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.

[1]  P. White.  Propofol: its role in changing the practice of anesthesia. , 2008, Anesthesiology.

[2]  Z. Bosnjak,et al.  Differences in cardiovascular sensitivity to propofol in a chromosome substitution rat model. , 2007, Croatian medical journal.

[3]  Andrew S Greene,et al.  Consomic strategies to localize genomic regions related to vascular reactivity in the Dahl salt-sensitive rat. , 2006, Physiological genomics.

[4]  Lingyun Wu,et al.  Altered expression of BK channel beta1 subunit in vascular tissues from spontaneously hypertensive rats. , 2006, American journal of hypertension.

[5]  Xiaoping Xu,et al.  Large-conductance, calcium-activated potassium channels: structural and functional implications. , 2006, Pharmacology & therapeutics.

[6]  Z. Bosnjak,et al.  Chromosomal Substitution-Dependent Differences in Cardiovascular Responses to Sodium Pentobarbital , 2006, Anesthesia and analgesia.

[7]  E. Stefani,et al.  MaxiK channel partners: physiological impact , 2006, The Journal of physiology.

[8]  J. Lombard,et al.  Reduced Angiotensin II and Oxidative Stress Contribute to Impaired Vasodilation in Dahl Salt-Sensitive Rats on Low-Salt Diet , 2005, Hypertension.

[9]  Z. Bosnjak,et al.  Reversal of Minimum Alveolar Concentrations of Volatile Anesthetics by Chromosomal Substitution , 2004, Anesthesiology.

[10]  R J Roman,et al.  Consomic rat model systems for physiological genomics. , 2004, Acta physiologica Scandinavica.

[11]  H. Schulze,et al.  Activation of the K+ channel BKCa is involved in the relaxing effect of propofol on coronary arteries , 2004, European journal of anaesthesiology.

[12]  B. Sakmann,et al.  Improved patch-clamp techniques for high-resolution current recording from cells and cell-free membrane patches , 1981, Pflügers Archiv.

[13]  E. Stefani,et al.  MaxiK, c-Src and vasoconstriction. , 2004, Journal of Muscle Research and Cell Motility.

[14]  M. Yamazaki,et al.  The Mechanisms of Propofol-Mediated Hyperpolarization of In Situ Rat Mesenteric Vascular Smooth Muscle , 2003, Anesthesia and analgesia.

[15]  M. Garrett,et al.  Time-course genetic analysis of albuminuria in Dahl salt-sensitive rats on low-salt diet. , 2003, Journal of the American Society of Nephrology : JASN.

[16]  E. Stefani,et al.  Coupling of c-Src to large conductance voltage- and Ca2+-activated K+ channels as a new mechanism of agonist-induced vasoconstriction , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[17]  N. Rusch,et al.  New Expression Profiles of Voltage‐gated Ion Channels in Arteries Exposed to High Blood Pressure , 2002, Microcirculation.

[18]  R. J. Bray.  The propofol infusion syndrome in infants and children: can we predict the risk? , 2002, Current opinion in anaesthesiology.

[19]  N. Shibuya,et al.  The Effects of Propofol on Neural and Endothelial Control of In Situ Rat Mesenteric Vascular Smooth Muscle Transmembrane Potentials , 2002, Anesthesia and analgesia.

[20]  R. Cox.  Changes in the expression and function of arterial potassium channels during hypertension. , 2002, Vascular pharmacology.

[21]  H. Jacob,et al.  Consomic rats for the identification of genes and pathways underlying cardiovascular disease. , 2002, Cold Spring Harbor Symposia on Quantitative Biology.

[22]  R. Cox,et al.  Differences in K+ current components in mesenteric artery myocytes from WKY and SHR. , 2001, American journal of hypertension.

[23]  Z. Bosnjak,et al.  Mechanisms of Isoflurane-mediated Hyperpolarization of Vascular Smooth Muscle in Chronically Hypertensive and Normotensive Conditions , 2001, Anesthesiology.

[24]  R J Roman,et al.  Brown Norway Chromosome 13 Confers Protection From High Salt to Consomic Dahl S Rat , 2001, Hypertension.

[25]  R. Aldrich,et al.  Vasoregulation by the β1 subunit of the calcium-activated potassium channel , 2000, Nature.

[26]  T. Itoh,et al.  Inhibitory effects of propofol on acetylcholine-induced, endothelium-dependent relaxation and prostacyclin synthesis in rabbit mesenteric resistance arteries. , 1999, Anesthesiology.

[27]  F. Barale,et al.  Effects of propofol on vascular reactivity in isolated aortae from normotensive and spontaneously hypertensive rats. , 1999, British journal of anaesthesia.

[28]  M Yamazaki,et al.  Potassium channel-mediated hyperpolarization of mesenteric vascular smooth muscle by isoflurane. , 1999, Anesthesiology.

[29]  N. Standen,et al.  K+ channel modulation in arterial smooth muscle. , 1998, Acta physiologica Scandinavica.

[30]  L. Toro,et al.  Maxi-K(Ca), a Unique Member of the Voltage-Gated K Channel Superfamily. , 1998, News in physiological sciences : an international journal of physiology produced jointly by the International Union of Physiological Sciences and the American Physiological Society.

[31]  Z. Bosnjak,et al.  Effects of Volatile Anesthetic Agents on In Situ Vascular Smooth Muscle Transmembrane Potential in Resistance‐ and Capacitance‐regulating Blood Vessels , 1998, Anesthesiology.

[32]  N. Standen,et al.  Angiotensin II Inhibition of ATP‐Sensitive K+ Currents in Rat Arterial Smooth Muscle Cells Through Protein Kinase C , 1997, The Journal of physiology.

[33]  L. Toro,et al.  A calcium switch for the functional coupling between α (hslo) and β subunits (K V , Ca β) of maxi K channels , 1996 .

[34]  M. Rubart,et al.  Relaxation of Arterial Smooth Muscle by Calcium Sparks , 1995, Science.

[35]  A. Krassioukov,et al.  Action of propofol on central sympathetic mechanisms controlling blood pressure , 1993, Canadian journal of anaesthesia = Journal canadien d'anesthesie.

[36]  J. Álvarez,et al.  Effects of propofol on mean arterial pressure and systemic vascular resistance during cardiopulmonary bypass , 1993, Acta anaesthesiologica Scandinavica.

[37]  H. Toda,et al.  Direct vasoconstrictor and vasodilator effects of propofol in isolated dog arteries. , 1992, British journal of anaesthesia.

[38]  W. Littler.  Handbook of hypertension, vol. 4: Experimental and genetic models of hypertension: Editor: W. de Jong Elsevier Science Publishers B.V., Amsterdam, 1984; 556 pp.; $123.00 (Dfl. 320.00); ISBN 0-444-90336-4 , 1985 .

[39]  D. Ganten,et al.  Experimental and genetic models of hypertension , 1984 .

[40]  J. Rapp.  Dahl Salt‐Susceptible and Salt‐Resistant Rats , 1982 .