Pulmonary and cardiac drugs: clinically relevant interactions.

Chronic heart and lung diseases are very common in the elderly population. The combination of chronic heart failure and chronic obstructive pulmonary disease (COPD) is also common and, according to current guidelines, these patients should be treated for both diseases. In patients with heart failure, beta-blockers are very important drugs because their use is associated with significantly improved morbidity and mortality. These beneficial effects were documented in patients with and without COPD, although theoretically there is a risk for bronchoconstriction, particularly with non-beta1 selective blockers. In COPD patients, long-acting sympathomimetics (LABA) improve lung function, dyspnea, and quality of life and their combination with a beta-blocker makes sense from a pharmacological and a clinical point of view, because any potential arrhythmogenic effects of the LABA will be ameliorated by the beta-blocker. Inhaled tiotropium, a long-acting muscarinic antagonist (LAMA), has been extensively investigated and no safety concerns were reported in terms of cardiac adverse effects. The same applies for the other approved LAMA preparations and LAMA-LABA combinations. Severe COPD causes air-trapping with increasing pressures in the thorax, leading to limitations in blood return into the thorax from the periphery of the body. This causes a decrease in stroke volume and cardiac index and is associated with dyspnea. All these adverse effects can be ameliorated by potent anti-obstructive therapy as recently shown by means of a LABA-LAMA combination.

[Research in Austria - the Ludwig Boltzmann Institute for Lung Vascular Research]. / Forschung in Österreich - das Ludwig Boltzmann Institut für Lungengefäßforschung.

The Ludwig Boltzmann Institute for Lung Vascular Research was founded in 2010 and performs basic and clinical research on the field of chronic pulmonary vascular diseases. The major projects of the institute focus on the investigation of the pathomechanisms of pulmonary vascular remodeling, the development of novel non-invasive diagnostic techniques of pulmonary hypertension and the early detection of pulmonary vascular diseases. The institute closely cooperates with patient organizations and aims to contribute to the development of improved diagnostic and therapeutic approaches for patients with pulmonary vascular diseases. In this short overview the most important results of the first six years of the institute will be summarized.

[Pulmonary (Arterial) Hypertension]. / Pulmonal (arterielle) Hypertonie.

Pulmonary arterial hypertension (PAH) is a rare disease characterised by vascular remodelling of the small lung arteries leading to a decrease of the vessel lumen and eventually to occlusion. According to the current guidelines, PAH is defined by a pulmonary arterial pressure ≥ 25 mmHg, an arterial wedge pressure ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR > 3 WU). The current pathophysiological concepts include disturbances in the production, deposition and composition of the extracellular matrix, inflammatory processes, mutations in the BMPR2 gene as well as mutations in the KCNK3 gene. During the last few years, epigenetic and genetic investigations resulted in new findings which are highly relevant for the diagnosis, prognosis and therapy of PAH. These findings could lead to the development of new, individualised therapy strategies. Currently, several phase I and phase II studies are in progress, in which promising new substances are examined.

[ESC guidelines 2015 on pulmonary hypertension]. / ESC-Leitlinien 2015 zur pulmonalen Hypertonie.

The European Society of Cardiology (ESC) and European Respiratory Society (ERS) guidelines published in 2015 include the most important recommendations for the diagnosis and treatment of pulmonary hypertension (PH). The classification of PH into five groups remained unchanged as compared to the previous recommendations; however, there are minor shifts within the groups. Accordingly, a distinction is made between pulmonary arterial hypertension (PAH), PH due to left heart disease, PH due to chronic hypoxia or lung disease, chronic thromboembolic PH and PH due to unclear or multifactorial mechanisms. The diagnosis of PH is based on right heart catheterization where PH is defined as a mean pulmonary arterial pressure ≥ 25 mmHg at rest. For the definition of PAH, in addition to a pulmonary capillary wedge pressure ≤ 15 mmHg, a pulmonary vascular resistance > 3 Wood units is obligatory. Echocardiography is considered to be the most important non-invasive procedure within the diagnostic algorithm and for patients with collagen vascular disease. This is recommended during initial diagnostic work-up and should be followed-up annually. Several novel drugs which were approved since publication of the previous guidelines, were included in the new recommendations. For the first time there is a recommendation for a targeted drug for inoperable chronic thromboembolic PH. An important part of the guidelines is the discussion on PAH upfront combination therapy.

