Pulmonary Vascular Response Research Articles

Long-Term Chronic Intermittent Hypobaric Hypoxia in Rats Causes an Imbalance in the Asymmetric Dimethylarginine/Nitric Oxide Pathway and ROS Activity: A Possible Synergistic Mechanism for Altitude Pulmonary Hypertension?

Chronic intermittent hypoxia (CIH) and chronic hypoxia (CH) are associated with high-altitude pulmonary hypertension (HAPH). Asymmetric dimethylarginine (ADMA), a NO synthase (NOS) inhibitor, may contribute to HAPH. This study assessed changes in the ADMA/NO pathway and the underlying mechanisms in rat lungs following exposure to CIH or CH simulated in a hypobaric chamber at 428 Torr. Twenty-four adult Wistar rats were randomly assigned to three groups: CIH2x2 (2 days of hypoxia/2 days of normoxia), CH, and NX (permanent normoxia), for 30 days. All analyses were performed in whole lung tissue. L-Arginine and ADMA were analyzed using LC-MS/MS. Under both hypoxic conditions right ventricular hypertrophy was observed (p < 0.01) and endothelial NOS mRNA increased (p < 0.001), but the phosphorylated/nonphosphorylated vasodilator-stimulated phosphoprotein (VASP) ratio was unchanged. ADMA increased (p < 0.001), whereas dimethylarginine dimethylaminohydrolase (DDAH) activity decreased only under CH (p < 0.05). Although arginase activity increased (p < 0.001) and L-arginine exhibited no changes, the L-arginine/ADMA ratio decreased significantly (p < 0.001). Moreover, NOX4 expression increased only under CH (p < 0.01), but malondialdehyde (MDA) increased (up to 2-fold) equally in CIH2x2 and CH (p < 0.001). Our results suggest that ADMA and oxidative stress likely reduce NO bioavailability under altitude hypoxia, which implies greater pulmonary vascular reactivity and tone, despite the more subdued effects observed under CIH.

Age-related upper limits of normal for maximum upright exercise pulmonary haemodynamics.

The exercise definition of pulmonary hypertension was eliminated from the pulmonary hypertension guidelines in part due to uncertainty of the upper limits of normal (ULNs) for exercise haemodynamics in subjects >50 years old.The present study, therefore, evaluated the pulmonary haemodynamic responses to maximum upright incremental cycling exercise in consecutive subjects who underwent an invasive cardiopulmonary exercise testing for unexplained exertional intolerance, deemed normal based on preserved exercise capacity and normal resting supine haemodynamics. Subjects aged >50 years old (n=41) were compared with subjects ≤50 years old (n=25). ULNs were calculated as mean + 2 sdPeak exercise mean pulmonary arterial pressure was not different for subjects >50 and ≤50 years old (23 ± 5 versus 22 ± 4 mmHg, p=0.22), with ULN of 33 and 30 mmHg, respectively. Peak cardiac output was lower in older subjects (median (interquartile range): 12.1 (9.4-14.2)versus16.2 (13.8-19.2) L·min(-1), p<0.001). Peak pulmonary vascular resistance was higher in older subjects compared with younger subjects (mean ± sd: 1.20 ± 0.45 versus 0.82 ± 0.26 Wood units, p<0.001), with ULN of 2.10 and 1.34 Wood units, respectively.We observed that subjects >50 and ≤ 50 years old have different pulmonary vascular responses to exercise. Older subjects have higher pulmonary vascular resistance at peak exercise, resulting in different exercise haemodynamics ULNs compared with the younger population.

Hepatic Shunting of Eggs and Pulmonary Vascular Remodeling in Bmpr2(+/-) Mice with Schistosomiasis.

