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(Chest. 2005;128:3705-3710.)
© 2005 American College of Chest Physicians

L-arginine Attenuates Acute Pulmonary Embolism-Induced Increases in Lung Matrix Metalloproteinase-2 and Matrix Metalloproteinase-9*

Debora C. Souza-Costa, PharmD, MSc; Talita Zerbini; Ana C. Palei; Raquel F. Gerlach, DDS, PhD and Jose E. Tanus-Santos, MD, PhD

* From the Department of Pharmacology (Dr. Souza-Costa, Ms. Zerbini, Ms. Palei, and Dr. Tanus-Santos), Faculty of Medicine of Ribeirao Preto, University of Sao Paulo; and Department of Morphology, Estomatology and Physiology (Dr. Gerlach), Dental School of Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, Brazil.

Correspondence to: Jose Eduardo Tanus-Santos, MD, PhD, Assistant Professor, Department of Pharmacology, Faculty of Medicine of Ribeirao Preto, University of Sao Paulo, Av. Bandeirantes, 3900, 14049-900 Ribeirao Preto, SP, Brazil; e-mail: tanus{at}fmrp.usp.br

Study objectives: To evaluate the effects of L-arginine on acute pulmonary embolism (APE)-induced pulmonary hypertension and increases in lung matrix metalloproteinase (MMP)-2 and MMP-9 activities.

Design: Prospective trial.

Setting: University laboratory.

Interventions: Using an isolated lung perfusion rat model of APE, we examined whether L-arginine (0, 0.5, 3, and 10 mmol/L; five to seven rats per group) attenuates the pulmonary hypertension induced by the injection of 6.6 mg/kg of 300 µm microspheres into the pulmonary artery. In a second series of experiments (6 to 11 rats per group), we investigated whether nonselective inhibition of nitric oxide (NO) synthases with NG-nitro-L-arginine methyl ester (L-NAME; 4 mmol/L) decreases the effects produced by L-arginine. Lung MMP-2 and MMP-9 activities were determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis gelatin zymography.

Results: L-arginine at 0.5, 3, and 10 mmol/L attenuated APE-induced pulmonary hypertension by 25 to 42% (all p < 0.05). The protective effect of L-arginine was completely reversed by inhibition of NO synthesis with L-NAME. APE was associated with increased lung MMP-2 and MMP-9 activities (both p < 0.05). While L-arginine at 0.5 mmol/L produced no effect on MMPs, L-arginine 3 at mmol/L and 10 mmol/L attenuated the increases in MMP-2 and MMP-9 activities after APE (both p < 0.05).

Conclusions: L-arginine attenuates APE-induced pulmonary hypertension through mechanisms involving increased NO synthesis and maybe attenuation of lung MMP-2 and MMP-9 activities.

Key Words: embolism • L-arginine • matrix metalloproteinases • nitric oxide • pathophysiology • pulmonary hypertension






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