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In the pulmonary circulation, alveolar hypoxia contributes to blood flow regulation. Hypoxic pulmonary vasoconstriction (HPV) involves both pulmonary arteries and veins, but little is known of the contractile mechanisms specific to the veins. The aim of these studies was to examine the hypoxic response in small porcine intrapulmonary veins in relation to the arterial response, and investigate the effects of hypoxia on ion conductances in single myocytes from intrapulmonary veins. In wire myography experiments, intrapulmonary veins contracted more than sizematched arteries in response to hypoxia and agonists KCl and PGF2α. Venous contractions were inhibited by removal of extracellular Ca2+ or in the presence of Clchannel blocker NFA, effects not seen in the arteries. To examine the mechanisms of venous contraction at cellular level, single pulmonary vein smooth muscle cells (PVSMC) were freshly isolated and characterised morphologically and electrophysiologically for the first time. In patch-clamp studies, hypoxia reversibly inhibited a whole-cell outward current in the presence of BKCa channel antagonist Penitrem A. By subtracting currents recorded in normoxia and hypoxia, a novel hypoxia-sensitive K+ current (IK(H)) was revealed in PVSMC. IK(H) was a rapidly activating, partially inactivating current and was sensitive to KV channel blocker 4-AP. The biophysical properties of IK(H) revealed the voltage window of current availability with a peak near the resting membrane potential of PVSMC. In conclusion, these findings highlight differences between the contractile properties of veins and arteries and reveal a significant contribution of Ca2+ influx and an NFA-sensitive conductance during venous contraction to agonists and hypoxia. Furthermore, the results suggest that a novel hypoxia-sensitive KV current contributes to membrane potential under resting conditions in PVSMC and its inhibition by hypoxia may contribute to the initiation of HPV in porcine intrapulmonary veins.

When spontaneous breathing (SB) is allowed during mechanical ventilation (MV), atelectatic lung areas are recruited and oxygenation improves thereby. Whether unsupported SB at its natural pattern (without PEEP and at low pressure/small tidal volume) equally recruits and improves oxygenation, and if so by which mechanism, has not been studied. A porcine lung collapse model was designed to study this question. The cardiac output dependency of the pulmonary shunt was investigated with healthy lungs and with major shunt (during one-lung ventilation) and with SB, MV and continuous positive airway pressure (CPAP). The hypoxic pulmonary vasoconstriction (HPV) was blocked with sodium nitroprusside (SNP) to see whether HPV is the only mechanism available for ventilation/perfusion (VA/Q) matching during MV and SB. In all experiments, respiratory rate and tidal volume during MV were matched to SB. Oxygenation was assessed by serial blood gas measurements, recruitment by thoracic CTs; pulmonary shunt was assessed by multiple inert gas elimination or venous admixture. SB attained better oxygenation and lower pulmonary shunt compared with MV, although it did not recruit collapsed lung. Pulmonary shunt did not correlate with cardiac output during SB, whereas a correlation was found during MV and CPAP. With blocked HPV, pulmonary shunt was considerably lower during SB than MV. In conclusion, SB improves VA/Q matching as compared with MV, even when no recruitment occurs. In contrast to MV and CPAP, cardiac output has no major effect on pulmonary shunt during SB. The improved VA/Q matching during SB despite a blocked HPV might indicate the presence of a SB-specific mechanism that improves pulmonary blood flow redistribution towards ventilated lung regions independent of or supplementary to HPV.

