The protective effect of HMG-CoA reductase inhibitors against monocrotaline-induced pulmonary hypertension in the rat might not be a class effect: comparison of pravastatin and atorvastatin.
Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, so called statins, improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study aimed at comparing the protective effects of two statins, pravastatin and atorvastatin, against monocrotaline (MC)-induced pulmonary hypertension in rats. Pravastatin or atorvastatin (PS or AS, 10 mg/kg per day) or vehicle were given orally for 28 days to Wistar male rats injected or not with MC (60 mg/kg intraperitoneally). At 4 weeks, MC-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle + septum weight ratio associated with a decrease in acetylcholine- or sodium-nitroprusside-induced pulmonary artery dilation observed in vitro. Hypertensive pulmonary arteries exhibited an increase in medial thickness and endothelial cell apoptosis and a decrease of endothelial nitric oxide synthase (eNOS) expression. MC-rat lungs showed a significant decrease of eNOS (P < 0.01) and increase of cleaved caspase-3 (P < 0.05) expression determined by Western blotting. PS (P = 0.02) but not AS (P = 0.30) significantly limited the development of pulmonary hypertension (RVP in mmHg: 30 +/- 3, 36 +/- 4 vs. 45 +/- 4 and 14 +/- 1 for MC + PS, MC + AS, MC, and control groups, respectively). Both statins significantly reduced MC-induced right ventricle hypertrophy [RV/left ventricular (LV) + S, in mg/g: 0.46 +/- 0.04, 0.39 +/- 0.03, 0.62 +/- 0.05 and 0.29 +/- 0.01 for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05),and reduced MC-induced thickening (61 +/- 6 microm, 82 +/- 5 microm, 154 +/- 4 microm, and 59 +/- 2 microm for MC + PS, MC + AS, MC, and control groups, respectively; P = 0.01) of small intrapulmonary artery medial wall, with MC + AS still being different from the control group. PS but not AS partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (E(max)=65 +/- 5%, 49 +/- 6%, 46 +/- 3%, and 76 +/- 4% for MC + PS, MC + AS, MC, and control groups, respectively; P < 0.05 for MC + PS vs. other groups). Both statins prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells as well as in the whole lung with a more pronounced effect with PS compared with AS. In conclusion, despite its effects on eNOS expression, apoptosis, and medial wall thickening, AS was unable to significantly reduce pulmonary hypertension and to restore endothelium-dependent relaxation, suggesting intermolecular differences between the two HMG-CoA reductase inhibitors in the protection against MC-induced hypertension.
Rakotoniaina
Zo
Z
Laboratory of Experimental Cardiovascular Physiopathology and Pharmacology (EA2979), University of Burgundy, BP 87900, 21000, Dijon, France.
Guerard
Pascal
P
Lirussi
Frederic
F
Goirand
Françoise
F
Rochette
Luc
L
Dumas
Monique
M
Bardou
Marc
M
D000109:Acetylcholine; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000069059:Atorvastatin; D053148:Caspase 3 / Q000378:metabolism; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006538:Heptanoic Acids / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D006976:Hypertension, Pulmonary / Q000139:chemically induced / Q000188:drug therapy*; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D016686:Monocrotaline; D052250:Nitric Oxide Synthase Type III / Q000187:drug effects / Q000378:metabolism; D009599:Nitroprusside; D017035:Pravastatin / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000187:drug effects / Q000503:physiopathology; D011758:Pyrroles / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D017725:Ventricular Pressure / Q000187:drug effects
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011758:Pyrroles; D009599:Nitroprusside; D016686:Monocrotaline; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; D053148:Caspase 3; D017035:Pravastatin; D000109:Acetylcholine