Alpha-thrombin-induced pulmonary vasoconstriction.
We examined the direct effects of thrombin on pulmonary vasomotor tone in isolated guinea pig lungs perfused with Ringer albumin (0.5% g/100 ml). The injection of alpha-thrombin (the native enzyme) resulted in rapid dose-dependent increases in pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Ppc), which were associated with an increase in the lung effluent thromboxane B2 concentration. The Ppa and Ppc responses decreased with time but then increased again within 40 min after thrombin injection. The increases in Ppc were primarily the result of postcapillary vasoconstriction. Pulmonary edema as evidenced by marked increases (60% from base line) in lung weight occurred within 90 min after thrombin injection. Injection of modified thrombins (i.e., gamma-thrombin lacking the fibrinogen recognition site or i-Pr2P-alpha-thrombin lacking the serine proteolytic site) was not associated with pulmonary hemodynamic or weight changes nor did they block the effects of alpha-thrombin. Indomethacin (a cyclooxygenase inhibitor), dazoxiben (a thromboxane synthase inhibitor), or hirudin (a thrombin antagonist) inhibited the thrombin-induced pulmonary vasoconstriction, as well as the pulmonary edema. We conclude that thrombin-induced pulmonary vasoconstriction is primarily the result of constriction of postcapillary vessels, and the response is mediated by generation of cyclooxygenase-derived metabolites. The edema formation is also dependent on activation of the cyclooxygenase pathway. The proteolytic site of alpha-thrombin is required for the pulmonary vasoconstrictor and edemogenic responses.
Department of Physiology, Albany Medical College of Union University, New York.
M J
MJ
Horgan
J W
JW
Fenton
A B
AB
Malik
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006629:Hirudins / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects; D008297:Male; D009929:Organ Size / Q000187:drug effects; D011651:Pulmonary Artery / Q000187:drug effects*; D011669:Pulmonary Wedge Pressure / Q000187:drug effects; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects*
D006629:Hirudins; D007093:Imidazoles; C029166:dazoxiben; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D013917:Thrombin; D013930:Thromboxane-A Synthase; D007213:Indomethacin