Proceedings of The Physiological Society
University College Cork (2004) J Physiol 560P, C20
INCREASED SENSITIVITY OF HUMAN PULMONARY CIRCULATION TO ACUTE ISOCAPNIC HYPOXIA FOLLOWING 8 HOURS OF DESFERRIOXAMINE INFUSION.
Balanos,George M; Talbot,Nicholas P; Dorrington,Keith L; Robbins,Peter A;
1. School of Sport and Exercise Sciences, University of Birmingham, Birmingham, United Kingdom. 2. University Laboratory of Physiology, University of Oxford, Oxford, United Kingdom.
Desferrioxamine (DFO) is an iron chelator that has been shown to mimic hypoxia by upregulating erythropoietin production (Ren et al. 2000), and by increasing tricuspid maximum pressure gradient (ΔPmax) in healthy humans (Balanos et al. 2002), possibly through the hypoxia inducible factor (HIF-1) pathway. HIF-1 is a transcription factor that accumulates in hypoxia or under conditions of iron chelation, and it is involved in the production of a number of hypoxia-related proteins. We hypothesized that, if HIF-1 is involved in the regulation of the pulmonary circulation, the acute hypoxic response would be altered after the infusion of DFO. Eight healthy volunteers (4 women, 4 men) were each studied twice. On each occasion volunteers received an intravenous infusion of DFO (4 g/70 kg body weight, infused at a constant rate) or saline for 8 h, and underwent three hypoxic challenges while breathing through a mouthpiece: 1) pre-infusion, 2) post-infusion, and 3) 24 h post infusion. Each hypoxic challenge consisted of 5 min of isocapnic euoxia (end-tidal PO2 (PETO2)=100 mmHg), followed by 20 min of isocapnic hypoxia (PETO2=50 mmHg), followed by 10 min of eucapnic euoxia (as above). Doppler echocardiography was used to measure changes in the maximum velocity of tricuspid valve regurgitation. ΔPmax was calculated from this velocity using Bernoulli's equation. In the absence of DFO, hypoxia caused a rapid increase in ΔPmax (~7 mmHg), which reached a plateau within 5-10 min. Following an 8-h infusion of DFO, ΔPmax started at a ~3 mmHg higher baseline and continued to rise gradually throughout the 20 min of hypoxia to about 14 mmHg above baseline. The pulmonary vascular response to hypoxia was significantly different when compared to both pre-DFO and post-saline infusions (p<0.002, repeated measures ANOVA). Cardiac output was similar during all hypoxic challenges. We conclude that DFO acts as a 'primer' on the pulmonary circulation, by promoting the production of vasoactive substances that normally appear in response to sustained hypoxia (hours rather than minutes). As a result, following the infusion of DFO the shape of the response is changed, and the intensity matches what is normally observed after ~4 h of hypoxia (Balanos et al. 2002). This suggests that the sensitivity of the acute pulmonary vascular response to hypoxia may be regulated by the HIF-1 pathway.
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