Effects of Angiotensin II Infusion and Inhibition of Nitric Oxide Synthase on the Rat Aorta

Abstract

In previous studies, we showed that in vivo infusion of angiotensin II (Ang II) to adult rats induced vascular changes in gene expression, and this effect did not depend solely on blood pressure elevation. To determine whether nitric oxide can influence the effects of Ang II on the vessel wall, we administered to rats Ang II separately or in combination with the arginine analogue N ^ω -nitro- l -arginine methyl ester, which inhibits nitric oxide synthase chronically when given in vivo. We measured changes in aortic medial thickness, the association of macrophages with the endothelial surface of the aorta, the presence of proliferating cell nuclear antigen in the intima and adventitia as an index of aortic cell cycle changes, and the expression of immunodetectable fibronectin as an index of changes in the extracellular matrix. After 18 days of nitric oxide inhibition, the major changes were increased medial thickness and a 3.5-fold increase in the number of adherent macrophages. Rats treated with two different doses of Ang II for 3 days had a fivefold and threefold increase in the number of proliferating cells from the intimal and adventitial regions, respectively. Combined treatment resulted in increased medial thickness, intimal and adventitial cell proliferation, and macrophage adherence. An increased and altered pattern of fibronectin distribution was found in all treatment groups. Losartan administration prevented the effects of Ang II but not of nitric oxide inhibition, whereas administration of l -arginine prevented both intimal macrophage adherence and increased adventitial proliferation in rats given combined treatment. The data suggest that nitric oxide selectively influences macrophage association with the arterial wall, whereas Ang II and nitric oxide may have opposing effects on arterial cell proliferation.