Biomedical subjects

C Sartori

Publications and source records attributed to C Sartori.

At least 19 recordsLinked to original sources

PubMed2004

High altitude impairs nasal transepithelial sodium transport in HAPE-prone subjects.

High-altitude pulmonary oedema (HAPE) occurs in predisposed individuals at altitudes >2,500 m. Defective alveolar fluid clearance secondary to a constitutive impairment of the respiratory transepithelial sodium transport contributes to its pathogenesis. Hypoxia impairs the transepithelial sodium transport in alveolar epithelial type II cells in vitro. If this impairment is also present in vivo, high-altitude exposure could aggravate the constitutive defect in sodium transport in HAPE-prone subjects, and thereby further facilitate pulmonary oedema. Therefore, the aim of the current study was to measure the nasal potential difference (PD) in 21 HAPE-prone and 29 HAPE-resistant subjects at low altitude and 30 h after arrival at high altitude (4,559 m). High-altitude exposure significantly decreased the mean +/- SD nasal PD in HAPE-prone (18.0 +/- 6.2 versus 12.5 +/- 6.8 mV) but not in HAPE-resistant subjects (25.6 +/- 9.4 versus 22.9 +/- 9.2 mV). This altitude-induced decrease was not associated with an altered amiloride-sensitive fraction, but was associated with a significantly lower amiloride-insensitive fraction of the nasal PD. These findings provide evidence in vivo that an environmental factor may impair respiratory transepithelial sodium transport in humans. They are consistent with the concept that in high-altitude pulmonary oedema-susceptible subjects, the combination of a constitutive and an acquired defect in this transport mechanism facilitates the development of pulmonary oedema during high-altitude exposure.

Adult↗

PubMed2003

Chromatin sphingomyelin changes in cell proliferation and/or apoptosis induced by ciprofibrate.

It has been shown that neutral-sphingomyelinase and sphingomyelin-synthase activities are present in chromatin and they modify the sphingomyelin (SM) content. The activity of the first enzyme is stimulated and the second inhibited, when the hepatocytes enter into the S-phase after partial hepatectomy, thus suggesting that ceramide may have a pivotal role in cell proliferation. An opposite function was attributed to ceramide in hepatocytes which undergo apoptosis after lobular ligature. In order to clarify this point, a model was developed in which the same liver cells undergo proliferation followed by induced apoptosis. To this purpose, the rats were treated for 7 days with ciprofibrate and then left without treatment for 4 days. During the treatment, the peroxisome enzyme markers increase their activity and the number of proliferating cells increases, reaching a maximum after 3 days of treatment, as shown by the number of cells positive for the proliferating cell nuclear antigen. At the same time, the chromatin sphingomyelinase activity reaches the maximum, while a similar increase is not found in the cytoplasm or in the isolated nuclei. On the contrary, SM-synthase activity is depressed in chromatin, but not in the nuclei in which a peak is shown after 3 days of ciprofibrate treatment. After drug withdrawal, the hepatocytes undergo apoptosis as confirmed by the increase of Bax and tissue transglutaminase (tTGase) expression; the chromatin SM increases as a consequence of an increase of SM-synthase activity. It can be hypothesised that chromatin SM may have a role in cell duplication by influencing the chromatin structure stability.

Animals↗

PubMed2002

Novel role for CFTR in fluid absorption from the distal airspaces of the lung.

