Exercise-induced inhibition of angiotensin II vasoconstriction in human thigh muscle

Abstract

It is well established that metabolic inhibition of adrenergic vasoconstriction contributes to the maintenance of adequate perfusion to exercising skeletal muscle. However, little is known regarding nonadrenergic vasoconstriction during exercise. We tested the hypothesis that a non-adrenergic vasoconstrictor, angiotensin II (AngII), would be less sensitive to metabolic inhibition than an alpha1-agonist, phenylephrine (PE), in the exercising human thigh. In 11 healthy men, femoral blood flow (FBF, ultrasound Doppler and thermodilution) and blood pressure were evaluated during wide-ranging doses of intra-arterial (femoral) infusions of PE and AngII at rest and during two workloads of steady-state knee-extensor exercise (7 W and 27 W). At rest, the maximal decrease in femoral artery diameter (FAD) during AngII (9.0+/-0.2 to 8.4+/-0.4 mm) was markedly less than during PE (9.0+/-0.3 to 5.7+/-0.5 mm), whereas maximal reductions in FBF and femoral vascular conductance (FVC) were similar during AngII (FBF: -65+/-6 and FVC: -66+/-6%) and PE (-57+/-5 and -59+/-4%). During exercise, FAD was not changed by AngII, but moderately decreased by PE. The maximal reductions in FBF and FVC were blunted during exercise compared to rest for both AngII (7 W: -28+/-5 and -40+/-5%; 27 W: -15+/-4% and -29+/-5%) and PE (7 W: -30+/-4 and -37+/-6%; 27 W: -15+/-2 and -24+/-6%), with no significant differences between drugs. The major new findings are (1) an exercise-induced intensity-dependent metabolic attenuation of non-adrenergic vasoconstriction in the human leg; and (2) functional evidence that AngII-vasoconstriction is predominantly distal, whereas alpha1-vasoconstriction is proximal and distal within the muscle vascular bed of the human thigh.

Figure 1. Protocol outline for constant intra-arterial (femoral) infusions of 7 AngII doses (0.25–16 ng kg⁻¹ min⁻¹) and 7 PE doses (0.0125–0.8 μg kg⁻¹ min⁻¹) during rest; as well as 6 AngII doses (0.5–32 ng kg⁻¹ min⁻¹) and 6 PE doses (0.05–1.6 μg·kg⁻¹ min⁻¹) during 7 w and 27 W ipsilateral knee-extensor exercise

The time course is represented on the top axis in minutes. The order of the drugs and of the exercise levels were random and balanced. There was a resting period of at least 45 min between exercise bouts. Measurements of femoral blood flow during baseline and each drug dose are marked by arrows. Each dose was administered as a constant intra-arterial infusion for at least 2 min, with measurements obtained during the last 45 s. Each shift of dose was a doubling of the previous dose. BL, baseline; PE, phenylephrine; AngII, angiotensin II.

Figure 2. Femoral artery diameter and blood velocity

Dose–response relationships for intra-arterial AngII and PE during rest, 7 W, and 27 W exercise. AngII, angiotensin II; PE, phenylephrine; FAD; femoral artery diameter; FBV, femoral blood velocity. *P < 0.05 compared to baseline; §P < 0.05 between PE and AngII. Error bars are s.e.m.

Figure 3. Femoral blood flow and conductance

Dose–response relationships for intra-arterial AngII and PE during rest, 7 W, and 27 W exercise. AngII, angiotensin II; PE, phenylephrine; ΔFBF, changes in femoral blood flow (absolute in top panels and relative in middle panels); ΔFVC, changes in femoral vascular conductance (relative in bottom panels). *P < 0.05 compared to baseline; †P < 0.05 between rest and 7 W; ‡P < 0.05 between rest and 27 W; δP < 0.05 between rest and 7 W. Error bars are s.e.m.

Figure 4. Femoral blood flow, conductance and resistance

Flow-adjusted dose–response relationships for intra-arterial AngII and PE during rest, 7 W, and 27 W exercise. AngII, angiotensin II; PE, phenylephrine; ΔFBF, relative changes in femoral blood flow; ΔFVC, relative changes in femoral vascular conductance; ΔFVR, relative changes in femoral vascular resistance. †P < 0.05 between rest and 7 W; ‡P < 0.05 between rest and 27 W. Error bars are s.e.m.