Schistosomiasis is a major cause of pulmonary arterial hypertension (PAH). Mutations in the bone morphogenetic protein type-II receptor (BMPR-II) are the commonest genetic cause of PAH. To determine whether Bmpr2(+/-) mice are more susceptible to schistosomiasis-induced pulmonary vascular remodeling. Wild-type (WT) and Bmpr2(+/-) mice were infected percutaneously with Schistosoma mansoni. At 17 weeks postinfection, right ventricular systolic pressure and liver and lung egg counts were measured. Serum, lung and liver cytokine, pulmonary vascular remodeling, and liver histology were assessed. By 17 weeks postinfection, there was a significant increase in pulmonary vascular remodeling in infected mice. This was greater in Bmpr2(+/-) mice and was associated with an increase in egg deposition and cytokine expression, which induced pulmonary arterial smooth muscle cell proliferation, in the lungs of these mice. Interestingly, Bmpr2(+/-) mice demonstrated dilatation of the hepatic central vein at baseline and postinfection, compared with WT. Bmpr2(+/-) mice also showed significant dilatation of the liver sinusoids and an increase in inflammatory cells surrounding the central hepatic vein, compared with WT. This is consistent with an increase in the transhepatic passage of eggs. This study has shown that levels of BMPR-II expression modify the pulmonary vascular response to chronic schistosomiasis. The likely mechanism involves the increased passage of eggs to the lungs, caused by altered diameter of the hepatic veins and sinusoids in Bmpr2(+/-) mice. Genetically determined differences in the remodeling of hepatic vessels may represent a new risk factor for PAH associated with schistosomiasis.

C1q Deficiency Promotes Pulmonary Vascular Inflammation and Enhances the Susceptibility of the Lung Endothelium to Injury

The collectin proteins are innate immune molecules found in high concentrations on the epithelial and endothelial surfaces of the lung. While these proteins are known to have important anti-inflammatory actions in the airways of the lung little is known of their functional importance in the pulmonary circulation. We recently demonstrated that the circulating collectin protein adiponectin has potent anti-inflammatory effects on the lung endothelium, leading us to reason that other structurally related proteins might have similar effects. To test this hypothesis, we investigated the anti-inflammatory actions of C1q in lung endothelial homeostasis and the pulmonary vascular response to LPS or HCl injury. We show that lung endothelium from C1q-deficient (C1q(-/-)) mice expresses higher baseline levels of the vascular adhesion markers ICAM-1, VCAM-1, and E-selectin when compared with wild-type mice. Further, we demonstrate that these changes are associated with enhanced susceptibility of the lung to injury as evident by increased expression of adhesion markers, enhanced production of pro-inflammatory cytokines, and augmented neutrophil recruitment. Additionally, we found that C1q(-/-) mice also exhibited enhanced endothelial barrier dysfunction after injury as manifested by decreased expression of junctional adherens proteins and enhanced vascular leakage. Mechanistically, C1q appears to mediate its effects by inhibiting phosphorylation of p38 mitogen-activated protein kinase (MAPK) and blocking nuclear translocation of the P65 subunit of nuclear factor (NF)-κB. In summary, our findings indicate a previously unrecognized role for C1q in pulmonary vascular homeostasis and provide added support for the hypothesis that circulating collectin proteins have protective effects on the lung endothelium.

Editorial: Pediatric Pulmonary Hypertension.

Editorial: Pediatric Pulmonary Hypertension.

Oxygen transport adaptations to exercise in native highland populations.

Oxygen transport adaptations to exercise in native highland populations.

OC21.01: Assessment of fetal pulmonary artery pulsatility during maternal hyperoxygenation: a reliable index of pulmonary vascular reactivity?*

OC21.01: Assessment of fetal pulmonary artery pulsatility during maternal hyperoxygenation: a reliable index of pulmonary vascular reactivity?^*

Leukocyte expression of heme oxygenase-1 [hmox1] varies inversely with severity of tricuspid regurgitation in acute pulmonary embolism

