Skip to main content
NCBI home page
Heart logoLink to Heart
. 1999 Oct;82(4):505–508. doi: 10.1136/hrt.82.4.505

Early therapeutic experience with the endothelin antagonist BQ-123 in pulmonary hypertension after congenital heart surgery

B Prendergast 1, D Newby 1, L Wilson 1, D Webb 1, P Mankad 1
PMCID: PMC1760282  PMID: 10490569

Abstract

OBJECTIVE—To assess the effect of endothelin type A (ETA) receptor antagonism in infants with pulmonary hypertension following corrective surgery for congenital heart disease.
DESIGN—Open label, preliminary study.
SETTING—Tertiary paediatric cardiothoracic surgical centre.
PATIENTS—Three infants (aged 3 weeks, 7 weeks, and 8 months) with postoperative pulmonary hypertension unresponsive to conventional treatment, including inhaled nitric oxide.
INTERVENTIONS—Patients received incremental intravenous infusions (0.1 to 0.3 mg/kg/h) of the ETA receptor antagonist BQ-123.
MAIN OUTCOME MEASURES—The response to BQ-123 administration was determined using continuous invasive monitoring of cardiorespiratory variables.
RESULTS—BQ-123 infusion caused a reduction in the ratio of pulmonary to systemic pressures (0.62 (0.01) to 0.52 (0.03), mean (SEM)) with an accompanying decrease in right ventricular stroke work index (4.6 (0.4) to 2.5 (0.3) g/m) and a tendency for the cardiac index to rise (2.1 (0.2) to 2.7 (0.6) l/min/kg/m2). This was associated with a well tolerated fall in the arterial partial pressure of oxygen (16.5 (4.1) to 12.4 (3.3) kPa) and mean systemic arterial pressure (57 (3) to 39 (3) mm Hg).
CONCLUSIONS—ETA receptor antagonism in infants with postoperative pulmonary hypertension after corrective surgery for congenital heart disease led to significant improvement in pulmonary haemodynamic indices. However, these benefits were associated with reductions in systemic blood pressure and arterial oxygen saturation, the latter consistent with a ventilation-perfusion mismatch. On the basis of these results, studies in pulmonary hypertension will need to proceed with caution.


Keywords: endothelin-1; pulmonary hypertension; receptor antagonism; congenital heart disease

Full Text

The Full Text of this article is available as a PDF (94.9 KB).

Figure 1  .

Figure 1  

Open in a new tab

Effect of BQ-123 (0.1 to 0.3 mg/kg/min) on cardiac index (•), pulmonary/systemic ratio (∘), heart rate (⋄), and mean systemic (□) and pulmonary (▪) arterial pressure in infants with postoperative pulmonary hypertension following corrective surgery for congenital heart disease. (Error bars are SEM, n = 3.)