The active absorption of fluid from the airspaces of the lung is important for the resolution of clinical pulmonary edema. Although ENaC channels provide a major route for Na(+) absorption, the route of Cl(-) transport has been unclear. We applied a series of complementary approaches to define the role of Cl(-) transport in fluid clearance in the distal airspaces of the intact mouse lung, using wild-type and cystic fibrosis Delta F508 mice. Initial studies in wild-type mice showed marked inhibition of fluid clearance by Cl(-) channel inhibitors and Cl(-) ion substitution, providing evidence for a transcellular route for Cl(-) transport. In response to cAMP stimulation by isoproterenol, clearance was inhibited by the CFTR inhibitor glibenclamide in both wild-type mice and the normal human lung. Although isoproterenol markedly increased fluid absorption in wild-type mice, there was no effect in Delta F508 mice. Radioisotopic clearance studies done at 23 degrees C (to block active fluid absorption) showed approximately 20% clearance of (22)Na in 30 min both without and with isoproterenol. However, the clearance of (36)Cl was increased by 47% by isoproterenol in wild-type mice but was not changed in Delta F508 mice, providing independent evidence for involvement of CFTR in cAMP-stimulated Cl(-) transport. Further, CFTR played a major role in fluid clearance in a mouse model of acute volume-overload pulmonary edema. After infusion of saline (40% body weight), the lung wet-to-dry weight ratio increased by 28% in wild-type versus 64% in Delta F508 mice. These results provide direct evidence for a functionally important role for CFTR in the distal airspaces of the lung.

Absorption↗

PubMed2002

Selected contribution: long-term effects of beta(2)-adrenergic receptor stimulation on alveolar fluid clearance in mice.

Stimulation of active fluid transport with beta-adrenergic receptor (betaAR) agonists can accelerate the resolution of alveolar edema. However, chronic betaAR-agonist administration may cause betaAR desensitization and downregulation that may impair physiological responsiveness to betaAR-agonist stimulation. Therefore, we measured baseline and terbutaline- (10(-3) M) stimulated alveolar fluid clearance in mice that received subcutaneously (miniosmotic pumps) either saline or albuterol (2 mg. kg(-1). day(-1)) for 1, 3, or 6 days. Continuous albuterol administration increased plasma albuterol levels (10(-5) M), an effect that was associated with 1) a significant decrease in betaAR density and 2) attenuation, but not ablation, of maximal terbutaline-induced cAMP production. Forskolin-mediated cAMP-release was unaffected. Continuous albuterol infusion stimulated alveolar fluid clearance on day 1 but did not increase alveolar fluid clearance on days 3 and 6. However, terbutaline-stimulated alveolar fluid clearance in albuterol-treated mice was not reduced compared with saline-treated mice. Despite significant reductions in betaAR density and agonist-mediated cAMP production by long-term betaAR-agonist exposure, maximal betaAR-agonist-mediated increase in alveolar fluid clearance is not diminished in mice.

Adrenergic beta-Agonists↗

PubMed2002

Alveolar epithelial fluid transport in acute lung injury: new insights.

Pulmonary oedema is a life-threatening condition that frequently leads to acute respiratory failure. From a physiological perspective, pulmonary oedema develops either because of an increase in lung vascular hydrostatic pressure or an increase in lung vascular permeability. Resolution of alveolar oedema depends on the active removal of salt and water from the distal air spaces of the lung across the distal lung epithelial barrier. Much has been learned about the molecular and cellular basis for oedema fluid reabsorption, including the role of apical ion transporters for sodium (epithelial sodium channel) and chloride (cystic fibrosis transmembrane conductance regulator), as well as the central importance of the sodium pump. The rate of fluid clearance can be upregulated by both catecholamine-dependent and -independent mechanisms. Injury to the alveolar epithelium can disrupt the integrity of the alveolar barrier or downregulate ion transport pathways, thus, reducing net alveolar fluid reabsorption and enhancing the extent of alveolar oedema. Endogenous catecholamines upregulate alveolar fluid clearance in several experimental models of acute lung injury, but this upregulation may be short term and insufficient to counterbalance alveolar flooding. There is new evidence, however, that pharmacological treatment with beta2-adrenergic agonists and/or epithelial growth factors may influence a more sustained stimulation of alveolar fluid reabsorption and in turn facilitate recovery from experimental pulmonary oedema. Similar results have been achieved experimentally by gene transfer to enhance the abundance of sodium transporters in the alveolar epithelium. Clinical studies show that impaired alveolar fluid transport mechanisms contribute to the development, severity and outcome of pulmonary oedema in humans. Very recent data suggest that mechanisms that augment transepithelial sodium transport and enhance the clearance of alveolar oedema may lead to more effective prevention or treatment for some types of pulmonary oedema.