ObjectivePulmonary embolism (PE) can cause intracardiac hemolysis and increased plasma hemoglobin and arginase-1, which can worsen pulmonary vasoconstriction. We test the hypothesis that patients with PE that causes tricuspid regurgitation (TR), indicative of higher pulmonary arterial pressures, have decreased leukocyte expression of hmox-1 compared with patients with PE and no TR and patients without PE. DesignProspective, noninterventional study. PatientsNormotensive patients with suspected PE (n=87) who underwent CT pulmonary angiography and transthoracic Doppler-echocardiography. MeasurementsSignificant TR was defined as a jet velocity >2.7m/s. Leukocyte expression of hmox-1, haptoglobin, haptoglobin related gene, the haptoglobin receptor, CD163 and cox-2 genes were assessed by quantitative rtPCR, and the hmox-1 promoter was examined for the −413 A→T SNP and GT repeat polymorphisms. ResultsOf the 44 (50%) with PE+, 22 had TR+, and their mean pulmonary vascular occlusion (39±32%) did not differ significantly from patients who were TR− (28±26%, P=0.15). Patients with PE+ and TR+ had significantly lower expression of hmox-1 and haptoglobin genes than patients without PE+ and no TR. Expression of hmox-1 varied inversely with TR velocity (r2=0.45, P<0.001) for PE+ (n=22) but not patients without PE. Hmox-1 expression did not vary significantly with genotype. Cox-2 did not differ between groups and had no correlation with TR. ConclusionsSeverity of TR varied inversely with hmox-1 expression, suggesting that hmox-1 expression affects pulmonary vascular reactivity after PE.

Rebuttal to the Con Statement.

There is no large overlap in the variables derived from our exercise testing. In any clinical score, for example, the Framingham score for cardiovascular diseases, there is a large overlap for individual makers. For example, you may have a high value of systemic arterial pressure, you may be at low risk if this is not associated with other risk factors such as high cholesterol or inactivity. The proper use of sophisticated statistical analyses such as the one used in our previous study (Richalet et al., 2012) is that you take into account a combination of risk factors. The usefulness of our test cannot be evaluated only by the 7% increase in AUC. The best tool to evaluate the benefits of a new score is the Net Reclassification Index. We showed that adding the physiological variables to the model of prediction allowed us to correctly re-classify 30% of subjects with previous experience at high altitude and 54% of subjects with no previous experience. This is a very clear gain of efficiency, as mentioned in the recent paper validating the risk prediction score (Canoui-Poitrine et al., 2014). Even if only one third of the participants returned their questionnaire, this cohort is still the largest ever studied. Moreover, there was no difference in the clinical or physiological characteristics between the responders and the nonresponders, so that no argument is available to suppose that this could be a bias in the prediction model. Pre-acclimatization is clearly a protecting factor for SHAI. However, from a practical point of view, this is not relevant since people who come to the consultation before a planned trip to high altitude are not acclimatized, unless they live permanently at high altitude, which is rarely the case, at least in Europe (Richalet et al., 2013). The strength of our study is the large number of subjects, which was obtained by pooling all severe cases (severe AMS, HAPE, HACE). This is a crucial point, which derives from our definition of SHAI. Our approach, here, is not mechanistic, looking at the precise pathophysiological causes of HAPE or HACE, although we address the basic common reason of all severe manifestations, i.e., severe hypoxemia, whatever the following effects on the lungs or on the brain. Our approach is very practical for a physician meeting with a person who wants to know his own level of risk. The common trait of all SHAI manifestations is that the subject has to stop his trip and take urgent measures (such as descent, re-oxygenation, drugs, etc.). With the standards of epidemiological studies (cancer, cardiovascular, etc.) no score has ever been proposed with small groups of patients such as the ones mentioned by Bartsch (2014) with pulmonary vascular response to hypoxia or exercise. Therefore, we can bet that there will never be any study capable to propose a specific risk score for HAPE or HACE, due to the small number of cases, unless we develop a very large multicentric study regrouping all mountain medicine consultations around the world. This is our proposal!

The zinc transporter ZIP12 regulates the pulmonary vascular response to chronic hypoxia.

