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Abstract

Inhalation of endothelin (ET)-A receptor antagonists has been shown to improve gas exchange in experimental acute lung injury (ALI) but may induce side effects by increasing circulating ET-1 levels. We investigated whether the inhaled ET_A receptor antagonist, LU-135252, at low doses, improves gas exchange without affecting ET-1 plasma concentrations and lung injury in an animal model of ALI. Twenty-two piglets were examined in a prospective, randomized, controlled study. In anesthetized animals, ALI was induced by surfactant depletion. Animals received either LU-135252 at a dose of 0.3 mg/kg during 20 mins (LU group; n = 11), or nebulization of saline buffer (control group; n = 11). The Mann-Whitney U test was used to compare groups (P < 0.05). In the LU group, arterial partial pressure of oxygen (PaO₂) and mean pulmonary artery pressure (MPAP) improved compared with the control group (PaO₂, 319 ± 44 mm Hg vs. 57 ± 3 mm Hg; MPAP, 32 ± 2 mm Hg vs. 41 ± 2 mm Hg; values at 6 hrs after induction of ALI; P < 0.05). Mean arterial pressure and cardiac output were not different between groups. ET-1 plasma concentrations increased from 0.96 ± 0.06 fmol/ml after induction of ALI to a maximum of 1.17 ± 0.09 fmol/ml at 3 hrs after ALI onset in the LU group and did not differ significantly from the control group (1.21 ± 0.08 fmol/ml, not significant). On histologic examination, we found no differences in total lung injury score between groups. However, the LU group revealed significantly reduced interstitial inflammation and hemorrhage (P < 0.05 vs. control group). In this animal model of ALI, inhalation of LU-135252 at a dose of 0.3 mg/kg induced a significant and sustained improvement in gas exchange, whereas there were no changes in ET-1 plasma concentrations. Furthermore, our data indicate a trend toward decreased pulmonary inflammation in the group receiving the inhaled ET_A receptor antagonist

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References

Michael JR, Markewitz BA. Endothelins and the lung. Am J Respir Crit Care Med 154:555–581, 1996.

Druml W, Steltzer H, Waldhäusl W, Lenz K, Hammerle A, Vierhapper H, Gasic S, Wagner OF. Endothelin-1 in adult respiratory distress syndrome. Am Rev Respir Dis 148:1169–1173, 1993.

Langleben D, DeMarchie M, Laporta D, Spanier AH, Schlesinger RD, Stewart DJ. Endothelin-1 in acute lung injury and the adult respiratory distress syndrome. Am Rev Respir Dis 148:1646–1650, 1993.

Albertine KH, Wang ZM, Michael JR. Expression of endothelial nitric oxide synthase, inducible nitric oxide synthase, and endothelin-1 in lungs of subjects who dies with ARDS. Chest 116:S101–102, 1999.

Yanagisawa M, Kurihara H, Kimura S, Tomobe Y, Kobayashi M, Mitsui Y, Yazaki Y, Goto K, Masaki T. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 332:411–415, 1988.

Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res 2:90–101, 2001.

Fujitani Y, Trifilieff A, Tsuyuki S, Coyle AJ, Bertrand C. Endothelin receptor antagonists inhibit antigen-induced lung inflammation in mice. Am J Respir Crit Care Med 155:1890–1894, 1997.

Goldie RG. Endothelin receptor subtypes: distribution and function in the lung. Pulm Pharmacol Therap 11:89–95, 1998.

Finsnes F, Skjonsberg OH, Tonnessen T, Naess O, Lyberg T, Christensen G. Endothelin production and effects of endothelin antagonism during experimental airway inflammation. Am J Respir Crit Care Med 155:1404–1412, 1997.

10.

DiCarlo VS, Chen SJ, Meng QC, Durand J, Yano M, Chen YF, Oparil S. ETA-receptor antagonist prevents and reverses chronic hypoxia-induced pulmonary hypertension in rat. Am J Physiol 269:L690–697, 1995.

11.

Kaisers U, Busch T, Wolf S, Lohbrunner H, Wilkens K, Hocher B, Boemke W. Inhaled endothelin A antagonist improves arterial oxygenation in experimental acute lung injury. Intensive Care Med 26:1334–1342, 2000.

12.

Rossaint R, Falke KJ, Lopez F, Slama K, Pison U, Zapol WM. Inhaled nitric oxide for the adult respiratory distress syndrome. N Engl J Med 328:399–405, 1993.

13.

Deja M, Wolf S, Busch T, Petersen B, Jaghzies U, Boemke W, Kaisers U. The inhaled endothelin A receptor antagonist LU-135252 acts as a selective pulmonary vasodilator. Clin Sci 103:S21–24, 2002.

14.

Lachmann B, Robertson B, Vogel J. In vivo lavage as an experimental model of the respiratory distress syndrome. Acta Anaesth Scand 24:231–236, 1980.

15.

Mrozek JD, Smith KM, Bing DR, Meyers PA, Simonton SC, Connett JE, Mammel MC. Exogenous surfactant and partial liquid ventilation: physiologic and pathologic effects. Am J Respir Crit Care Med 156:1058–1065, 1997.

16.

Deja M, Busch T, Wolf S, Donaubauer B, Petersen B, Skomrock J, Boemke W, Kaisers U. Inhalation of the endothelin-A receptor antagonist LU-135252 at various doses in experimental acute lung injury. J Cardiovasc Pharmacol 44:S151–155, 2004.

17.

Münter K, Ehmke H, Kirchengast M. Maintenance of blood pressure in normotensive dogs by endothelin. Am J Physiol 276:H1022–1027, 1999.

18.

Battistini B, Dussault P. Biosynthesis, distribution and metabolism of endothelins in the pulmonary system. Pulm Pharmacol Ther 11:79–88, 1998.

19.

Hirata Y, Emori T, Eguchi S, Kanno K, Imai T, Ohta K, Marumo F. Endothelin receptor subtype B mediates synthesis of nitric oxide by cultured bovine endothelial cells. J Clin Invest 91:1367–1373, 1993.

20.

Battistini B, Steil AA, Jancar S, Sirois P. Roles of endothelins and their receptors in immune complex-induced/polymorphonuclear-mediated lung injury (recersed passive Arthus reaction) in CD-1 mice. Pulmonary Pharmacol Therap 11:165–172, 1998.

21.

Filep JG, Sirois MG, Foldes-Filep E, Rousseau A, Plante GE, Fournier A, Yano M, Sirois P. Enhancement by endothelin-1 of microvascular permeability via the activation of ETA receptors. Br J Pharmacol 109:880–886, 1993.

Low-Dose Inhalation of an Endothelin-A Receptor Antagonist in Experimental Acute Lung Injury: ET-1 Plasma Concentration and Pulmonary Inflammation

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