Detection of pulmonary vasculopathy by novel analysis of oxygen uptake in patients with systemic sclerosis: association with pulmonary arterial pressures.

OBJECTIVES: During cardiopulmonary exercise testing (CPET) compromised pulmonary vasculature in patients with systemic sclerosis (SSc) may lead to increases in pulmonary arterial pressures (PAP) and decreased oxygen uptake. We hypothesised that this may lead into a disproportional heart rate (HR) increase with a corresponding V'O2/HR breakpoint and relates to systolic PAP at rest. METHODS: In a prospective design we evaluated V'O2/HR slopes for breakpoints. To understand its physiological meaning, we evaluated V'O2/HR and V'O2/mPAP slopes for breakpoints in a historic data set of SSc patients, in which CPET and right heart catheterisation was performed simultaneously. V'O2/HR slopes with a peak oxygen uptake outside the normal range were defined as pathologic. RESULTS: A breakpoint occurred in both V'O2/mPAP and V'O2/HR slope in 16/34 patients in the historic dataset and occurred in the V'O2/mPAP slope at a lower V'O2in 15 patients. In the prospective dataset, 73/121 patients showed a V'O2/HR breakpoint and achieved a significantly lower peak oxygen uptake compared to 48/121 patients without a V'O2/HR breakpoint (p=0.036). Mean systolic PAP in 41/121 patients with a pathologic V'O2/HR slope differed significantly from patients without a pathologic V'O2/HR slope (p=0.027). In 27/121 patients with a systolic PAP < 35 mmHg a pathologic V'O2/HR slope was observed. CONCLUSIONS: SSc patients with a V'O2/HR breakpoint are characterised by a decreased oxygen uptake, likely caused by sudden PAP increases during exercise. Importantly, in patients with normal resting SPAP pathologic V'O2/HR slopes were observed. This suggests that these patients are at risk for developing pulmonary hypertension.

[Early diagnosis and therapy in pulmonary hypertension--aspects of a vision]. / Die frühe Diagnose und Therapie der pulmonalen Hypertonie--Aspekte einer Vision.

In patients with pulmonary hypertension progressive vascular changes in the lung precede the clinical and hemodynamic manifestations of the disease. Therefore, early diagnosis and timely treatment of the disease are crucial. This has been the topic of an expert meeting in Greifswald, Germany in June 2012. The current definition of pulmonary hypertension requires a mean pulmonary artery pressure ≥ 25 mmHg at rest, a hemodynamic abnormality already reflecting pulmonary vascular changes beyond early disease. There is increasing evidence supporting the concept that a lower pressure threshold at rest or an abnormal pressure response with exercise better characterize early disease. While right heart catheterization at rest remains the diagnostic gold standard other methods for detecting early disease are explored with echocardiography being the most frequently used technique. Targeted therapy has been approved for patients with pulmonary arterial hypertension (PAH, WHO-group I) in functional class II-IV. Preliminary data in functional class I patients suggest therapeutic potential of theses drugs in early disease as well. Current guidelines propose therapeutic goals based on parameters with prognostic importance. However, these recommendations are based on mostly retrospective analyses of pre-treatment data obtained in patients with pulmonary hypertension in functional class II-IV. Therefore, evidence-based therapeutic goals for early interventions in functional class I patients are lacking.

Pulmonary vascular resistances during exercise in normal subjects: a systematic review.

