Chronic hypoxic pulmonary hypertension. Is thrombin involved?
Thrombin contracts vascular smooth muscle and stimulates its proliferation. Using a specific thrombin inhibitor, hirudin, we studied whether thrombin contributes to the pulmonary vasoconstriction and vascular proliferation that occurs in pulmonary hypertension. Hirudin was infused intravenously (0.2 mg/h/kg) by minipumps in nine rats during a 3-wk exposure to hypobaric hypoxia (HH). Vehicle (normal saline) was infused in eight hypoxic control (HC) and seven normoxic control (NC) rats. Sufficient hirudin delivery was confirmed by a failure of undiluted plasma from HH, but not from NC and HC, to clot in response to thrombin. When the plasma samples were diluted 1:10, the thrombin time was significantly prolonged in HH when compared with that in both NC and HC. Although hirudin slightly reduced mean pulmonary arterial pressure in open-chest rats, there was no significant difference between the hypoxic groups in total pulmonary resistance, right ventricle weight, morphologic remodeling of lung vessels, or the perfusion pressure-flow relationship in isolated lungs. Vasoconstrictor responses of isolated lungs to angiotensin II and acute hypoxic challenges were not affected by hirudin treatment. We conclude that hirudin, in a dose sufficient to reduce thrombin's catalytic effect on fibrinogen, does not significantly prevent the development of chronic hypoxic pulmonary hypertension.
Hampl
V
V
Department of Medicine, Veterans Administration Medical Center, Minneapolis, Minnesota 55417.
Archer
S L
SL
Bach
R
R
Nelson
D P
DP
Weir
E K
EK
D000818:Animals; D002908:Chronic Disease; D006439:Hemodynamics / Q000187:drug effects; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006976:Hypertension, Pulmonary / Q000209:etiology / Q000503:physiopathology*; D000860:Hypoxia / Q000209:etiology / Q000503:physiopathology*; D015918:Infusion Pumps, Implantable; D008168:Lung / Q000187:drug effects / Q000503:physiopathology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013047:Specific Pathogen-Free Organisms; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000502:physiology*; D013918:Thrombin Time
D006629:Hirudins; D011994:Recombinant Proteins; D013917:Thrombin; C060225:desirudin