title: The contribution of the coronary concentrations of propofol to its cardiovascular effects in anesthetized sheep.
abstract: Linking physiological pharmacokinetic models to models of the cardiovascular system requires knowledge of the sites in the body that mediate a drug's cardiovascular effects. We examined the role of the coronary concentrations of propofol. Nine sheep anesthetized with isoflurane (2%) were instrumented acutely for cardiovascular measurements. In a random crossover design, they were administered ramped coronary artery (CA) infusions of propofol to selectively enrich the myocardium (as indicated by the coronary sinus blood concentration) or IV infusions to achieve the same concentration range in all sites of the body. Reductions in left ventricular myocardial contractility (LV dP/dt(max)) and mean arterial blood pressure were linearly related to the propofol concentration. For the CA route, LV dP/dt(max) was reduced by 52 mm Hg/s for each milligram per liter increase in coronary sinus propofol concentration. For the IV route, the reduction in LV dP/dt(max) was equivalent to that with the CA route, showing that the coronary propofol concentration was the major contribution to this effect. For the CA route, mean arterial blood pressure was reduced by 0.6 mm Hg for each milligram per liter. There was a larger reduction (2.5 mm Hg x mg(-1) x L(-1)) for the IV route. Therefore, this effect was predominantly mediated by propofol concentrations elsewhere in the body.
  
  
  CONCLUSIONS
  With use of selective coronary artery infusions in sheep, the coronary concentrations of propofol were shown to be the major contributor to the cardiac depression caused by propofol but were a less significant contributor to the hypotension caused by this drug. Models of the cardiovascular effects of propofol should account for these relationships.
authors.affiliation: Department of Anaesthesia and Intensive Care, Royal Adelaide Hospital/University of Adelaide, North Terrace, Adelaide, Australia.
authors.forename: Da
authors.initials: D
authors.lastname: Zheng
authors.forename: Richard N
authors.initials: RN
authors.lastname: Upton
authors.forename: Allison M
authors.initials: AM
authors.lastname: Martinez
mesh_terms: D000758:Anesthesia; D018686:Anesthetics, Intravenous / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D002302:Cardiac Output / Q000187:drug effects; D003331:Coronary Vessels / Q000378:metabolism*; D004301:Doppler Effect; D004305:Dose-Response Relationship, Drug; D006339:Heart Rate / Q000187:drug effects; D006439:Hemodynamics / Q000187:drug effects*; D007262:Infusions, Intravenous; D009200:Myocardial Contraction / Q000187:drug effects; D010100:Oxygen / Q000097:blood; D015742:Propofol / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D012756:Sheep; D013908:Thoracotomy; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D018686:Anesthetics, Intravenous; D010100:Oxygen; D015742:Propofol