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Published on: June 3, 2019
Spironolactone Prevents Endothelial Nitric Oxide Synthase Uncoupling and Vascular Dysfunction Induced by β-Adrenergic
Jamaira A Victorio1, Stefano P Clerici1, Roberto Palacios1
1From the Department of Structural and Functional Biology, Institute of Biology, University of Campinas, Brazil (J.A.V., S.P.C., A.P.D.); Department of Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, Alcorcón, Spain (R.P., M.J.A.); Department of Physiological Sciences, Federal University of Espírito Santo, Vitoria, Espírito Santo, Brazil (D.V.V.); Molecular Cardiology Research Institute, Tufts Medical Center, Boston, MA (I.Z.J.); and Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, Brazil (L.V.R.).
Insights
Mineralocorticoid receptor (MR) activation contributes to vascular dysfunction from sustained beta-adrenoceptor (β-AR) overstimulation. Blocking MR with spironolactone, but not AT1 receptor blockade, improved vascular function and nitric oxide bioavailability in a rat model.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Endocrinology
Background:
- Sustained β-adrenoceptor (β-AR) stimulation and renin-angiotensin-aldosterone system activation are hallmarks of cardiovascular diseases.
- Essential hypertension, myocardial infarction, and heart failure often involve increased sympathetic activity.
Purpose of the Study:
- To investigate the roles of the angiotensin II type 1 (AT1) receptor and mineralocorticoid receptor (MR) in vascular alterations induced by β-AR overstimulation.
- To elucidate the mechanisms underlying β-AR overstimulation-induced vascular dysfunction.
Main Methods:
- A rat model of β-AR overstimulation was established using 7-day isoproterenol treatment, inducing cardiac hypertrophy and increased aortic vasoconstriction.
- The effects of MR antagonist spironolactone and AT1 receptor antagonist losartan on vascular responses, cardiac hypertrophy, and endothelial function were assessed.
- Mechanisms involving nitric oxide (NO) bioavailability, endothelial nitric oxide synthase (eNOS) activity, HSP90, and MR signaling pathways were examined.
Main Results:
- MR blockade with spironolactone, but not AT1 receptor blockade with losartan, blunted the increased vasoconstrictor response to phenylephrine.
- Spironolactone restored NO bioavailability, reduced superoxide production, increased eNOS dimerization, and upregulated aortic HSP90.
- Vascular MR signaling was activated, and perivascular adipose tissue corticosterone levels increased, contributing to impaired anticontractile effects, which were restored by MR blockade.
Conclusions:
- Activation of vascular MR signaling contributes significantly to the vascular dysfunction caused by β-AR overstimulation, particularly through endothelial nitric oxide synthase uncoupling.
- These findings highlight MR antagonists as a potential therapeutic strategy for cardiovascular disorders characterized by sympathetic activation and vascular dysfunction.
Abstract:
Sustained stimulation of β-adrenoceptors (β-ARs) and activation of renin-angiotensin-aldosterone system are common features of cardiovascular diseases with rising sympathetic activation, including essential hypertension, myocardial infarction, and heart failure. In this study, we investigated the role of AT1 receptor and mineralocorticoid receptor (MR) in the vascular alterations caused by β-AR overstimulation. β-AR overstimulation with associated cardiac hypertrophy and increased vasoconstrictor response to phenylephrine in aorta were modeled in rats by 7-day isoproterenol treatment. The increased vasoconstrictor response to phenylephrine in this model was blunted by the MR antagonist spironolactone, but not by the AT1 receptor antagonist losartan, despite the blunting of cardiac hypertrophy with both drugs. Spironolactone, but not losartan, restored NO bioavailability in association with lower endothelial nitric oxide synthase-derived superoxide production, increased endothelial nitric oxide synthase dimerization, and aortic HSP90 upregulation. MR genomic and nongenomic functions were activated in aortas from isoproterenol-treated rats. Isoproterenol did not modify plasma levels of MR ligands aldosterone and corticosterone but rather increased perivascular adipose tissue-derived corticosterone in association with increased expression of 11β-hydroxysteroid dehydrogenase type 1. The anticontractile effect of aortic perivascular adipose tissue was impaired by β-AR overstimulation and restored by MR blockade. These results suggest that activation of vascular MR signaling contributes to the vascular dysfunction induced by β-AR overstimulation associated with endothelial nitric oxide synthase uncoupling. These findings reveal an additional explanation for the protective effects of MR antagonists in cardiovascular disorders with sympathetic activation.
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