Skip to main content
SpringerLink
Log in

Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility

  • Experimental
  • Published:
Intensive Care Medicine Aims and scope Submit manuscript

Abstract

Objective

Prostacyclins have been suggested to exert positive inotropic effects which would render them particularly suitable for the treatment of right ventricular (RV) dysfunction due to acute pulmonary hypertension (PHT). Data on this subject are controversial, however, and vary with the experimental conditions. We studied the inotropic effects of epoprostenol at clinically recommended doses in an experimental model of acute PHT.

Design and setting

Prospective laboratory investigation in a university hospital laboratory.

Subjects

Six pigs (36 ± 7 kg).

Interventions

Pigs were instrumented with biventricular conductance catheters, a pulmonary artery (PA) flow probe, and a high-fidelity pulmonary pressure catheter. Incremental doses of epoprostenol (10, 15, 20, 30, 40 ng kg–1 min–1) were administered in undiseased animals and after induction of acute hypoxia-induced PHT.

Measurements and results

In acute PHT epoprostenol markedly reduced RV afterload (slopes of pressure-flow relationship in the PA from 7.0 ± 0.6 to 4.2 ± 0.7 mmHg min l–1). This was associated with a paradoxical and dose-dependent decrease in RV contractility (slope of preload-recruitable stroke-work relationship from 3.0 ± 0.4 to 1.6 ± 0.2 mW s ml–1; slope of endsystolic pressure-volume relationship from 1.5 ± 0.3 to 0.7 ± 0.3 mmHg ml–1). Left ventricular contractility was reduced only at the highest dose. In undiseased animals epoprostenol did not affect vascular tone and produced a mild biventricular decrease in contractility.

Conclusions

Epoprostenol has no positive inotropic effects in vivo. In contrast, epoprostenol-induced pulmonary vasodilation in animals with acute PHT was associated with a paradoxical decrease in RV contractility. This effect is probably caused indirectly by the close coupling of RV contractility to RV afterload. However, data from normal animals suggest that mechanisms unrelated to vasodilation are also involved in the observed negative inotropic response to epoprostenol.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Monchi M, Bellenfant F, Cariou A, Joly LM, Thebert D, Laurent I, Dhainaut JF, Brunet F (1998) Early predictive factors of survival in the acute respiratory distress syndrome. A multivariate analysis. Am J Respir Crit Care Med 158:1076–1081

    PubMed  CAS  Google Scholar 

  2. Davila-Roman VG, Waggoner AD, Hopkins WE, Barzilai B (1995) Right ventricular dysfunction in low output syndrome after cardiac operations: assessment by transesophageal echocardiography. Ann Thorac Surg 60:1081–1086

    Article  PubMed  CAS  Google Scholar 

  3. D'Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT (1991) Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115:343–349

    PubMed  Google Scholar 

  4. Graham TP Jr, Bernard YD, Mellen BG, Celermajer D, Baumgartner H, Cetta F, Connolly HM, Davidson WR, Dellborg M, Foster E, Gersony WM, Gessner IH, Hurwitz RA, Kaemmerer H, Kugler JD, Murphy DJ, Noonan JA, Morris C, Perloff JK, Sanders SP, Sutherland JL (2000) Long-term outcome in congenitally corrected transposition of the great arteries: a multi-institutional study. J Am Coll Cardiol 36:255–261

    Article  PubMed  Google Scholar 

  5. Hinderliter AL, Willis PW, Barst RJ, Rich S, Rubin LJ, Badesch DB, Groves BM, McGoon MD, Tapson VF, Bourge RC, Brundage BH, Koerner SK, Langleben D, Keller CA, Murali S, Uretsky BF, Koch G, Li S, Clayton LM, Jobsis MM, Blackburn SD Jr, Crow JW, Long WA (1997) Effects of long-term infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Primary Pulmonary Hypertension Study Group. Circulation 95:1479–1486

    PubMed  CAS  Google Scholar 

  6. McLaughlin VV, Genthner DE, Panella MM, Rich S (1998) Reduction in pulmonary vascular resistance with long-term epoprostenol (prostacyclin) therapy in primary pulmonary hypertension. N Engl J Med 338:273–277

