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In this study we have tested the hypothesis that levels of epinephrine simulating those occurring during hypoglycemia of 70, 60, or 50 mg/dl will result in pro-coagulant and pro-atherothrombotic responses and endothelial dysfunction.

32 healthy humans (16M/16F) participated in 4 separate, single blind, randomized, 1-day studies: Placebo (Protoco1 1) and epinephrine infusions of 0.015, 0.03 and 0.06µg/kg/min (Protocols 2-4) respectively. Studies consisted of 2-hour hyperinsulinemic (133±7µU/ml) euglycemic clamps of 92±1mg/dl. 2D Doppler imaging determined flow mediated dilation (FMD) of the brachial artery.

Increases of IL-6, P-selectin, E-selectin, ICAM-1, and VCAM-1 were higher and reductions in FMD and ET-1 greater during all epinephrine infusions compared to Placebo (p<0.05). (Table 1)

Table 1. Changes from baseline to final 30 min

 Protocol 1 Protocol 2 Protocol3 Protocol 4 
Δ IL-6 (pg/ml) -3.0±1.2 2.8±2.9* 3.6±2.7* 8.1±2.9* 
Δ P-selectin (pg/ml) -13.7±6.5 1.3±0.8* 2.0±2.0* 5.6±1.8* 
Δ ICAM-1 (ng/ml) -18.7±12.3 24.1±13.3* 65.5±36.9* 114.3±69.6* 
Δ ET-1 (pg/ml) -0.2±0.05 -0.4±0.05* -0.5±0.12* -0.6±0.09* 
Δ FMD (mean maximum%) 0.8±0.7 -2.0±0.5* -2.6±0.6* -3.7±0.7* 
Δ Epinephrine (pg/ml) 18±2 299±38* 532±41* 1011±12* 
Mean±SEM * p<0.0007-0.compared to Protocol 1 
 Protocol 1 Protocol 2 Protocol3 Protocol 4 
Δ IL-6 (pg/ml) -3.0±1.2 2.8±2.9* 3.6±2.7* 8.1±2.9* 
Δ P-selectin (pg/ml) -13.7±6.5 1.3±0.8* 2.0±2.0* 5.6±1.8* 
Δ ICAM-1 (ng/ml) -18.7±12.3 24.1±13.3* 65.5±36.9* 114.3±69.6* 
Δ ET-1 (pg/ml) -0.2±0.05 -0.4±0.05* -0.5±0.12* -0.6±0.09* 
Δ FMD (mean maximum%) 0.8±0.7 -2.0±0.5* -2.6±0.6* -3.7±0.7* 
Δ Epinephrine (pg/ml) 18±2 299±38* 532±41* 1011±12* 
Mean±SEM * p<0.0007-0.compared to Protocol 1 

Epinephrine activated pro-coagulant, inflammatory and pro-atherothrombotic mechanisms while impairing endogenous and exogenous nitric oxide mediated endothelial function.

In conclusion, during hyperinsulinemic euglycemia, epinephrine levels simulating those occurring during hypo of only 70mg/dl produced significant inflammatory effects. Increasing doses of epinephrine resulted in greater inflammatory responses and in-vivo endothelial dysfunction (p<0.001). Epinephrine may be an important mechanism responsible for adverse vascular biologic effects during hypo in healthy humans.

Disclosure

M. Mikeladze: None. M. Hedrington: None. S. Dumbadze: None. V.J. Briscoe: None. D. Tate: None. E. Thayer: None. S. Davis: None.

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