Phosphoramidon abolishes the increases in endothelin-1 release induced by ischemia-hypoxia in isolated perfused guinea pig lungs.
Endothelin (ET)-1 is a potent vasoactive peptide elaborated by the vascular endothelial cells. In the present study we examined the effects of ischemia-hypoxia (I/H) on ET-1 release from isolated perfused guinea pig lungs and heart. Guinea pig lungs subjected to 15 min I/H followed by reperfusion and reventilation significantly (P less than .05) augmented ET-1 release from 14.1 +/- 2.7 to 30.4 +/- 5.6, 27.3 +/- 4.0 and 28.0 +/- 5.0 pg/g of dry weight of lung at 15, 30 and 45 min after I/H, respectively. Pretreatment of guinea pigs with phosphoramidon (10 mg/kg i.v.), an ET converting enzyme inhibitor, 10 min before the removal of lungs abrogated the I/H-induced increases in ET-1 release without affecting the base-line values of ET-1. Phosphoramidon also attenuated the elevations in pulmonary insufflation pressure (PIP) produced by I/H. Moreover, infusion of big ET-1 (BET-1; 30 micrograms/over 15 min) into isolated perfused guinea pig lungs enhanced PIP that was abolished by phosphoramidon. Isolated guinea pig hearts subjected to 15 or 30 min of global ischemia exhibited no disturbances in ET-1 release or mechanical activity. In addition, the increases in perfusion pressure elicited by BET-1 infusion (12 micrograms/over 30 min) into isolated guinea pig hearts was unaffected by phosphoramidon. In a separate study in anesthetized guinea pigs, phosphoramidon significantly attenuated the increases in blood pressure and PIP elicited by BET-1 (10 micrograms/kg i.v.); the pressor and PIP responses to ET-1 (4 micrograms/kg i.v.) were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
Vemulapalli
S
S
Department of Pharmacology, Schering-Plough Research Institute, Bloomfield, New Jersey.
Rivelli
M
M
Chiu
P J
PJ
del Prado
M
M
Hey
J A
JA
D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016232:Endothelins / Q000378:metabolism* / Q000494:pharmacology; D006020:Glycopeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects*; D000860:Hypoxia / Q000378:metabolism*; D007511:Ischemia / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D009206:Myocardium / Q000378:metabolism
D000900:Anti-Bacterial Agents; D016232:Endothelins; D006020:Glycopeptides; C008890:phosphoramidon