ZD1611, an orally active endothelin-A receptor antagonist, prevents chronic hypoxia-induced pulmonary hypertension in the rat.
Endothelin-1 (ET-1) is a potent vasoconstrictor and comitogen implicated in the pathogenesis of pulmonary hypertension (PH). We evaluated the effects of an ET(A)receptor-selective antagonist, ZD1611, on hypoxia-induced PH in rats. <<Prophylactic>> and <<therapeutic>> paradigms were established in which rats were administered placebo or ZD1611 (1-3 mg/kg, q.i.dpo) concomitant with hypoxic exposure (10% O(2)1 ATM) for 14 days or beginning after 7-day hypoxic exposure for 21 days. Compared with normoxic controls, hypoxic exposure plus placebo increased (P<0.05) hematocrit, mass ratio of right ventricle over left ventricle plus septum (RV/LV+S), and right intraventricular peak systolic pressure (RVSP). These latter two effects were decreased (P<0.05) by ZD1611 in both experimental paradigms [RV/LV+S(%)::RVSP(%); prophylactic, 14::32; therapeutic, 28::37]. Hypoxic exposure did not change mean systemic arterial pressure (MSAP). ZD1611 did not affect MSAP, plasma ET-1 concentrations, or blood gases measured when rats respired room air. In mechanistic studies, ZD1611 decreased (P<0.01) smooth muscle hypertrophy of small pulmonary arteries and abolished hypoxia-induced decreases in sensitivity and maximum contraction to ET-1 in isolated extralobar branch pulmonary artery. In conclusion, the ET(A)receptor-selective antagonist, ZD1611, attenuates hypoxia-induced PH in the rat.
Bialecki
R A
RA
Respiratory, Inflammatory and Neurological Diseases Research Section, ZENECA Pharmaceuticals, Wilmington, Delaware, 19850-5437, USA. russell.bialecki@phwilm.zeneca.com
Fisher
C S
CS
Abbott
B M
BM
Barthlow
H G
HG
Caccese
R G
RG
Stow
R B
RB
Rumsey
J
J
Rumsey
W
W
D000758:Anesthesia; D000818:Animals; D001784:Blood Gas Analysis; D001794:Blood Pressure / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology; D006400:Hematocrit; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000517:prevention & control*; D000860:Hypoxia / Q000150:complications*; D007537:Isometric Contraction / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000473:pathology; D009929:Organ Size / Q000187:drug effects; D011651:Pulmonary Artery / Q000473:pathology; D011652:Pulmonary Circulation / Q000187:drug effects; D011719:Pyrazines / Q000494:pharmacology*; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D013449:Sulfonamides / Q000494:pharmacology*; D016278:Ventricular Function, Right / Q000187:drug effects
D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D011719:Pyrazines; D044022:Receptor, Endothelin A; D013449:Sulfonamides; C121226:ZD 1611