Submitted on July 24, 2007
Accepted on August 9, 2007
Endothelin-1-mediated vasoconstriction at rest and during dynamic exercise in healthy humans
David Walter Wray1*, Steven K. Nishiyama2, Anthony John Donato3, Mikael Sander4, Peter D. Wagner5, and Russell S. Richardson6
1 Medicine, University of California San Diego, La Jolla, California, United States
2 La Jolla, California, United States; Medicine, University of California San Diego, La Jolla, California, United States; Department of Medicine, University of California San Diego, La Jolla, California, United States
3 Integrative Physiology, University of Colorado at Boulder, Boulder, Colorado, United States
4 Cardiology, Natl Hosp, Copenhagen, Denmark
5 Departments of Medicine and Bioengineering, University of California-San Diego, La Jolla, California, United States
6 Department of Medicine, UC San Diego, La Jolla, California, United States; Medicine, University of California San Diego, La Jolla, California, United States
* To whom correspondence should be addressed. E-mail: dwray{at}ucsd.edu.
It is now generally accepted that alpha adrenoreceptor-mediated vasoconstriction is attenuated during exercise, but the efficacy of non-adrenergic vasoconstrictor pathways during exercise remains unclear. Thus, in 8 young (23 ± 1 yrs), healthy volunteers we contrasted changes in leg blood flow (ultrasound Doppler) before and during intra-arterial infusion of the 
1- adrenoreceptor agonist phenylephrine (PE) with that of the non-adrenergic ETA/ETB receptor agonist endothelin-1 (ET-1). Heart rate, arterial blood pressure, common femoral artery (CFA) diameter, and mean blood velocity were measured at rest and during knee-extensor exercise at 20, 40, and 60% of maximal work rate (WRmax). Drug infusion rates were adjusted for blood flow to maintain comparable doses across all subjects and conditions. At rest, PE infusion (8 ng/ml/min) provoked a rapid and significant decrease in leg blood flow (-51 ± 3%) within 2.5 minutes. Resting ET-1 infusion (40 pg/ml/min) significantly decreased leg blood flow within five minutes, reaching a maximal vasoconstriction (-34 ± 3 %) after 25-30 minutes of continuous infusion. Compared to rest, an exercise intensity-dependent attenuation to PE-mediated vasoconstriction was observed (-18 ± 5 %, -7 ± 2 %, and -1 ± 3 % change in leg blood flow at 20, 40, and 60% of WRmax, respectively). Vasoconstriction in response to ET-1 was also blunted in an exercise intensity-dependent manner (-13 ± 3 %, -7 ± 4 %, and +2 ± 3 % change in leg blood flow at 20, 40, and 60% of WRmax, respectively). These findings support a significant contribution of ET-1 and -adrenergic receptors in the regulation of skeletal muscle blood flow in the human leg at rest, and suggest a similar, intensity-dependent "lysis" of peripheral endothelin and -adrenergic vasoconstriction during dynamic exercise.