Adrenergic beta-Agonists↗

PubMed2001

Insulin resistance, hyperlipidemia, and hypertension in mice lacking endothelial nitric oxide synthase.

BACKGROUND: Insulin resistance and arterial hypertension are related, but the underlying mechanism is unknown. Endothelial nitric oxide synthase (eNOS) is expressed in skeletal muscle, where it may govern metabolic processes, and in the vascular endothelium, where it regulates arterial pressure. METHODS AND RESULTS: To study the role of eNOS in the control of the metabolic action of insulin, we assessed insulin sensitivity in conscious mice with disruption of the gene encoding for eNOS. eNOS(-/-) mice were hypertensive and had fasting hyperinsulinemia, hyperlipidemia, and a 40% lower insulin-stimulated glucose uptake than control mice. Insulin resistance in eNOS(-/-) mice was related specifically to impaired NO synthesis, because in equally hypertensive 1-kidney/1-clip mice (a model of renovascular hypertension), insulin-stimulated glucose uptake was normal. CONCLUSIONS: These results indicate that eNOS is important for the control not only of arterial pressure but also of glucose and lipid homeostasis. A single gene defect, eNOS deficiency, may represent the link between metabolic and cardiovascular disease.

Animals↗

PubMed2001

High-altitude pulmonary edema is initially caused by an increase in capillary pressure.

BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation. It is not known, however, whether the primary event is an increase in pressure or an increase in permeability of the pulmonary capillaries. METHODS AND RESULTS: We studied pulmonary hemodynamics, including capillary pressure determined by the occlusion method, and capillary permeability evaluated by the pulmonary transvascular escape of 67Ga-labeled transferrin, in 16 subjects with a previous HAPE and in 14 control subjects, first at low altitude (490 m) and then within the first 48 hours of ascent to a high-altitude laboratory (4559 m). The HAPE-susceptible subjects, compared with the control subjects, had an enhanced pulmonary vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery pressures (37 +/- 2 versus 26 +/- 1 mmHg, P<0.001) and pulmonary capillary pressures (19 +/- 1 versus 13 +/- 1 mmHg, P < 0.001) at high altitude. Nine of the susceptible subjects developed HAPE. All of them had a pulmonary capillary pressure >19 mm Hg (range 20 to 26 mmHg), whereas all 7 susceptible subjects without HAPE had a pulmonary capillary pressure < 19 mm Hg (range 14 to 18 mm Hg). The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did not differ significantly from the control subjects. CONCLUSIONS: HAPE is initially caused by an increase in pulmonary capillary pressure.

Adult↗

PubMed2001

Transepithelial sodium and water transport in the lung. Major player and novel therapeutic target in pulmonary edema.

Active transepithelial transport of sodium from the airspaces to the lung interstitium is a primary mechanism driving alveolar fluid clearance. This mechanism depends on sodium uptake by amiloride-sensitive sodium channels on the apical membrane of alveolar type II cells followed by extrusion of sodium on the basolateral surface by the Na-K-ATPase. Injury to the alveolar epithelium can disrupt the integrity of the alveolar barrier or downregulate ion transport pathways thus reducing net alveolar fluid reabsorption, and enhancing the extent of alveolar edema. Endogenous catecholamines upregulate alveolar fluid clearance in several experimental models of acute lung injury, but this upregulation is short-term and often not sufficient to counterbalance alveolar flooding. There is new evidence, however, that pharmacological treatment with beta-adrenergic agonists and/or epithelial growth factors may induce a more sustained stimulation of alveolar fluid reabsorption and in turn facilitate recovery from experimental pulmonary edema. Similar results have been achieved experimentally by gene transfer enhancing the abundance of sodium transporters in the alveolar epithelium. Clinical studies show that impaired alveolar fluid transport mechanisms contribute to the development, severity and outcome of pulmonary edema in humans. Very recent data suggest that mechanisms that augment transepithelial sodium transport and enhance the clearance of alveolar edema may lead to more effective prevention or treatment for pulmonary edema and acute lung injury.

