Modulation of the β-adrenergic receptor system of vascular smooth muscle cells in vitro and in vivo by chronically elevated endothelin-1 levels

• Published in: Biochemical pharmacology 2002-04, Vol.63 (7), p.1361-1369
• Main Authors: Brehm, Bernhard R., Wolf, Sabine C., Freudenberg, Jens, Friedmann, Folkert, Heinle, Helmut, Schulze-Osthoff, Klaus
• Format: Article
• Language: English
• Subjects: Adenylyl Cyclases - metabolism; Adrenergic beta-Agonists - pharmacology; Animals; Biological and medical sciences; Blood vessels and receptors; Cells, Cultured; Cyclic AMP - metabolism; Dose-Response Relationship, Drug; Endothelin-1; Endothelin-1 - metabolism; Endothelin-1 - pharmacology; Fundamental and applied biological sciences. Psychology; Heterotrimeric GTP-Binding Proteins - metabolism; Isoproterenol - pharmacology; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - metabolism; Muscle, Smooth, Vascular - physiology; Rat; Rats; Receptors; Receptors, Adrenergic, beta-2 - metabolism; Signal transduction; Smooth muscle; Vertebrates: cardiovascular system; β-Adrenergic
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(02)00862-6

Endothelin-1 (ET-1) levels are chronically elevated in several cardiovascular diseases and correlate with an increased mortality. However, in contrast to acute biological activities such as vasoconstriction, little is known about long-term effects of ET-1. In this study we determined the effects of ET-1 on the β 2-adrenergic receptor (AR) system. Incubation of smooth muscle cells with ET-1 for 72 hr led to increased β 2AR density as determined by radioligand binding. Experiments with inhibitors of protein and RNA synthesis as well as RT-PCR revealed that β 2AR upregulation required de novo synthesis. In addition, protein kinase C but neither NO nor prostaglandin metabolism were involved in this effect. The enhanced expression of β 2AR was associated with an increased expression of its stimulatory G-protein and the receptor’s ability to stimulate adenylyl cyclase. To study chronic effects of ET-1 in vivo, rats were infused with ET-1 for 3 weeks. Similarly as in cultured cells, prolonged ET-1 exposure led to increased βAR expression in vivo. As a consequence, β 2AR-induced vasodilatation was increased in aortic rings from ET-1-treated animals. Our results therefore suggest that chronically elevated ET-1 levels in vitro and in vivo induce counterregulatory mechanisms by increasing βARs that attenuate the vasoconstrictive effects of ET-1.