The physiological range of pulmonary vascular resistance (PVR) and total pulmonary resistance (TPR), and the impact of exercise, age and posture have been a matter of debate for many years. We performed a systematic literature review including all right heart catheterisation data where individual PVR and TPR of healthy subjects both at rest and exercise were available. Data were stratified according to age, exercise level and posture. Supine resting PVR in subjects aged <24 yrs, 24-50 yrs, 51-69 yrs and ≥70 yrs was 61±23, 69±28, 86±15 and 90±39 dyn·s·cm(-5), respectively. Corresponding TPR was 165±50, 164±46, 226±64 and 223±45 dyn·s·cm(-5), respectively. During moderate exercise in subjects aged ≤50 yrs, an 85% increase in cardiac output was associated with a 25% decrease in TPR (p<0.0001) and a 12% decrease in PVR (p<0.01). At 51-69 yrs of age there was no significant decrease in TPR and PVR. In individuals aged ≥70 yrs TPR even increased by 17% (p=0.01), while PVR did not change significantly. At higher exercise levels, TPR decreased in all age groups. In the upright position, based on a limited number of data, resting TPR and PVR were higher than in the supine position and decreased more prominently during exercise, suggesting the release of resting pulmonary vasoconstriction. These data may form a basis to define normal PVR at rest and exercise.

Diagnosis of CTEPH versus IPAH using capillary to end-tidal carbon dioxide gradients.

Chronic thromboembolic pulmonary hypertension (CTEPH) represents an important differential diagnosis to idiopathic pulmonary arterial hypertension (IPAH). We hypothesised that the capillary to end-tidal carbon dioxide gradient at rest and during exercise might help differentiate CTEPH from IPAH. Patients who presented with unequivocal IPAH or CTEPH according to ventilation/perfusion scanning, pulmonary angiography, computed tomography and right heart catheterisation were included in this retrospective study and compared with healthy controls. 21 IPAH patients and 16 CTEPH patients fulfilled the inclusion criteria. Haemodynamics and peak oxygen uptake were comparable, but respiratory rates at rest and during exercise were significantly higher in CTEPH than in IPAH. End-tidal carbon dioxide was significantly lower in CTEPH versus IPAH at rest and during exercise, while capillary carbon dioxide values were similar. Correspondingly, capillary to end-tidal carbon dioxide gradients were significantly increased in CTEPH versus IPAH at rest and during exercise (median (range) 8.6 (3.0-13.7) versus 4.4 (0.9-9.0) (p<0.001) and 9.3 (3.3-13.1) versus 4.1 (0.0-8.8) mmHg (p<0.001), respectively). Although these values were closer to normal in IPAH they were still significantly elevated compared with healthy controls (2.3 (-4.8-8.1) and -1.9 (-5.7-6.2) mmHg, respectively). Capillary to end-tidal carbon dioxide gradients may help to distinguish CTEPH from IPAH based on resting and exercise values.

[Statement of the Austrian Society of Pneumology (ASP)]. / Stellungnahme der Österreichischen Gesellschaft für Pneumologie (ÖGP): Management von Patienten mit SARS-CoV-2-Infektionen und von Patienten mit chronischen Lungenerkrankungen während der COVID-19-Pandemie (Stand 27.04.2020).

The COVID-19 pandemic is currently a challenge worldwide. In Austria, a crisis within the health care system has so far been avoided. The treatment of patients with community-acquired pneumonia (CAP), including SARS-CoV­2 infections, should continue to be based on evidence-based CAP guidelines during the pandemic. However, COVID-19-specific adjustments are useful. The treatment of patients with chronic lung diseases must be adapted during the pandemic, but must still be guaranteed.

Pulmonary arterial pressure during rest and exercise in healthy subjects: a systematic review.

