title: Propofol increases contractility during alpha1a-adrenoreceptor activation in adult rat cardiomyocytes.
abstract: BACKGROUND
  The objective of this study was to identify the extent to which propofol alters intracellular free Ca2+ concentration ([Ca2+]i), myofilament Ca sensitivity, and contraction of individual cardiomyocytes during activation of alpha1a adrenoreceptors and to determine the cellular mechanism of action.
  
  
  METHODS
  Freshly isolated ventricular myocytes were obtained from adult rat hearts. Myocyte shortening and [Ca2+]i were simultaneously monitored in individual cardiomyocytes exposed to phenylephrine after treatment with chloroethylclonidine (alpha1b-adrenoreceptor antagonist) and BMY 7378 (alpha1d-adrenoreceptor antagonist). Data are reported as mean +/- SD.
  
  
  RESULTS
  Phenylephrine increased myocyte shortening by 124 +/- 9% (P = 0.002), whereas peak [Ca2+]i only increased by 8 +/- 3% (P = 0.110). Inhibition of phospholipase A2 and phospholipase C attenuated the phenylephrine-induced increase in shortening by 84 +/- 11% (P = 0.004) and 15 +/- 6% (P = 0.010), respectively. Inhibition of protein kinase C (PKC) and Rho kinase attenuated the phenylephrine-induced increase in shortening by 17 +/- 8% (P = 0.010) and 74 +/- 13% (P = 0.006), respectively. In the presence of phenylephrine, propofol increased shortening by 40 +/- 6% (P = 0.002), with no concomitant increase in [Ca2+]i. PKC inhibition prevented the propofol-induced increase in shortening. Selective inhibition of PKCalpha, PKCdelta, PKCepsilon, and PKCzeta reduced the propofol-induced increase in shortening by 12 +/- 5% (P = 0.011), 36 +/- 8% (P = 0.001), 32 +/- 9% (P = 0.007), and 19 +/- 5% (P = 0.008), respectively. Na+ - H+ exchange inhibition reduced the propofol-induced increase in shortening by 56 +/- 7% (P = 0.001).
  
  
  CONCLUSIONS
  Activation of alpha1a adrenoreceptors increases cardiomyocyte shortening primarily via a phospholipase A2-dependent, Rho kinase-dependent increase in myofilament Ca2+ sensitivity. Propofol further increases myofilament Ca2+ sensitivity and shortening via a PKC-dependent pathway and an increase in Na+ - H+ exchange activity.
authors.affiliation: Center for Anesthesiology Research, Division of Anesthesiology and Critical care Medicine, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
authors.forename: Brad D
authors.initials: BD
authors.lastname: Gable
authors.forename: Toshiya
authors.initials: T
authors.lastname: Shiga
authors.forename: Paul A
authors.initials: PA
authors.lastname: Murray
authors.forename: Derek S
authors.initials: DS
authors.lastname: Damron
mesh_terms: D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000502:physiology; D010740:Phospholipases / Q000037:antagonists & inhibitors / Q000502:physiology; D015742:Propofol / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects* / Q000502:physiology; D017923:Sodium-Hydrogen Exchangers / Q000502:physiology
chemical_list: D018686:Anesthetics, Intravenous; D047428:Protein Kinase Inhibitors; D018340:Receptors, Adrenergic, alpha-1; D017923:Sodium-Hydrogen Exchangers; D011493:Protein Kinase C; D010740:Phospholipases; D002118:Calcium; D015742:Propofol