Protective effects of atorvastatin in rat models of acute pulmonary embolism: involvement of matrix metalloproteinase-9.
OBJECTIVE
Matrix metalloproteinases (MMPs) have been implicated in the pathophysiology of acute pulmonary embolism (APE)-induced pulmonary hypertension. Here, we evaluate the effects of atorvastatin pretreatment on APE-induced pulmonary hypertension, 24-hr mortality rate, and changes in plasma and lung MMP-2 and MMP-9 activities.


METHODS
Controlled animal study.


METHODS
University research laboratory.


METHODS
Male Wistar rats.


METHODS
Rats received atorvastatin (30 mg/kg/day orally) or tap water for 2 wks. In study 1, we examined whether atorvastatin affected APE-induced pulmonary hypertension by using a rat isolated lung perfusion model of APE. In study 2, we examined whether atorvastatin affects the survival rate after APE, which was induced by rapid intravenous injection of 14 mg/kg of a suspension of microspheres (or saline) into the tail vein.


RESULTS
Plasma nitrite/nitrate concentrations were measured by chemiluminescence. Pretreatment with atorvastatin was associated with 49% higher nitrite/nitrate levels compared with controls (p < .05). In study 1, whereas APE increased mean pulmonary artery pressure (MPAP) by 13.0 +/- 1.6 mm Hg in perfused lungs isolated from rats pretreated with water, pretreatment with atorvastatin attenuated by 27% the increases in MPAP after APE. In study 2, pretreatment with atorvastatin was associated with a significant increase in 24-hr survival rate after APE, which was 48% in embolized rats pretreated with water and 64% in rats pretreated with atorvastatin (p < .05). Gelatin zymography of lung and plasma MMP-2 and MMP-9 was performed. Lungs and plasma from embolized rats showed higher levels of both pro- and activated forms of MMP-9 compared with those from nonembolized animals (all p < .05). However, pretreatment with atorvastatin attenuated by 32% the increases in lung-activated MMP-9 levels after APE (p < .05).


CONCLUSIONS
These results suggest that pretreatment with atorvastatin attenuates APE-induced pulmonary hypertension and increases 24-hr survival rate by mechanisms that result in attenuated increases in lung activated MMP-9 after APE.
Souza-Costa
Debora C
DC
Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes 3900, 14049-900 Ribeirao Preto, SP, Brazil.
Figueiredo-Lopes
Livia
L
Alves-Filho
Jose C
JC
Semprini
Maria C
MC
Gerlach
Raquel F
RF
Cunha
Fernando Q
FQ
Tanus-Santos
Jose E
JE
D000208:Acute Disease; D000704:Analysis of Variance; D000818:Animals; D000069059:Atorvastatin; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D006538:Heptanoic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006976:Hypertension, Pulmonary / Q000209:etiology* / Q000378:metabolism / Q000401:mortality / Q000517:prevention & control*; D007275:Injections, Intravenous; D049449:Luminescence; D008168:Lung / Q000737:chemistry; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000032:analysis / Q000187:drug effects / Q000378:metabolism; D008863:Microspheres; D009566:Nitrates / Q000097:blood; D009573:Nitrites / Q000097:blood; D016016:Proportional Hazards Models; D011655:Pulmonary Embolism / Q000150:complications; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D015996:Survival Rate
D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009566:Nitrates; D009573:Nitrites; D011758:Pyrroles; D000069059:Atorvastatin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9