Effect of ET(A) receptor antagonist on pulmonary hypertension and vascular reactivity in rats with congestive heart failure.
BACKGROUND
We evaluated the effects of chronic therapy with the selective ET(A)receptor antagonist LU 135252 (LU) on pulmonary vascular reactivity in congestive heart failure.


RESULTS
After myocardial infarction (MI) or sham operation, rats were gavaged with LU or saline for 4 weeks. Studies were performed in isolated lungs and to differentiate acute from chronic effects, some experiments were performed with LU in the perfusate. The MI+saline group developed moderate pulmonary hypertension (PH) and right ventricular hypertrophy (RVH). This was improved by LU therapy despite no change in left ventricular function and a larger scar area. Vasodilation to sodium nitroprusside (SNP) was reduced after MI and modestly improved by LU therapy. Vasodilation to acetylcholine (Ach) was similar among the four groups, but accentuated after acute LU administration in the sham+saline and MI+saline groups. A23187 produced higher vasoconstriction (18+/-4%) in the MI+LU compared to the MI+saline (10+/-3%, P<0.05) and the two control groups (3+/-1% and 4+/-3%, with and without LU, P<0.01): this was reversed to vasodilation following the acute addition of LU.


CONCLUSIONS
ET(A)receptor blockade after MI reduces PH and RVH. LU therapy mildly improves dilation to SNP and favorably modulates pulmonary endothelium-dependent responses. These results support future studies to better define the mechanisms of improvement in pulmonary vascular reactivity after ET receptor antagonist therapy.
Lucas
M
M
Research Center and Department of Medicine, Montreal Heart Institute, 5000 Belanger Street East, Montreal, Quebec, H1T 1C8, Canada.
Jasmin
J F
JF
Dupuis
J
J
D000818:Animals; D004195:Disease Models, Animal; D006333:Heart Failure / Q000150:complications* / Q000662:veterinary; D006976:Hypertension, Pulmonary / Q000188:drug therapy* / Q000662:veterinary; D017380:Hypertrophy, Right Ventricular / Q000209:etiology; D008168:Lung / Q000098:blood supply*; D008297:Male; D009203:Myocardial Infarction; D010666:Phenylpropionates / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017466:Receptors, Endothelin / Q000502:physiology*; D014661:Vasoconstriction; D014664:Vasodilation
D010666:Phenylpropionates; D011743:Pyrimidines; D017466:Receptors, Endothelin; C107831:darusentan