Selective Aldosterone Blockade Prevents Angiotensin II/Salt-Induced Vascular Inflammation in the Rat Heart

Abstract

We studied the role of aldosterone (aldo) in myocardial injury in a model of angiotensin (Ang) II-hypertension. Wistar rats were given 1% NaCl (salt) to drink and randomized into one of the following groups (n = 10; treatment, 21 d): 1) vehicle control (VEH); 2) Ang II infusion (25 ng/min, sc); 3) Ang II infusion plus the selective aldo blocker, eplerenone (epl, 100 mg/kg.d, orally); 4) Ang II infusion in adrenalectomized (ADX) rats; and 5) Ang II infusion in ADX rats with aldo treatment (20 micro g/kg.d, sc). ADX rats received also dexamethasone (12 micro g/kg.d, sc). Systolic blood pressure increased with time in all treatment groups except the VEH group (VEH, 136 +/- 6; Ang II/NaCl, 203 +/- 12; Ang II/NaCl/epl, 196 +/- 10; Ang II/NaCl/ADX, 181 +/- 7; Ang II/NaCl/ADX/aldo, 236 +/- 8 mm Hg). Despite similar levels of hypertension, epl and ADX attenuated the increase in heart weight/body weight induced by Ang II. Histological examination of the hearts evidenced myocardial and vascular injury in the Ang II/salt (7 of 10 hearts with damage, P < 0.05 vs. VEH) and Ang II/salt/ADX/aldo groups (10 of 10 hearts with damage, P < 0.05). Injury included arterial fibrinoid necrosis, perivascular inflammation (primarily macrophages), and focal infarctions. Vascular lesions were associated with expression of the inflammatory mediators cyclooxygenase 2 (COX-2) and osteopontin in the media of coronary arteries. Myocardial injury, COX-2, and osteopontin expression were markedly attenuated by epl treatment (1 of 10 hearts with damage, P < 0.05 vs. Ang II/salt) and adrenalectomy (2 of 10 hearts with damage, P < 0.05 vs. Ang II/salt). Our data indicate that aldo plays a major role in Ang II-induced vascular inflammation in the heart and implicate COX-2 and osteopontin as potential mediators of the damage.

Role of mineralocorticoid receptor on atrial structural remodeling and inducibility of atrial fibrillation in hypertensive rats

“…Previous papers have shown that MR stimulation with aldosterone and inappropriate salt intake caused cardiac hypertrophy and fibrosis, which were independent of blood pressure and preceded by perivascular and interstitial inflammation. [13][14][15] These factors are known to have important roles in developing a pathogenic substrate for AF. 8 Recently, Milliez et al reported that spironolactone decreased atrial ectopy and fibrosis after myocardial infarction in rats.…”

“…[9][10][11][12] However, little is known about the effects of the MR antagonist on atrial remodeling in hypertension. MR stimulation is linked to interstitial fibrosis, inflammation, hypertrophy and superoxide production in the heart, [13][14][15] all of which are known to provide a pathogenic substrate for AF. 8 Thus, it is possible that MR is closely linked with atrial structural remodeling and AF inducibility, and MR inhibition might reverse them.…”

Effects of Aldosterone on the Vasculature

“…11,[35][36][37] This may occur more frequently in the presence of high salt, which sensitizes the cardiovascular system to the nefarious cardiovascular inflammatory effects of aldosterone. Inflammatory responses have increasingly been associated with mechanisms involved in the pathophysiology of cardiovascular disease.…”

Effects of Eplerenone and Salt Intake on Left Ventricular Remodeling after Myocardial Infarction in Rats

“…Regarding the mechanism of this effect, it has been reported that prior to the occurrence of cardiac fibrosis, the infiltration of inflammatory cells such as monocytes and macrophages, and the expression of proinflammatory molecules such as cyclooxygenase-2 (COX-2), monocyte chemoattractant protein-1 (MCP-1), and osteopontin all increased in rats given aldosterone and salt (24). Moreover, eplerenone has been reported to suppress the infiltration of inflammatory cells and the expression of these proinflammatory molecules (6). These reports supported our present results that the progression of cardiac fibrosis induced by salt loading is significantly suppressed by eplerenone.…”

“…Eplerenone has been reported to show very high selectivity for the mineralocorticoid receptors, and has fewer anti-androgenic-and progesterone-related side effects than spironolactone (3,4). In some experimental studies, eplerenone has been reported to have a variety of actions, such as an anti-inflammatory effect, the prevention of cardiac fibrosis (5,6), the suppression of nicotinamide adenine dinucleotide (phosphate) NAD(P)H oxidase activity, and the prevention of endothelial dysfunction (7). Recently, various reports have noted the relationship between salt intake and the impact of aldosterone on the cardiovascular system (8)(9)(10)(11), and aldosterone blockers have been reported to prevent salt-induced cardiac injury (12)(13)(14).…”