Reduction of plasma angiotensin II to normal levels by antisense oligodeoxynucleotides against liver angiotensinogen cannot completely attenuate vascular remodeling in spontaneously hypertensive rats

Objective The exact role of angiotensinogen (AGT) in vascular remodeling ha s yet to be determined. In the present study, we examined the effects of re ducing plasma AGT by intravenous injections with antisense oligodeoxynucleo tides (ODNs) against AGT targeted to the liver on vascular remodeling in sp ontaneously hypertensive rats (SHRs). Design and methods The ODNs against rat AGT were coupled to asialoglycoprot ein (ASOR) carrier molecules, which serve as an important method for regula ting liver gene expression. Male SHRs (n = 18) and age-matched male Wistar- Kyoto (WKY) rats (n = 4) were used for this study. All animals were fed a s tandard rat diet throughout the experiment. At 10 weeks of age, the SHRs we re divided into three groups (n = 6); systolic blood pressure (SBP) was sim ilar in each group. The control group received saline, the sense group was injected with the sense ODN complex and the antisense group was injected wi th the antisense ODN complex, WKY rats were fed for the same period of time . The ASOR-poly(L)lysine-ODN complex was injected into the tail veins twice a week Results At the end of the treatment, a reduction in AGT mRNA levels in the liver and plasma AGT was observed only in the animals injected with antisen se ODNs, Antisense ODNs significantly reduced the plasma angiotensin II (An g II) concentrations to levels similar to those observed in WKY rats. Antis ense ODNs significantly reduced the SEP (180.7 +/- 4.4 mmHg) and media cros s-sectional areas of the aorta (1.11 +/- 0.02 mm(2)), which were still larg er than those seen in WKY rats (140.3 +/- 2.1 mmHg, 0.84 +/- 0.02 mm(2)), c ompared with the SHRs injected with sense ODNs (225.2 +/- 4.4 mmHg, 1.24 +/ - 0.02 mm(2)) and control SHRs (223.7 +/- 4.8 mmHg, 1.25 +/- 0.02 mm(2)). T he aortic angiotensin-converting enzyme (ACE) activity and collagen concent rations, which were significantly higher than those seen in WKY rats, did n ot significantly change among the SHR groups. The aortic AGT, ACE, angioten sin II type 1 (AT(1)) receptor and angiotensin II type 2 (AT(2)) receptor m RNA also did not significantly change among the SHR groups. Conclusion On the basis of these findings, plasma AGT is thus considered to play a role in the development of hypertrophy of smooth muscle in the aort a of SHRs, it is thought to have only a slight effect, however, on the remo deling of the matrix tissue when the suppression of hypertension is insuffi cient. J Hypertens 2000, 18:725-731 (C) Lippincott Williams & Wilkins.