Modulation of the β-adrenergic receptor system of vascular smooth muscle cells in vitro and in vivo by chronically elevated endothelin-1 levels
| Autor: | Folkert Friedmann, Sabine C. Wolf, Jens Freudenberg, Helmut Heinle, Klaus Schulze-Osthoff, Bernhard R. Brehm |
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| Rok vydání: | 2002 |
| Předmět: |
medicine.medical_specialty
Vascular smooth muscle Adrenergic receptor Biology Biochemistry Muscle Smooth Vascular Adenylyl cyclase chemistry.chemical_compound Downregulation and upregulation In vivo Internal medicine Cyclic AMP medicine Animals Receptor Cells Cultured Pharmacology Dose-Response Relationship Drug Endothelin-1 Isoproterenol Adrenergic beta-Agonists Heterotrimeric GTP-Binding Proteins Endothelin 1 Rats Endocrinology chemistry Receptors Adrenergic beta-2 Signal transduction Adenylyl Cyclases |
| Zdroj: | Biochemical Pharmacology. 63:1361-1369 |
| ISSN: | 0006-2952 |
| DOI: | 10.1016/s0006-2952(02)00862-6 |
| Popis: | 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 beta(2)-adrenergic receptor (AR) system. Incubation of smooth muscle cells with ET-1 for 72 hr led to increased beta(2)AR density as determined by radioligand binding. Experiments with inhibitors of protein and RNA synthesis as well as RT-PCR revealed that beta(2)AR 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 beta(2)AR 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 betaAR expression in vivo. As a consequence, beta(2)AR-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 betaARs that attenuate the vasoconstrictive effects of ET-1. |
| Databáze: | OpenAIRE |
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