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(Circulation. 2001;103:e94.)
© 2001 American Heart Association, Inc.

Correspondence

Acute Endothelin A Receptor Blockade in Heart Failure

Alison Seed; John McMurray

Clinical Research Initiative in Heart Failure, University of Glasgow, Glasgow, Scotland

To the Editor:

We were surprised by the findings of Givertz et al and their interpretation.¹

These authors describe the acute (6-hour) hemodynamic effects of 3 doses of the intravenous endothelin (ET) A receptor-selective antagonist sitaxsentan, compared with placebo, in patients with severe chronic heart failure. The patients studied had a strikingly high pulmonary vascular resistance (PVR) and mean pulmonary artery pressure compared with those in similar studies of other ET-1 receptor antagonists.^{2 3 4 5} Sixteen patients received placebo, 8 received sitaxsentan 1.5 mg/kg, 16 received sitaxsentan 3.0 mg/kg, and 8 received sitaxsentan 6.0 mg/kg.

Curiously, the 1.5 mg/kg and 3 mg/kg doses seemed to have greater hemodynamic effects than the 6 mg/kg dose. The peak effect occurred at 2 to 4 hours. Although only the pulmonary vascular effects were statistically significant, there was also an apparent reduction in systemic vascular resistance (SVR) by 19% 2 hours after the 3 mg/kg dose compared with a 34% reduction in PVR at this time after the same dose.

The only other published, placebo-controlled study of this type used the nonselective (ET_A/B) ET-1 receptor antagonist bosentan.² In that study, 24 patients received intravenous placebo or 100 mg of bosentan followed by placebo or 200 mg of bosentan, respectively, 1 hour later. The average reductions in PVR and SVR 2 hours after dosing were 33% and 17%, which are remarkably similar to the findings in the sitaxsentan study (although both SVR and PVR were reduced significantly after bosentan). Consequently, it is hard to support the view that there is a difference in the acute hemodynamic actions of an ET_A-selective and a nonselective (ET_A/B) ET-1 receptor antagonist. In addition, it seems premature to conclude that sitaxsentan has a selective pulmonary vascular action and has no systemic vascular effects.

References

1. Givertz MM, Colucci WS, LeJemtel TH, et al. Acute endothelin a receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation. 2000;101:2922–2927.[Abstract/Free Full Text]
   
2. Kiowski W, Sutsch G, Hunziker P, et al. Evidence for endothelin-1-mediated vasoconstriction in severe chronic heart failure. Lancet. 1995;346:732–736.[Medline] [Order article via Infotrieve]
   
3. Cowburn PJ, Cleland JG, McArthur JD, et al. Short-term hemodynamic effects of BQ-123, a selective endothelin ET(A)- receptor antagonist, in chronic heart failure. Lancet. 1998;352:201–202.[Medline] [Order article via Infotrieve]
   
4. Spieker LE, Mitrovic V, Noll G, et al. Acute hemodynamic and neurohumoral effects of selective ET(A) receptor blockade in patients with congestive heart failure: ET 003 Investigators. J Am Coll Cardiol. 2000;35:1745–1752.[Abstract/Free Full Text]
   
5. Torre-Amione G, Durand J, Bozkurt B, et al. Results of a randomized, placebo controlled, hemodynamic trial with an intravenous endothelin-1 receptor antagonist in patients with congestive cardiac failure.
   

Response

Michael M. Givertz, MD; Wilson S. Colucci, MD

Section of Cardiovascular Medicine, Boston University Medical Center, Boston, Mass

Thierry H. LeJemtel, MD

Albert Einstein College of Medicine, Bronx, NY

Stephen S. Gottlieb, MD

University of Maryland, Baltimore, Md

Joshua M. Hare, MD

Johns Hopkins Medical Institutions, Baltimore, Md

Mara T. Slawsky, MD, PhD

Boston Veterans Affairs Medical Center, Boston, Mass

Carl V. Leier, MD

Ohio State University, Columbus, Ohio

Evan Loh, MD

University of Pennsylvania, Philadelphia, Pa

John M. Nicklas, MD

University of Michigan, Ann Arbor, Mich

Bruce E. Lewis, MD

Loyola University, Maywood, Ill

Our study population had substantial decompensation, as evidenced by an elevated pulmonary capillary wedge pressure, low cardiac index, and moderate-to-severe pulmonary hypertension. The finding that the baseline pulmonary vascular resistance (PVR) predicted the magnitude of the decrease in PVR with sitaxsentan may explain the reduced pulmonary vasodilator effect of sitaxsentan in the 6.0 mg/kg (high-dose) group, because baseline PVR tended to be lower in this group. Another potential explanation for the attenuated pulmonary vasodilator effects of sitaxsentan in the 6.0 mg/kg group may be that higher doses of sitaxsentan are less endothelin (ET)-A selective, such that antagonism of vasodilator ET_B receptors in the pulmonary circulation counteracts the dilator effects of ET_A receptor blockade.^R1

In our study population, we did not observe a reduction in systemic vascular resistance with sitaxsentan (overall treatment P=0.446). Potential explanations for the lack of systemic vasodilator effects are discussed in the original article.^R2 Further studies will be needed to determine whether these observations are drug-specific or related to ET_A versus ET_B selectivity, patient population, or other factors.

References

1. Higashi T, Ishizaki T, Shigemori K, et al. Pharmacological characterization of endothelin-induced rat pulmonary arterial dilatation. Br J Pharmacol. 1997;121:782–786.[Medline] [Order article via Infotrieve]
   
2. Givertz MM, Colucci WS, LeJemtel TH, et al. Acute endothelin A receptor blockade causes selective pulmonary vasodilation in patients with chronic heart failure. Circulation. 2000;101:2922–2927.
   

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