The typical response of the adult mammalian pulmonary circulation to a low oxygen environment is vasoconstriction and structural remodelling of pulmonary arterioles, leading to chronic elevation of pulmonary artery pressure (pulmonary hypertension) and right ventricular hypertrophy. Some mammals, however, exhibit genetic resistance to hypoxia-induced pulmonary hypertension1-3. We used a congenic breeding program and comparative genomics to exploit this variation in the rat and identified the gene, Slc39a12, as a major regulator of hypoxia-induced pulmonary vascular remodelling. Slc39a12 encodes the zinc transporter, ZIP12. We report that ZIP12 expression is increased in many cell types, including endothelial, smooth muscle and interstitial cells, in the remodelled pulmonary arterioles of rats, cows and humans susceptible to hypoxia-induced pulmonary hypertension. We show that ZIP12 expression in pulmonary vascular smooth muscle cells is hypoxia-dependent and that targeted inhibition of ZIP12 inhibits the rise in intracellular labile zinc in hypoxia-exposed pulmonary vascular smooth muscle cells and their proliferation in culture. We demonstrate that genetic disruption of ZIP12 expression attenuates the development of pulmonary hypertension in rats housed in a hypoxic atmosphere. This entirely novel and unexpected insight into the fundamental role of a zinc transporter in mammalian pulmonary vascular homeostasis suggests a new drug target for the pharmacological management of pulmonary hypertension.

Genetic deficit of KCa 3.1 channels protects against pulmonary circulatory collapse induced by TRPV4 channel activation.

The intermediate conductance calcium/calmodulin-regulated K+ channel KCa 3.1 produces hyperpolarizing K+ currents that counteract depolarizing currents carried by transient receptor potential (TRP) channels, and provide the electrochemical driving force for Cl- and fluid movements. We investigated whether a deficiency in KCa 3.1 (KCa 3.1-/- ) protects against fatal pulmonary circulatory collapse in mice after pharmacological activation of the calcium-permeable TRP subfamily vanilloid type 4 (TRPV4) channels. An opener of TRPV4 channels, GSK1016790A, was infused in wild-type (wt) and KCa 3.1-/- mice; haemodynamic parameters, histology and pulmonary vascular reactivity were measured; and patch clamp was performed on pulmonary arterial endothelial cells (PAEC). In wt mice, GSK1016790A decreased right ventricular and systemic pressure leading to a fatal circulatory collapse that was accompanied by increased protein permeability, lung haemorrhage and fluid extravasation. In contrast, KCa 3.1-/- mice exhibited a significantly smaller drop in pressure to GSK1016790A infusion, no haemorrhage and fluid water extravasation, and the mice survived. Moreover, the GSK1016790A-induced relaxation of pulmonary arteries of KCa 3.1-/- mice was significantly less than that of wt mice. GSK1016790A induced TRPV4 currents in PAEC from wt and KCa 3.1-/- mice, which co-activated KCa 3.1 and disrupted membrane resistance in wt PAEC, but not in KCa 3.1-/- PAEC. Our findings show that a genetic deficiency of KCa 3.1 channels prevented fatal pulmonary circulatory collapse and reduced lung damage caused by pharmacological activation of calcium-permeable TRPV4 channels. Therefore, inhibition of KCa 3.1channels may have therapeutic potential in conditions characterized by abnormal high endothelial calcium signalling, barrier disruption, lung oedema and pulmonary circulatory collapse.

Hemodynamic Characteristics Including Pulmonary Hypertension at Rest and During Exercise Before and After Heart Transplantation.