Animals↗

PubMed2001

Interaction between cholinergic and nitrergic vasodilation: a novel mechanism of blood pressure control.

OBJECTIVE: Cholinergic vasodilation has been thought to play little if any role in the regulation of blood pressure in humans. Autonomic denervation potentiates the vasoconstriction evoked by nitric oxide synthase inhibition in humans, but the mechanism is unclear. We hypothesized that this may be related to loss of neuronal, non-nitric-oxide-dependent vasodilation. METHODS: To test this hypothesis, we examined effects of cholinergic blockade on blood pressure, heart rate and peripheral vascular responses to systemic infusion of the nitric-oxide-dependent vasoconstrictor L-NMMA (0.5 mg/kg/min over 15 min) in eight normal subjects. RESULTS: The L-NMMA-induced increase in mean (+/-S.E.) arterial pressure was roughly three times larger (P=0.002) in the presence than in the absence of cholinergic blockade (38+/-6 vs. 13+/-2 mmHg). Similarly, the increase in systemic and calf vascular resistance was more than twofold larger during L-NMMA-atropine. This potentiation was specific for nitric-oxide-dependent vasoconstriction, because atropine did not alter the responses to phenylephrine infusion. Cholinergic blockade also altered (P=0.004) the heart rate response to nitric oxide synthase inhibition; during L-NMMA alone heart rate decreased by 10+/-2 beats/min, whereas during L-NMMA-atropine infusion it increased by 14+/-4 beats/min. CONCLUSION: Cholinergic mechanisms play an important hitherto unrecognized role in offsetting the hypertension and cardiac sympathetic activation caused by nitric oxide synthase inhibition in humans. Decreased parasympathetic activity and impaired nitric oxide synthesis characterize several cardiovascular disease states, as well as normal aging. The conjunction of these two defects could trigger sudden death and contribute to the hypertension of the elderly.

Adrenergic beta-Antagonists↗

PubMed2001

Partial restoration of defective chloride conductance in DeltaF508 CF mice by trimethylamine oxide.

This study was designed to test the in vivo efficacy of the chemical chaperone trimethylamine oxide (TMAO) in correcting the Cl- transport defect in a mouse model of cystic fibrosis (CF). Rectal potential difference (RPD) measurements were done in matched wild-type and DeltaF508 CF mice. Mice were treated by subcutaneous injections of TMAO. Wild-type mice demonstrated a forskolin-stimulated, Cl--dependent hyperpolarization of -6.4 +/- 0.8 mV (n = 11), which was significantly increased to -13.1 +/- 1.4 mV after treatment with TMAO. DeltaF508 CF mice showed no significant responses to forskolin. Treatment with TMAO recovered a forskolin-activated RPD in DeltaF508 CF mice (-1.1 +/- 0.2 mV; n = 17) but not in CFTR null mice. The effects of TMAO were dose dependent, resulting in a slope of -0.4 +/- 0.1 mV x g(-1) x kg(-1) in DeltaF508 CF mice. The forskolin-stimulated RPD in TMAO-treated DeltaF508 CF mice was partially blocked by glibenclamide and further stimulated by apigenin. The total response to forskolin plus apigenin was -2.5 +/- 0.45 mV (n = 6 mice), corresponding to 39% of the response evoked by forskolin only in wild-type mice.

Animals↗

PubMed2000

Exaggerated pulmonary hypertension is not sufficient to trigger high-altitude pulmonary oedema in humans.

