title: Vascular Dilation, Tachycardia, and Increased Inotropy Occur Sequentially with Increasing Epinephrine Dose Rate, Plasma and Myocardial Concentrations, and cAMP.
abstract: BACKGROUND
  While epinephrine infusion is widely used in critical care for inotropic support, there is no direct method to detect the onset and measure the magnitude of this response. We hypothesised that surrogate measurements, such as heart rate and vascular tone, may indicate if the plasma and tissue concentrations of epinephrine and cAMP are in a range sufficient to increase myocardial contractility.
  
  
  METHODS
  Cardiovascular responses to epinephrine infusion (0.05-0.5 mcgkg(-1)min(-1)) were measured in rats using arterial and left ventricular catheters. Epinephrine and cAMP levels were measured using ELISA techniques.
  
  
  RESULTS
  The lowest dose of epinephrine infusion (0.05 mcgkg(-1)min(-1)) did not raise plasma epinephrine levels and did not lead to cardiovascular response. Incremental increase in epinephrine infusion (0.1 mcgkg(-1)min(-1)) elevated plasma but not myocardial epinephrine levels, providing vascular, but not cardiac effects. Further increase in the infusion rate (0.2 mcgkg(-1)min(-1)) raised myocardial tissue epinephrine levels sufficient to increase heart rate but not contractility. Inotropic and lusitropic effects were significant at the infusion rate of 0.3 mcgkg(-1)min(-1). Correlation of plasma epinephrine to haemodynamic parameters suggest that as plasma concentration increases, systemic vascular resistance falls (EC50=47 pg/ml), then HR increases (ED50=168 pg/ml), followed by a rise in contractility and lusitropy (ED50=346 pg/ml and ED50=324 pg/ml accordingly).
  
  
  CONCLUSIONS
  The dose response of epinephrine is distinct for vascular tone, HR and contractility. The need for higher doses to see cardiac effects is likely due to the threshold for drug accumulation in tissue. Successful inotropic support with epinephrine cannot be achieved unless the infusion is sufficient to raise the heart rate.
authors: Tufts University School of Medicine, Department of Anesthesiology and Pain Medicine, Elizabeth's Medical Center, Boston, Massachusetts, 02135, USA. Electronic address: mikhail.maslov@steward.org.
authors: Mikhail Y
authors: MY
authors: Maslov
authors: Tufts University School of Medicine, Department of Anesthesiology and Pain Medicine, Elizabeth's Medical Center, Boston, Massachusetts, 02135, USA.
authors: Abraham E
authors: AE
authors: Wei
authors: Tufts University School of Medicine, Department of Anesthesiology and Pain Medicine, Elizabeth's Medical Center, Boston, Massachusetts, 02135, USA.
authors: Matthew J
authors: MJ
authors: Pezone
authors: Harvard-MIT Division of Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
authors: Elazer R
authors: ER
authors: Edelman
authors: Tufts University School of Medicine, Department of Anesthesiology and Pain Medicine, Elizabeth's Medical Center, Boston, Massachusetts, 02135, USA.
authors: Mark A
authors: MA
authors: Lovich
mesh_terms: D000818:Animals; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004837:Epinephrine / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D006339:Heart Rate / Q000187:drug effects; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D051381:Rats; D013610:Tachycardia / Q000097:blood / Q000139:chemically induced / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D002316:Cardiotonic Agents; D000242:Cyclic AMP; D004837:Epinephrine
keywords: Contractility; Epinephrine; Heart rate; Myocardial tissue; Vascular tone; cAMP