Inhibitory Effect of an Angiotensin II Type 1 Receptor Antagonist on Growth of Vascular Smooth Muscle Cells from Spontaneously Hypertensive Rats

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Abstract
Summary: To investigate the role of endogenous angiotensin II (Ang II) in the growth of vascular smooth muscle cells (VSMC), we examined the effect of the novel nonpeptide Ang II type 1 (AT1) receptor antagonist CV-11974 on basal and stimulated-growth of VSMC from normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). CV-11974 inhibited basal DNA synthesis by VSMC from SHR, but not from WKY, in the absence of serum. In the presence of 10% calf serum, DNA synthesis was significantly higher in VSMC from SHR than in cells from WKY, and the inhibitory effect of CV-11974 was attenuated. Ang II dose-dependently stimulated DNA synthesis by VSMC from both rat strains, and this effect was abolished by CV-11974. CV-11974 slightly but significantly suppressed proliferation of VSMC from both rat strains. CV-11974 competitively inhibited the specific binding of 125I-labeled Ang II to VSMC from both rat strains. The angiotensin-converting enzyme inhibitor (ACEI) delapril also reduced basal DNA synthesis by VSMC from SHR, but did not affect proliferation of VSMC from either rat strain. These findings suggest that VSMC from SHR may synthesize Ang II which promotes their basal growth in an autocrine/paracrine manner through the AT1 receptor, and that this system may be associated with the exaggerated growth of VSMC from SHR.