Spironolactone and hydrochlorothiazide exert antioxidant effects and reduce vascular matrix metalloproteinase-2 activity and expression in a model of renovascular hypertension.

Abstract

BACKGROUND AND PURPOSE:

Increased oxidative stress and up-regulation of matrix metalloproteinases (MMPs) may cause structural and functional vascular changes in renovascular hypertension. We examined whether treatment with spironolactone (SPRL), hydrochlorothiazide (HCTZ) or both drugs together modified hypertension-induced changes in arterial blood pressure, aortic remodelling, vascular reactivity, oxidative stress and MMP levels and activity, in a model of renovascular hypertension.

EXPERIMENTAL APPROACH:

We used the two-kidney,one-clip (2K1C) model of hypertension in Wistar rats. Sham-operated or hypertensive rats were treated with vehicle, SPRL (25 mg.kg(-1).day(-1)), HCTZ (20 mg.kg(-1).day(-1)) or a combination for 8 weeks. Systolic blood pressure was monitored weekly. Aortic rings were isolated to assess endothelium-dependent and -independent relaxations. Morphometry of the vascular wall was carried out in sections of aorta. Aortic NADPH oxidase activity and superoxide production were evaluated. Formation of reactive oxygen species was measured in plasma as thiobarbituric acid-reactive substances. Aortic MMP-2 levels and activity were determined by gelatin and in situ zymography, fluorimetry and immunohistochemistry.

KEY RESULTS:

Treatment with SPRL, HCTZ or the combination attenuated 2K1C-induced hypertension, and reversed the endothelial dysfunction in 2K1C rats. Both drugs or the combination reversed vascular aortic remodelling induced by hypertension, attenuated hypertension-induced increases in oxidative stress and reduced MMP-2 levels and activity.

CONCLUSIONS AND IMPLICATIONS:

SPRL or HCTZ, alone or combined, exerted antioxidant effects, and decreased renovascular hypertension-induced MMP-2 up-regulation, thus improving the vascular dysfunction and remodelling found in this model of hypertension.

• Authors: C S Ceron, M M Castro, E Rizzi, M F Montenegro, V Fontana, M C O Salgado, R F Gerlach, J E Tanus-Santos
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 160 Issue 1 Pg. 77-87 (May 2010) ISSN: 1476-5381 [Electronic] England
• PMID: 20331602 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antioxidants
• Lipid Peroxides
• Reactive Oxygen Species
• Hydrochlorothiazide
• Spironolactone
• Matrix Metalloproteinase 2
• Mmp2 protein, rat

Topics

• Animals
• Antioxidants (pharmacology, therapeutic use)
• Aorta (drug effects, enzymology, physiopathology)
• Blood Pressure (drug effects)
• Drug Therapy, Combination
• Hydrochlorothiazide (pharmacology, therapeutic use)
• Hypertension, Renovascular (drug therapy, metabolism, physiopathology)
• In Vitro Techniques
• Lipid Peroxides (metabolism)
• Matrix Metalloproteinase 2 (metabolism)
• Muscle, Smooth, Vascular (drug effects, physiopathology)
• Oxidative Stress (drug effects)
• Rats
• Reactive Oxygen Species (metabolism)
• Spironolactone (pharmacology, therapeutic use)
• Vasodilation (drug effects)