This thesis is concerned with a very common disorder of iron homeostasis: iron deficiency. The specific focus is the manner in which iron deficiency influences physiological responses to hypoxia in humans. This work is predicated on observations made over many decades in vitro and in vivo, suggesting that variations in the bioavailability of iron have important consequences for certain biological processes known to depend on oxygen availability. Three separate but related studies together form the basis for this thesis. The first two, Study A and Study B, adopt a similar approach in recruiting healthy volunteers who differ according to iron status, yielding iron-deficient and iron-replete groups in both cases. In Study A, the behaviour of the pulmonary circulation is investigated during a sustained hypoxic exposure, before and after an intravenous infusion of iron. In Study B, skeletal muscle metabolism is explored, both at the level of high-energy phosphate metabolism and the integrated physiological responses to exercise on a cycle ergometer. In the third study, Study C, a different approach is taken, recruiting patients with chronic obstructive pulmonary disease (COPD), and exploring the prevalence and associations of iron deficiency in this condition. Chapters 2 and 3 describe experiments using sustained hypoxia in a normobaric chamber, during which the pulmonary circulation is assessed non-invasively using Doppler echocardiography. These reveal augmented hypoxic pulmonary vasoconstriction (HPV) in iron-deficient individuals, who also exhibit greater sensitivity to the effects of an infusion of intravenous iron. Additionally, the way in which certain circulating mediators important for iron haemostasis change over the course of these hypoxic exposures, and how iron status influences these responses, is explored. Chapter 4 reports the findings of experiments using 31P-magnetic resonance spectroscopy and cardiopulmonary exercise testing, which demonstrate abnormal whole-body metabolism in iron-deficient individuals during large muscle-mass exercise, despite the absence of a clear defect in mitochondrial oxidative phosphorylation. Intravenous iron is found to have significant effects to alter the lactate threshold in healthy individuals, but the effects are more striking in iron-deficient individuals. Collectively, these experiments imply that iron deficiency promotes a more glycolytic phenotype. Chapter 5 explores iron deficiency in COPD, a condition in which pulmonary vascular disease, hypoxia and skeletal muscle dysfunction coexist, and examines some of the difficulties in assessing iron status in the setting of a chronic inflammatory disorder. Iron deficiency is found to be common, and unexpectedly associated with significantly more severe hypoxaemia, in patients with COPD. Possible reasons for these findings, and their clinical implications, are considered. Chapter 6 provides a summary of the main conclusions to be drawn from the studies presented in this thesis.

This thesis is concerned with the role of iron in modulating right ventricular (RV) afterload during exercise in healthy people aged between 50 and 80 years. This is predicated on the requirement of the hypoxia-inducible factor (HIF) pathway for ferrous iron. A secondary objective is to examine the reactive oxygen species (ROS) hypothesis in human hypoxic pulmonary vasoconstriction (HPV) using exposure to hyperoxia. Chapters 3 and 4 describe basal relationships that may affect the HIF pathway and exercise capacity during ageing. These were explored in 113 participants using blood tests and exercise tests. Age and inflammatory factors, C-reactive protein, and ferritin were associated with impaired exercise capacity. In addition, ageing did not significantly affect haematological variables or iron status indicators. Chapters 5 and 6 describe the effect of a single intravenous iron infusion on the haematological variables in 32 participants in a randomised, placebo-controlled and double-blinded study. The effects of iron infusion on RV afterload during light exercise, and exercise capacity during heavy exercise, were examined in these participants. With iron infusion, erythropoietin production, and the increase in RV afterload during light exercise were blunted, potentially indicating involvement of the HIF pathway. However, blunting of RV afterload neither influenced the cardiac output during light exercise nor exercise capacity. Chapter 7 describes a study of 11 healthy volunteers, which investigated the ROS hypothesis in HPV using acute isocapnic hypoxia following an 8-hour exposure to hyperoxia. This sustained hyperoxic exposure did not influence the hypoxic behavior of the pulmonary vasculature. This thesis demonstrates the complex relationship between iron status and exercise capacity in older adults. It shows that the decrease in RV afterload during exercise caused by intravenous iron supplementation does not lead to an augmented cardiac output or exercise capacity. Finally, it calls into question the role of ROS in HPV.