High altitude pulmonary oedema (HAPE) is a paradigm of pulmonary oedema that occurs in otherwise healthy subjects and thereby allows us to study underlying mechanisms in the absence of damning factors. Exaggerated pulmonary hypertension, which is related at least in part to endothelial dysfunction, is a hallmark of high-altitude pulmonary oedema. It is thought to play an important part in the pathogenesis of HAPE, but the predisposing factors are not clear. In rats, transient exposure to hypoxia during the first few days of life predisposes to exaggerated hypoxic pulmonary vasoconstriction in adulthood. We hypothesised that a similar mechanism may operate in humans, and if so may predispose to high-altitude pulmonary oedema. To test this hypothesis we studied the effects of high-altitude exposure (4559 m) on pulmonary-artery pressure and incidence of pulmonary oedema in 10 healthy young adults who had suffered from transient hypoxic pulmonary hypertension during perinatal period, and compared these effects with those observed in 10 controls of similar age and sex distribution, and in 14 HAPE-prone mountaineers. We found that at high altitude, the subjects who had suffered from transient perinatal hypoxic pulmonary hypertension had exaggerated pulmonary hypertension compared to controls (62 +/- 7 vs 50 +/- 11 mm Hg, p < 0.01). Despite exaggerated pulmonary vasoconstriction of similar magnitude to that observed in HAPE-prone subjects (59 +/- 10 mm Hg), none of the young adults developed HAPE. In contrast, 8 of the 14 HAPE-prone subjects had radiographic evidence of lung oedema (p < 0.001 for the comparison with the other 2 groups). These data challenge previous concepts and indicate that exaggerated hypoxic pulmonary vasoconstriction, while consistently associated with HAPE, is not sufficient to trigger pulmonary oedema. This suggests that additional mechanisms play a role.

Adult↗

PubMed2000

Echocardiographic and invasive measurements of pulmonary artery pressure correlate closely at high altitude.

Exaggerated hypoxia-induced pulmonary hypertension is a hallmark of high-altitude pulmonary edema (HAPE) and plays a major role in its pathogenesis. Many studies of HAPE have estimated systolic pulmonary arterial pressure (SPAP) with Doppler echocardiography. Whereas at low altitude, Doppler echocardiographic estimation of SPAP correlates closely with its invasive measurement, no such evidence exists for estimations obtained at high altitude, where alterations of blood viscosity may invalidate the simplified Bernoulli equation. We measured SPAP by Doppler echocardiography and invasively in 14 mountaineers prone to HAPE and in 14 mountaineers resistant to this condition at 4,559 m. Mountaineers prone to HAPE had more pronounced pulmonary hypertension (57 +/- 12 and 58 +/- 10 mmHg for noninvasive and invasive determination, respectively; means +/- SD) than subjects resistant to HAPE (37 +/- 8 and 37 +/- 6 mmHg, respectively), and the values measured in the two groups as a whole covered a wide range of pulmonary arterial pressures (30-83 mmHg). Spearman test showed a highly significant correlation (r = 0.89, P < 0.0001) between estimated and invasively measured SPAP values. The mean difference between invasively measured and Doppler-estimated SPAP was 0.5 +/- 8 mmHg. At high altitude, estimation of SPAP by Doppler echocardiography is an accurate and reproducible method that correlates closely with its invasive measurement.

Adult↗

PubMed2000

Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation.

