Can intravenous endothelin-1 be used to enhance hypoxic pulmonary vasoconstriction in healthy humans?
BACKGROUND
Hypoxic pulmonary vasoconstriction (HPV) helps match pulmonary perfusion to ventilation. The peptide endothelin-1 (ET-1) may be involved in the cellular mechanisms of this response. We hypothesized that increasing plasma ET-1 concentration during hypoxia would enhance HPV in humans and might represent a strategy for improving gas exchange during single-lung anaesthesia or respiratory disease.


METHODS
Nine healthy volunteers were each exposed twice to a 7-h protocol consisting of 1 h breathing air, 4 h of eucapnic hypoxia (end-tidal Po(2), 50 mm Hg), and 2 h of eucapnic euoxia (end-tidal Po(2), 100 mm Hg). Volunteers received a 7-h i.v. infusion of ET-1 during one protocol (1.0-2.5 ng kg(-1) min(-1)) and normal saline during the other. At intervals of 30-60 min, cardiac output and the maximum tricuspid pressure gradient during systole (DeltaP(max), an index of HPV) were measured using Doppler echocardiography, systemic arterial pressure was measured using sphygmomanometry, and plasma samples were obtained to determine ET-1 concentration.


RESULTS
During hypoxia, DeltaP(max) increased for around 2 h before reaching a plateau. Compared with saline, ET-1 had no effect on DeltaP(max), either at baseline or during hypoxia. ET-1 infusion slightly increased diastolic arterial pressure and reduced cardiac output, but had no specific effect on the change in these variables during hypoxia. During the final 1 h of hypoxia, plasma ET-1 concentration was 1.7 (0.4) pg ml(-1) [mean (sd)] in the saline protocol and 21.9 (12.2) pg ml(-1) in the ET-1 protocol.


CONCLUSIONS
ET-1 infusion seems unlikely to represent a therapeutic strategy for enhancing HPV during acute (<4 h) hypoxia.
Talbot
N P
NP
Department of Physiology, Anatomy and Genetics, University of Oxford, Sherrington Building, Parks Road, Oxford OX1 3PT, UK.
Balanos
G M
GM
Robbins
P A
PA
Dorrington
K L
KL
D000328:Adult; D001794:Blood Pressure / Q000187:drug effects; D002245:Carbon Dioxide / Q000097:blood; D002302:Cardiac Output / Q000187:drug effects; D015150:Echocardiography, Doppler; D019332:Endothelin-1 / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D005260:Female; D006801:Humans; D000860:Hypoxia / Q000097:blood / Q000503:physiopathology*; D008297:Male; D010100:Oxygen / Q000097:blood; D010313:Partial Pressure; D011652:Pulmonary Circulation / Q000187:drug effects*; D014661:Vasoconstriction / Q000187:drug effects*
D019332:Endothelin-1; D002245:Carbon Dioxide; D010100:Oxygen