Einleitung: Das ARDS (acute respiratory distress syndrome) stellt mit einer schweren Hypoxämie aufgrund eines hohen pulmonalen Recht-Linksshunts, mit einer pulmonalen Hypertonie und einer diffusen inflammatorischen Reaktion der gesamten Lunge trotz einiger etablierter Therapieansätze ein häufig letal endendes Krankheitsbild dar. Neben zahlreichen neuen klinisch-experimentellen Therapieansätzen erlangt die i.v.-Aplikation von Almitrindimesilat größere Beachtung. Zuerst verabreicht bei chronisch obstruktiven Atemwegserkrankungen erkannte man bald, daß neben der ventilationssteigernden Wirkung auch Effekte an der pulmonalen Gefäßstrombahn im Sinne einer Optimierung des Ventilations-Perfusions-Verhältnisses für die zu beobachtende Verbesserung der pulmonalen Oxygenation verantwortlich sind. Eine Potentierung der Hypoxischen Pulmonalen Vasokonstriktion (HPV) wird dafür verantwortlich gemacht. Kontrovers diskutierte Dosierungen in Tierversuchen und vereinzelten Anwendungen am Menschen legten nahe, daß systemische Dosis-Wirkungsanalysen erfolgen mußten. Desweiteren sollte untersucht werden ob die im Rahmen des ARDS zu beobachtende Pulmonalarterielle Hypertonie durch das Medikament zunimmt. Methoden: Mit Hilfe eines durch repetitive saline bronchoalveoläre Lavage induzierten ARDS-Modells am Schwein wurden an 14 Schweinen in Narkose prospektiv randomisiert entweder sechs ansteigende Dosen (0,5, 1, 2, 4, 8, und 16 (g/kgKG/min) Almitrindimesilat oder dessen Solvens Apfelsäure appliziert. Während des Versuches wurde volumenkontrolliert beatmet (FiO2 1,0 , PEEP 5 cm H2O). Nach je 30 minütiger Infusion der entsprechenden Dosierungen wurde Parameter des Gasaustausches und der pulmonalen sowie der systemischen Hämodynamik erhoben. Innerhalb der Gruppen wurde mittels des einfachen ANOVA-Test mit Bonferonikorrekturfaktor, zwischen den Gruppen mit dem Mann-Whitney-Test auf signifikante Unterschiede hin untersucht. Signifikanz der Unterschiede wurde bei einer Irrtumswahrscheinlichkeit p ( 0,05 angenommen. Ergebnisse: Niedrige Dosierungen, 0,5 - 2 (g/kgKG/min, reduzieren die venöse Beimischung und führen zu einem statistisch signifikanten Anstieg des Sauerstoffpartialdruckes mit einem Optimum für diesen günstigen Einfluß bei einer Infusionsrate von 1 µg/kgKG/ min. Hohe Dosierungen hingegen erhöhen die venöse Beimischung und senken den Sauerstoffpartialdruck und führen damit zu einer erheblichen Verschlechterung des Krankheitsbildes im Vergleich zu niedrigen Dosen und der Ausgangssituation bzw. dem nichttherapierten Tieren. Der Pulmonalarterielle Mitteldruck nahm nach Almitrindimesilatgabe geringfügig zu. Mit zunehmender Dosierung erreichte der MPAP höhere Werte als zum Zeitpunkt des stabilen Lungenschadens, jedoch waren keine dieser Steigerungen statistisch signifikant. Diskussion: Almitrindimesilat zeigte einen dosisabhängigen Einfluß auf den pulmonalen Gasaustausch. Dieser wirkt sich in niedrigen Dosierungen positiv auf die Hypoxämie aus. Der Pulmonalarterielle Druck bleibt konstant. Als Mechanismus der positiven Auswirkung liegt eine Potenzierung der HPV für niedrige Dosierungen nahe. / Objectives: The ARDS (acute respiratory distress syndrome) is characterized by a diffuse inflammatory response, a pulmonary hypertension and a severe hypoxemia mainly because of ventilation-perfusion-mismatching. Despite of some new therapeutical strageties the mortality remains high. Almitrine bismesylate was first described to improve arterial oxygenation in COPD- patients primary by increasing alveolar ventilation due to a stimulating effect on