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Expression of components of the RAS during prolonged blockade at different levels in primates
1Department of Medicine, University of Leicester, United Kingdom.
Abstract:
To assess the effects of inhibition of the renin-angiotensin system at different levels on plasma concentrations of components of the system and on renin and angiotensinogen gene expression, marmosets on a low-sodium diet were treated for 1 wk by continuous intraperitoneal infusion with either the renin inhibitor CGP-29287, the ACE inhibitor benazeprilat, the angiotensin II antagonist valsartan, the renin inhibitory monoclonal antibody R-3-36-16, or vehicle. Plasma total immunoreactive renin increased (14- to 20-fold) after all three modes of interference. Plasma angiotensinogen was significantly reduced in the benazeprilat- and valsartan-treated marmosets but not in the CGP-29287-treated animals. Plasma concentration of angiotensin II was significantly decreased in the benazeprilat-, CGP-29287-, and R-3-36-16-treated marmosets and was increased in the valsartan-treated marmosets. Kidney renin mRNA level increased 8- to 15-fold in all groups. Hepatic angiotensinogen mRNA level increased with CGP-29287 treatment but decreased with the other treatments. Kidney angiotensinogen mRNA level was not affected by any treatment. Different modes of inhibition of the renin-angiotensin system have different effects on plasma components of the system and liver angiotensinogen expression.
Insights
Inhibiting the renin-angiotensin system differently impacts its components. Different drug targets affect plasma levels and gene expression of renin and angiotensinogen.
Area of Science:
- Pharmacology
- Endocrinology
- Molecular Biology
Background:
- The renin-angiotensin system (RAS) plays a crucial role in regulating blood pressure and fluid balance.
- Understanding how different inhibition points within the RAS affect its components is vital for therapeutic development.
Purpose of the Study:
- To investigate the distinct effects of inhibiting the RAS at various levels on plasma component concentrations.
- To examine the impact of different RAS inhibition strategies on renin and angiotensinogen gene expression.
Main Methods:
- Marmosets on a low-sodium diet received 1-week intraperitoneal infusions of renin inhibitor (CGP-29287), ACE inhibitor (benazeprilat), angiotensin II antagonist (valsartan), or a renin inhibitory monoclonal antibody (R-3-36-16).
- Plasma levels of renin, angiotensinogen, and angiotensin II were measured.
- Renin and angiotensinogen mRNA levels in the kidney and liver were quantified.
Main Results:
- Plasma total renin increased significantly (14- to 20-fold) across all tested inhibition groups.
- Plasma angiotensinogen decreased with benazeprilat and valsartan but not CGP-29287.
- Angiotensin II levels decreased with benazeprilat, CGP-29287, and R-3-36-16, but increased with valsartan.
- Kidney renin mRNA levels rose 8- to 15-fold in all groups.
- Hepatic angiotensinogen mRNA increased with CGP-29287 but decreased with other treatments; kidney angiotensinogen mRNA remained unaffected.
Conclusions:
- Different methods of inhibiting the renin-angiotensin system produce varied effects on plasma concentrations of its components.
- The expression of liver angiotensinogen is differentially regulated depending on the specific RAS inhibition strategy employed.
- These findings highlight the complexity of RAS regulation and the need for targeted approaches in therapeutic interventions.