Selective proteolitic activation and degradation of ETs and big ETs in parenchymal strips of the guinea-pig lung.
Human and porcine big ET-1 and big ET-2 are similarly potent in contracting parenchymal strips of the guinea-pig lung while big ET-3 is inactive, suggesting that the endothelin-converting enzyme (ECE) which converts big ET-3 is not present and that at least two distinct ECE activities exist, one selective for big ET-1 and big ET-2 and one for big ET-3. Metalloendoprotease inhibitors (phosphoramidon and DL-thiorphan), but not captopril, inhibited the contractions elicited by human big ET-1 and big ET-2 but DL-thiorphan was less active, suggesting that a non-selective enzymatic process is involved in conversion of big ET-1 and big ET-2 in addition to a phosphoramidon-sensitive ECE. Big ET-1 and big ET-2 induced much higher contractions than their corresponding mature peptides. Both metalloendoprotease inhibitors, but not captopril, similarly potentiated contractions induced by ET-1, ET-2 or ET-3 to the level of those evoked by big ET-1 and big ET-2, indicating that only mature ET isopeptides and not their precursors are susceptible to degradation by metalloendoproteases.
Battistini
B
B
William Harvey Research Institute, St. Bartholomew's Hospital Medical College, London, U.K.
Brown
M
M
Vane
J R
JR
D000818:Animals; D002216:Captopril / Q000494:pharmacology; D010450:Endopeptidases / Q000378:metabolism*; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology*; D006020:Glycopeptides / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000502:physiology*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects* / Q000502:physiology; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D011480:Protease Inhibitors / Q000494:pharmacology*; D011498:Protein Precursors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D015244:Thiorphan / Q000494:pharmacology
D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011480:Protease Inhibitors; D011498:Protein Precursors; D002216:Captopril; D015244:Thiorphan; D010450:Endopeptidases; C008890:phosphoramidon