infusion rates caused both a 50% reduction in mean arterial pressure and ultimate cardiovascular collapse in SS compared to BN. Substitution of BN chromosome 13, but not of any other BN chromosome, reversed the enhanced propofol sensitivity in SS rats to the level of BN rats. Conclusions: Differential propofol sensitivity exhibited by SS and BN rat strains is associated with chromosome 13. This is consistent with earlier findings and represents the first complete screening of all rat autosomes for their relationship to anesthetic sensitivity. Initial localization of this sensitivity reversal to chromosome 13 provides a basis upon which additional, more selective genetic screening studies can be applied. Such studies may serve to identify specific regions of the genome responsible for different physiological responses to various anesthetic agents

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-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

Pharmacogenomic Strain Differences in Cardiovascular Sensitivity to Propofol

ABSTRACT Introduction: A pharmacogenomic approach was used to further localize the genetic region responsible for previously observed enhanced cardiovascular sensitivity to propofol in Dahl Salt Sensitive (SS) versus control Brown Norway (BN) rats. Methods: Propofol infusion levels that decreased blood pressure by 50% were measured in BN.13 SS rats (substitution of SS chromosome 13 into BN) and in five congenic (partial substitution) strains of SS.1