Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1

Abstract

Balanos, George M., Keith L. Dorrington, and Peter A. Robbins. Desferrioxamine elevates pulmonary vascular resistance in humans: potential for involvement of HIF-1. J Appl Physiol 92: 2501-2507, 2002. First published February 15, 2002 10.1152/japplphysiol.00965.2001.-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 (endtidal PO 2 ϭ 50 Torr), followed by 2 h of recovery with isocapnic euoxia (end-tidal PO 2 ϭ 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 Ͻ 0.001) and desferrioxamine infusion (P Ͻ 0.005) to increases of ϳ16 and 4 Torr, respectively. These results support a role for HIF-regulated gene activation in human hypoxic pulmonary vasoconstriction. hypoxia inducible factor-1; hypoxic pulmonary vasoconstriction; pulmonary circulation THERE IS EVIDENCE TO SUGGEST that the human pulmonary circulation responds to sustained hypoxia by developing a progressively more intense constriction over a period of a few hours. In anesthetized patients, Fiser et al. (4) observed a gradual decline in pulmonary venous admixture during unilateral atelectasis over 90 min, suggesting that blood flow diversion by hypoxic pulmonary vasoconstriction was intensifying during this time. Exposure of healthy humans to an 8-h isocapnic reduction in end-tidal oxygen partial pressure (PET O 2 ) to 50 Torr, approximately half its normal value, results in a progressive rise in pulmonary vascular resistance (PVR) over 2 h to ϳ2.5 times its euoxic value as determined by right heart catheterization (3).The mechanisms responsible for this slower component of the pulmonary vascular response to hypoxia remain unclear (13,22), but one possibility is that the transcriptional regulator hypoxia-inducible factor (HIF)-1 is involved, as it is in some other homeostatic responses to hypoxia (18). Yu et al. (23) examined the kinetics of induction of increased levels of the subunit HIF-1␣ in isolated ferret lungs exposed to 8 h of hypoxia. They found that HIF-1␣ was not detectable at 0 h, increased at 1-2 h, peaked at 4 h, and remained elevated thereafter (23). Furthermore, the work of Yu et ...

Human pulmonary vascular response to 4 h of hypercapnia and hypocapnia measured using Doppler echocardiography

“…For data from animal experiments, hypoxic pulmonary vasoconstriction has been modeled as a sigmoidal function of PA O 2 , in which the sensitivity of the vascular response increases as PA O 2 decreases from ϳ100 Torr toward ϳ30 Torr (13). If the human response is similar in this respect, it is to be anticipated that the sensitivity of the pulmonary vascular response to hypoxia in the PA O 2 range of 80-140 Torr given for the normal erect lung (24) would be considerably less that the value of the 0.3 Torr change in ⌬P max per Torr change in PA O 2 , which is the average over the range of 50-100 Torr in our previous study (2). In contrast to this probably weak vascular response to hypoxia within the physiological range of PA O 2 in the healthy lung, the results presented here show a vigorous response to changes in PA CO 2 within the physiological range.…”

“…Because ⌬Pmax is a measure of the difference between systolic pressure in the right ventricle and the fairly constant pressure in the right atrium, it can be used as an index of PVR. Indeed, we have recently argued that it may be a more direct indicator of smooth muscle activity in the pulmonary arteries than PVR itself (2). A standard technique was used for measuring ⌬P max (20).…”

“…The pulmonary vascular effects of hypocapnia in the right apical lobe of conscious sheep were explored by Sheehan and Farhi (22). They found that hypocapnia increased blood flow to the lobe substantially, and they suggested that variations in both CO 2 and O 2 about normal values play an important role in the physiological matching of ventilation to perfusion when these values are perturbed in the lung by gravity.…”

“…In this study, we set out to compare the effects of sustained (4 h) hypocapnia and hypercapnia on the human pulmonary circulation, with a view to establishing whether normal tone can be reduced and whether changes in end-tidal PCO 2 (PET CO 2 ) produce substantial or small proportionate changes in an index of pulmonary vascular resistance (PVR). A second aim was to define the time course of the pulmonary vascular responses to these stimuli and of the recovery from these stimuli during a subsequent 2 h of eucapnia.…”

The expanding universe of hypoxia

“…He also reported that infusion of the iron chelator desferrioxamine results in enhanced pulmonary vascular responses to hypoxia in normal volunteers (44).…”