Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1.
Hypoxia-inducible factor (HIF)-1 is stabilized by hypoxia and iron chelation. We hypothesized that HIF-1 might be involved in pulmonary vascular regulation and that infusion of desferrioxamine over 8 h would consequently mimic hypoxia and elevate pulmonary vascular resistance. In study A, we characterized the pulmonary vascular response to 4 h of isocapnic hypoxia; in study B, we measured the pulmonary vascular response to 8 h of desferrioxamine infusion. For study A, 11 volunteers undertook two protocols: 1) 4 h of isocapnic hypoxia (end-tidal PO(2) = 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal PO(2) = 100 Torr), and 2) 6 h of air breathing (control). For study B, nine volunteers undertook two protocols while breathing air: 1) continuous infusion of desferrioxamine (4 g/70 kg) over 8 h and 2) continuous infusion of saline over 8 h (control). In both studies, pulmonary vascular resistance was assessed at 0.5- to 1-h intervals by Doppler echocardiography via the maximum pressure gradient during systole across the tricuspid valve. Results show a progressive rise in pressure gradient over the first 3-4 h with both isocapnic hypoxia (P < 0.001) and desferrioxamine infusion (P < 0.005) to increases of ~16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction.
Balanos
George M
GM
University Laboratory of Physiology, University of Oxford, Parks Road, Oxford OX1 3PT, United Kingdom.
Dorrington
Keith L
KL
Robbins
Peter A
PA
D002302:Cardiac Output / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000502:physiology*; D003676:Deferoxamine / Q000494:pharmacology*; D004452:Echocardiography; D005260:Female; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents / Q000494:pharmacology*; D008297:Male; D009687:Nuclear Proteins / Q000502:physiology*; D011652:Pulmonary Circulation / Q000187:drug effects* / Q000502:physiology*; D013318:Stroke Volume / Q000187:drug effects; D014157:Transcription Factors; D014655:Vascular Resistance / Q000187:drug effects* / Q000502:physiology*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D007502:Iron Chelating Agents; D009687:Nuclear Proteins; D014157:Transcription Factors; D003676:Deferoxamine