Vascular Dilation, Tachycardia, and Increased Inotropy Occur Sequentially with Increasing Epinephrine Dose Rate, Plasma and Myocardial Concentrations, and cAMP

• Published in: Heart, lung & circulation Vol. 24; no. 9; pp. 912 - 918
• Main Authors: Maslov, Mikhail Y., MD, PhD, Wei, Abraham E., BA, Pezone, Matthew J., BA, Edelman, Elazer R., MD, PhD, Lovich, Mark A., MD, PhD
• Format: Journal Article
• Language: English
• Published: Australia Elsevier B.V 01.09.2015
• Subjects: Animals; cAMP; Cardiotonic Agents - adverse effects; Cardiotonic Agents - pharmacokinetics; Cardiotonic Agents - pharmacology; Cardiovascular; Contractility; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Epinephrine; Epinephrine - adverse effects; Epinephrine - pharmacokinetics; Epinephrine - pharmacology; Heart rate; Heart Rate - drug effects; Myocardial Contraction - drug effects; Myocardial tissue; Myocardium - metabolism; Rats; Tachycardia - blood; Tachycardia - chemically induced; Tachycardia - physiopathology; Vascular tone; Vasodilation - drug effects; Epinephrine; Heart rate; Myocardial tissue; cAMP; Vascular tone; Contractility
• ISSN: 1443-9506; 1444-2892
• DOI: 10.1016/j.hlc.2015.02.012

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 mcg kg−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 mcg kg−1 min−1 ) did not raise plasma epinephrine levels and did not lead to cardiovascular response. Incremental increase in epinephrine infusion (0.1 mcg kg−1 min−1 ) elevated plasma but not myocardial epinephrine levels, providing vascular, but not cardiac effects. Further increase in the infusion rate (0.2 mcg kg−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 mcg kg−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.