High-altitude pulmonary edema (HAPE) is a life-threatening condition occurring in predisposed subjects at altitudes above 2,500 m. It is not clear whether, in addition to hemodynamic factors and defective alveolar fluid clearance, inflammation plays a pathogenic role in HAPE. We therefore made serial measurements of exhaled pulmonary nitric oxide (NO), a marker of airway inflammation, in 28 HAPE-prone and 24 control subjects during high-altitude exposure (4,559 m). To examine the relationship between pulmonary NO synthesis and pulmonary vascular tone, we also measured systolic pulmonary artery pressure (Ppa). In the 13 subjects who developed HAPE, exhaled NO did not show any tendency to increase during the development of lung edema. Throughout the entire sojourn at high altitude, pulmonary exhaled NO was roughly 30% lower in HAPE-prone than in control subjects, and there existed an inverse relationship between Ppa and exhaled NO (r = -0.51, p < 0.001). These findings suggest that HAPE is not preceded by airway inflammation. Reduced exhaled NO may be related to altered pulmonary NO synthesis and/or transport and clearance, and the data in our study could be consistent with the novel concept that in HAPE-prone subjects, a defect in pulmonary epithelial NO synthesis may contribute to exaggerated hypoxic pulmonary vasoconstriction and in turn to pulmonary edema.

Adult↗

PubMed2000

Defective nitric oxide synthesis: a link between metabolic insulin resistance, sympathetic overactivity and cardiovascular morbidity.

Epidemiological studies demonstrate an association between insulin resistance, hypertension and cardiovascular morbidity. In addition to its metabolic effects, insulin also has important cardiovascular actions. The sympathetic nervous system and the nitric oxide-l-arginine pathway have emerged as central players in the mediation of these actions. Over the past decade, the underlying mechanisms and the factors that may govern the interaction between insulin and these two major cardiovascular regulatory systems have been studied extensively in healthy people and insulin-resistant individuals. Here we summarize the current understanding and gaps in knowledge on these interactions. We propose that a genetic and/or acquired defect of nitric oxide synthesis could represent a central defect triggering many of the metabolic, vascular and sympathetic abnormalities characteristic of insulin-resistant states, all of which may predispose to cardiovascular disease.

Cardiovascular Diseases↗

PubMed2000

Selective autophagy of clofibrate-induced rat liver peroxisomes. Cytochemistry and immunocytochemistry on tissue specimens and on fractions obtained by Nycodenz density gradient centrifugation.

Following short treatments with peroxisomal proliferators rodent liver undergoes a significant increase in the peroxisomal population, accompanied by specific induction of some peroxisomal enzymes; both phenomena are reversible and in a few days after drug withdrawal the control parameters are recovered. The involvement of lysosomal system in removal of proliferated peroxisomes has been widely suggested, and the autophagic phenomenon was mainly investigated in experimental conditions in which the administration of lysosomotropic drugs or, more generally, of digestive process inhibitors caused an accumulation of autophagic vacuoles. In the present research the removal of clofibrate-induced rat liver peroxisomes was investigated under physiological conditions, i.e. in the absence of drugs interfering with the autophagic process. In a previous paper the lysosomal involvement in peroxisomal removal was suggested on the basis both of biochemical and cytochemical-immunocytochemical data. In the present paper the autophagic vacuoles and autolysosomes involved in the digestion of excess peroxisomes are more extensively described, mainly by means of colloidal gold immunocytochemistry, carried out also on density gradient subfractions.

Acid Phosphatase↗

PubMed1999

Sympathectomy potentiates the vasoconstrictor response to nitric oxide synthase inhibition in humans.

OBJECTIVE: Nitric oxide exerts its cardiovascular actions at least in part by modulation of the sympathetic vasoconstrictor tone. There is increasing evidence that nitric oxide inhibits central neural sympathetic outflow, and preliminary evidence suggests that it may also modulate peripheral sympathetic vasoconstrictor tone. METHODS: To test this latter concept, in six subjects having undergone thoracic sympathectomy for hyperhydrosis, we compared the vascular responses to systemic L-NMMA infusion (1 mg/kg/min over 10 min) in the innervated and the denervated limb. We also studied vascular responses to the infusion of the non-nitric-oxide-dependent vasoconstrictor phenylephrine. RESULTS: L-NMMA infusion evoked a roughly 3-fold larger increase in vascular resistance in the denervated forearm than in the innervated calf. In the denervated forearm, vascular resistance increased by 58 +/- 10 percent (mean +/- SE), whereas in the innervated calf it increased only by 21 +/- 6 percent (P < 0.01, forearm vs. calf). This augmented vasoconstrictor response was specific for L-NMMA, and not related to augmented non-specific vasoconstrictor responsiveness secondary to sympathectomy, because phenylephrine infusion increased vascular resistance similarly in the denervated forearm and the innervated calf (by 24 +/- 7, and 29 +/- 8 percent, respectively). The augmented vasoconstrictor response was related specifically to denervation, because in control subjects, the vasoconstrictor responses to L-NMMA were comparable in the forearm and the calf. CONCLUSIONS: These findings indicate that in the absence of sympathetic innervation, the vasoconstrictor responses to nitric oxide synthase inhibition are augmented.

