Etiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension

doi:10.1378/chest.129.3.689

Chest

Volume 129, Issue 3, March 2006, Pages 689-695

https://doi.org/10.1378/chest.129.3.689 Get rights and content

Study objectives

Endothelin (ET)-1 is a mediator of vascular remodeling seen in human pulmonary hypertension (PH), and it is normally cleared via endothelial ET-B receptors. Increased levels of ET-1 are found in precapillary PH, partly from increased synthesis. We hypothesized that the endothelial dysfunction and vascular remodeling seen in human precapillary PH would also reduce ET-1 clearance.

Design and setting

Case series from a single institutional PH center.

Patients

Thirty-four patients with pulmonary arterial hypertension (PAH; idiopathic [IPAH], n = 19; connective tissue disease [CTD], n = 15) and 11 patients with chronic thromboembolic PH were studied.

Measurements and results

Using indicator dilution methods, the first-pass extraction of radiolabeled ET-1 through the pulmonary circulation, and permeability surface (PS) area, an index of functional microvascular surface available for ET-1 clearance, were determined. Mean extraction for IPAH and thromboembolic PH groups was normal, but it was reduced in PAH from CTD; 69% of all patients studied had normal extraction. The mean PS product was reduced significantly for all three etiologies as compared to normal, but 58% of IPAH patients and 40% of CTD-related PAH patients had normal PS products.

Conclusions

Receptor-mediated ET-1 extraction and functional vascular surface area for clearance vary between etiologies of PAH. However, contrary to our hypothesis, endothelial ET-B receptor-mediated extraction is preserved in many patients. The scientifically significant finding of our study is that high ET-1 levels seen in patients with PAH must be predominantly due to excess synthesis rather than reduced clearance. The finding that endothelial ET-B receptors are still present and functional in PAH may also be of relevance to the choice of selective vs nonselective ET receptor antagonists.

Section snippets

Study Subjects

Forty-five consecutive patients with precapillary PH (19 patients with idiopathic PAH [IPAH]¹⁶; 15 patients with PAH related to connective tissue disease [CTD]; 11 patients with CTEPH) and meeting the following criteria were studied. During ET-1 sampling, all patients were undergoing routine hemodynamic study as part of their evaluation or prior to initiation of therapy. IPAH was diagnosed when the patients fulfilled the criteria as established by the consensus group of the third World

Patient Characteristics

There were no significant differences between the disease groups with regard to age; heart rate; mean systemic, right atrial, pulmonary arterial, and wedge pressures; cardiac output; or systemic and pulmonary vascular resistances, with marked abnormalities in the hemodynamic characteristics being seen in all groups (Table 1). There was a very good (r = 0.89, p < 0.01) correlation between the thermodilution-derived plasma flow and the indicator dilution-derived plasma flow. However, the

Discussion

ET-1 may play a detrimental role in human PH.2, 22 ET receptor blockade improves hemodynamics, functional capacity, and survival in PAH patients.4, 5, 6, 23However, there is still incomplete understanding of ET homeostasis in the human pulmonary hypertensive lung. While excess pulmonary ET-1 synthesis contributes to the abnormally high levels,¹¹ the importance of altered ET-1 extraction has not been studied. Furthermore, the importance of changes in ET receptor density and availability for

ACKNOWLEDGMENT

We are grateful to Alexandre Caron, Alan Moskovic, Nathalie Ruel, and Joseph Khoury for expert technical assistance. Drs. Robert Schlesinger, Leonidas Dragatakis, and Mark J. Eisenberg were of great assistance with cardiac catheterizations. We thank the nurses and technicians of the Jewish General Hospital Cardiac Catheterization Laboratory, and the Coronary Care Unit, for their generous and patient assistance.

