Chronically elevated endothelin-1 concentrations modulate the beta-adrenergic receptor system in vitro and in vivo.
In atherosclerosis and heart failure chronically elevated endothelin-1 (ET-1) plasma concentrations have been found which correlate with an increased mortality. The aim of this study was to determine the effects of chronically elevated ET-1 concentrations in vitro on the expression of the beta-adrenergic receptor (betaAR), the alpha-subunit of the stimulatory guanine-nucleotide-binding protein (G(s alpha)), and to determine betaAR's ability to activate adenylyl cyclase. In order to elucidate the effects of elevated ET-1 concentrations in vivo, male rats were infused with ET-1 and betaAR density was measured. Smooth muscle cells were incubated with ET-1 (10(-7) mol/l) for 6 to 48 h. Densities of betaARs were determined by radioligand binding studies and the G(s alpha) was analyzed by Western blotting. Isoproterenol-mediated adenylyl cyclase activity was measured. Additionally male rats were infused with ET-1 for 3 weeks. In vitro the betaAR density increased by 52% (p < 0.05, n = 5). The G(s alpha) increased to 260%. The isoproterenol-stimulated adenylyl cyclase activity was increased to 228%. In vivo, the pulmonary and myocardial betaAR density was elevated by 43% and 97%, respectively. Chronic ET receptor activation induces a transregulation of betaARs in vitro and in vivo.
Brehm
B R
BR
Medical Clinic III, University of Tübingen, Germany. 101566.341@compuserve.com
Heinle
H
H
Risler
T
T
Wolf
S C
SC
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D019332:Endothelin-1 / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D051381:Rats; D011921:Rats, Inbred WKY; D011943:Receptors, Adrenergic, beta / Q000032:analysis / Q000187:drug effects* / Q000502:physiology
D019332:Endothelin-1; D011943:Receptors, Adrenergic, beta; D000262:Adenylyl Cyclases; D007545:Isoproterenol