Involvement of a phosphoramidon-sensitive endopeptidase in the processing of big endothelin-1 in the guinea-pig.
In anaesthetized and ventilated guinea-pigs, i.v. injection of 1 nmol/kg big endothelin-1 (big ET-1) did not evoke significant changes in pulmonary inflation pressure (PIP) and mean arterial blood pressure (MBP), whereas injection of the same dose of endothelin-1 (ET-1) induced marked and rapid bronchoconstrictor and pressor responses. Administered at the dose of 10 nmol/kg, big ET-1 provoked significant increases in PIP and MBP, which developed slowly and were long-lasting as compared to those evoked by ET-1. When big ET-1 was incubated for 45 min at 37 degrees C with alpha-chymotrypsin (2 mU/nmol) or pepsin (1 microgram/nmol) and then injected into guinea-pigs at the dose of 1 nmol/kg, marked bronchoconstrictor and pressor responses were observed, with kinetics similar to those noted after administration of the same dose of ET-1. The magnitude of the alpha-chymotrypsin- or pepsin-treated big ET-1 responses was similar to that induced by ET-1, incubated or not with the enzymes. Injected i.v. at the dose of 5 mg/kg, 5 min before the challenge, phosphoramidon almost totally inhibited the bronchoconstrictor and pressor responses induced by 10 nmol/kg big ET-1, whereas thiorphan (5 mg/kg) partially reduced the increase in PIP and exerted a minimal effect on the changes in MBP. Administered at the dose of 20 mg/kg per os, 1 h before i.v. administration of 10 nmol/kg big ET-1, enalapril maleate and captopril did not significantly alter the bronchoconstriction and the hypertensive response evoked by the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)
Pons
F
F
Department of Immunology, Institut Henri Beaufour, Les Ulis, France.
Touvay
C
C
Lagente
V
V
Mencia-Huerta
J M
JM
Braquet
P
P
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology; D001980:Bronchi / Q000187:drug effects / Q000502:physiology; D002918:Chymotrypsin / Q000494:pharmacology; D019332:Endothelin-1; D016232:Endothelins / Q000494:pharmacology / Q000502:physiology*; D006020:Glycopeptides / Q000494:pharmacology*; D006168:Guinea Pigs; D008168:Lung / Q000187:drug effects / Q000502:physiology; D008297:Male; D015260:Neprilysin / Q000037:antagonists & inhibitors* / Q000187:drug effects / Q000502:physiology; D010434:Pepsin A / Q000494:pharmacology; D011498:Protein Precursors / Q000494:pharmacology / Q000502:physiology*; D012680:Sensitivity and Specificity; D015244:Thiorphan / Q000494:pharmacology
D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D016232:Endothelins; D006020:Glycopeptides; D011498:Protein Precursors; D015244:Thiorphan; D002918:Chymotrypsin; D010434:Pepsin A; D015260:Neprilysin; C008890:phosphoramidon