Adult↗

PubMed1999

Augmented vasoreactivity in adult life associated with perinatal vascular insult.

BACKGROUND: Adverse environmental events occurring early in life have received little attention as predictors of disease in the later stages of life. At birth, the transition from gas exchange by the placenta to gas exchange by the lungs requires dramatic changes in the pulmonary circulation, which during this period is particularly vulnerable to noxious stimuli. We measured pulmonary-artery pressure responses to high-altitude exposure, a stimulus that causes pronounced pulmonary vasoconstriction, in young adults who had had transient perinatal hypoxic pulmonary hypertension and in controls of similar age and sex distribution. METHODS: Review of neonatal-care records at the Lausanne University Hospital for Children identified 15 individuals who met the eligibility criteria (birth at > or = 34 weeks of gestation, persistence of hypoxaemia during ventilation with oxygen during the first week of life, and persistence of fetal circulation). Ten of these individuals agreed to take part; the control group was ten volunteers without any history of perinatal complications. Systolic pulmonary-artery pressure (by echocardiography) and arterial oxygen saturation were measured at baseline and at high altitude (4559 m). FINDINGS: The mean increase in pulmonary-artery pressure at high altitude was significantly greater (p=0.01) in the participants who had had perinatal pulmonary hypertension (from 26.2 mm Hg [SD 2.1] to 62.3 mm Hg [7.3]) than in the controls (from 25.8 mm Hg [2.3] to 49.7 mm Hg [11.3]). The fall in arterial oxygen saturation was similar in the two groups. INTERPRETATION: These findings suggest that a transient perinatal insult to the pulmonary circulation leaves a persistent and potentially fatal imprint, which when activated in adult life predisposes to a pathological response. Survivors of perinatal pulmonary hypertension may be at risk of developing this disorder in later life.

Adult↗

PubMed1999

Exaggerated endothelin release in high-altitude pulmonary edema.

BACKGROUND: Exaggerated pulmonary hypertension is thought to play an important part in the pathogenesis of high-altitude pulmonary edema (HAPE). Endothelin-1 is a potent pulmonary vasoconstrictor peptide that also augments microvascular permeability. METHODS AND RESULTS: We measured endothelin-1 plasma levels and pulmonary artery pressure in 16 mountaineers prone to HAPE and in 16 mountaineers resistant to this condition at low (580 m) and high (4559 m) altitudes. At high altitude, in mountaineers prone to HAPE, mean (+/-SE) endothelin-1 plasma levels were approximately 33% higher than in HAPE-resistant mountaineers (22.2+/-1.1 versus 16.8+/-1.1 pg/mL, P<0.01). There was a direct relationship between the changes from low to high altitude in endothelin-1 plasma levels and systolic pulmonary artery pressure (r=0.82, P<0.01) and between endothelin-1 plasma levels and pulmonary artery pressure measured at high altitude (r=0.35, P=0.05). CONCLUSIONS: These findings suggest that in HAPE-susceptible mountaineers, an augmented release of the potent pulmonary vasoconstrictor peptide endothelin-1 and/or its reduced pulmonary clearance could represent one of the mechanisms contributing to exaggerated pulmonary hypertension at high altitude.

Adult↗