    Article  PubMed  CAS  Google Scholar 

  7. Lowson SM (2002) Inhaled alternatives to nitric oxide. Anesthesiology 96:1504–1513

    Article  PubMed  CAS  Google Scholar 

  8. Barst RJ, Rubin LJ, Long WA, McGoon MD, Rich S, Badesch DB, Groves BM, Tapson VF, Bourge RC, Brundage BH (1996) A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med 334:296–302

    Article  PubMed  CAS  Google Scholar 

  9. Olschewski H, Rose F, Schermuly R, Ghofrani HA, Enke B, Olschewski A, Seeger W (2004) Prostacyclin and its analogues in the treatment of pulmonary hypertension. Pharmacol Ther 102:139–153

    Article  PubMed  CAS  Google Scholar 

  10. Kisch-Wedel H, Kemming G, Meisner F, Flondor M, Kuebler WM, Bruhn S, Koehler C, Zwissler B (2003) The prostaglandins epoprostenol and iloprost increase left ventricular contractility in vivo. Intensive Care Med 29:1574–1583

    Article  PubMed  Google Scholar 

  11. Montalescot G, Drobinski G, Meurin P, Maclouf J, Sotirov I, Philippe F, Choussat R, Morin E, Thomas D (1998) Effects of prostacyclin on the pulmonary vascular tone and cardiac contractility of patients with pulmonary hypertension secondary to end-stage heart failure. Am J Cardiol 82:749–755

    Article  PubMed  CAS  Google Scholar 

  12. Fassina G, Tessari F, Dorigo P (1983) Positive inotropic effect of a stable analogue of PGI2 and of PGI2 on isolated guinea pig atria. Mechanism of action. Pharmacol Res Commun 15:735–749

    Article  PubMed  CAS  Google Scholar 

  13. Pavlovic M, Petkovic D, Cvetkovic M, Macut DJ, Zdjelar K, Nesic M, Bosnic O, Radulovic R, Mihajlovic M (1995) The influence of prostacyclin (PGI2) on contractile properties of isolated right ventricle of rat heart. Experientia 51:941–944

    Article  PubMed  CAS  Google Scholar 

  14. Rimoldi O, Pierini S, Pagani MR, Pagani M (1991) Reduced cardiovascular sympathetic excitatory responses during iloprost infusion in conscious dogs. Cardiovasc Res 25:793–801

    PubMed  CAS  Google Scholar 

  15. Malik KU, Sehic E (1990) Prostaglandins and the release of the adrenergic transmitter. Ann N Y Acad Sci 604:222–236

    Article  PubMed  CAS  Google Scholar 

  16. Panzenbeck MJ, Tan W, Hajdu MA, Zucker IH (1988) Intracoronary infusion of prostaglandin I2 attenuates arterial baroreflex control of heart rate in conscious dogs. Circ Res 63:860–868

    PubMed  CAS  Google Scholar 

  17. Lanier SM, Malik KU (1985) Inhibition by prostaglandins of adrenergic transmission in the left ventricular myocardium of anesthetized dogs. J Cardiovasc Pharmacol 7:653–659

    Article  PubMed  CAS  Google Scholar 

  18. Kisch-Wedel H, Kemming G, Meisner F, Flondor M, Bruhn S, Koehler C, Messmer K, Zwissler B (2005) Effect of prostaglandin I2 analogues on left ventricular diastolic function in vivo. Eur J Pharmacol 517:208–216

    Article  PubMed  CAS  Google Scholar 

  19. Baan J, van der Velde ET, de Bruin HG, Smeenk GJ, Koops J, van Dijk AD, Temmerman D, Senden J, Buis B (1984) Continuous measurement of left ventricular volume in animals and humans by conductance catheter. Circulation 70:812–823

    PubMed  CAS  Google Scholar 

  20. Steendijk P, Staal E, Jukema JW, Baan J (2001) Hypertonic saline method accurately determines parallel conductance for dual-field conductance catheter. Am J Physiol Heart Circ Physiol 281:H755–H763

    PubMed  CAS  Google Scholar 

  21. Dickstein ML, Yano O, Spotnitz HM, Burkhoff D (1995) Assessment of right ventricular contractile state with the conductance catheter technique in the pig. Cardiovasc Res 29:820–826

