The nonsteroidal mineralocorticoid receptor blocker, esaxerenone, is effective in reducing blood pressure (BP) in hypertensive patients. However, the mechanism responsible for anti-hypertensive effect of esaxerenone is not clear. Therefore, we investigated esaxerenone-driven sodium homeostasis and its association with changes in BP in Dahl salt-sensitive (DSS) hypertensive rats. BP was measured by a radiotelemetry system, and sodium homeostasis was determined by an approach of sodium intake (food intake) and excretion (urinary excretion) in DSS rats with a lowsalt diet (0.3% NaCl), high-salt diet (HSD, 8% NaCl), HSD plus 0.001% esaxerenone (w/w), and HSD plus 0.05% furosemide. HSD-fed DSS rats showed a dramatic increase in BP with a non-dipper pattern, while esaxerenone treatment, but not furosemide, significantly reduced BP with a dipper pattern. The cumulative sodium excretion in the active period was significantly elevated in esaxerenone-and furosemide-treated rats compared with their HSD-fed counterparts. However, a significant increase in the sodium/potassium ratio was only observed in esaxerenone-treated rats. Sodium content in the skin, skinned carcass, and total body tended to be lower in esaxerenone-treated rats than in their HSD-fed counterparts, while these values were unchanged in furosemide-treated rats. Consistently, sodium balance tended to be reduced in esaxerenone-treated rats during the active period. These data indicate that esaxerenone-induced reduction in BP is associated with improvement of body sodium homeostasis in salt-dependent hypertension.
Recent clinical studies have indicated that the nonsteroidal mineralocorticoid receptor (MR) antagonist, finerenone, elicits significant cardioprotective effects. However, its precise mechanism is not clear. Here, we aimed to test the hypothesis that cardioprotective effects of finerenone is associated with sodium and macrophage accumulations in heart tissues. Effects of finerenone (10 mg/kg body weight by oral gavage) on myocardial injury and sodium accumulation were examined in Sprague-Dawley rats with chronic aldosterone infusion (0.75 μg/hr) and salt loading through drinking water (1% NaCl). In a survival study, we have started treatment from 6 weeks of age and found that all aldosterone-infused rats died within 30 days infusion, while all those concomitantly treated with finerenone survived until 42 days. In other experiments, we started all treatments from 7 weeks of age, and echocardiography and gene expression analyses revealed an adverse cardiac remodeling as well as diastolic dysfunction with preserved ejection fraction in rats with salt loading and aldosterone infusion for 4 weeks. Notably, finerenone treatment completely prevented the cardiac dysfunction with the improved cardiac remodeling in these rats. Furthermore, Na+ content as well as Na+/K+ ratio in left ventricular tissues were markedly elevated in salt-loaded aldosterone-infused rats, but significantly reduced in rats with concomitant finerenone treatment. Moreover, gene expression of F4/80 (a macrophage marker) was significantly reduced by finerenone treatment. These data indicate that finerenone has the potential to mitigate cardiac diastolic dysfunction in salt-loaded and aldosterone-infused rats by suppressing sodium accumulation in left ventricular tissues. These effects of finerenone may attenuate a subsequent inflammation by macrophages and adverse cardiovascular remodeling.
Conclusions: CIH-induced macrophage infiltration, an important source of myofibroblasts, might participate in the development of renal interstitial fibrosis. These effects were reversed by EPL. Therefore, we speculate MR activation may be related to CIH-induced renal fibrosis.
Homeostasis of body fluid is a key component for maintaining health. An imbalance of body sodium and water causes various pathological states, such as dehydration, volume overload, hypertension, cardiovascular and renal diseases, and metabolic disorders. Conventional concepts regarding physiology and pathophysiology of body sodium and water balance have been established by several assumptions. These assumptions are that the kidneys are the master regulator of body sodium and water content, and that sodium moves inside the body in parallel with water. However, recent clinical and basic studies have proposed alternative concepts. These concepts are that body sodium and water balance are regulated by various organs and multiple factors, such as physical activity and the environment, and that sodium accumulates locally in tissues independently of the blood status and/or water. Various concerns remain unclear, and the regulatory mechanism of body sodium, fluid, and blood pressure needs to be readdressed. In the present review article, we discuss novel concepts regarding the regulation of body sodium, water, and blood pressure with a particular focus on the systemic water conservation system and fluid loss-triggered elevation in blood pressure.
Objectives: Endocrinometabolic disorders in women of child-bearing age, including polycystic ovarian syndrome (PCOS) has contributed to increased prevalence of cardiovascular disease (CVD) risk and its attendant complications, which often degenerate to cardiovascular morbidity and mortality, that is among the leading cause of death globally. Acetate, the most abundant endogenously produced short chain fatty acid has been linked to metabolic health. However, the impact of acetate on CVD-driven pathologies in PCOS is unknown. The present study therefore hypothesized that acetate would attenuate cardiometabolic abnormalities in experimentally induced rat model of PCOS, possibly by suppression of PCSK9/NF-kB-dependent pathways. Materials and Methods:Eight-week-old female Wistar rats were allotted into four groups (n = 6) and the groups received vehicle, acetate (200 mg/kg), letrozole (1 mg/kg) and letrozole plus acetate respectively. The administrations were done once daily by oral gavage and lasted for 21 days. Results:In letrozole-induced PCOS rats characterized with insulin resistance, glucose dysregulation, elevated plasma testosterone and decreased 17-Beta estradiol as well as degenerated ovarian follicles and reduced normal follicles. There was also a significant increase in plasma and cardiac lipid/lipoproteins, lipid peroxidation, inflammatory mediators (NF-kB and TNF-alpha), gamma-glutamyl transferase/lactate dehydrogenase and lactate content, PCSK9 and reduction in plasma and cardiac antioxidants (glutathione peroxidase and reduced glutathione) and plasma nitric oxide synthesis (eNOS and NO) compared with the control rats. In addition, immunohistochemical assessment of cardiac tissue showed severe expression of inflammasome in letrozole-induced PCOS rats compared with the control rats. Nevertheless, supplementation with acetate significantly attenuated these alterations. Conclusions:The current study demonstrates cardiac inflammation in experimentally induced PCOS, which is accompanied by elevated atherogenic lipid/ LDLc, NO-dependent oxidative stress and endothelial dysfunction and mediated by elevated levels of PCSK9 and NF-kB. The results in addition suggest that acetate attenuates PCOS-associated cardiac inflammation by suppression of PCSK9/ NF-kB-dependent mechanisms.
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