Downregulation of beta-adrenergic receptors by low density lipoproteins and its prevention by beta-adrenergic receptor antagonists.
OBJECTIVE
Vasodilation by beta-adrenergic receptors of smooth muscle cells appears to be impaired early after the onset of hypercholesteremia. The aim of this study was to analyze the modulation of beta-adrenergic receptor density and adenylyl cyclase activity in the presence of moderately elevated concentrations of LDL. The effects of beta 1- and beta 2-adrenergic receptor antagonists on LDL-induced receptor changes were studied.


RESULTS
Media explants of porcine coronary arteries were incubated with moderately elevated LDL concentrations (0.7-3.9 mmol/l). The density of beta-adrenergic receptors was determined in plasma membranes using the radioligand [125I]iodocyanopinodolol. LDL (3.9 mmol/l) resulted in a decrease of beta-adrenergic receptor density (control 137 +/- 5 vs. 89 +/- 7 fmol/mg protein, P < 0.01). After removal of LDL and cultivation for an additional 3 days beta-adrenergic receptors increased to 129 +/- 5 fmol/mg. In the presence of the beta 1- or beta 2-adrenergic receptor antagonists the LDL-mediated decrease was inhibited. Addition of metoprolol after 3 days of LDL incubation caused a restoration of receptor density. The basal, isoproterenol- and forskolin-stimulated adenylyl cyclase activities were increased after LDL incubation by 180, 110 or 80%, respectively.


CONCLUSIONS
Moderately elevated LDL levels decreased beta-adrenergic receptor density while adenylyl cyclase activity was simultaneously increased. beta 1- or beta 2-adrenergic receptor antagonists prevented this receptor decrease and might preserve the beta-adrenergic receptor density in the presence of moderately elevated LDL levels.
Department of Cardiology, University of Tübingen, Germany. 101566.341@compuserve.com
B R
BR
Brehm
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M
Meergans
D I
DI
Axel
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M
Pfohl
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H
Heinle
K R
KR
Karsch
D000262:Adenylyl Cyclases / Q000378:metabolism; D000319:Adrenergic beta-Antagonists / Q000378:metabolism* / Q000494:pharmacology; D000818:Animals; D017298:Bisoprolol / Q000494:pharmacology; D002462:Cell Membrane / Q000378:metabolism; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008077:Lipoproteins, LDL / Q000494:pharmacology*; D008297:Male; D008790:Metoprolol / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism; D011412:Propanolamines / Q000494:pharmacology; D013552:Swine
D000319:Adrenergic beta-Antagonists; D008077:Lipoproteins, LDL; D011412:Propanolamines; C026777:ICI 118551; D000262:Adenylyl Cyclases; D008790:Metoprolol; D017298:Bisoprolol