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Intensive Care Medicine

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01-05-2008 | Original

Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction

Authors: Patrik Rossi, Björn Persson, Piet J. M. Boels, Anders Arner, Eddie Weitzberg, Anders Oldner

Published in: Intensive Care Medicine | Issue 5/2008

Abstract

Objective

To analyze the effect of endothelin-1 on pulmonary arterial and venous contractile force in vitro and on up- and downstream pulmonary vascular resistance in vivo under sham and endotoxemic conditions in pigs.

Materials and methods

In vitro: paired preparations of pulmonary arteries and veins were mounted in a myograph (n = 13) for measurements of contractile responses to increasing concentrations of phenylephrine, endothelin-1, and sarafotoxin (endothelin receptor type B agonist). In vivo: 20 pigs were anesthetized, mechanically ventilated, and subjected to phenylephrine (reference substance), endothelin-1, sarafotoxin, endotoxin, and tezosentan (dual endothelin receptor antagonist). Hemodynamic and gas-exchange variables were monitored. Pulmonary capillary pressure, used for calculation of upstream and downstream vascular resistance, was assessed by the pulmonary vascular occlusion technique.

Measurements and results

Pulmonary veins were more sensitive than arteries to endothelin-1 both in vitro and in vivo. This difference was more pronounced with sarafotoxin, where almost no arterial effects were noted. In vivo and in vitro exposure to phenylephrine resulted in selective arterial constriction. Endotoxin infusion resulted in pulmonary hypertension with a clear downstream dominance. The latter changes including the increase in capillary pressure were totally abolished by intervention with the dual endothelin receptor antagonist tezosentan.

Conclusions

The endothelin system is extensively involved in endotoxemic pulmonary venous hypertension, an effect possibly mediated by the endothelin B receptor.

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Martin M, Salim A, Murray J, Demetriades D, Belzberg H, Rhee P (2005) The decreasing incidence and mortality of acute respiratory distress syndrome after injury: a 5-year observational study. J Trauma 59:1107–1113PubMedCrossRef

Matthay MA, Zimmerman GA (2005) Acute lung injury and the acute respiratory distress syndrome: four decades of inquiry into pathogenesis and rational management. Am J Respir Cell Mol Biol 33:319–327PubMedCrossRef

Weitzberg E, Lundberg JM, Rudehill A (1991) Elevated plasma levels of endothelin in patients with sepsis syndrome. Circ Shock 33:222–227PubMed

Takakuwa T, Endo S, Nakae H, Kikichi M, Suzuki T, Inada K, Yoshida M (1994) Plasma levels of TNF-alpha, endothelin-1 and thrombomodulin in patients with sepsis. Res Commun Chem Pathol Pharmacol 84:261–269PubMed

Motte S, McEntee K, Naeije R (2006) Endothelin receptor antagonists. Pharmacol Ther 110:386–414PubMedCrossRef

Nucci G de, Thomas R, D'Orleans-Juste P, Antunes E, Walder C, Warner TD, Vane JR (1988) 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 USA 85:9797–9800CrossRef

Dupuis J, Goresky CA, Fournier A (1996) Pulmonary clearance of circulating endothelin-1 in dogs in vivo: exclusive role of ETB receptors. J Appl Physiol 81:1510–1515PubMed

Schoene RB (2004) Unraveling the mechanism of high altitude pulmonary edema. High Alt Med Biol 5:125–135PubMedCrossRef

Shennib H, Serrick C, Saleh D, Reis A, Stewart DJ, Giaid A (1995) Plasma endothelin-1 levels in human lung transplant recipients. J Cardiovasc Pharmacol 26 [Suppl 3]:S516–518

10.

Kuo C, Chen J (1999) Effect of meconium aspiration on plasma endothelin-1 level and pulmonary hemodynamics in a piglet model. Biol Neonate 76:228–234PubMedCrossRef

11.

Kuklin VN, Kirov MY, Evgenov OV, Sovershaev MA, Sjoberg J, Kirova SS, Bjertnaes LJ (2004) Novel endothelin receptor antagonist attenuates endotoxin-induced lung injury in sheep. Crit Care Med 32:766–773PubMedCrossRef

12.

Rossi P, Wanecek M, Konrad D, Oldner A (2004) Tezosentan counteracts endotoxin-induced pulmonary edema and improves gas exchange. Shock 21:543–548PubMedCrossRef

13.

Giaid A, Yanagisawa M, Langleben D, Michel RP, Levy R, Shennib H, Kimura S, Masaki T, Duguid WP, Stewart DJ (1993) Expression of endothelin-1 in the lungs of patients with pulmonary hypertension. N Engl J Med 328:1732–1739PubMedCrossRef

14.

Kuklin V, Kirov M, Sovershaev M, Andreasen T, Ingebretsen OC, Ytrehus K, Bjertnaes L (2005) Tezosentan-induced attenuation of lung injury in endotoxemic sheep is associated with reduced activation of protein kinase C. Crit Care 9:R211–R217PubMedCrossRef

15.

Gao Y, Raj JU (2005) Role of veins in regulation of pulmonary circulation. Am J Physiol Lung Cell Mol Physiol 288:L213–L226PubMedCrossRef

16.

Rossi P, Oldner A, Weitzberg E, Persson B, Boels PJ, Arner A (2006) Endotoxemic pulmonary hypertension is mediated by endothelin receptor-induced venous constriction. Intensive Care Med 32:S277CrossRef

17.

