Endothelin receptor blockade does not improve hypoxemia following acute pulmonary thromboembolism.

We studied the roles of endothelins in determining ventilation (Va) and perfusion (Q) mismatch in a porcine model of acute pulmonary thromboembolism (APTE), using a nonspecific endothelin antagonist, tezosentan. Nine anesthetized piglets (approximately 23 kg) received autologous clots (approximately 20 g) via a central venous catheter at time = 0 min. The distribution of Va and Q at five different time points (-30, -5, 30, 60, 120 min) was mapped by fluorescent microspheres of 10 different colors. Five piglets (group 1) received tezosentan (courtesy of Actelion) starting at time = 40 min for 2 h, and four piglets (group 2) received only saline and served as control. Our results showed that, in all of the animals at 30 min following APTE but before tezosentan, the mean Va/Q was increased, as was Va/Q heterogeneity (log SD Va/Q), which represented a widening of its main peak. Afterwards, tezosentan attenuated the pulmonary hypertension in group 1 but also produced moderate systemic hypotension. However, it did not improve arterial PO2 or Va/Q mismatch. We concluded that endothelin antagonism had minimal impact on gas exchange following APTE and confirmed our earlier observation that the main mechanism for hypoxemia in APTE was due to the mechanical redistribution of pulmonary regional blood flow away from the embolized vessels, resulting in the creation of many divergent low and high Va/Q regions.

[1]  A. Heller,et al.  The role of endothelin-1 as a mediator of the pressure response after air embolism in blood perfused lungs , 1998, Intensive Care Medicine.

[2]  F. Barale,et al.  Inhaled nitric oxide in patients with pulmonary embolism , 1998, Intensive Care Medicine.

[3]  M. Hlastala,et al.  Spatial pattern of ventilation-perfusion mismatch following acute pulmonary thromboembolism in pigs. , 2005, Journal of applied physiology.

[4]  S. Beppu,et al.  Involvement of cyclo-oxygenase-generated vasodilating eicosanoid(s) in addition to nitric oxide in endothelin-1-induced endothelium-dependent vasorelaxation in guinea pig aorta , 2005, Heart and Vessels.

[5]  Yong Jo Kim,et al.  Plasma levels of endothelin-1, big endothelin-1 and thromboxane following acute pulmonary air embolism , 2003, Respiratory Physiology & Neurobiology.

[6]  T. Shim,et al.  Pathogenic role of endothelin 1 in hemodynamic dysfunction in experimental acute pulmonary thromboembolism. , 2001, American journal of respiratory and critical care medicine.

[7]  K. Qayumi,et al.  Biphasic release of immunoreactive endothelins following acute pulmonary thromboembolism in pigs. , 2000, Journal of cardiovascular pharmacology.

[8]  J. Tanus-Santos,et al.  Nonselective endothelin-receptor antagonism attenuates hemodynamic changes after massive pulmonary air embolism in dogs. , 2000, Chest.

[9]  S. Roux,et al.  Pharmacology of tezosentan, new endothelin receptor antagonist designed for parenteral use. , 1999, The Journal of pharmacology and experimental therapeutics.

[10]  P. Henry,et al.  ENDOTHELIN RECEPTOR DISTRIBUTION AND FUNCTION IN THE AIRWAYS , 1999, Clinical and experimental pharmacology & physiology.

[11]  G. Remuzzi,et al.  Endothelin antagonists , 1999, The Lancet.

[12]  R. Glenny,et al.  Pulmonary gas-exchange analysis by using simultaneous deposition of aerosolized and injected microspheres. , 1998, Journal of applied physiology.

[13]  C. Fields,et al.  Vasomotor tone and the role of nitric oxide. , 1998, Seminars in vascular surgery.

[14]  T. Masaki,et al.  The discovery of endothelins. , 1998, Cardiovascular research.

[15]  B. Battistini,et al.  Biosynthesis, distribution and metabolism of endothelins in the pulmonary system. , 1998, Pulmonary pharmacology & therapeutics.

[16]  T. Dschietzig,et al.  Coronary constriction and consequent cardiodepression in pulmonary embolism are mediated by pulmonary big endothelin and enhanced in early endothelial dysfunction. , 1998, Critical care medicine.

[17]  L. Kohman.  Controversies in the management of malignant thymoma. , 1997, Chest.

[18]  J. Zijlstra,et al.  Oxygen desaturation after treatment with inhaled nitric oxide for obstructive shock due to massive pulmonary embolism. , 1997, Chest.

[19]  M. Alifano,et al.  Endothelin abnormalities in patients with pulmonary embolism. , 1997, Chest.

[20]  R W Glenny,et al.  High-resolution maps of regional ventilation utilizing inhaled fluorescent microspheres. , 1997, Journal of applied physiology.

[21]  C. Bode,et al.  Inhaled Nitric Oxide Inhibits Platelet Aggregation after Pulmonary Embolism in Pigs , 1997, Anesthesiology.

[22]  E. Martin,et al.  Inhaled nitric oxide selectively decreases pulmonary artery pressure and pulmonary vascular resistance following acute massive pulmonary microembolism in piglets. , 1996, Chest.

[23]  B. Markewitz,et al.  Endothelins and the lung. , 1996, American journal of respiratory and critical care medicine.

[24]  K. Rådegran,et al.  Nitric oxide improves hypoxaemia following reperfusion oedema after pulmonary thromboendarterectomy. , 1995, British journal of anaesthesia.

[25]  S. Uhlig,et al.  Pharmacologic characterization of endothelin receptor responses in the isolated perfused rat lung. , 1995, American journal of respiratory and critical care medicine.

[26]  C. Mélot,et al.  Starling resistor vs. distensible vessel models for embolic pulmonary hypertension. , 1995, The American journal of physiology.

[27]  Y. Matsuda,et al.  Subtypes of endothelin ETA and ETB receptors mediating venous smooth muscle contraction. , 1994, Biochemical and biophysical research communications.

[28]  Y. Urade,et al.  Induction of endothelium‐dependent relaxation in the rat aorta by IRL 1620, a novel and selective agonist at the endothelin ETB receptor , 1993, British journal of pharmacology.

[29]  R W Glenny,et al.  Validation of fluorescent-labeled microspheres for measurement of regional organ perfusion. , 1993, Journal of applied physiology.

[30]  B. Haendler,et al.  Molecular Cloning of Human Endothelin (ET) Receptors ETA and ETB , 1992, Journal of cardiovascular pharmacology.

[31]  C. Mélot,et al.  Effects of vasodilators on gas exchange in acute canine embolic pulmonary hypertension. , 1990, Anesthesiology.

[32]  D. Webb,et al.  Endothelin is a potent long-lasting vasoconstrictor in men. , 1989, The American journal of physiology.

[33]  D. Simmons,et al.  Redistribution of alveolar ventilation following pulmonary thromboembolism in the dog. , 1974, Journal of applied physiology.