Metalloproteinase inhibition by Batimastat attenuates pulmonary hypertension in chronically hypoxic rats. 2003

Jan Herget, and Jana Novotna, and Jana Bibova, and Viera Povysilova, and Marie Vankova, and Vaclav Hampl
Department of Physiology, Charles Univ. Second Medical School, Plzenská 130/221, 15000 Praha 5, Czech Republic. jan.herget@lfmotol.cuni.cz

Chronic hypoxia induces lung vascular remodeling, which results in pulmonary hypertension. We hypothesized that a previously found increase in collagenolytic activity of matrix metalloproteinases during hypoxia promotes pulmonary vascular remodeling and hypertension. To test this hypothesis, we exposed rats to hypoxia (fraction of inspired oxygen = 0.1, 3 wk) and treated them with a metalloproteinase inhibitor, Batimastat (30 mg/kg body wt, daily ip injection). Hypoxia-induced increases in concentration of collagen breakdown products and in collagenolytic activity in pulmonary vessels were inhibited by Batimastat, attesting to the effectiveness of Batimastat administration. Batimastat markedly reduced hypoxic pulmonary hypertension: pulmonary arterial blood pressure was 32 +/- 3 mmHg in hypoxic controls, 24 +/- 1 mmHg in Batimastat-treated hypoxic rats, and 16 +/- 1 mmHg in normoxic controls. Right ventricular hypertrophy and muscularization of peripheral lung vessels were also diminished. Batimastat had no influence on systemic arterial pressure or cardiac output and was without any effect in rats kept in normoxia. We conclude that stimulation of collagenolytic activity in chronic hypoxia is a substantial causative factor in the pathogenesis of pulmonary vascular remodeling and hypertension.

UI MeSH Term Description Entries
D006976 Hypertension, Pulmonary Increased VASCULAR RESISTANCE in the PULMONARY CIRCULATION, usually secondary to HEART DISEASES or LUNG DISEASES. Pulmonary Hypertension
D008297 Male Males
D008666 Metalloendopeptidases ENDOPEPTIDASES which use a metal such as ZINC in the catalytic mechanism. Metallo-Endoproteinases,Metalloendopeptidase
D010649 Phenylalanine An essential aromatic amino acid that is a precursor of MELANIN; DOPAMINE; noradrenalin (NOREPINEPHRINE), and THYROXINE. Endorphenyl,L-Phenylalanine,Phenylalanine, L-Isomer,L-Isomer Phenylalanine,Phenylalanine, L Isomer
D011480 Protease Inhibitors Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES). Antiprotease,Endopeptidase Inhibitor,Endopeptidase Inhibitors,Peptidase Inhibitor,Peptidase Inhibitors,Peptide Hydrolase Inhibitor,Peptide Hydrolase Inhibitors,Peptide Peptidohydrolase Inhibitor,Peptide Peptidohydrolase Inhibitors,Protease Antagonist,Protease Antagonists,Antiproteases,Protease Inhibitor,Antagonist, Protease,Antagonists, Protease,Hydrolase Inhibitor, Peptide,Hydrolase Inhibitors, Peptide,Inhibitor, Endopeptidase,Inhibitor, Peptidase,Inhibitor, Peptide Hydrolase,Inhibitor, Peptide Peptidohydrolase,Inhibitor, Protease,Inhibitors, Endopeptidase,Inhibitors, Peptidase,Inhibitors, Peptide Hydrolase,Inhibitors, Peptide Peptidohydrolase,Inhibitors, Protease,Peptidohydrolase Inhibitor, Peptide,Peptidohydrolase Inhibitors, Peptide
D011652 Pulmonary Circulation The circulation of the BLOOD through the LUNGS. Pulmonary Blood Flow,Respiratory Circulation,Circulation, Pulmonary,Circulation, Respiratory,Blood Flow, Pulmonary,Flow, Pulmonary Blood,Pulmonary Blood Flows
D002908 Chronic Disease Diseases which have one or more of the following characteristics: they are permanent, leave residual disability, are caused by nonreversible pathological alteration, require special training of the patient for rehabilitation, or may be expected to require a long period of supervision, observation, or care (Dictionary of Health Services Management, 2d ed). For epidemiological studies chronic disease often includes HEART DISEASES; STROKE; CANCER; and diabetes (DIABETES MELLITUS, TYPE 2). Chronic Condition,Chronic Illness,Chronically Ill,Chronic Conditions,Chronic Diseases,Chronic Illnesses,Condition, Chronic,Disease, Chronic,Illness, Chronic
D003094 Collagen A polypeptide substance comprising about one third of the total protein in mammalian organisms. It is the main constituent of SKIN; CONNECTIVE TISSUE; and the organic substance of bones (BONE AND BONES) and teeth (TOOTH). Avicon,Avitene,Collagen Felt,Collagen Fleece,Collagenfleece,Collastat,Dermodress,Microfibril Collagen Hemostat,Pangen,Zyderm,alpha-Collagen,Collagen Hemostat, Microfibril,alpha Collagen
D000818 Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, Animalia was one of the kingdoms. Under the modern three domain model, Animalia represents one of the many groups in the domain EUKARYOTA. Animal,Metazoa,Animalia
D000860 Hypoxia Sub-optimal OXYGEN levels in the ambient air of living organisms. Anoxia,Oxygen Deficiency,Anoxemia,Deficiency, Oxygen,Hypoxemia,Deficiencies, Oxygen,Oxygen Deficiencies

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