Effects of endothelin a receptor blockade on endothelial function in patients with chronic heart failure.
BACKGROUND
Chronic heart failure (CHF) is associated with impaired endothelium-dependent vasodilation and increased basal vascular tone due, in part, to elevated endothelin-1 plasma levels. In the present study, we investigated whether a reduction of vascular tone using an endothelin A receptor blocker attenuates the impairment of endothelium-dependent, flow-mediated vasodilation (FMD).


RESULTS
Twenty-one patients with CHF randomly received either the endothelin A receptor blocker LU 135252 (30 mg/d, n=7; 300 mg/d, n=7) or a placebo (n=7). Using high-resolution ultrasound, FMD and endothelium-independent, nitroglycerin-induced dilation of the brachial artery were assessed at baseline in the 21 patients with CHF and in 11 controls and after 3 weeks treatment in the 21 patients with CHF. FMD at baseline was impaired in all 21 patients with CHF (3.2+/-2%) when compared with the 11 controls (9.7+/-4.9%; P=0.0005). In comparison with baseline, FMD significantly improved after 3 weeks of treatment with LU 135252 in all 14 patients receiving it (from 3.0+/-2.0% to 4.9+/-2.9%; P=0.04), but FMD remained unchanged with placebo. Subgroup analysis, according to different dosages, revealed a significant increase of FMD compared with baseline (from 2.4+/-1.5% to 5.5+/-2.4%; P=0.03) in the patients treated with the low-dose (30 mg/d), whereas a high dose of 300 mg/d failed to increase FMD significantly. Improvement in the high-dose group, however, may have been masked by reduced vasodilator capacity due to a significant increase in vessel size (from 4.8+/-0.4 to 5.1+/-0.7 mm; P=0.03).


CONCLUSIONS
These results suggest that endothelin A receptor blockade improves FMD in CHF patients.
Berger
R
R
Department of Cardiology, University of Vienna, Austria.
Stanek
B
B
Hülsmann
M
M
Frey
B
B
Heher
S
S
Pacher
R
R
Neunteufl
T
T
D001783:Blood Flow Velocity / Q000187:drug effects; D001916:Brachial Artery / Q000187:drug effects* / Q000503:physiopathology; D002908:Chronic Disease; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000503:physiopathology; D005260:Female; D006333:Heart Failure / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D006334:Heart Function Tests / Q000187:drug effects; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D005996:Nitroglycerin / Q000494:pharmacology; D010666:Phenylpropionates / Q000627:therapeutic use*; D011498:Protein Precursors / Q000097:blood; D011743:Pyrimidines / Q000627:therapeutic use*; D044022:Receptor, Endothelin A; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D010666:Phenylpropionates; D011498:Protein Precursors; D011743:Pyrimidines; D044022:Receptor, Endothelin A; C107831:darusentan; D005996:Nitroglycerin