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Am. J. Respir. Crit. Care Med., Volume 163, Number 2, February 2001, 498-502

40-O-(2-Hydroxyethyl)-rapamycin Attenuates Pulmonary Arterial Hypertension and Neointimal Formation in Rats

TOSHIHIKO NISHIMURA, JOHN L. FAUL, GERALD J. BERRY, ISIDRE VEVE, RONALD G. PEARL, and PETER N. KAO

Division of Pulmonary and Critical Care Medicine, Departments of Pathology, and Department of Anesthesiology, Stanford University Medical Center, Stanford, California

Pneumonectomized rats develop pulmonary hypertension (PH) and pulmonary vascular neointimal formation 4 wk after monocrotaline (MCT) administration. Male Sprague-Dawley rats were injected with MCT (60 mg/kg) on Day 7 after left pneumonectomy. Three groups (n = 5) received 40-O-(2-hydroxyethyl)-rapamycin (RAD, 2.5 mg/kg/d, by gavage): Group PMR5-35 from Day 5 to Day 35, Group PMR5-14 from Day 5 to Day 14, and Group PMR15-35 from Day 15 to Day 35. By Day 35, rats that received vehicle had higher mean pulmonary arterial pressures (<OVL>Ppa</OVL> = 41 ± 3 mm Hg) (p < 0.001), right ventricular systolic pressures (Prv,s = 45 ± 2 mm Hg) (p < 0.01), and right ventricle/(left ventricle plus septum) (0.55 ± 0.05) (p = 0.028) than rats in Groups PMR5-35 (<OVL>Ppa</OVL> = 25 ± 3 mm Hg, Prv,s = 32 ± 7 mm Hg, RV/LV&S = 0.42 ± 0.06) and PMR5-14 (<OVL>Ppa</OVL> = 29 ± 4 mm Hg, Prv,s = 30 ± 5 mm Hg, RV/LV&S = 0.43 ± 0.07). Pulmonary arterial neointimal formation (quantified by a vascular occlusion score) was more severe in vehicle-treated rats (1.93 ± 0.03) than in Groups PMR5-14 (1.56 ± 0.27) and PMR5-35 (1.57 ± 0.1) (p < 0.01). RAD attenuates the development of MCT-induced pulmonary arterial hypertension in the pneumonectomized rat.




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