BackgroundLittle is known about the hemodynamic response to exercise in heart failure patients at various ages before and after heart transplantation (HT). This information is important because postoperative hemodynamics may be a predictor of survival. To investigate the hemodynamic response to HT and exercise, we grouped our patients based on preoperative age and examined their hemodynamics at rest and during exercise before and after HT.Methods and ResultsNinety-four patients were evaluated at rest prior to HT with right heart catheterization at our laboratory. Of these patients, 32 were evaluated during slight supine exercise before and 1 year after HT. Postoperative evaluations were performed at rest 1 week after HT and at rest and during exercise at 4 weeks, 3 months, 6 months, and 1 year after HT. The exercise patients were divided into 2 groups based on preoperative age of ≤50 or >50 years. There were no age-dependent differences in the preoperative hemodynamic exercise responses. Hemodynamics markedly improved at rest and during exercise at 1 and 4 weeks, respectively, after HT; however, pulmonary and, in particular, ventricular filling pressures remained high during exercise at 1 year after HT, resulting in normalized pulmonary vascular resistance response but deranged total pulmonary vascular resistance response.ConclusionsOur findings suggest that, (1) in patients with heart failure age ≤50 or >50 years may not affect the hemodynamic response to exercise to the same extent as in healthy persons, and (2) total pulmonary vascular resistance may be more adequate than pulmonary vascular resistance for evaluating the exercise response after HT.

Effects of gender on severity and pulmonary artery vascular reactivity in chronic hypoxic pulmonary hypertension in mice

To explore the effects of gender on pathology and pulmonary vascular reactivity in chronic hypoxic pulmonary hypertension (HPH) in mice. HPH was induced by a 4-week exposure of male and female mice (8 weeks old C57BL/6, n = 15 each) to chronic hypoxia (10%O2). Normoxic controls were established both in male and female groups (n = 15 each). Right ventricular systolic pressure (RVSP) and Fulton index were detected.Isolated pulmonary artery ring contraction induced by high potassium (K(+)) and U-46619 was recorded and compared between two groups. Chronic hypoxia induced pulmonary hypertension after 4 weeks.RVSP significantly increased both in hypoxic female and male groups (normoxic vs hypoxic: (23.40 ± 0.16) vs (31.46 ± 2.33) and (24.71 ± 0.44) vs (33.66 ± 1.38) mmHg (1 mmHg = 0.133 kPa), P = 0.029 and P < 0.001).However, there were no inter-group differences (P = 0.447). The Fulton index of hypoxic female and male mice was higher than normoxic counterparts (P = 0.001, P < 0.001). But there were no gender differences (P = 0.471). Contraction of high K(+) and U-46619 was calcium ion (Ca(2+))-dependent and decreased markedly without calcium (P < 0.001, P = 0.007). High K(+) and U-46619-induced contraction of pulmonary artery was concentration dependent and greater in chronic hypoxic female (P = 0.002, P < 0.001) and male mice (both P < 0.001). But no differences existed between male and female mice in high K(+) (P = 0.657) or U-46619 (P = 0.751)-induced contraction. No significant correlation exists between gender and occurrence and severity of pulmonary hypertension or pulmonary artery vascular reactivity in HPH mice.

Determinants of ventilation and pulmonary artery pressure during early acclimatization to hypoxia in humans.

Key points Lung ventilation and pulmonary artery pressure rise progressively in response to 8 h of hypoxia, changes described as ‘acclimatization to hypoxia’. Acclimatization responses differ markedly between humans for unknown reasons.We explored whether the magnitudes of the ventilatory and vascular responses were related, and whether the degree of acclimatization could be predicted by acute measurements of ventilatory and vascular sensitivities.In 80 healthy human volunteers measurements of acclimatization were made before, during, and after a sustained exposure to 8 h of isocapnic hypoxia.No correlation was found between measures of ventilatory and pulmonary vascular acclimatization.The ventilatory chemoreflex sensitivities to acute hypoxia and hypercapnia all increased in proportion to their pre‐acclimatization values following 8 h of hypoxia. The peripheral (rapid) chemoreflex sensitivity to CO2, measured before sustained hypoxia against a background of hyperoxia, was a modest predictor of ventilatory acclimatization to hypoxia. This finding has relevance to predicting human acclimatization to the hypoxia of altitude. Pulmonary ventilation and pulmonary arterial pressure both rise progressively during the first few hours of human acclimatization to hypoxia. These responses are highly variable between individuals, but the origin of this variability is unknown. Here, we sought to determine whether the variabilities between different measures of response to sustained hypoxia were related, which would suggest a common source of variability. Eighty volunteers individually underwent an 8‐h isocapnic exposure to hypoxia (end‐tidal P O2=55 Torr) in a purpose‐built chamber. Measurements of ventilation and pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography were made during the exposure. Before and after the exposure, measurements were made of the ventilatory sensitivities to acute isocapnic hypoxia (GpO2) and hyperoxic hypercapnia, the latter divided into peripheral (G pC O2) and central (G cC O2) components. Substantial acclimatization was observed in both ventilation and PASP, the latter being 40% greater in women than men. No correlation was found between the magnitudes of pulmonary ventilatory and pulmonary vascular responses. For GpO2, G pC O2 and G cC O2, but not the sensitivity of PASP to acute hypoxia, the magnitude of the increase during acclimatization was proportional to the pre‐acclimatization value. Additionally, the change in GpO2 during acclimatization to hypoxia correlated well with most other measures of ventilatory acclimatization. Of the initial measurements prior to sustained hypoxia, only G pC O2 predicted the subsequent rise in ventilation and change in GpO2 during acclimatization. We conclude that the magnitudes of the ventilatory and pulmonary vascular responses to sustained hypoxia are predominantly determined by different factors and that the initial G pC O2 is a modest predictor of ventilatory acclimatization.