peripheral chemoreceptors. Furthermore several experimental studies have confirmed that almitrine improves PaO2 possibly because of reducing the ventilation- perfusion-mismatching by enhancing the hypoxic pulmonary vasoconstriction (HPV). Controversal results have been reported concernig the doses of intravenous Almitrine to be beneficial. Furthermore it remains unclear to what extend the pulmonary hypertension is augmented by a drug which is inhancing or restroring the HPV. Therefore we determined a dose-response-curve of almitrine in a animal model of ARDS. Methods: After induction of anaesthesia the ARDS-Modell was induced by repeated saline wash-0,5-2 ?g/kgKG/minout of surfactant. 14 swine received almitrine or the solvent in a prospective randomized manner. During the experiment the volume controlled mode of mechanical ventilation remained unchanged (FiO2 1,0 , PEEP 5 cm H2O). After the increasing doses of 0,5, 1, 2, 4, 8 and 16 ?g/kgKG/min each for 30 min we investigated the effects of i.v. almitrine on the pulmonary gasexchange and the pulomanry and systemic hemodynamics. Statistics were carried out by Two way Analysis of Variance p

Laparoscopic operations are a common and popular way for abdominal procedures. They are usually performed by insufflation of carbon dioxide (CO2) into the abdominal cavity. However, insufflation of CO2 may interfere with cardiac and circulatory as well as respiratory functions. The CO2-pneumoperitoneum (PP) may cause hypercarbia and acidosis. The direct effects of CO2 and acidosis lead to decreased cardiac contractility, sensitization of the myocardium to arrhythmogenic effects of catecholamines and systemic vasodilatation. There may even be long-lasting post-operative effects on breathing control. The pneumoperitoneum may also cause several respiratory changes, e.g. decreased functional residual capacity (FRC) and vital capacity (VC), formation of atelectasis, reduced respiratory compliance and increased airway pressure. Still, arterial oxygenation is mostly maintained or even improved during PP. In view of the apparently contradictory results in respiratory mechanics and gas exchange, the present studies were performed to evaluate respiratory changes on gas exchange and ventilation-perfusion distributions during PP in a porcine model. It was demonstrated that atelectasis during anaesthesia and PP may be estimated by an increased arterial to endtidal PCO2-gradient (study I). Perfusion was redistributed away from dorsal, collapsed lung regions when PP was established. This resulted in a better ventilation-perfusion match (study II). Increasing abdominal pressure shifted blood flow more and more away from collapsed lung tissue, decreased pulmonary shunt and improved oxygenation from 8 to 16 mmHg PP, despite an increase of atelectasis formation (study III). CO2-PP enhanced the shift of blood flow towards better ventilated parts of the lung compared to Air-PP. Moreover, sodium natriumprusside worsened the ventilation-perfusion match even more and blunted the effects previously seen with carbon dioxide. CO2 should therefore be the mediator of enhancing HPV during PP. In conclusion, pneumoperitoneum with CO2 causes atelectasis with elimination of ventilation in the dependent lung regions. However, an efficient shift of blood flow away from collapsed, non-ventilated regions results in a better ventilation-perfusion matching and better oxygenation of blood than without PP. A prerequisite for the beneficial effect is the use of carbon dioxide for the abdominal inflation, since it enhances HPV.

