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.

Mutation of the von Hippel-Lindau gene alters human cardiopulmonary physiology.

Intracellular responses to hypoxia are coordinated by the von Hippel-Lindau--hypoxia-inducible factor (VHL-HIF) transcriptional system. This study investigated the potential role of the VHL-HIF pathway in human systems-level physiology. Patients diagnosed with Chuvash polycythaemia, a rare disorder in which VHL signalling is specifically impaired, were studied during acute hypoxia and hypercapnia. Subjects breathed through a mouthpiece and ventilation was measured while pulmonary vascular tone was assessed echocardiographically. The patients were found to have elevated basal ventilation and pulmonary vascular tone, and ventilatory, pulmonary vasoconstrictive and heart rate responses to acute hypoxia were greatly increased, as were heart rate responses to hypercapnia. The patients also had abnormal pulmonary function on spirometry. This study's findings demonstrate that the VHL-HIF signalling pathway, which is so central to intracellular oxygen sensing, also regulates the organ systems upon which cellular oxygen delivery ultimately depends.

Human pulmonary vascular responses to hypoxia and hypercapnia.

The ability of alveolar gas composition to influence pulmonary vascular tone has been appreciated for over 50 years. In particular, it has been proposed that both O2 and CO2 could play a role in the matching of perfusion to ventilation within the lung, improving the overall efficiency of gas exchange. A wide variety of experimental approaches has been used to investigate pulmonary vascular effects of the respiratory gases in a range of mammalian species. In this article, we review experiments performed in healthy humans, identify particular difficulties in the interpretation of such experiments, and discuss possible approaches to future study.

Release by hypoxia of a soluble vasoconstrictor from rabbit small pulmonary arteries.

BACKGROUND: Soluble pulmonary vasoconstrictors released in response to hypoxia have been reported in pig and rat preparations, but not in rabbit preparations. METHODS: We used myography to evaluate the contribution of a soluble factor to constriction in rabbit small pulmonary arteries (external diameter 300-475 microm) exposed to 45 min hypoxia (PO(2)=9 mm Hg). RESULTS: Hypoxia produced gradually intensifying constriction. Return to euoxia (PO(2)=145 mm Hg) for 30 min relaxed only approximately 30% of the constriction, whereas elution of the myograph bath yielded full relaxation. Reapplication of the eluent gradually restored the constriction to its pre-elution level over a 30-min period. CONCLUSIONS: In this closed system, a soluble factor contributes substantially to hypoxic pulmonary vasoconstriction.