Biomaterial Database

Phosphoramidon inhibition of the in vivo conversion of big endothelin-1 to endothelin-1 in the human forearm. 1995

C Plumpton, and W G Haynes, and D J Webb, and A P Davenport

Clinical Pharmacology Unit, University of Cambridge, Addenbrooke's Hospital.

1. The vasoconstrictor peptide, endothelin-1 (ET-1) and a biologically inactive C-terminal fragment (CTF) are generated from an intermediate big ET-1 by a putative ET converting enzyme, sensitive to phosphoramidon. We have developed a procedure using selective solid-phase extraction and specific radioimmunoassays to measure the levels of immunoreactive (IR) big ET-1 and the products of conversion (ET-1 and CTF) in human plasma. These techniques have been used to determine the levels of the three peptides in venous plasma following local infusions of ET-1 and big ET-1, both alone and together with phosphoramidon. 2. Infusion of ET-1 into the brachial artery (5 pmol min-1) significantly increased (P < 0.05) IR ET levels from a basal level of 2.3 pM to 55.2 pM in plasma from the infused arm after 60 min of infusion. This corresponded with a marked decrease in forearm blood flow from a basal level of 2.6 ml dl-1 min-1 to 1.7 ml dl-1 min-1. The levels of IR big ET-1 and CTF were unchanged. Co-infusion of phosphoramidon (30 nmol min-1) with ET-1 had no significant effect on the plasma IR levels of ET, big ET-1, CTF, or blood flow. 3. Big ET-1 (50 pmol min-1) significantly increased (P < 0.05) venous concentrations of all three IR peptides after 60 min compared to basal (ET: from 2.2 to 7.7 pM, big ET-1; from 0 to 386.0 pM, CTF: from 0.2 to 37.0 pM). Forearm blood flow decreased significantly (P<0.05) from a basal level of 3.0 ml dl-1 min-1 to 1.6 ml dl-1 min-1.4. When phosphoramidon was co-infused with big ET-1, both the rise in IR ET and associated vasoconstriction were abolished. However, IR CTF was still detected, suggesting that either some conversion by phosphoramidon-insensitive enzyme(s) was occurring, and/or that CTF was being protected from further degradation by phosphoramidon.5. These data show that in the human forearm the activity of a phosphoramidon-sensitive ET converting enzyme is at least in part responsible for the vasoconstrictor properties of exogenous big ET-1. Furthermore, because measurable levels of newly synthesized ET-1 are likely to be rapidly reduced in the blood/plasma through receptor binding, assay of IR big ET-1 and CTF may be a more sensitive measure of ET-1 generation in disease.

UI	MeSH Term	Description	Entries
D008297	Male		Males
D011480	Protease Inhibitors	Compounds which inhibit or antagonize biosynthesis or actions of proteases (ENDOPEPTIDASES).	Antiprotease,Endopeptidase Inhibitor,Endopeptidase Inhibitors,Peptidase Inhibitor,Peptidase Inhibitors,Peptide Hydrolase Inhibitor,Peptide Hydrolase Inhibitors,Peptide Peptidohydrolase Inhibitor,Peptide Peptidohydrolase Inhibitors,Protease Antagonist,Protease Antagonists,Antiproteases,Protease Inhibitor,Antagonist, Protease,Antagonists, Protease,Hydrolase Inhibitor, Peptide,Hydrolase Inhibitors, Peptide,Inhibitor, Endopeptidase,Inhibitor, Peptidase,Inhibitor, Peptide Hydrolase,Inhibitor, Peptide Peptidohydrolase,Inhibitor, Protease,Inhibitors, Endopeptidase,Inhibitors, Peptidase,Inhibitors, Peptide Hydrolase,Inhibitors, Peptide Peptidohydrolase,Inhibitors, Protease,Peptidohydrolase Inhibitor, Peptide,Peptidohydrolase Inhibitors, Peptide
D011863	Radioimmunoassay	Classic quantitative assay for detection of antigen-antibody reactions using a radioactively labeled substance (radioligand) either directly or indirectly to measure the binding of the unlabeled substance to a specific antibody or other receptor system. Non-immunogenic substances (e.g., haptens) can be measured if coupled to larger carrier proteins (e.g., bovine gamma-globulin or human serum albumin) capable of inducing antibody formation.	Radioimmunoassays
D001916	Brachial Artery	The continuation of the axillary artery; it branches into the radial and ulnar arteries.	Arteries, Brachial,Artery, Brachial,Brachial Arteries
D005542	Forearm	Part of the upper extremity in humans and primates extending from the ELBOW to the WRIST.	Antebrachium,Antebrachiums,Forearms
D006020	Glycopeptides	Proteins which contain carbohydrate groups attached covalently to the polypeptide chain. The protein moiety is the predominant group with the carbohydrate making up only a small percentage of the total weight.	Glycopeptide
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000328	Adult	A person having attained full growth or maturity. Adults are of 19 through 44 years of age. For a person between 19 and 24 years of age, YOUNG ADULT is available.	Adults
D013997	Time Factors	Elements of limited time intervals, contributing to particular results or situations.	Time Series,Factor, Time,Time Factor
D014838	Volunteers	Persons who donate their services.	Voluntary Workers,Volunteer Personnel,Untrained Personnel,Volunteer Workers,Volunteerism,Personnel, Untrained,Personnel, Volunteer,Voluntary Worker,Volunteer,Volunteer Worker,Worker, Voluntary,Worker, Volunteer