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Pulmonary vascular endothelial cells control tone through numerous pathways and molecules like nitric oxide (NO), endothelium-derived hyperpolarizing factor (EDHF), prostacyclin (PGI2), endothelin-1 (ET-1) as well as many additional factors including platelet-derived growth factor (PDGF), vascular endothelium growth factor (VEGF), vasoactive intestitinal peptide (VIP), urotensin, adrenomedullin and leukotrienes. In addition, the pulmonary vascular endothelium is an important site for metabolism and clearance of circulating mediators such as angiotensin-I, endothelin, serotonin, adrenomedullin, and many others through specific receptors, enzymes and transporters.11–17 The pulmonary endothelium will therefore modulate local, but also systemic vascular biology.
Left heart diseases (LHD) represent the most prevalent cause of pulmonary hypertension (PH), yet there are still no approved therapies that selectively target the pulmonary circulation in LHD. The increase in pulmonary capillary pressure due to LHD is a triggering event leading to physical and biological alterations of the pulmonary circulation. Acutely, mechanosensitive endothelial dysfunction and increased capillary permeability combined with reduced fluid resorption lead to the development of interstitial and alveolar oedema. From repeated cycles of such capillary stress failure originate more profound changes with pulmonary endothelial dysfunction causing increased basal and reactive pulmonary vascular tone. This contributes to pulmonary vascular remodelling with increased arterial wall thickness, but most prominently, to alveolar wall remodelling characterized by myofibroblasts proliferation with collagen and interstitial matrix deposition. Although protective against acute pulmonary oedema, alveolar wall thickening becomes maladaptive and is responsible for the development of a restrictive lung syndrome and impaired gas exchanges contributing to shortness of breath and PH. Increasing awareness of these processes is unraveling novel pathophysiologic processes that could represent selective therapeutic targets. Thus, the roles of caveolins, of the intermediate myofilament nestin and of endothelial calcium dyshomeostasis were recently evaluated in pre-clinical models. The pathophysiology of PH due to LHD (group II PH) is distinctive from other groups of PH. Therefore, therapies targeting PH due to LHD must be evaluated in that context.
The effect of deep hypothermia on the human pulmonary circulation
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These are associated with the NO–cGMP and PGI2–cAMP pathways as demonstrated in animal models of systemic arteries (Han et al., 2010). We used Endothelin-1 as this has been associated with the development of pulmonary hypertension (Langleben et al., 2006). The concentrations of Endothelin-1 were used as these have been shown by our group in the past to be the most effective in human pulmonary arteries (Bennett et al., 2004).
Acute rises in pulmonary artery pressures following complex cardiac surgery are associated with high morbidity and mortality. We hypothesised that periods of deep hypothermia predispose to elevated pulmonary pressures upon rewarming. We investigated the effect of this hypothermic preconditioning on isolated human pulmonary arteries and isolated perfused lungs.
Isometric tension was measured in human pulmonary artery rings (n=24). We assessed the constriction and dilation of these arteries at 37 °C and 17 °C. Isolated perfused human lung models consisted of lobes ventilated via a bronchial cannula and perfused with Krebs via a pulmonary artery cannula. Bronchial and pulmonary artery pressures were recorded. We investigated the effect of temperature using a heat exchanger.
Rewarming from 17 °C to 37 °C caused a 1.3 fold increase in resting tension (p<0.05). Arteries constricted 8.6 times greater to 30 nM KCl, constricted 17 times greater to 1 nM Endothelin-1 and dilated 30.3 times greater to 100 μM SNP at 37 °C than at 17 °C (p<0.005). No difference was observed in the responses of arteries originally maintained at 37 °C compared to those arteries maintained at 17 °C and rewarmed to 37 °C. Hypothermia blunted the increase in pulmonary artery pressures to stimulants such as potassium chloride as well as to H-R but did not precondition arteries to higher pulmonary artery pressures upon re-warming.
Deep hypothermia reduces the responsiveness of human pulmonary arteries but does not, however, precondition an exaggerated response to vasoactive agents upon re-warming.
Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload
2012, Journal of Thoracic and Cardiovascular Surgery
Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown.
Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB + AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment.
Contractile performance was significantly improved in the PAB + AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB + AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor β genes.
Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV.
The role of endothelin-1 in the pathogenesis of pulmonary arterial hypertension
2011, Pharmacological Research
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In these studies the overall picture is that ETA antagonism causes vasodilation, ETB antagonism causes vasoconstriction and that blocking ETB in conjunction with ETA blockade attenuates some of the vasodilatory effect of ETA blockade alone [95–97]. Although studies like these have not been performed in patients with PAH, it is likely that the ETB receptor is functional and that the raised levels of ET-1 seen in the human are from increased production rather than reduced clearance [98]. Furthermore, the selectivity of the ET receptor antagonist affects circulating levels of ET-1.
The term pulmonary arterial hypertension (PAH) describes a rare group of diseases characterized by raised pulmonary vascular resistance, resulting from vascular remodelling in the pre-capillary resistance arterioles (<100 mm). Left untreated, patients die from right heart failure, with a mortality approaching most serious cancers. Endothelin-1(ET-1) is not only a potent vasoconstrictor, but causes proliferation of many of the vascular cells involved in vascular remodelling. Although produced mainly by the vascular endothelium, other cells such as smooth muscle, fibroblasts and macrophages are known sources of ET-1 when these cells are challenged by relevant stimuli. Plasma ET-1 levels are raised in patients with PAH and correlate with important clinical outcomes. Furthermore, ET-1 receptor antagonism has been demonstrated to improve both morbidity and mortality in conditions associated with PAH. We review the literature supporting the role for ET-1 in the pathogenesis of PAH.
Bone morphogenic protein-9 stimulates endothelin-1 release from human pulmonary microvascular endothelial cells. A potential mechanism for elevated ET-1 levels in pulmonary arterial hypertension
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Abnormalities of signalling for the transforming growth factor beta (TGFβ) family of peptides, including bone morphogenic proteins (BMP), have been described in heritable pulmonary arterial hypertension (PAH). TGFβ can modulate synthesis of the vasoconstrictor and mitogen, endothelin-1 (ET-1), a mediator that contributes to the pathogenesis of PAH. BMP-9 is a circulating peptide recently recognized to affect endothelial function. The stimuli for increased microvascular endothelial production of ET-1 in PAH are unknown. We therefore studied the effects of BMP-9 on ET-1 production by human lung blood microvascular endothelial cells (HMVEC-LBl) in vitro. In vitro, BMP-9 increased ET-1 production by HMVEC-LBl. The effect was identical to TGFβ-1, but BMP-9 and TGFβ-1 combined further increased ET-1 levels by 29%. As compared to TGFβ-1, BMP-9 induced more potent and rapid phosphorylation of Smad 1/5, the downstream signalling molecules of the activin-like kinase 1 (ALK-1) receptor. Moreover, as has been previously shown for endothelial cells of other origin, BMP-9 also induced Smad 2 phosphorylation in HMVEC-LBl. In conclusion, BMP-9 stimulates ET-1 production by HMVEC-LBl in vitro. BMP-9 signals via several Smad pathways. These studies provide novel mechanisms for the potentiation of PAH.
Endothelin-1 response to glucose and insulin among African Americans
2010, Journal of the American Society of Hypertension
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Mechanisms for clearance of ET-1 in humans are controversial. Local clearance appears to be mediated by ET-B receptors.23–25 Previous studies indicate whole-body clearance of ET-1 via kidney, liver, and lung.26,27
Endothelin-1 (ET-1) is implicated in the pathogenesis of hypertension. In vitro studies demonstrate that ET-1 is upregulated by insulin and glucose. The purpose of this study was to determine the effects of insulin and glucose on ET-1 levels in young adult African Americans, a population with a high burden of hypertension and diabetes. Plasma and urine ET-1 levels were measured before and after an oral glucose tolerance test (OGTT) and insulin clamp procedure in 288 participants. Subjects were classified according to glucose tolerance and blood pressure (BP) status. Plasma and urine ET-1 were not significantly different among the glucose tolerance groups. There was a trend toward increased plasma ET-1 among those with diabetes compared with impaired glucose tolerance and normal glucose tolerance; however, this was not statistically significant (P = .085). According to BP status, plasma ET-1 was highest among the high BP group compared with the normal BP group (P = .01). After glucose challenge, plasma ET-1 levels decreased and urine ET-1 increased in all three BP groups (P = .037). Our data show that plasma ET-1 is higher among young adult African Americans with hypertension compared with normotension. Urine ET-1 levels increased in response to glucose challenge, possibly indicating early renal injury.