Pulmonary Artery Pressure Response to Simulated Air Travel in a Hypobaric Chamber.

Hypoxia-induced elevation in pulmonary artery pressure during air travel may contribute to the worldwide burden of in-flight medical emergencies. The pulmonary artery pressure response may be greater in older passengers, who are more likely to require flight diversion due to a medical event. Understanding these effects may ultimately improve the safety of air travel. We studied 16 healthy volunteers, consisting of a younger group (aged <25 yr) and an older group (aged >60 yr). Using a hypobaric chamber, subjects undertook a 2-h simulated flight at the maximum cabin pressure altitude for commercial airline flights (8000 ft; 2438 m). Higher and lower altitudes within the aeromedical range were also explored. Systolic pulmonary artery pressure (sPAP) was assessed by Doppler echocardiography. There was a progressive increase in sPAP which appeared to be biphasic, with a small initial increase and a larger subsequent rise. Overall, sPAP increased by 5±1 mmHg from baseline to 35±1 mmHg at 8000 ft, an increase of 18%. The sPAP response to 8000 ft was greater in the older group than the younger group. This study confirms that pulmonary artery pressure increases during simulated air travel, and provides preliminary evidence that this response is greater in older people. Advancing age may increase in-flight susceptibility to adverse pulmonary vascular responses in passengers, aircrew, and aeromedical patients.

Pulmonary vascular response patterns during exercise in interstitial lung disease

When overt pulmonary hypertension arises in interstitial lung disease (ILD), it contributes to exercise intolerance. We sought to determine the functional significance of abnormal pulmonary arterial pressure (PAP) responses to exercise in ILD.27 ILD patients and 11 age-matched controls underwent invasive cardiopulmonary exercise testing (iCPET). Mean PAP (mPAP) was indexed to cardiac output (Q'T) during exercise, with a mPAP-Q'T slope ≥3 mmHg·min·L(-1) defined as an abnormal pulmonary vascular response.All control subjects had mPAP-Q'T slopes <3 mmHg·min·L(-1) (mean±sem 1.5±0.1 mmHg·min·L(-1)). 15 ILD patients had mPAP-Q'T slopes ≥3 mmHg·min·L(-1) (4.1±0.2 mmHg·min·L(-1)) and were labelled as having ILD plus pulmonary vascular dysfunction (PVD). Subjects without pulmonary hypertension and with mPAP-Q´T slopes <3 mmHg·min·L(-1) (1.9±0. 2 mmHg·min·L(-1)) were labelled as ILD minus PVD (n=12). ILD+PVD and ILD-PVD patients did not differ in terms of age, sex, body mass index, pulmonary function testing or degree of exercise oxygen desaturation. Peak oxygen consumption was lower in ILD+PVD than in ILD-PVD (13.0±0.9 versus 17±1.1 mL·kg(-1)·min(-1), p=0.012) and controls (19.8±1.7 mL·kg(-1)·min(-1), p=0.003). ILD+PVD patients had increased dead space volume (VD)/tidal volume (VT) and minute ventilation/carbon dioxide production at the anaerobic threshold.In ILD, mPAP-Q'T slope ≥3 mmHg·min·L(-1) is associated with lower peak oxygen consumption, increased VD/VT and inefficient ventilation. While noninvasive parameters were unable to predict those with abnormal pulmonary vascular responses to exercise, iCPET-derived mPAP-Q'T slope may aid in identifying physiologically significant, early pulmonary vascular disease in ILD.