Ce travail a été consacré à l’étude non invasive de la circulation pulmonaire normale par mise en œuvre de l’échocardiographie Doppler. <p>En intégrant les mesures obtenues dans une approche physiopathologique, et en exploitant les nouvelles possibilités d’échocardiographes portables, techniquement performants, nous avons analysé les effets d’un inhibiteur de la phosphodiestérase-5 et d’une prostacycline, pour tenter d’en identifier d’éventuels effets introtropes intrinsèques, nous avons exploré le concept de réserve vasculaire pulmonaire comme facteur limitant de l’aptitude aérobie et indice potentiel d’une atteinte vasculaire pulmonaire précoce, et obtenu des résultats préliminaires permettant d’identifier une hypertension artérielle pulmonaire (HTAP) latente. Nos principaux résultats peuvent être résumés comme suit :<p>1. Chez le sujet sain, en normoxie ou dans un modèle expérimental d’HTAP induite par l’inhalation d’un mélange gazeux hypoxique, le sildenafil per os ou l’epoprostenol par voie intraveineuse, à des doses utilisées en clinique pour le traitement de l’HTAP, améliorent les indices de la fonction ventriculaire droite en proportion de leurs effets vasodilatatoires pulmonaires, sans effets inotropes intrinsèques détectables.<p>2. La consommation d’oxygène maximale du sujet sain augmente en raison directe de son volume capillaire pulmonaire (calculé à partir de sa capacité de diffusion pour l’oxyde nitrique et le monoxyde de carbone) et en raison inverse de sa résistance vasculaire pulmonaire, non seulement en altitude, mais aussi au niveau de la mer. Ce résultat suggère qu’une plus grande réserve vasculaire pulmonaire est propice aux efforts aérobiques intenses, probablement par moindre postcharge ventriculaire droite.<p>3. Des mesures réalisées chez un petit nombre de sujets suggèrent que la distensibilité vasculaire pulmonaire, calculée à partir d’une relation débit-pression vasculaire pulmonaire, est typiquement réduite chez des porteurs asymptomatiques de la mutation BMPR2, qui est actuellement le facteur de risque le plus élevé connu de l’HTAP. La mutation BMPR2 pourrait aussi être associée à une réactivité vasculaire pulmonaire accrue à l’hypoxie. <p>Nos résultats suggèrent indirectement que l’échocardiographie Doppler, de repos ou de stress, pourrait être davantage développée dans la mise au point de patients à risque d’HTAP./<p><p>Novel advances in echocardiography offer the opportunity to reliably characterize pulmonary circulation in terms of pressure-flow relationship, and to better understand the coupling of right ventricular (RV) function with normal and abnormal pulmonary hemodynamics. Moreover, when combined with the measurement of pulmonary capillary blood volume, this renewed methodological approach may help to understand the concept of pulmonary vascular reserve as a limiting factor of exercise capacity and potential sensitive marker of early vascular disease.<p><p>In the present work we used a model of hypoxic pulmonary vasoconstriction to analyse the effects of two targeted therapies of pulmonary arterial hypertension (PAH) on the RV function. We showed that the beneficial effects of these drugs are mainly driven by a decrease in RV afterload and not an enhanced myocardial inotropic state. Whether this is transposable to abnormal RV-arterial coupling in PAH patients remains to be investigated.<p><p>Echocardiography may be useful to explore the pulmonary vascular reserve as an important limiting factor of exercise capacity. We showed that a higher pulmonary vascular reserve, defined by a decreased PVR and increased lung diffusing capacity, allows for an improved aerobic exercise capacity (as assessed by a higher peak oxygen consumption), at a lower ventilatory cost, at sea level and at high altitude. <p><p>Stress echocardiography may detect an abnormal pulmonary vasoreactivity. We showed that asymptomatic relatives of patients suffering from idiopathic pulmonary arterial hypertension, and who carry a bone morphogenetic protein receptor type 2 mutation (BMPR2) present with a decreased pulmonary vascular distensibility and an enhanced pulmonary vasoreactivity to hypoxia, which are identifiable by echocardiography examination. However, the predictive value of these findings is not known. <p><p>Thus echocardiography may represent, in experienced and dedicated hands, a noninvasive, safe, widely available, applicable at the bed-side as well as in extreme environment (e.g. high altitudes), less expensive alternative for the evaluation of the pulmonary circulation, either by the interrogation of pressure-flow relationship (stress echocardiography), by the investigation of the right ventricle global and regional function in relation to its afterload (standard and Tissue Doppler Imaging), or by a combined approach with the measurement of lung diffusing capacity (DLNO / DLCO) to assess the pulmonary vascular reserve.<p><p>The present data are encouraging for further development and implementation of echocardiography for the detection, but also the diagnosis and follow-up of patients with pulmonary hypertension.<p><p> / Doctorat en Sciences médicales / info:eu-repo/semantics/nonPublished