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This work was funded by operating grants (MOP-42476 and 67145 to DL, MOP-12887 to JD, MOP-68966 to JLS) from the Canadian Institutes of Health Research, and by the Bank of Montreal Center for the Study of Heart Disease in Women at the Jewish General Hospital.

Dr. Langleben is a Chercheur-Boursier Clinicien National (National Clinical Research Scholar), and Dr. Dupuis is a Chercheur-Boursier Clinicien Senior (Senior Clinical Research Scholar), of the Fonds de la Recherche en Sante du Quebec. Dr. Senécal, M. Giovinazzo, and I. Langleben have no conflicts of interest to declare. Drs. D. Langleben, Dupuis, Hirsch, and Baron have served as speakers, investigators and/or consultants for one or more of Actelion Inc., Encysive Corporation, and Myogen Inc.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).

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Chest

Original Research: PULMONARY HYPERTENSIONEtiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension

Study objectives

Design and setting

Patients

Measurements and results

Conclusions

Section snippets

Study Subjects

Patient Characteristics

Discussion

ACKNOWLEDGMENT

Lancet

Am Heart J

J Cardiac Failure

Control Clin Trials

Clin Chest Med

Clin Chest Med

A novel potent vasoconstrictor peptide produced by vascular endothelial cells

Nature

Increased plasma endothelin-1 in pulmonary hypertension: marker or mediator of disease?

Ann Intern Med

Endogenously released endothelin-1 from human pulmonary artery smooth muscle promotes cellular proliferation

Am J Respir Cell Mol Biol

Bosentan therapy for pulmonary arterial hypertension

N Engl J Med

Sitaxsentan therapy for pulmonary arterial hypertension

Am J Respir Crit Care Med

Pressor effects of circulating endothelin are limited by its removal in the pulmonary circulation and by the release of prostacyclin and endothelium-derived relaxing factor

Proc Natl Acad Sci U S A

Human pulmonary circulation is an important site for both clearance and production of endothelin-1

Circulation

Plasma endothelin concentrations in patients with pulmonary hypertension associated with congenital heart defects

Circulation

Expression of endothelin-1 in the lungs of patients with pulmonary hypertension

N Engl J Med

Original Research: PULMONARY HYPERTENSION
Etiology-Specific Endothelin-1 Clearance in Human Precapillary Pulmonary Hypertension