Variations in Alveolar Partial Pressure for Carbon Dioxide and Oxygen Have Additive Not Synergistic Acute Effects on Human Pulmonary Vasoconstriction

et al. (2013) Variations in Alveolar Partial Pressure for Carbon Dioxide and Oxygen Have Additive Not Synergistic Acute Effects on Human Pulmonary Vasoconstriction. PLoS ONE 8(7): e67886. doi:10.1371/journal.pone.0067886 Variations in Alveolar Partial Pressure for Carbon Dioxide and Oxygen Have Additive Not Synergistic Acute Effects on Human Pulmonary Vasoconstriction Quentin P. P. Croft 0 Federico Formenti 0 Nick P. Talbot 0 Daniel Lunn 0 Peter A. Robbins 0 Keith L. Dorrington 0 Tim Lahm, Indiana University, United States of America 0 1 Department of Physiology , Anatomy and Genetics , University of Oxford , Oxford , United Kingdom , 2 Department of Statistics, University of Oxford , Oxford , United Kingdom The human pulmonary vasculature constricts in response to hypercapnia and hypoxia, with important consequences for homeostasis and adaptation. One function of these responses is to direct blood flow away from poorly-ventilated regions of the lung. In humans it is not known whether the stimuli of hypercapnia and hypoxia constrict the pulmonary blood vessels independently of each other or whether they act synergistically, such that the combination of hypercapnia and hypoxia is more effective than the sum of the responses to each stimulus on its own. We independently controlled the alveolar partial pressures of carbon dioxide (PACO2) and oxygen (PAO2) to examine their possible interaction on human pulmonary vasoconstriction. Nine volunteers each experienced sixteen possible combinations of four levels of PACO2 (+6, +1, 24 and 29 mmHg, relative to baseline) with four levels of PAO2 (175, 100, 75 and 50 mmHg). During each of these sixteen protocols Doppler echocardiography was used to evaluate cardiac output and systolic tricuspid pressure gradient, an index of pulmonary vasoconstriction. The degree of constriction varied linearly with both PACO2 and the calculated haemoglobin oxygen desaturation (1-SO2). Mixed effects modelling delivered coefficients defining the interdependence of cardiac output, systolic tricuspid pressure gradient, ventilation, PACO2 and SO2. No interaction was observed in the effects on pulmonary vasoconstriction of carbon dioxide and oxygen (p.0.64). Direct effects of the alveolar gases on systolic tricuspid pressure gradient greatly exceeded indirect effects arising from concurrent changes in cardiac output. - The human pulmonary vasculature constricts in response to both hypercapnia and hypoxia [14]. Sometimes, variations in CO2 and O2 are such as to work in synchrony on the vasculature. For example, this occurs in a poorly ventilated region of the lung where they both act to direct blood flow away from the region to better ventilated lung tissue, thereby enhancing the efficiency of gas exchange [5]. At other times, variations in CO2 and O2 are such as to act in opposition on the vasculature. An example is human exposure to high altitude, where the whole lung is exposed to coexisting hypoxia and hypocapnia [6], and the potentially harmful pressor effect of the alveolar hypoxia is obtunded by the dilatory effect of the alveolar hypocapnia. It is not known in what way a combination of the stimuli of hypercapnia and hypoxia affect the blood vessels in the human lung. It is unclear, therefore, whether the effects of the stimuli are additive or synergistic, that is to say, whether variations in O2 could potentially enhance the response to CO2 or vice-versa. The question of whether there is a synergy between the effects CO2 and O2 in the sensing mechanisms of the pulmonary vasculature is of broader interest than in the context of this tissue alone. In relation to the mammalian carotid body a stimulus interaction in the responses of single afferent fibres to CO2 and O2 has been known since 1975 [7], and considerable attention has been directed at establishing at what cellular level of transduction this synergy might occur [8,9]. The important consequences of this stimulus interaction on the control of breathing in humans in a wide variety of conditions has been recognized for many years [10,11]. In comparison, responses of pulmonary vascular smooth muscle to the combined stimuli CO2 and O2 have received little attention, but are arguably of a similar importance for understanding the behaviour of the lung in health and disease [12,13]. Animal preparations have not provided a clear indication of what one might expect for the human lung. Most, but not all [14], preparations show vasomotor responses to both respiratory gases, with some degree of synergistic interaction between the effects of CO2 and O2 being common but variable [1520]. Study of vasoconstrictor responses in the in vivo healthy human lung is made particularly difficult by the fact that changes in PACO2 and PAO2 induce changes in pulmonary artery pressure and pulmonary vascular resistance (PVR) that are a summation of a direct active effect of the gases on vascular smooth muscle and an indirect passive effect of concurrent changes in pulmonary blood flow and, potentially, ventilation [21]. The indirect effect may be quite small, because pulmonary vessels tend to be quite distensible, and thus accommodate large changes in flow with little rise in perfusion pressure and with a fall in resistance. This nevertheless makes it misleading to measure either pulmonary artery pressure or PVR as a sole index of pulmonary vascular smooth muscle constriction. The luxury available in animal preparations of being able to impose a constant pulmonary flow, and using pulmonary artery pressure or PVR as the index of vasoconstriction, has not been achieved in humans [22]. We address this problem by using mixed effects modelling to extract coefficients in direct and indirect pathways linking PACO2 and PAO2 with pulmonary artery pressure, and the relative contribution of each pathway. Direct effects of alveolar gases on pulmonary artery pressure are found to dominate. This approach also evaluates whether the gases have an additive or synergistic action; an additive action is observed, consistent with the approach adopted in an earlier model of feedback control of regional gas exchange in the human lung [13]. Ethics Statement The study was approved by the Oxfordshire Research Ethics Committee and performed in accordance with the Declaration of Helsinki. Informed written consent was obtained from all volunteers. General approach to the measurement of pulmonary vasoconstriction The general approach adopted was to use non-invasive measurement of systolic pulmonary artery pressure as our index of pulmonary vasoconstriction, whilst at the same time taking into account the dependence of this pressure upon other variables: ventilation and cardiac output. This separation of direct and indirect influences of PACO2 and PAO2 on systolic pulmonary artery pressure was achieved using mixed effects modelling. Volunteers Nine healthy volunteers (5 women and 4 men), aged 2464 years and with BMI 22.562 kg/m2 (mean 6 S (...truncated)