Boels PJ, Deutsch J, Gao B, Haworth SG (1999) Maturation of the response to bradykinin in resistance and conduit pulmonary arteries. Cardiovasc Res 44:416–428PubMedCrossRef

18.

Pellett AA, Johnson RW, Morrison GG, Champagne MS, deBoisblanc BP, Levitzky MG (1999) A comparison of pulmonary arterial occlusion algorithms for estimation of pulmonary capillary pressure. Am J Respir Crit Care Med 160:162–168PubMed

19.

Ganter BG, Jakob SM, Takala J (2006) Pulmonary capillary pressure. A review. Minerva Anestesiol 72:21–36PubMed

20.

Pellett AA, Lord KC, Champagne MS, deBoisblanc BP, Johnson RW, Levitzky MG (2002) Pulmonary capillary pressure during acute lung injury in dogs. Crit Care Med 30:403–409PubMedCrossRef

21.

Seo B, Oemar BS, Siebenmann R, von Segesser L, Luscher TF (1994) Both ETA and ETB receptors mediate contraction to endothelin-1 in human blood vessels. Circulation 89:1203–1208PubMed

22.

Brink C, Gillard V, Roubert P, Mencia-Huerta JM, Chabrier PE, Braquet P, Verley J (1991) Effects and specific binding sites of endothelin in human lung preparations. Pulm Pharmacol 4:54–59PubMedCrossRef

23.

Kafi SA, Melot C, Vachiery JL, Brimioulle S, Naeije R (1998) Partitioning of pulmonary vascular resistance in primary pulmonary hypertension. J Am Coll Cardiol 31:1372–1376PubMedCrossRef

24.

Fesler P, Pagnamenta A, Vachiery JL, Brimioulle S, Abdel Kafi S, Boonstra A, Delcroix M, Channick RN, Rubin LJ, Naeije R (2003) Single arterial occlusion to locate resistance in patients with pulmonary hypertension. Eur Respir J 21:31–36PubMedCrossRef

25.

Channick RN, Simonneau G, Sitbon O, Robbins IM, Frost A, Tapson VF, Badesch DB, Roux S, Rainisio M, Bodin F, Rubin LJ (2001) Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet 358:1119–1123PubMedCrossRef

26.

Zellers TM, McCormick J, Wu Y (1994) Interaction among ET-1, endothelium-derived nitric oxide, and prostacyclin in pulmonary arteries and veins. Am J Physiol 267:H139–H147PubMed

27.

Sudjarwo SA, Hori M, Takai M, Urade Y, Okada T, Karaki H (1993) A novel subtype of endothelin B receptor mediating contraction in swine pulmonary vein. Life Sci 53:431–437PubMedCrossRef

28.

Konrad D, Oldner A, Wanecek M, Rudehill A, Weitzberg E, Biber B, Johansson G, Haggmark S, Haney M (2005) Positive inotropic and negative lusitropic effects of endothelin receptor agonism in vivo. Am J Physiol Heart Circ Physiol 289:H1702–H1709PubMedCrossRef

29.

Odenstedt H, Aneman A, Karason S, Stenqvist O, Lundin S (2005) Acute hemodynamic changes during lung recruitment in lavage and endotoxin-induced ALI. Intensive Care Med 31:112–120PubMedCrossRef

30.

Kuklin V, Sovershaev M, Andreasen T, Skogen V, Ytrehus K, Bjertnaes L (2005) Tezosentan reduces the microvascular filtration coefficient in isolated lungs from rats subjected to cecum ligation and puncture. Crit Care 9:R677–R686PubMedCrossRef

31.

Ishimaru S, Shichiri M, Mineshita S, Hirata Y (2001) Role of endothelin-1/endothelin receptor system in endotoxic shock rats. Hypertens Res 24:119–126PubMedCrossRef

32.

Forni M, Mazzola S, Ribeiro LA, Pirrone F, Zannoni A, Bernardini C, Bacci ML, Albertini M (2005) Expression of endothelin-1 system in a pig model of endotoxic shock. Regul Pept 131:89–96PubMedCrossRef

33.

Benzing A, Mols G, Guttmann J, Kaltofen H, Geiger K (1998) Effect of different doses of inhaled nitric oxide on pulmonary capillary pressure and on longitudinal distribution of pulmonary vascular resistance in ARDS. Br J Anaesth 80:440–446PubMed

34.

Villar J, Blazquez MA, Lubillo S, Quintana J, Manzano JL (1989) Pulmonary hypertension in acute respiratory failure. Crit Care Med 17:523–526PubMedCrossRef

35.

Nunes S, Ruokonen E, Takala J (2003) Pulmonary capillary pressures during the acute respiratory distress syndrome. Intensive Care Med 29:2174–2179PubMedCrossRef

Title: Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction
Authors: Patrik Rossi
Björn Persson
Piet J. M. Boels
Anders Arner
Eddie Weitzberg
Anders Oldner
Publication date: 01-05-2008
Publisher: Springer-Verlag
Published in: Intensive Care Medicine / Issue 5/2008
Print ISSN: 0342-4642
Electronic ISSN: 1432-1238
DOI: https://doi.org/10.1007/s00134-007-0980-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Endotoxemic pulmonary hypertension is largely mediated by endothelin-induced venous constriction

Abstract

Objective

Materials and methods

Measurements and results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Objective

Materials and methods

Measurements and results

Conclusions

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