Pulmonary vascular and airway responses to systemic vasoconstrictors in anesthetized BALB/c mice.

There is no systematic study in which the effects of vasoactive substances were investigated on pulmonary vascular resistance (PVR) in in vivo mouse by directly measuring cardiac output and the inflow and outflow pressures in the pulmonary circulation. We determined the responses of PVR, total peripheral resistance (TPR), and airway pressure (AWP) to angiotensin II, endothelin-1, vasopressin, phenylephrine, and thromboxane A2 analog U46619 in anesthetized BALB/c mice. Pulmonary arterial pressure, left atrial pressure (LAP), and aortic blood flow were measured. TPR increased dose-dependently in response to consecutive administration of all vasoconstrictors except vasopressin which reduced TPR at the highest dose of 100 nmol/kg. At high doses of vasoconstrictors, pulmonary arterial pressure and AWP increased due to increased LAP, as demonstrated by the separate LAP elevation experiments. When LAP transiently increased at high doses, PVR did not increase but decreased. Nonetheless, enodothelin-1, angiotensin II, and U46619 increased PVR. Vasopressin at 100 nmol/kg increased AWP without LAP elevation. In conclusion, the high doses of the vasoconstrictors studied here exert indirectly a transient pulmonary vasodilatory and AWP increasing actions due to pulmonary congestion evoked by strong systemic vasoconstriction. Nevertheless, enodothelin-1, angiotensin II, and U46619 cause pulmonary vasoconstriction, and vasopressin constricts airway in anesthetized BALB/c mice.

AMP‐activated Protein Kinase is Necessary for Cardiorespiratory Adjustments during Hypoxia

The AMP‐activated protein kinase (AMPK) has been proposed to underpin appropriate cardiorespiratory adjustments during hypoxia (Evans et al., 2006), and has been identified as a mediator of hypoxic pulmonary vasoconstriction (HPV) (Evans et al., 2005). Our objective was to assess by non‐invasive Echo Doppler ultrasound, the effect(s) on HPV of deleting LKB1, CAMKK‐β or the AMPKα1 &amp; α2 catalytic subunits. Our preliminary investigations on wild type and transgenic mice suggest that the LKB1‐AMPK signalling pathway, but not CAMKK‐β, are required for HPV. Moreover, deletion of AMPK catalytic subunit(s) blocked hypoxia‐induced inhibition of voltage‐gated potassium currents (Kv) in acutely isolated pulmonary arterial smooth muscle cells. Therefore, AMPK underpins the regulation of pulmonary vascular responses to hypoxia at the molecular, cellular and system level.Evans et al. (2005). J. Biol Chem., 280, 41505‐41511.Evans (2006). J. Physiol., 574, 113‐123.

Comparison between the Acute Pulmonary Vascular Effects of Oxygen with Nitric Oxide and Sildenafil.