According to current guidelines, pulmonary arterial hypertension (PAH) is diagnosed when mean pulmonary arterial pressure (Ppa) exceeds 25 mmHg at rest or 30 mmHg during exercise. Issues that remain unclear are the classification of Ppa values <25 mmHg and whether Ppa >30 mmHg during exercise is always pathological. We performed a comprehensive literature review and analysed all accessible data obtained by right heart catheter studies from healthy individuals to determine normal Ppa at rest and during exercise. Data on 1,187 individuals from 47 studies in 13 countries were included. Data were stratified for sex, age, geographical origin, body position and exercise level. Ppa at rest was 14.0+/-3.3 mmHg and this value was independent of sex and ethnicity. Resting Ppa was slightly influenced by posture (supine 14.0+/-3.3 mmHg, upright 13.6+/-3.1 mmHg) and age (<30 yrs: 12.8+/- 3.1 mmHg; 30-50 yrs: 12.9+/-3.0 mmHg; > or = 50 yrs: 14.7+/-4.0 mmHg). Ppa during exercise was dependent on exercise level and age. During mild exercise, Ppa was 19.4+/-4.8 mmHg in subjects aged <50 yrs compared with 29.4+/-8.4 mmHg in subjects > or = 50 yrs (p<0.001). In conclusion, while Ppa at rest is virtually independent of age and rarely exceeds 20 mmHg, exercise Ppa is age-related and frequently exceeds 30 mmHg, especially in elderly individuals, which makes it difficult to define normal Ppa values during exercise.

Prostacyclin therapies for the treatment of pulmonary arterial hypertension.

Prostacyclin and its analogues (prostanoids) are potent vasodilators and possess antithrombotic, antiproliferative and anti-inflammatory properties. Pulmonary hypertension (PH) is associated with vasoconstriction, thrombosis and proliferation, and the lack of endogenous prostacyclin may considerably contribute to this condition. This supports a strong rationale for prostanoid use as therapy for this disease. The first experiences of prostanoid therapy in PH patients were published in 1980. Epoprostenol, a synthetic analogue of prostacyclin, and the chemically stable analogues iloprost, beraprost and treprostinil were tested in randomised controlled trials. The biological actions are mainly mediated by activation of specific receptors of the target cells; however, new data suggest effects on additional intracellular pathways. In the USA and some European countries, intravenous infusion of epoprostenol and treprostinil, as well as subcutaneous infusion of treprostinil and inhalation of iloprost, have been approved for therapy of pulmonary arterial hypertension. Iloprost infusion and beraprost tablets have been approved in few other countries. Ongoing clinical studies investigate oral treprostinil, inhaled treprostinil and the combination of inhaled iloprost and sildenafil in pulmonary arterial hypertension. Combination of other targeted therapies with prostanoids appears to be effective and safe. After 25 yrs of continued knowledge, prostanoids remain a mainstay in the treatment of pulmonary arterial hypertension.

Treprostinil potentiates the positive inotropic effect of catecholamines in adult rat ventricular cardiomyocytes.

BACKGROUND AND PURPOSE: Prostanoids have been shown to improve exercise tolerance, hemodynamics and quality of life in patients with pulmonary arterial hypertension (PAH). We investigated whether treprostinil exerts direct contractile effects on cardiomyocytes that may explain partly the beneficial effects of these drugs. EXPERIMENTAL APPROACH: Ventricular cardiomyocytes from adult rats were paced at a constant frequency of 0.5 to 2.0 Hz and cell shortening was monitored via a cell edge detection system. Twitch amplitudes, expressed as percent cell shortening of the diastolic cell length, and maximal contraction velocity, relaxation velocity, time to peak of contraction and time to reach 50% of relaxation were analyzed. KEY RESULTS: Treprostinil (0.15 - 15 ng ml(-1)) slightly increased contractile dynamics of cardiomyocytes at clinically relevant concentrations. However, the drug significantly improved cell shortening of cardiomyocytes in the presence of isoprenaline, a beta-adrenoceptor agonist. Treprostinil exerted this effect at all beating frequencies under investigation. Treprostinil mimicked this potentiating effect in a Langendorff preparation as well. The potentiating effect of treprostinil on isoprenaline-dependent cell shortening was no longer seen after phosphodiesterase inhibition. Long-term cultivation of cardiomyocytes with treprostinil did not modify load free cell shortening of these cells, but reduces the duration of contraction. CONCLUSIONS AND IMPLICATIONS: We conclude that the clinically used prostanoid treprostinil potentiates the positive inotropic effects of catecholamines in adult ventricular cardiomyocytes. This newly described effect may contribute to the beneficial clinical effects of prostanoids in patients with PAH.

