Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 373, Issue 6, pp 401–414

The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS

  • Pascal Guerard
  • Zo Rakotoniaina
  • Françoise Goirand
  • Luc Rochette
  • Monique Dumas
  • Frederic Lirussi
  • Marc Bardou
Original Article

DOI: 10.1007/s00210-006-0082-1

Cite this article as:
Guerard, P., Rakotoniaina, Z., Goirand, F. et al. Naunyn-Schmied Arch Pharmacol (2006) 373: 401. doi:10.1007/s00210-006-0082-1

Abstract

HMG-CoA reductase inhibitors improve endothelial function and exert antiproliferative effects on vascular smooth muscle cells of systemic vessels. This study was aimed to assess the protective effects of pravastatin (an HMG-CoA reductase inhibitor) against monocrotaline-induced pulmonary hypertension in rats. Pravastatin (PS, 10 mg/kg/day) or vehicle were given orally for 28 days to Wistar male rats injected or not with monocrotaline (MC, 60 mg/kg intraperitonealy) and treated or not by Nω-nitro-L-arginine methyl ester (L-NAME) 15 mg/kg/day. At 4 weeks, monocrotaline-injected rats developed severe pulmonary hypertension, with an increase in right ventricular pressure (RVP) and right ventricle/left ventricle+septum weight ratio (RV/LV+S), associated with a decrease in pulmonary artery dilation induced either by acetylcholine or sodium nitroprusside. Hypertensive pulmonary arteries exhibited an increase in medial thickness, medial wall area, endothelial cell apoptosis, and a decrease of endothelial nitric oxide synthase (eNOS) expression. Monocrotaline-rat lungs showed a significant decrease of eNOS expression (4080±27 vs 12189±761 arbitrary density units [ADU] for MC and control groups respectively, P<0.01) and a significant increase of cleaved caspase-3 expression by western blotting (Control=11628±2395 vs MC=2326±2243 ADU, P<0.05). A non-significant trend toward a reduced mortality was observed with pravastatin (relative risk of death = 0.33; 95% confidence interval [0.08–1.30], P= 0.12 for MC+PS vs MC groups). Pravastatine induced a protection against the development of the pulmonary hypertension (RVP in mmHg: 30±3 vs 45±4 and RV/LV+S: 0.46±0.04 vs 0.62±0.05 for MC+PS and MC groups respectively, P<0.05) and was associated with a significant reduction of MC-induced thickening (61±6 μm vs 81±3 μm for MC+PS and MC groups respectively, P= 0.01) of the medial wall of the small intrapulmonary arteries. Pravastatin partially restored acetylcholine-induced pulmonary artery vasodilation in MC rats (Emax=65±5% and 46±3% for MC+PS and MC group respectively, P<0.05) but had no effect on acetylcholine-induced pulmonary artery vasodilation in MC+L-NAME rats. It also prevented apoptosis and restored eNOS expression of pulmonary artery endothelial cells, as well as in the whole lung. Pravastatin reduces the development of monocrotaline-induced pulmonary hypertension and improves endothelium-dependent pulmonary artery relaxation, probably through a reduced apoptosis and a restored eNOS expression of endothelial cells.

Keywords

HMG-CoA reductase inhibitors Pravastatin Pulmonary hypertension Pulmonary artery relaxation Apoptosis 

Copyright information

© Springer-Verlag 2006

Authors and Affiliations

  • Pascal Guerard
    • 1
    • 3
  • Zo Rakotoniaina
    • 1
  • Françoise Goirand
    • 2
  • Luc Rochette
    • 1
  • Monique Dumas
    • 1
  • Frederic Lirussi
    • 1
  • Marc Bardou
    • 1
  1. 1.Laboratory of Experimental Cardiovascular Physiopathology and Pharmacology (EA2979)IFR 100 Faculty of MedicineDijonFrance
  2. 2.UMR 1154, INRA-PhysiologyFaculty of PharmacyChâtenay-MalabryFrance
  3. 3.LPPCE Faculté de MédecineDijonFrance