Global REACH Expedition: Chronic Hypoxia Attenuates α1‐Adrenergic‐Mediated Vasoconstriction in Humans: Mechanisms of “Chronic‐Hypoxic Sympatholysis”
Authors: Hearon Christopher M , Hansen Alex B , Moralez Gilbert , Romero Steven A , Levine Benjamin D , Lawley Justin S 
Published: June 2021

Introduction

Acute exposure to hypoxia initiates a complex interplay between local vasodilatory signaling and sympathetic neural vasoconstriction that serves to maintain blood pressure and oxygen delivery to peripheral tissues. With prolonged exposure to hypoxia, sympathetic nervous system activity remains markedly elevated, however there is only a mild increase in blood pressure and peripheral vascular tone. Data from animal models indicate that exposure to chronic hypoxia (CH) attenuates sympathetic vasoconstriction due to blunted α‐adrenergic receptor responsiveness, termed ‘hypoxic sympatholysis’. The presence of hypoxic sympatholysis remains controversial and the potential mechanisms have not been identified in humans after exposure to CH.

Purpose

To test the hypothesis that three weeks exposure to chronic hypoxia would attenuate the forearm vasoconstrictor response to intra‐arterial infusion of a direct α1‐adrenergic agonist; and sympathoexcitation via cycle exercise.

Method

In 9 healthy lowland natives, we measured forearm blood flow (Doppler ultrasound), mean arterial pressure (MAP, intra‐arterial catheter), heart rate (HR, ECG) and calculated changes in vascular conductance (ΔFVC) during semi‐recumbent cycle exercise (60% VO2 max) and intra‐arterial infusion of phenylephrine (PE; α1 ‐agonist; 0.0625, 0.125, and 0.250 μg/dl forearm volume/min) at baseline (BL: 344m) and after three weeks of sojourn at high‐altitude (CH: 4,380m). All data are quantified as mean±SD.

Results

As expected, MAP and HR were mildly elevated after CH (MAP: BL: 93±8 vs. CH: 98±6 mmHg; p=0.05), (HR: 62±10 vs. CH: 72±9 mmHg; p<0.05), and resting FVC not different (BL: 38.0±9.3 vs. CH: 32.6±15.1ml/100 mmHg/min; p=0.42). Strikingly, CH abolished the forearm vasoconstrictor response to the lowest dose of PE (ΔFVC: BL: −19.1±11.6 vs. CH: 0.6±5.4 ml/100mmHg/min, P<0.01) and the response remained attenuated by ~50% at the medium dose (ΔFVC: BL: −23.2.1±12.0 vs. CH: −11.0±6.6 ml/100mmHg/min, P<0.01), and highest dose (ΔFVC: BL: −24.2±11.9 vs. CH: −13.8/±10.3 ml/100mmHg/min, P<0.01). During 60% cycle exercise (BL: 334±44 vs. CH: 236±34 W; P<0.05) there was no difference in MAP or HR (MAP: BL: 122±12 vs. CH: 124±12 mmHg; p=0.28), (HR: 141±10 vs. CH: 134±17 BPM; p<0.26). However, the forearm vasoconstrictor response to 60% cycle exercise was attenuated by ~50% after CH (ΔFVC: BL: −15.7±11.5 vs. −6.8±8.0 ml/100mmHg/min; P<0.05), similar to higher doses of PE.

Conclusion

Exposure to CH attenuates vascular α1‐adrenergic responsiveness in healthy altitude‐acclimatized lowland natives. Further, reduced α‐adrenergic responsiveness is associated with attenuated forearm vasoconstriction during sympathoexcitation via cycle exercise. These data identify a potential mechanism of hypoxic sympatholysis after exposure to CH in humans.

This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.