ANGIOTENSIN TYPE-1 RECEPTORS MEDIATE SMOOTH-MUSCLE PROLIFERATION AND ENDOTHELIN BIOSYNTHESIS IN RAT VASCULAR SMOOTH-MUSCLE

Angiotensin II (All) has the potential to promote vascular smooth musc le (VSM) hypertrophy and hyperplasia; however, the mechanisms involved in All stimulation of VSM growth are not fully understood. The All re ceptor subtypes in VSM responsible for several biological events leadi ng to cell proliferation have been evaluated. All-induced mitogenesis in explants of rat VSM cells was antagonized by the angiotensin type 1 (AT(1))-selective receptor antagonists SK&F 108566 (IC50 = 5.3 +/- 0. 96 nM) and DUP 753 (IC50 = 3.5 +/- 0.97 nM), but not by AT(2) receptor antagonists. All-stimulated endothelin (ET)-1 gene expression was ant agonized by SK&F 108566 (50% at 1 mu M), but not by selective AT(2) re ceptor antagonists. Similarly, All stimulated the release of immunorea ctive ET (irET) from cultured VSM cells that was antagonized by 1 mu M SK&F 108566 (72%) and DuP 753 (66%), but not by AT(2) receptor antago nists. All and growth factors that stimulated the release of irET down regulated the number of ET receptor binding sites. All (1-100 nM) mark edly (6- to 10-fold) stimulated mitogen-activated protein kinase, an e nzyme believed to be involved in the pathway for cell proliferation, a nd this stimulation was blocked (50-75%) by SK&F 108566(1 nM-1 mu M). Phosphoramidon (50 mu M) inhibited (60%) both All-induced irET release and cell proliferation. These data demonstrate that All-mediated VSM growth is via AT(1) receptors, and suggest that All-induced ET product ion may contribute to the proliferative response in these cells.