Angiotensin type 1 receptors mediate smooth muscle proliferation and endothelin biosynthesis in rat vascular smooth muscle.
Angiotensin II (AII) has the potential to promote vascular smooth muscle (VSM) hypertrophy and hyperplasia; however, the mechanisms involved in AII stimulation of VSM growth are not fully understood. The AII receptor subtypes in VSM responsible for several biological events leading to cell proliferation have been evaluated. All-induced mitogenesis in explants of rat VSM cells was antagonized by the angiotensin type 1 (AT1)-selective receptor antagonists SK&F 108566 (IC50 = 5.3 +/- 0.96 nM) and DuP 753 (IC50 = 3.5 +/- 0.97 nM), but not by AT2 receptor antagonists. AII-stimulated endothelin (ET)-1 gene expression was antagonized by SK&F 108566 (50% at 1 microM), but not by selective AT2 receptor antagonists. Similarly, AII stimulated the release of immunoreactive ET (irET) from cultured VSM cells that was antagonized by 1 microM SK&F 108566 (72%) and DuP 753 (66%), but not by AT2 receptor antagonists. AII and growth factors that stimulated the release of irET down-regulated the number of ET receptor binding sites. AII (1-100 nM) markedly (6- to 10-fold) stimulated mitogen-activated protein kinase, an enzyme believed to be involved in the pathway for cell proliferation, and this stimulation was blocked (50-75%) by SK&F 108566 (1 nM-1 microM). Phosphoramidon (50 microM) inhibited (60%) both AII-induced irET release and cell proliferation. These data demonstrate that AII-mediated VSM growth is via AT1 receptors, and suggest that AII-induced ET production may contribute to the proliferative response in these cells.
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
C P
CP
Sung
A J
AJ
Arleth
B L
BL
Storer
E H
EH
Ohlstein
D000179:Acrylates / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D016232:Endothelins / Q000096:biosynthesis*; D006020:Glycopeptides / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011945:Receptors, Angiotensin / Q000502:physiology*; D013876:Thiophenes
D000179:Acrylates; D057911:Angiotensin Receptor Antagonists; D016232:Endothelins; D006020:Glycopeptides; D007093:Imidazoles; D011945:Receptors, Angiotensin; D013876:Thiophenes; D000804:Angiotensin II; C068373:eprosartan; D017871:Calcium-Calmodulin-Dependent Protein Kinases; C008890:phosphoramidon