    Article  PubMed  CAS  Google Scholar 

  22. Karunanithi MK, Michniewicz J, Copeland SE, Feneley MP (1992) Right ventricular preload recruitable stroke work, end-systolic pressure-volume, and dP/dtmax-end-diastolic volume relations compared as indexes of right ventricular contractile performance in conscious dogs. Circ Res 70:1169–1179

    PubMed  CAS  Google Scholar 

  23. Burkhoff D, Mirsky I, Suga H (2005) Assessment of systolic and diastolic ventricular properties via pressure-volume analysis: a guide for clinical, translational, and basic researchers. Am J Physiol Heart Circ Physiol 289:H501–H512

    Article  PubMed  CAS  Google Scholar 

  24. Vroomen M de, Steendijk P, Lopes Cardozo RH, Brouwers HH, van Bel F, Baan J (2001) Enhanced systolic function of the right ventricle during respiratory distress syndrome in newborn lambs. Am J Physiol Heart Circ Physiol 280:H392–H400

    Google Scholar 

  25. Hettrick DA, Warltier DC (1995) Ventriculoarterial Coupling. 1:153–180

    Google Scholar 

  26. Brimioulle S, Maggiorini M, Stephanazzi J, Vermeulen F, Lejeune P, Naeije R (1999) Effects of low flow on pulmonary vascular flow-pressure curves and pulmonary vascular impedance. Cardiovasc Res 42:183–192

    Article  PubMed  CAS  Google Scholar 

  27. Rex S, Missant C, Segers P, Wouters PF (2007) Thoracic epidural anesthesia impairs the hemodynamic response to acute pulmonary hypertension by deteriorating right ventricular-pulmonary arterial coupling. Crit Care Med 35:222–229

    Article  PubMed  Google Scholar 

  28. Leeuwenburgh BP, Steendijk P, Helbing WA, Baan J (2002) Indexes of diastolic RV function: load dependence and changes after chronic RV pressure overload in lambs. Am J Physiol Heart Circ Physiol 282:H1350–H1358

    PubMed  CAS  Google Scholar 

  29. Huez S, Retailleau K, Unger P, Pavelescu A, Vachiery JL, Derumeaux G, Naeije R (2005) Right and left ventricular adaptation to hypoxia: a tissue Doppler imaging study. Am J Physiol Heart Circ Physiol 289:H1391–H1398

    Article  PubMed  CAS  Google Scholar 

  30. Ludbrook J (1994) Repeated measurements and multiple comparisons in cardiovascular research. Cardiovasc Res 28:303–311

    Article  PubMed  CAS  Google Scholar 

  31. Ludbrook J (1998) Multiple comparison procedures updated. Clin Exp Pharmacol Physiol 25:1032–1037

    Article  PubMed  CAS  Google Scholar 

  32. Wauthy P, Pagnamenta A, Vassalli F, Naeije R, Brimioulle S (2004) Right ventricular adaptation to pulmonary hypertension: an interspecies comparison. Am J Physiol Heart Circ Physiol 286:H1441–H1447

    Article  PubMed  CAS  Google Scholar 

  33. Gaynor SL, Maniar HS, Bloch JB, Steendijk P, Moon MR (2005) Right atrial and ventricular adaptation to chronic right ventricular pressure overload. Circulation 112:I212–I218

    PubMed  Google Scholar 

  34. Sarnoff SJ, Mitchell JH, Gilmore JP, Remensnyder JP (1960) Homeometric autoregulation in the heart. Circ Res 8:1077–1091

    PubMed  CAS  Google Scholar 

  35. Wauthy P, Abdel KS, Mooi WJ, Naeije R, Brimioulle S (2003) Inhaled nitric oxide versus prostacyclin in chronic shunt-induced pulmonary hypertension. J Thorac Cardiovasc Surg 126:1434–1441

    Article  PubMed  CAS  Google Scholar 

  36. Segers P, Stergiopulos N, Westerhof N (2002) Relation of effective arterial elastance to arterial system properties. Am J Physiol Heart Circ Physiol 282:H1041–H1046

