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Effects of human plasma proteins on endothelin binding and function
J R Wu-Wong1, D B Dixon, T J Opgenorth
1Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA.
Journal of Cardiovascular Pharmacology
|May 22, 1998
Summary
Human plasma proteins, particularly human serum albumin (HSA), inhibit endothelin-1 (ET-1) binding to cells. However, these proteins do not significantly affect ET-1
Area of Science:
- Biochemistry
- Pharmacology
- Endocrinology
Background:
- Endothelin (ET) isoforms and receptor antagonists bind extensively to plasma proteins.
- Human serum albumin (HSA) is a major plasma protein involved in binding ET-1 and ET receptor antagonists.
Purpose of the Study:
- To investigate the impact of human plasma proteins on ET-1 binding and ET-1-stimulated biological responses.
- To explore how plasma proteins influence the efficacy of ET receptor antagonists.
Main Methods:
- Experiments using rat pituitary MMQ cells and human pericardial smooth-muscle cells.
- Assessing ET-1 binding inhibition by human serum albumin (HSA) and human plasma.
- Measuring ET-1-stimulated phosphatidylinositol (PI) hydrolysis and arachidonic acid release.
- Evaluating the effect of human plasma on the potency of an ETA-selective antagonist (PD-156707).
Main Results:
- HSA and human plasma significantly inhibited ET-1 binding to MMQ cells and smooth-muscle cells.
- Despite reduced binding, ET-1-stimulated PI hydrolysis and arachidonic acid release were not significantly affected by HSA or plasma.
- Human plasma decreased the potency of an ET receptor antagonist in blocking ET-1-stimulated PI hydrolysis.
Conclusions:
- Human plasma proteins, especially HSA, inhibit ET-1 receptor binding but do not significantly impair ET-1-induced signal transduction.
- Plasma proteins reduce the apparent potency of ET receptor antagonists.
- These findings may reconcile discrepancies between in vitro and in vivo potencies of ET receptor antagonists.