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Abman S. H. Pathogenesis and treatment of neonatal and postnatal pulmonary hypertension. Curr Opin Pediatr. 1994 Jun;6(3):239–247. [PubMed] [Google Scholar]
  2. Allen S. W., Chatfield B. A., Koppenhafer S. A., Schaffer M. S., Wolfe R. R., Abman S. H. Circulating immunoreactive endothelin-1 in children with pulmonary hypertension. Association with acute hypoxic pulmonary vasoreactivity. Am Rev Respir Dis. 1993 Aug;148(2):519–522. doi: 10.1164/ajrccm/148.2.519. [DOI] [PubMed] [Google Scholar]
  3. Bando K., Turrentine M. W., Sharp T. G., Sekine Y., Aufiero T. X., Sun K., Sekine E., Brown J. W. Pulmonary hypertension after operations for congenital heart disease: analysis of risk factors and management. J Thorac Cardiovasc Surg. 1996 Dec;112(6):1600–1609. doi: 10.1016/S0022-5223(96)70019-3. [DOI] [PubMed] [Google Scholar]
  4. Berrazueta J. R., Bhagat K., Vallance P., MacAllister R. J. Dose- and time-dependency of the dilator effects of the endothelin antagonist, BQ-123, in the human forearm. Br J Clin Pharmacol. 1997 Dec;44(6):569–571. doi: 10.1046/j.1365-2125.1997.t01-1-00631.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Black S., Fineman J., Johengen M., Bristow J., Soifer S. Increased pulmonary blood flow alters the molecular regulation of vascular reactivity in the lamb. Chest. 1998 Jul;114(1 Suppl):39S–39S. doi: 10.1378/chest.114.1_supplement.39s. [DOI] [PubMed] [Google Scholar]
  6. Cacoub P., Dorent R., Nataf P., Carayon A., Riquet M., Noe E., Piette J. C., Godeau P., Gandjbakhch I. Endothelin-1 in the lungs of patients with pulmonary hypertension. Cardiovasc Res. 1997 Jan;33(1):196–200. doi: 10.1016/s0008-6363(96)00189-7. [DOI] [PubMed] [Google Scholar]
  7. Cody R. J., Haas G. J., Binkley P. F., Capers Q., Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension in patients with chronic congestive heart failure. Circulation. 1992 Feb;85(2):504–509. doi: 10.1161/01.cir.85.2.504. [DOI] [PubMed] [Google Scholar]
  8. Cowburn P. J., Cleland J. G., McArthur J. D., MacLean M. R., McMurray J. J., Dargie H. J. Short-term haemodynamic effects of BQ-123, a selective endothelin ET(A)-receptor antagonist, in chronic heart failure. Lancet. 1998 Jul 18;352(9123):201–202. doi: 10.1016/S0140-6736(05)77807-7. [DOI] [PubMed] [Google Scholar]
  9. Dupuis J., Stewart D. J., Cernacek P., Gosselin G. Human pulmonary circulation is an important site for both clearance and production of endothelin-1. Circulation. 1996 Oct 1;94(7):1578–1584. doi: 10.1161/01.cir.94.7.1578. [DOI] [PubMed] [Google Scholar]
  10. Goerre S., Wenk M., Bärtsch P., Lüscher T. F., Niroomand F., Hohenhaus E., Oelz O., Reinhart W. H. Endothelin-1 in pulmonary hypertension associated with high-altitude exposure. Circulation. 1995 Jan 15;91(2):359–364. doi: 10.1161/01.cir.91.2.359. [DOI] [PubMed] [Google Scholar]
  11. Gray G. A., Webb D. J. The endothelin system and its potential as a therapeutic target in cardiovascular disease. Pharmacol Ther. 1996;72(2):109–148. doi: 10.1016/s0163-7258(96)00101-5. [DOI] [PubMed] [Google Scholar]
  12. Haynes W. G., Ferro C. J., O'Kane K. P., Somerville D., Lomax C. C., Webb D. J. Systemic endothelin receptor blockade decreases peripheral vascular resistance and blood pressure in humans. Circulation. 1996 May 15;93(10):1860–1870. doi: 10.1161/01.cir.93.10.1860. [DOI] [PubMed] [Google Scholar]
  13. Haynes W. G., Webb D. J. Contribution of endogenous generation of endothelin-1 to basal vascular tone. Lancet. 1994 Sep 24;344(8926):852–854. doi: 10.1016/s0140-6736(94)92827-4. [DOI] [PubMed] [Google Scholar]
  14. Kirshbom P. M., Tsui S. S., DiBernardo L. R., Meliones J. N., Schwinn D. A., Ungerleider R. M., Gaynor J. W. Blockade of endothelin-converting enzyme reduces pulmonary hypertension after cardiopulmonary bypass and circulatory arrest. Surgery. 1995 Aug;118(2):440–445. doi: 10.1016/s0039-6060(05)80356-3. [DOI] [PubMed] [Google Scholar]
  15. Komai H., Adatia I. T., Elliott M. J., de Leval M. R., Haworth S. G. Increased plasma levels of endothelin-1 after cardiopulmonary bypass in patients with pulmonary hypertension and congenital heart disease. J Thorac Cardiovasc Surg. 1993 Sep;106(3):473–478. [PubMed] [Google Scholar]
  16. Krum H., Viskoper R. J., Lacourciere Y., Budde M., Charlon V. The effect of an endothelin-receptor antagonist, bosentan, on blood pressure in patients with essential hypertension. Bosentan Hypertension Investigators. N Engl J Med. 1998 Mar 19;338(12):784–790. doi: 10.1056/NEJM199803193381202. [DOI] [PubMed] [Google Scholar]
  17. Kumar P., Kazzi N. J., Shankaran S. Plasma immunoreactive endothelin-1 concentrations in infants with persistent pulmonary hypertension of the newborn. Am J Perinatol. 1996 Aug;13(6):335–341. doi: 10.1055/s-2007-994352. [DOI] [PubMed] [Google Scholar]
  18. Prié S., Leung T. K., Cernacek P., Ryan J. W., Dupuis J. The orally active ET(A) receptor antagonist (+)-(S)-2-(4,6-dimethoxy-pyrimidin-2-yloxy)-3-methoxy-3,3-diphe nyl-propionic acid (LU 135252) prevents the development of pulmonary hypertension and endothelial metabolic dysfunction in monocrotaline-treated rats. J Pharmacol Exp Ther. 1997 Sep;282(3):1312–1318. [PubMed] [Google Scholar]
  19. Prié S., Stewart D. J., Dupuis J. EndothelinA receptor blockade improves nitric oxide-mediated vasodilation in monocrotaline-induced pulmonary hypertension. Circulation. 1998 Jun 2;97(21):2169–2174. doi: 10.1161/01.cir.97.21.2169. [DOI] [PubMed] [Google Scholar]
  20. Reddy V. M., Hendricks-Munoz K. D., Rajasinghe H. A., Petrossian E., Hanley F. L., Fineman J. R. Post-cardiopulmonary bypass pulmonary hypertension in lambs with increased pulmonary blood flow. A role for endothelin 1. Circulation. 1997 Feb 18;95(4):1054–1061. doi: 10.1161/01.cir.95.4.1054. [DOI] [PubMed] [Google Scholar]
  21. Wong J., Reddy V. M., Hendricks-Munoz K., Liddicoat J. R., Gerrets R., Fineman J. R. Endothelin-1 vasoactive responses in lambs with pulmonary hypertension and increased pulmonary blood flow. Am J Physiol. 1995 Dec;269(6 Pt 2):H1965–H1972. doi: 10.1152/ajpheart.1995.269.6.H1965. [DOI] [PubMed] [Google Scholar]

Articles from Heart are provided here courtesy of BMJ Publishing Group

RESOURCES