Objective: Right heart catheterization is performed in patients with pulmonary arterial hypertension to determine the severity of disease and their pulmonary vascular reactivity. The acute pulmonary vascular effect of inhaled nitric oxide is frequently used to identify patients who will respond favorably to long-term vasodilator therapy. This study sought to determine whether the acute pulmonary vascular effects of oxygen with nitric oxide and intravenous sildenafil are similar.Methods: A retrospective, descriptive study of 13 individuals with pulmonary hypertension who underwent heart catheterization and acute vasodilator testing was performed. The hemodynamic measurements during five phases (21–53% oxygen, 100% oxygen, 100% oxygen with 20 ppm nitric oxide, 21–51% oxygen, and 21–51% oxygen with 0.05–0.29 mg/kg intravenous sildenafil) of the procedures were compared using analysis of variance. A linear regression analysis and a Bland Altman plot were used to compare the percent change in mean pulmonary arterial pressure and the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil.Results: Mean pulmonary arterial pressure and pulmonary vascular resistance acutely decreased with 100% oxygen with nitric oxide and 21–51% oxygen with sildenafil. Pulmonary blood flow during sildenafil was greater than pulmonary blood flow during 100% oxygen and 100% oxygen with nitric oxide. The pH, right atrial pressure, and left atrial pressure did not change during the five phase of heart catheterization. Mean pulmonary arterial pressure (millimeter of mercury, mean ± standard error of the mean) was 38 ± 4 during 21–53% oxygen, 32 ± 3 during 100% oxygen, 29 ± 2 during 100% oxygen with nitric oxide, 37 ± 3 during 21–51% oxygen, and 32 ± 2 during 21–51% oxygen with sildenafil. There was not a significant correlation between the percent change in pulmonary vascular resistance from baseline with oxygen and nitric oxide, and from baseline with sildenafil (r2 = 0.011, p = 0.738). The Bland Altman analysis demonstrated statistical agreement between the effects of oxygen with nitric oxide and sildenafil. However, differences were large enough to limit the interchangeable use of these vasodilators in a clinical setting.Conclusion: Oxygen with nitric oxide and sildenafil decreased pulmonary vascular resistance. However, the pulmonary vascular effects of oxygen and nitric oxide do not reliably predict the acute response to sildenafil. Additional studies are needed to determine whether the acute response to sildenafil can be used to predict the long-term response to treatment with an oral phosphodiesterase V inhibitor.

Central cardiac limit to aerobic capacity in patients with exertional pulmonary venous hypertension: implications for heart failure with preserved ejection fraction.

The mechanism of functional limitation in heart failure with preserved ejection fraction remains controversial. We examined the contributions of central cardiac and peripheral mechanisms and hypothesized that the pulmonary vascular response to exercise is an important determinant of aerobic capacity among patients with exertional pulmonary venous hypertension (ePVH). We compared 31 ePVH patients (peak VO2<80% of predicted and peak pulmonary arterial wedge pressure≥20 mm Hg) with 31 age- and sex-matched controls (peak VO2>80% predicted) who underwent invasive cardiopulmonary exercise testing for unexplained exertional intolerance. ePVH patients had lower peak cardiac output (73±14% versus 103±18% predicted; P<0.001) compared with controls, related both to impaired chronotropic response (peak heart rate 111±25 beats per minute versus 136±24 beats per minute; P<0.001) and to reduced peak stroke volume index (47±10 mL/min per m(2) versus 54±15 mL/min per m(2); P=0.03). Peak systemic O2 extraction was not different between groups (arterial-mixed venous oxygen content difference: 13.0±2.1 mL/dL versus 13.4±2.4 mL/dL; P=0.46). ePVH patients had higher resting (150±74 versus 106±50 dyne/s per cm(-5); P=0.009), peak (124±74 dyne/s per cm(-5) versus 70±41 dyne/s per cm(-5); P<0.001), and isoflow pulmonary vascular resistance (124±74 dyne/s per cm(-5) versus 91±33 dyne/s per cm(-5) at cardiac output≈10.6 L/min; P=0.04). Pulmonary vascular resistance decreased with exercise in all control subjects but increased in 36% (n=11) of ePVH patients. Abnormal pulmonary vascular response was not associated with peak VO2. Reduced cardiac output response, rather than impaired peripheral O2 extraction, constrains oxygen delivery and aerobic capacity in ePVH. Pulmonary vascular dysfunction is common in patients with ePVH at rest and during exercise.