[Pulmonary hypertension due to chronic lung disease: Recommendations of the Cologne Consensus Conference 2016]. / Pulmonale Hypertonie bei Lungenkrankheiten: Empfehlungen der Kölner Konsensus-Konferenz 2016.

The 2015 European Guidelines on Pulmonary Hypertension did not cover only pulmonary arterial hypertension (PAH) but also some aspects of pulmonary hypertension (PH) associated with chronic lung disease. The European Guidelines point out that the drugs currently used to treat patients with PAH (prostanoids, endothelin receptor antagonists, phosphodiesterase-5 inhibitors, sGC stimulators) have not been sufficiently investigated in other forms of PH. Therefore, the European Guidelines do not recommend the use of these drugs in patients with chronic lung disease and PH. This recommendation, however, is not always in agreement with medical ethics as physicians feel sometimes inclined to treat other form of PH which may affect quality of life and survival of these patients in a similar manner. To this end, it is crucial to consider the severity of both PH and the underlying lung disease. In June 2016, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany, to discuss open and controversial issues surrounding the practical implementation of the European Guidelines. Several working groups were initiated, one of which was dedicated to the diagnosis and treatment of PH in patients with chronic lung disease. The recommendations of this working group are summarized in the present paper.

Abnormal pulmonary artery pressure response in asymptomatic carriers of primary pulmonary hypertension gene.

BACKGROUND: Familial primary pulmonary hypertension (PPH) is an autosomal-dominant inherited disease with incomplete penetrance and poor prognosis. This study was performed to examine whether asymptomatic carriers of a mutated PPH gene can be identified at an early stage by their pulmonary artery systolic pressure (PASP) response to exercise. METHODS AND RESULTS: Stress Doppler echocardiography during supine bicycle exercise and genetic linkage analysis were performed on 52 members of 2 families with PPH. In 4 PPH patients, the mean PASP was increased at rest (73+/-16 mm Hg). Fourteen additional family members with normal PASP at rest revealed an abnormal PASP response to exercise (from 23+/-4 to 56+/-11 mm Hg) without secondary cause (abnormal response [AR] group). Twenty-seven other members (NR group) revealed a normal PASP response (maximal pressure <40 mm Hg) to exercise (from 24+/-4 to 37+/-3 mm Hg, P<0. 0001). All 14 AR but only 2 NR members shared the risk haplotype with the PPH patients. The molecular genetic analysis supported linkage to chromosome 2q31-32 with a logarithm of the odds score of 4.4 when the 4 patients and the 14 AR members were classified as affected. CONCLUSIONS: We conclude that the pathological rise of PASP in asymptomatic family members is linked to chromosome 2q31-32 and is probably an early sign of PPH. Therefore, stress Doppler echocardiography may be a useful tool to identify persons at risk for PPH even before pulmonary artery pressures at rest are elevated.

Atrial natriuretic peptide in severe primary and nonprimary pulmonary hypertension: response to iloprost inhalation.

