Endothelin mediates increased pulmonary vascular tone in patients with heart failure: demonstration by direct intrapulmonary infusion of sitaxsentan.
BACKGROUND
In patients with chronic heart failure (HF), the pulmonary circulation is a major source of endothelin-1 (ET), and ET levels correlate with pulmonary vascular resistance (PVR). The role of ET in causing pulmonary vasoconstriction in HF is not known, however, in part because of the confounding effects of ET receptor antagonists on systemic hemodynamics.


RESULTS
To directly test the hypothesis that ET causes pulmonary vasoconstriction in patients with HF, we infused the selective ET(A) receptor antagonist sitaxsentan at increasing rates (0.3125 to 10 mg/min) into a left lower-lobe segmental pulmonary artery in 8 patients with left ventricular (LV) systolic failure (LV ejection fraction, 24+/-4%) and 4 control subjects with normal LV function. Changes in local PVR distal to the infusion site were assessed by measuring the change in pulmonary blood flow velocity with a Doppler-tipped wire and the mean pulmonary artery pressure (MPAP). Total PVR at baseline was elevated in HF patients (177+/-23 dyne x s x cm(-5)) versus controls (89+/-21 dyne x s x cm(-5); P<0.05). In patients with HF, sitaxsentan caused an infusion rate-dependent decrease in local PVR (P<0.05 versus baseline; P<0.05 versus controls). In contrast, sitaxsentan infusion had no effect on local PVR in controls. Heart rate, mean arterial pressure, cardiac index, and MPAP were not affected by sitaxsentan in either group.


CONCLUSIONS
Selective ET(A) receptor blockade caused local pulmonary vasodilation in patients with HF, but not in control subjects with normal LV function. These data indicate that ET contributes to the secondary pulmonary hypertension associated with HF.
Ooi
Henry
H
Cardiovascular Section, Department of Medicine and the Cardiomyopathy Program, Boston University School of Medicine, Boston, Mass, USA.
Colucci
Wilson S
WS
Givertz
Michael M
MM
D001783:Blood Flow Velocity / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005260:Female; D006333:Heart Failure / Q000150:complications / Q000503:physiopathology*; D006801:Humans; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy / Q000503:physiopathology*; D007261:Infusions, Intra-Arterial; D007555:Isoxazoles / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology*; D011652:Pulmonary Circulation / Q000187:drug effects; D044022:Receptor, Endothelin A; D012016:Reference Values; D013876:Thiophenes / Q000008:administration & dosage*; D014655:Vascular Resistance / Q000187:drug effects; D014666:Vasomotor System / Q000187:drug effects; D016277:Ventricular Function, Left
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007555:Isoxazoles; D044022:Receptor, Endothelin A; D013876:Thiophenes; C106276:sitaxsentan