Radiation-induced early pulmonary endothelial ectoenzyme dysfunction in vivo: effect of indomethacin.
We investigated the early effects of radiation on pulmonary endothelial function in vivo 7-8 hr after exposure of rabbits to a single dose of 30 Gy to the chest. Utilizing multiple indicator-dilution techniques, we measured rates and kinetics of hydrolysis of the synthetic substrates [3H]benzoyl-Phe-Ala-Pro (BPAP) and [14C]benzoyl-Ala-Gly-Pro (BAGP) by endothelial-bound angiotensin-converting enzyme (ACE) and of 5'[14C]-AMP by endothelial-bound 5'-nucleotidase (NCT) and binding of the synthetic ACE inhibitor [3H]RAC-X-65 during a single transpulmonary passage in anesthetized, artificially ventilated, open-chest rabbits in which both systemic and pulmonary circulations were fully supported by an extracorporeal pump. We have shown that these techniques and the use of the aforementioned probes provide reliable information on pulmonary endothelial function in vivo. Radiation to the chest produced endothelial ectoenzyme dysfunction, as reflected in altered available perfused capillary surface area and altered enzyme kinetics of all probes (decreases in substrate hydrolysis, inhibitor binding, first- and second-order kinetic constants) over a wide range of pulmonary blood flow values (reflecting approximately 60-200% of normal cardiac output). Indomethacin prevented most of these alterations in partially as well as fully recruited lungs. We conclude that impairment of endothelial ectoenzyme activity is an early event in the pathogenesis of radiation-induced lung damage, which occurs independently of hemodynamic influences and may involve synthesis of arachidonic acid metabolites.
Orfanos
S E
SE
Department of Pharmacology & Toxicology, Medical College of Georgia, Augusta 30912.
Chen
X L
XL
Burch
S E
SE
Ryan
J W
JW
Chung
A Y
AY
Catravas
J D
JD
D000818:Animals; D004730:Endothelium, Vascular / Q000187:drug effects / Q000201:enzymology* / Q000528:radiation effects*; D006439:Hemodynamics / Q000187:drug effects / Q000528:radiation effects; D007201:Indicator Dilution Techniques; D007213:Indomethacin / Q000494:pharmacology*; D008168:Lung / Q000098:blood supply / Q000187:drug effects / Q000528:radiation effects*; D008297:Male; D008954:Models, Biological; D007703:Peptidyl-Dipeptidase A / Q000032:analysis* / Q000187:drug effects / Q000528:radiation effects; D011817:Rabbits; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents / Q000494:pharmacology*
D011837:Radiation-Protective Agents; D007703:Peptidyl-Dipeptidase A; D007213:Indomethacin