OBJECTIVES: The goal of this study was to assess atrial natriuretic peptide (ANP) levels during inhalation of iloprost in severe primary (PPH) and nonprimary pulmonary hypertension (NPPH). BACKGROUND: The ANP system is activated in pulmonary hypertension and may help protect from right ventricular (RV) decompensation. It is unknown if ANP regulation is the same in severe PPH and NPPH and if the dynamic regulation is intact in a highly activated ANP system. METHODS: In 11 patients with PPH and seven patients with NPPH, right heart catheter investigations were performed. Pulmonary and systemic artery ANP and cyclic guanosine monophosphate (cGMP) levels as well as hemodynamics were measured before and after iloprost inhalation. RESULTS: The baseline hemodynamics of patients with PPH and patients with NPPH were comparable (mean pulmonary artery pressure [mPAP]: 61 +/- 5 mm Hg vs. 52 +/- 5 mm Hg, pulmonary vascular resistance [PVR]: 1,504 +/- 153 dyne.s.cm(-5) vs. 1,219 +/- 270 dyne.s.cm(-5). Atrial natriuretic peptide and cGMP levels were increased about tenfold and fivefold compared with controls in both PPH and NPPH. Iloprost inhalation significantly decreased mPAP (-9.1 +/- 2.5 mm Hg vs. -7.9 +/- 1.5 mm Hg), PVR (-453 +/- 103 dyne.s.cm(-5) vs. -381 +/- 114 dyne.s.cm(-5)), ANP (-99 +/- 63 pg/ml vs. -108 +/- 47 pg/ml) and cGMP (-4.6 +/- 0.9 nM vs. -4.2 +/- 1.6 nM). Baseline ANP including all patients significantly correlated with PVR, right atrial pressure, cardiac index, RV ejection fraction, mixed venous oxygen saturation and cGMP. CONCLUSIONS: The ANP system is highly activated in patients with severe PPH and NPPH. Atrial natriuretic peptide levels are significantly correlated with parameters of RV function and pre- and afterload. Iloprost inhalation causes a rapid decrease in ANP and cGMP in parallel with pulmonary vasodilation and hemodynamic improvement.

A comparison of the acute hemodynamic effects of inhaled nitric oxide and aerosolized iloprost in primary pulmonary hypertension. German PPH study group.

OBJECTIVE: We sought to compare the acute hemodynamic effects of inhaled nitric oxide (NO) and aerosolized iloprost in primary pulmonary hypertension (PPH). BACKGROUND: Inhalation of the stable prostacyclin analogue iloprost has recently been described as a novel therapeutic strategy for PPH and may offer an alternative to continuous intravenous infusion of prostacyclin or inhalation of NO. METHODS: During right heart catheterization, 35 patients with PPH sequentially inhaled 40 ppm of NO and 14 to 17 microg of iloprost, and the effects on hemodynamics and blood gases were monitored. RESULTS: Both NO and iloprost caused significant increases in cardiac output, mixed-venous oxygen saturation and stroke volume as well as significant decreases in pulmonary artery pressure and pulmonary vascular resistance, whereas only inhaled iloprost significantly increased the arterial PO2 (p = 0.01). Compared with inhaled NO, aerosolized iloprost was more effective in reducing pulmonary artery pressure (-8.3 +/- 7.5 mm Hg vs. -4.3 +/- 8.8 mm Hg; p = 0.0001) and the pulmonary vascular resistance (-447 +/- 340 dynes x s x cm(-5) vs. -183 +/- 305 dyne x s x cm(-5); p < 0.0001). Furthermore, aerosolized iloprost caused a significantly greater increase of the cardiac output compared with NO (+0.7 +/- 0.6 liter/min vs. +0.3 +/- 0.4 liter/min; p = 0.0002) and had a more pronounced effect on the mixed-venous oxygen saturation (p = 0.003). CONCLUSIONS: During acute drug testing, aerosolized iloprost was more potent than inhaled NO as a pulmonary vasodilator in PPH at the doses used in this study.

Molecular and functional analysis identifies ALK-1 as the predominant cause of pulmonary hypertension related to hereditary haemorrhagic telangiectasia.

BACKGROUND: Mutations of the transforming growth factor beta (TGFbeta) receptor components ENDOGLIN and ALK-1 cause the autosomal dominant vascular disorder hereditary haemorrhagic telangiectasia (HHT). Heterozygous mutations of the type II receptor BMPR2 underlie familial primary pulmonary hypertension. OBJECTIVE: To investigate kindreds presenting with both pulmonary hypertension and HHT. METHODS: Probands and families were identified by specialist pulmonary hypertension centres in five countries. DNA sequence analysis of ALK-1, ENDOGLIN, and BMPR2 was undertaken. Cellular localisation was investigated by heterologous overexpression of mutant constructs in both BAEC and HeLa cells. The impact of a novel sequence variant was assessed through comparative analysis and computer modelling. RESULTS: Molecular analysis of 11 probands identified eight missense mutations of ALK-1, one of which was observed in two families. Mutations were located within exons 5 to 10 of the ALK-1 gene. The majority of ALK-1 mutant constructs appeared to be retained within the cell cytoplasm, in the endoplasmic reticulum. A novel GS domain mutation, when overexpressed, reached the cell surface but is predicted to disrupt conformational changes owing to loss of a critical hydrogen bond. Two novel missense mutations were identified in ENDOGLIN. CONCLUSIONS: The association of pulmonary arterial hypertension and HHT identifies an important disease complication and appears most common among subjects with defects in ALK-1 receptor signalling. Future studies should focus on detailed molecular analysis of the common cellular pathways disrupted by mutations of ALK-1 and BMPR2 that cause inherited pulmonary vascular disease.