    PubMed  CAS  Google Scholar 

  37. Naeije R (2003) Pulmonary vascular resistance. A meaningless variable? Intensive Care Med 29:526–529

    PubMed  Google Scholar 

  38. Murray PA, Lodato RF, Michael JR (1986) Neural antagonists modulate pulmonary vascular pressure-flow plots in conscious dogs. J Appl Physiol 60:1900–1907

    Article  PubMed  CAS  Google Scholar 

  39. Auclair MC, Vernimmen C, Lechat P (1988) Influence of prostacyclin and two metabolites on the contractility of cultured rat heart cells. Prostaglandins Leukot Essent Fatty Acids 32:33–38

    Article  PubMed  CAS  Google Scholar 

  40. Lawler OA, Miggin SM, Kinsella BT (2001) Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to G(s)-, to G(i)-, and to G(q)-coupled effector signaling. J Biol Chem 276:33596–33607

    Article  PubMed  CAS  Google Scholar 

  41. Nilius SM, Hasse A, Kuger P, Schror K, Meyer-Kirchrath J (2000) Agonist-induced long-term desensitization of the human prostacyclin receptor. FEBS Lett 484:211–216

    Article  PubMed  CAS  Google Scholar 

  42. Panzenbeck MJ, Hintze TH, Kaley G (1988) 6-Keto-prostaglandin E1 is a potent coronary vasodilator and stimulates a vagal reflex in dogs. J Pharmacol Exp Ther 244:814–819

    PubMed  CAS  Google Scholar 

  43. Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T, Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG, Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF, Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J (2004) Guidelines on diagnosis and treatment of pulmonary arterial hypertension. The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 25:2243–2278

    Article  PubMed  Google Scholar 

  44. Ricksten SE (2003) Is prostacyclin an inodilator? Intensive Care Med 29:1403–1405

    Article  PubMed  Google Scholar 

  45. Teerlink JR (2005) Overview of randomized clinical trials in acute heart failure syndromes. Am J Cardiol 96:59G–67G

    Article  PubMed  CAS  Google Scholar 

  46. Kerbaul F, Brimioulle S, Rondelet B, Dewachter C, Hubloue I, Naeije R (2007) How prostacyclin improves cardiac output in right heart failure in conjunction with pulmonary hypertension. Am J Respir Crit Care Med 175:846–850

    Article  PubMed  CAS  Google Scholar 

  47. Guth BD, Schulz R, Heusch G (1991) Pressure-flow characteristics in the right and left ventricular perfusion territories of the right coronary artery in swine. Pflugers Arch 419:622–628

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Anesthesiology, University Hospitals Katholieke Universiteit Leuven, Herestraat 49, 3000, Leuven, Belgium

    Patrick F. Wouters

  2. Section Centre for Experimental Anesthesiology, Emergency and Intensive Care Medicine, Department of Acute Medical Sciences, Katholieke Universiteit Leuven, Minderbroederstraat 19 – bus 7003, 3000, Leuven, Belgium

    Steffen Rex, Carlo Missant & Patrick F. Wouters

  3. Department of Anesthesiology, University Hospital of the RWTH Aachen, Pauwelsstrasse 30, 52074, Aachen, Germany

    Steffen Rex & Rolf Rossaint

  4. Cardiovascular Mechanics and Biofluid Dynamics Research Unit, Institute Biomedical Technology, Ghent University Hospital, De Pintelaan 185, 9000, Ghent, Belgium

    Patrick Segers

Authors
  1. Steffen Rex
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carlo Missant
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Patrick Segers
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rolf Rossaint
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Patrick F. Wouters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Patrick F. Wouters.

Additional information

S. Rex, C. Missant contributed equally to this study.

Supported in part by university funds of the Medizinische Fakultät, RWTH Aachen (S.R.) and the Katholieke Universiteit Leuven (C.M.). None of the authors has current or potential conflicts of interest or has an involvement with organization(s) with financial interest in the subject matter.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Rex, S., Missant, C., Segers, P. et al. Epoprostenol treatment of acute pulmonary hypertension is associated with a paradoxical decrease in right ventricular contractility. Intensive Care Med 34, 179–189 (2008). https://doi.org/10.1007/s00134-007-0831-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00134-007-0831-8

Keywords

Search

Navigation