Dynamic regulation of beta-adrenergic receptors by endothelin-1 in smooth-muscle cells.
Elevated endothelin-1 (ET-1) levels are found in atherosclerosis, myocardial ischemia, and heart failure, and are correlated with increased mortality rates. Contrary to expectations, elevations of endogenous ET-1 levels in transgenic mice are not associated with increases in arterial blood pressure or with vasospasm, although these effects can be observed after i.v. ET-1 administration. The aim of this study was to determine the regulatory effects of ET-1 on the expression of vasodilator beta-adrenergic receptors and their ability to activate adenylyl cyclase. Smooth-muscle cells were incubated with ET-1 (10(-7) mol/L) for 3 days. The density of ET-1 or beta-adrenergic receptor binding sites was determined using a radioligand binding procedure. Adenylyl cyclase activity was measured to assess any functional changes in the beta-adrenergic receptor density. ET-1 incubation reduced ET-1 binding sites by 70%. In contrast, the beta-adrenergic receptor density increased from 354 +/- 35 to 538 +/- 50 fmol/mg protein (p < 0.01; n = 7) after 3 days. ET-1 increased beta-adrenergic receptors dose-dependently. Incubation with ET-1 for different periods of time showed an initial decrease of 30% after 6 h of ET-1 incubation. However, after 24 h ET-1 induced an increase of beta-adrenergic receptors, reaching a maximal amount after 48 h. An increased stimulation of beta-adrenergic receptor-activated adenylyl cyclase was observed after 3-day ET-1 incubation compared to controls. These data demonstrate that chronic ET receptor activation by ET-1 results in a functionally significant increase in beta-adrenergic receptor density and adenylyl cyclase activity.
Brehm
B R
BR
Department of Cardiology, University of Tübingen, Germany.
Zvizdic
M
M
Bernhard
R
R
Hoffmeister
H M
HM
Wolf
S C
SC
Karsch
K R
KR
D000262:Adenylyl Cyclases / Q000378:metabolism / Q000502:physiology; D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D020120:Iodocyanopindolol; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D010869:Pindolol / Q000031:analogs & derivatives; D011869:Radioligand Assay; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000187:drug effects*; D017466:Receptors, Endothelin / Q000378:metabolism; D013997:Time Factors; D014664:Vasodilation / Q000502:physiology
D019332:Endothelin-1; D011943:Receptors, Adrenergic, beta; D017466:Receptors, Endothelin; D020120:Iodocyanopindolol; D010869:Pindolol; D000262:Adenylyl Cyclases