PCK2 activation mediates an adaptive response to glucose depletion in lung cancer.

Cancer cells are reprogrammed to utilize glycolysis at high rates, which provides metabolic precursors for cell growth. Consequently, glucose levels may decrease substantially in underperfused tumor areas. Gluconeogenesis results in the generation of glucose from smaller carbon substrates such as lactate and amino acids. The key gluconeogenic enzyme, phosphoenolpyruvate carboxykinase (PEPCK), has been shown to provide metabolites for cell growth. Still, the role of gluconeogenesis in cancer is unknown. Here we show that the mitochondrial isoform of PEPCK (PCK2) is expressed and active in three lung cancer cell lines and in non-small cell lung cancer samples. PCK2 expression and activity were enhanced under low-glucose conditions. PEPCK activity was elevated threefold in lung cancer samples over normal lungs. To track the conversion of metabolites along the gluconeogenesis pathway, lung cancer cell lines were incubated with (13)C3-lactate and label enrichment in the phosphoenolpyruvate (PEP) pool was measured. Under low glucose, all three carbons from (13)C3-lactate appeared in the PEP pool, further supporting a conversion of lactate to pyruvate, via pyruvate carboxylase to oxaloacetate, and via PCK2 to phosphoenolpyruvate. PCK2 small interfering RNA and the pharmacological PEPCK inhibitor 3-mercaptopicolinate significantly enhanced glucose depletion-induced apoptosis in A549 and H23 cells, but not in H1299 cells. The growth of H23 multicellular spheroids was significantly reduced by 3-mercaptopicolinate. The results of this study suggest that lung cancer cells may utilize at least some steps of gluconeogenesis to overcome the detrimental metabolic situation during glucose deprivation and that in human lung cancers this pathway is activated in vivo.

Advantage of buffered solutions or automated capnometry in air-filled balloons for use in gastric tonometry.

OBJECTIVE: To test accuracy, reproducibility and time constants of pCO2 measurement with the tonometric technique, using different media for filling the silastic balloon (saline, phosphate buffer, citrate buffer, air) and employing different analyzer devices (ABL3, ABL330, Nova Stat 5, automated capnometry). DESIGN: Comparative laboratory study of different tonometric techniques, measuring test solutions with known pCO2 values due to pre-equilibration with three different pCO2 concentrations. SETTING: Clinical laboratory of a university hospital intensive care unit. MEASUREMENTS AND RESULTS: The use of saline, as suggested for routine tonometry, led to negative bias values throughout, i.e. underestimation of pCO2 values, the extent of which depended on the blood gas analyzer device employed. Registration of the equilibration kinetics showed that full equilibration demanded 90 min regardless of the environmental pCO2 level. Replacing saline by buffered electrolyte solutions resulted in a significant improvement of bias, but did not change the kinetics of pCO2 equilibration. The employment of air-filled balloons, combined with automated capnometry, led to very low bias values, approaching zero, for all pCO2 levels, along with excellent precision. Time constants of equilibration were dramatically reduced, with full equilibration being achieved within 12.5 min. CONCLUSIONS: Buffered electrolyte solutions are preferable to saline for achieving reliable pCO2 measurements in gastric tonometry. Air-filled balloons, combined with automated capnometry, present excellent accuracy and reproducibility together with short equilibration times, thus offering "on-line" monitoring of even rapid changes in environmental pCO2.