Increased Carotid Wall Elastic Modulus and Fibronectin in Aldosterone-Salt–Treated Rats

Abstract

Background-Previous studies have demonstrated the development of cardiac fibrosis in aldosterone (Aldo)-salt hypertensive rats. Our aim was to determine the effects of Aldo and the Aldo receptor antagonist eplerenone (Epl) on in vivo mechanical properties of the carotid artery using echo-tracking system. Methods and Results-Aldo was administered (1 g/h) in uninephrectomized Sprague-Dawley rats (SD) receiving a high-salt diet from 8 to 12 weeks of age. Uninephrectomized control SD rats received a normal salt diet without Aldo. Three groups of Aldo-salt rats were treated with 1, 10, or 30 mg/kg Ϫ1 · d Ϫ1 of Epl by gavage. Elasticity was measured by elastic modulus (Einc)-wall stress curves using medial cross-sectional area (MCSA). The structure of the arterial wall was analyzed by histomorphometry (elastin and collagen), immunohistochemistry (EIIIA fibronectin, Fn), and Northern blot (collagens I and III). Aldo produced increased systolic arterial pressure, pulse pressure, Einc, MCSA, and EIIIA Fn with no change in wall stress or elastin and collagen densities compared with controls without Aldo. No differences in collagen mRNA levels were detected between groups. Epl blunted the increase in pulse pressure in Aldo rats and normalized Einc-wall stress curves, MCSA, and EIIIA Fn. These effects were dose dependent and not accompanied by a reduction in wall stress. Conclusions-Aldo is able to increase arterial stiffness associated with Fn accumulation, independently of wall stress. The preventive effects of Epl suggest a direct role for mineralocorticoid receptors in mechanical and structural alterations of large vessels in rat hyperaldosteronism.

AAV delivery of mineralocorticoid receptor shRNA prevents progression of cold-induced hypertension and attenuates renal damage

“…As a key component of the RAAS, mineralocorticoid receptor (MR) is an attractive target for therapeutic intervention for hypertension and end organ damage. 1,2 Indeed, MR antagonists prevented left ventricular inflammation and fibrosis, 3,4 stiffening of the carotid artery, 5 endothelial dysfunction and activation of nicotinamide adenine dinucleotide phosphate oxidase 6,7 in aldosterone-infused rats. Eplerenone prevented the BP increase in response to salt loading and attenuated cardiac and vascular remodeling in stroke-prone spontaneously hypertensive rat (SHRSP) rats.…”

Current Perspectives on Arterial Stiffness and Pulse Pressure in Hypertension and Cardiovascular Diseases

“…33 On the other hand, chronic aldosterone excess produces increased isobaric carotid stiffness and arterial fibronectin, a process reversed by the aldosterone antagonist eplerenone. 34 Finally, VSM cells do not represent a homogenous population. For the same genomic background, they may have different mixtures of phenotypes, not only with contractile and synthetic but also with proliferative and apoptotic behavior.…”

Ventricular Arterial Stiffening

“…46 Another tactic gaining interest is to reduce fibrosis and/or modify structural proteins thought linked to stiffness. Drugs that inhibit angiotensin II and particularly aldosterone 47,48 are intriguing in this regard. Both may have the added advantages to targeting both vascular and ventricular changes.…”