40-O-(2-hydroxyethyl)-rapamycin attenuates pulmonary arterial hypertension and neointimal formation in rats.
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 PMR(5-35) 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 (Ppa = 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 (Ppa = 25 +/- 3 mm Hg, Prv,s = 32 +/- 7 mm Hg, RV/LV&S = 0.42 +/- 0.06) and PMR5-14 (Ppa = 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 PMR(5-35) (1.57 +/- 0.1) (p < 0.01). RAD attenuates the development of MCT-induced pulmonary arterial hypertension in the pneumonectomized rat.
Nishimura
T
T
Division of Pulmonary and Critical Care Medicine, Department of Pathology, Stanford University Medical Center, Stanford, California 94305-5236, USA.
Faul
J L
JL
Berry
G J
GJ
Veve
I
I
Pearl
R G
RG
Kao
P N
PN
D000818:Animals; D002455:Cell Division / Q000187:drug effects*; D004195:Disease Models, Animal; D000068338:Everolimus; D005352:Fibromuscular Dysplasia / Q000473:pathology*; D006439:Hemodynamics / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000473:pathology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D016686:Monocrotaline; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology*; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology
D007166:Immunosuppressive Agents; D016686:Monocrotaline; D000068338:Everolimus; D020123:Sirolimus