Adrenergic control of skeletal muscle blood flow during chronic hypoxia in healthy males

Abstract

Sympathetic transduction is reduced following chronic high-altitude (HA) exposure; however, vascular α-adrenergic signaling, the primary mechanism mediating sympathetic vasoconstriction at sea level (SL), has not been examined at HA. In nine male lowlanders, we measured forearm blood flow (Doppler ultrasound) and calculated changes in vascular conductance (ΔFVC) during 1) incremental intra-arterial infusion of phenylephrine to assess α₁-adrenergic receptor responsiveness and 2) combined intra-arterial infusion of β-adrenergic and α-adrenergic antagonists propranolol and phentolamine (α-β-blockade) to assess adrenergic vascular restraint at rest and during exercise-induced sympathoexcitation (cycling; 60% peak power). Experiments were performed near SL (344 m) and after 3 wk at HA (4,383 m). HA abolished the vasoconstrictor response to low-dose phenylephrine (ΔFVC: SL: -34 ± 15%, vs. HA; +3 ± 18%; P < 0.0001) and markedly attenuated the response to medium (ΔFVC: SL: -45 ± 18% vs. HA: -28 ± 11%; P = 0.009) and high (ΔFVC: SL: -47 ± 20%, vs. HA: -35 ± 20%; P = 0.041) doses. Blockade of β-adrenergic receptors alone had no effect on resting FVC (P = 0.500) and combined α-β-blockade induced a similar vasodilatory response at SL and HA (P = 0.580). Forearm vasoconstriction during cycling was not different at SL and HA (P = 0.999). Interestingly, cycling-induced forearm vasoconstriction was attenuated by α-β-blockade at SL (ΔFVC: Control: -27 ± 128 vs. α-β-blockade: +19 ± 23%; P = 0.0004), but unaffected at HA (ΔFVC: Control: -20 ± 22 vs. α-β-blockade: -23 ± 11%; P = 0.999). Our results indicate that in healthy males, altitude acclimatization attenuates α₁-adrenergic receptor responsiveness; however, resting α-adrenergic restraint remains intact, due to concurrent resting sympathoexcitation. Furthermore, forearm vasoconstrictor responses to cycling are preserved, although the contribution of adrenergic receptors is diminished, indicating a reliance on alternative vasoconstrictor mechanisms.

Keywords: exercise; high altitude; skeletal muscle blood flow; sympathetic nervous system; α-adrenergic receptors.

Figure 1.

Schematic of the experimental protocol. After instrumentation, catheterization and a period of stabilization, forearm blood flow was assessed at rest and during moderate intensity cycling (60% peak power output), under control conditions. After a period of recovery, nonselective β-adrenergic receptor antagonist propranolol was infused to achieve complete β-adrenergic receptor blockade. Forearm blood flow was then assessed at rest and during graded infusion of α₁-adrenergic receptor agonist phenylephrine. After a washout period, nonselective α-adrenergic receptor antagonist phentolamine was coinfused with propranolol to achieve combined + α-β-adrenergic receptor blockade. Thereafter, forearm blood flow was measured at rest and during moderate intensity cycling exercise to assess α-adrenergic-mediated restraint of skeletal muscle vascular tone. There was a minimum five and a half half-lives washout between interventions if applicable, or until full restoration of resting forearm and systemic hemodynamics. An identical protocol was performed at SL and HA. Participants also completed assessments of local forearm endothelial function and mild handgrip exercise, which have been presented elsewhere (25, 27, 35), and are indicated by //. FAV, forearm volume.

Figure 2.

Absolute (A) and relative (B) change in forearm vascular conductance during graded infusion of phenylephrine (PE, α₁-adrenergic agonist) at sea level (SL) and at high altitude (HA). *P < 0.05 vs. SL. The vasoconstrictor response to the lowest dose of PE is abolished at HA, and the vasoconstrictor response to medium and high doses of PE is attenuated, compared with SL. Statistical comparisons performed using two-way repeated-measures ANOVA, with Sidak post hoc comparisons between conditions at SL and HA. Subject sample size n = 9.

Figure 3.

A: resting forearm vascular conductance during control and + α/β-blockade conditions at sea level (SL) and high altitude (HA). Absolute (B) and relative (C) change in forearm vascular conductance after +α-β-blockade vs. control conditions. +α/β-Blockade significantly increased forearm vascular conductance, with no difference in magnitude of change at SL and HA, indicating similar degree of resting sympathetic restraint. Statistical comparisons performed using two-way repeated-measures ANOVA, with Sidak post hoc comparisons or dependent t tests. Subject sample size n = 9.

Figure 4.

A and B: absolute and relative change in forearm vascular conductance. C and D: forearm vascular resistance during cycling exercise at sea level and high altitude during control and +α/β-blockade conditions. Magnitude of cycling-induced forearm vasoconstriction was not different at SL and HA, under control conditions. +α/β-Blockade attenuates exercise-induced vasoconstriction in the nonactive muscle at SL, but has no effect at HA. Statistical comparisons performed using two-way repeated-measures ANOVA and Sidak post hoc comparisons. Subject sample size n = 9. HA, high altitude; SL, sea level.