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


METHODS
Prospective laboratory investigation in a university hospital laboratory.


METHODS
Six pigs (36 +/- 7kg).


METHODS
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, 40ng kg(-1) min(-1)) were administered in undiseased animals and after induction of acute hypoxia-induced PHT.


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 +/- 0.7mmHg minl(-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 +/- 0.3mmHg 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.
Rex
Steffen
S
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.
Missant
Carlo
C
Segers
Patrick
P
Rossaint
Rolf
R
Wouters
Patrick F
PF
D000208:Acute Disease; D000818:Animals; D000959:Antihypertensive Agents / Q000009:adverse effects* / Q000627:therapeutic use; D011464:Epoprostenol / Q000009:adverse effects* / Q000627:therapeutic use; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000503:physiopathology; D009200:Myocardial Contraction / Q000187:drug effects; D013552:Swine; D018497:Ventricular Dysfunction, Right / Q000139:chemically induced*
D000959:Antihypertensive Agents; D011464:Epoprostenol
Ann Thorac Surg. 1995 Oct;60(4):1081-6
7574953
Cardiovasc Res. 1995 Jun;29(6):820-6
7656285
Pharmacol Ther. 2004 May;102(2):139-53
15163595
Circ Res. 1988 Nov;63(5):860-8
3052904
J Cardiovasc Pharmacol. 1985 Jul-Aug;7(4):653-9
2410704
Am J Physiol Heart Circ Physiol. 2002 Apr;282(4):H1350-8
11893571
Am J Physiol Heart Circ Physiol. 2002 Mar;282(3):H1041-6
11834502
Am J Physiol Heart Circ Physiol. 2005 Oct;289(4):H1391-8
15923316
FEBS Lett. 2000 Nov 10;484(3):211-6
11078881
J Biol Chem. 2001 Sep 7;276(36):33596-607
11443126
J Thorac Cardiovasc Surg. 2003 Nov;126(5):1434-41
14666016
Am J Respir Crit Care Med. 1998 Oct;158(4):1076-81
9769263
N Engl J Med. 1998 Jan 29;338(5):273-7
9445406
Am J Cardiol. 1998 Sep 15;82(6):749-55
9761085
J Pharmacol Exp Ther. 1988 Mar;244(3):814-9
3075239
Am J Physiol Heart Circ Physiol. 2001 Aug;281(2):H755-63
11454580
Circulation. 2005 Aug 30;112(9 Suppl):I212-8
16159819
Ann N Y Acad Sci. 1990;604:222-36
1977349
Pharmacol Res Commun. 1983 Sep;15(8):735-49
6138778
Cardiovasc Res. 1991 Oct;25(10):793-801
1721003
Experientia. 1995 Sep 29;51(9-10):941-4
7556575
Circulation. 1997 Mar 18;95(6):1479-86
9118516
Intensive Care Med. 2003 Apr;29(4):526-9
12800831
Circ Res. 1960 Sep;8:1077-91
13746560
Eur Heart J. 2004 Dec;25(24):2243-78
15589643
J Appl Physiol (1985). 1986 Jun;60(6):1900-7
2873121
Clin Exp Pharmacol Physiol. 1998 Dec;25(12):1032-7
9888002
Pflugers Arch. 1991 Dec;419(6):622-8
1788057
Cardiovasc Res. 1994 Mar;28(3):303-11
8174149
Am J Cardiol. 2005 Sep 19;96(6A):59G-67G
16181824
Am J Physiol Heart Circ Physiol. 2001 Jan;280(1):H392-400
11123256
Eur J Pharmacol. 2005 Jul 11;517(3):208-16
15993879
Intensive Care Med. 2003 Sep;29(9):1403-5
12904857
Am J Respir Crit Care Med. 2007 Apr 15;175(8):846-50
17272784
J Am Coll Cardiol. 2000 Jul;36(1):255-61
10898443
Crit Care Med. 2007 Jan;35(1):222-9
17095942
Prostaglandins Leukot Essent Fatty Acids. 1988 Apr;32(1):33-8
3290904
Intensive Care Med. 2003 Sep;29(9):1574-83
12908096
Circulation. 1984 Nov;70(5):812-23
6386218
Cardiovasc Res. 1999 Apr;42(1):183-92
10435009
Anesthesiology. 2002 Jun;96(6):1504-13
12170067
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H501-12
16014610
N Engl J Med. 1996 Feb 1;334(5):296-301
8532025
Circ Res. 1992 Jun;70(6):1169-79
1576738
Am J Physiol Heart Circ Physiol. 2004 Apr;286(4):H1441-7
14684368
Ann Intern Med. 1991 Sep 1;115(5):343-9
1863023