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(Circulation. 1998;97:2169-2174.)
© 1998 American Heart Association, Inc.

Basic Science Reports

Endothelin_A Receptor Blockade Improves Nitric Oxide–Mediated Vasodilation in Monocrotaline-Induced Pulmonary Hypertension

Stéphane Prié, PhD; Duncan J. Stewart, MD; ; Jocelyn Dupuis, MD, PhD

From the Departments of Medicine, Montreal Heart Institute (S.P., J.D.), Montreal, Quebec, and St Michael's Hospital (D.J.S.), Toronto, Ontario, Canada.

Correspondence to Dr J. Dupuis, Research Center, Montreal Heart Institute, 5000 Belanger St E, Montreal, Quebec, Canada H1T 1C8. E-mail dupuisj{at}icm.umontreal.ca

Background—Nitric oxide (NO) and endothelin (ET) have been implicated in the pathogenesis of pulmonary hypertension (PH). Chronic ET_A antagonist therapy reduces PH in monocrotaline (MCT)-treated rats. Interactions between the L-arginine–NO pathway and the ET system have been described. We therefore studied the effect of long-term treatment with an oral ET_A antagonist (LU 135252) on NO-related vasodilation in isolated lungs from control rats and rats with MCT-induced PH.

Methods and Results—Three weeks after MCT injection, PH was associated with an increase in right ventricular pressure (from 27.4±0.9 to 66.6±4.1 mm Hg) and a decrease in endothelium-independent vasodilation in response to sodium nitroprusside (10^-10 to 10^-5 mol/L E_max, from 11.1±0.9 to 2.7±0.3 mm Hg). Endothelium-dependent vasodilation in response to acetylcholine (10^-9 to 10^-4 mol/L) and the calcium ionophore A23187 (10^-9 to 10^-7 mol/L) remained unaffected. Treatment with LU 135252 did not significantly affect the endothelium-dependent and -independent vasodilations in control rats. However, in MCT-treated rats, LU 135252 therapy significantly reduced right ventricular pressure (39.7±2.1 mm Hg), potentiated acetylcholine-induced vasodilatation (E_max, from 1.6±0.2 to 3.7±0.4 mm Hg), and improved the responses to sodium nitroprusside (E_max, from 2.7±0.3 to 5.6±0.6 mm Hg). LU 135252 did not significantly alter the non–receptor-mediated endothelium-dependent vasodilation to A23187 or pulmonary constitutive NO synthase activity.

Conclusions—MCT PH is associated with a reduced smooth muscle responsiveness to NO but a maintained endothelium-dependent vasodilatory potency. Long-term ET_A antagonist therapy not only restores smooth muscle responsiveness to NO but also increases endothelium-dependent dilation in response to acetylcholine. This mechanism may contribute to the therapeutic benefit of ET_A antagonists in PH.

Key Words: endothelin • pulmonary heart disease • endothelium • drugs

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