Mineralocorticoid receptors, inflammation and sympathetic drive in a rat model of systolic heart failure

Abstract

Appreciation for the role of aldosterone and mineralocorticoid receptors in cardiovascular disease is accelerating rapidly. Recent experimental work has unveiled a strong relationship between brain mineralocorticoid receptors and sympathetic drive, an important determinant of outcome in heart failure and hypertension. Two putative mechanisms are explored in this manuscript. First, brain mineralocorticoid receptors may influence sympathetic discharge by regulating the release of pro-inflammatory cytokines into the circulation. Blood-borne pro-inflammatory cytokines act upon receptors in the microvasculature of the brain to induce cyclooxygenase-2 activity and the production of prostaglandin E(2), which penetrates the blood-brain barrier to activate the sympathetic nervous system. Second, brain mineralocorticoid receptors may influence sympathetic drive by upregulating the activity of the brain renin-angiotensin system, resulting in NAD(P)H oxidase-dependent superoxide production. A potential role for superoxide-dependent mitogen-activated protein kinase signalling pathways in the regulation of sympathetic nerve activity is also considered. Other potential downstream signalling mechanisms contributing to mineralocorticoid receptor-mediated sympathetic excitation are under investigation.

Figure 1

Effect of central mineralocorticoid receptor blockade on plasma TNF-α levels in rats following myocardial infarction (MI). Rats underwent implantation of a cannula for chronic ICV administration of the mineralocorticoid receptor antagonist spironolactone (SL) or vehicle (VEH). Two weeks later they underwent coronary artery ligation (CL) to induce MI or a sham operation (SHAM). MI and SHAM rats received a continuous ICV infusion of SL or VEH via osmotic minipump for three weeks, beginning approximately 24 hours after coronary artery ligation and echocardiographic confirmation of left ventricular function. Jugular venous samples were collected for measurement (by ELISA) of plasma TNF-α level at the intervals indicated. * P<0.05, SL vs VEH in MI rats. Adapted from (Francis et al., 2003b)

Figure 2

Effect of chronic oral administration of the mineralocorticoid receptor antagonist eplerenone (EPL) on cyclooxygenase-2 (COX-2) expression and neuronal excitation in the paraventricular nucleus of hypothalamus (PVN) in rats with ischemia-induced heart failure (HF). Representative immunohistochemical images showing COX-2 (blue stain) and Fra-like activity (black dots) in sections taken from the PVN of rats with HF six weeks following coronary artery ligation. Left panel: coronal section showing the full expanse of the PVN in a rat with HF. Bar = 100 μm. Middle panel: a higher power view illustrating the localization of COX-2 staining to the extensive microvasculature penetrating the PVN and the proximity of COX-2 staining to chronically excited (Fra-like positive) neurons in a rat with HF. Bar = 30 μm. Right panel: coronal section showing the full expanse of the PVN in a HF rat treated orally with EPL for six weeks. Bar = 100 μm. Adapted from (Kang et al., 2006)

Figure 3

Effect of central mineralocorticoid receptor blockade on components of the brain renin-angiotensin system. mRNA and protein expression of angiotensin converting enzyme (ACE, left panels) and angiotensin II type 1 receptors (AT₁R, right panels) in hypothalamus and cortex of rats with heart failure (HF) treated for 4 weeks with a continuous ICV infusion via osmotic minipump of VEH or the mineralocorticoid receptor antagonist RU28318 and of sham operated control rats (SHAM) * P<0.05 vs. SHAM; † P<0.05, HF+ICV RU28318 vs. HF+ ICV VEH. Adapted from (Yu et al., 2008).