Effects of endothelin-1 and conversion of big endothelin-1 in the isolated perfused rabbit lung.
We examined the effects of endothelin-1 (ET-1) on pulmonary hemodynamic and transvascular fluid filtration and the conversion of big endothelin-1 (big ET-1), a precursor of ET-1, in isolated perfused rabbit lungs at constant vascular and airway pressures. Furthermore we examined whether ET-1 contributes to cyclooxygenase metabolism. The perfusate flow decreased significantly after bolus administration of 1 or 0.1 nmol of ET-1. Lung weight did not increase throughout the experimental period. Big ET-1- (1 nmol) induced decrease in the flow was slow in developing, although the maximum response was comparable to that induced by the same dose of ET-1. The concentration of bit ET-1 in the perfusate progressively decreased, while that of ET-1 increased in a time-dependent manner. Phosphoramidon, an inhibitor of metalloproteinase, suppressed the pressor effect of big ET-1 (P less than 0.01) and the increase in the concentration of ET-1 in the perfusate (P less than 0.05). The present findings provide the first evidence suggesting that the potent vasocontractile effect of big ET-1 in pulmonary circulation can be attributed to the production of ET-1 by the conversion from big ET-1 in the vascular bed. ET-1-induced perfusate flow changes were not affected by indomethacin, and the concentration of 6-ketoprostaglandin F1 alpha, a metabolite of prostacyclin, did not increase after ET-1 administration.
Ishikawa
S
S
Department of Surgery, University of Tsukuba, Ibaraki, Japan.
Tsukada
H
H
Yuasa
H
H
Fukue
M
M
Wei
S
S
Onizuka
M
M
Miyauchi
T
T
Ishikawa
T
T
Mitsui
K
K
Goto
K
K
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D019332:Endothelin-1; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D066298:In Vitro Techniques; D008168:Lung / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors; D008729:Methoxamine / Q000494:pharmacology; D009929:Organ Size / Q000187:drug effects; D010477:Perfusion; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011498:Protein Precursors / Q000378:metabolism*; D011652:Pulmonary Circulation / Q000187:drug effects; D011817:Rabbits
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D011451:Prostaglandin-Endoperoxide Synthases; D008666:Metalloendopeptidases; D008729:Methoxamine; C008890:phosphoramidon