Aldosterone and mineralocorticoid receptors in regulation of the cardiovascular system and pathological remodelling of the heart and arteries.

In the review we discuss the role of mineralocorticoid receptors (MRs) in regulation and pathological remodelling of the cardiovascular system and the therapeutic potential of pharmacological targeting of MRs in cardiovascular diseases. MRs are expressed in organs involved in cardiovascular homeostasis: brain, heart, kidneys and vessels. The excessive activation of MRs has deleterious effects on the cardiovascular system through sympatho-excitation, elevated salt appetite, and renal retention of salt with consequent positive sodium balance, fibrosis and remodelling of the heart and arteries, and with propensity for atrial and ventricular arrhythmias. Hence, it provides basis for a common pathophysiological milieu of hypertension and heart failure. Furthermore, MR-mediated changes in the cardiovascular system are potentiated by renin-angiotensin system and activation of angiotensin type 1 receptors. Due to low selectivity, MRs bind both aldosterone and GCs - cortisol in humans and corticosterone in laboratory rodents. The binding of GCs to MRs is determined by availability of tissue specific 11ß-hydroxysteroid dehydrogenase of type 1 (11ß-HSD1) or type 2 (11ß-HSD2). 11ß-HSD1 metabolizes GCs to either active or inactive metabolites depending on the presence of special cofactors, whereas 11ß-HSD2 transforms GCs only into inactive metabolites allowing for selective stimulation of MRs by aldosterone. 11ß-HSD2 is expressed in the vascular wall, renal epithelium and some groups of cardiovascular neurons in the brain. In contrast, cardiac expression of 11ß-HSD2 is low, thus, both aldosterone and GCs interact with cardiac MRs. The importance of MRs in the cardiovascular pathology is reflected in clinical guidelines that recommend use of MR blockers, spironolactone and eplerenone, in the treatment of heart failure, myocardial infarction and hypertension. Furthermore, new MR blockers and selective inhibitors of 11ß-HSD1 have been developed and are currently tested in clinical trials.

Brain and cardiovascular diseases: common neurogenic background of cardiovascular, metabolic and inflammatory diseases.

In spite of significant progress in pharmacotherapy the incidence of newly diagnosed cases of cardiovascular diseases and cardiovascular morbidity is alarmingly high. Treatment of hypertension or heart failure still remains a serious challenge. Continuous attempts are made to identify the mechanisms that decide about susceptibility to pathogenic factors, and to determine effectiveness of a specific therapeutic approach. Coincidence of cardiovascular diseases with metabolic disorders and obesity has initiated intensive research for their common background. In the recent years increasing attention has been drawn to disproportionately greater number of depressive disorders and susceptibility to stress in patients with coronary artery disease. An opposite relationship, i.e. a greater number of sudden cardiovascular complications in patients with depression, has been also postulated. Progress in functional neuroanatomy and neurochemistry provided new information about the neural network responsible for regulation of cardiovascular functions, metabolism and emotionality in health and under pathological conditions. In this review we will focus on the role of neuromodulators and neurotransmitters engaged in regulation of the cardiovascular system, neuroendocrine and metabolic functions in health and in pathogenesis of cardiovascular diseases and obesity. Among them are classical neurotransmitters (epinephrine and norepinephrine, serotonin, GABA), classical (CRH, vasopressin, neuropeptide Y) and newly discovered (orexins, apelin, leptin IL-1beta, TNF-alpha, ghrelin) neuropeptides, gasotransmitters, eicozanoids, endocannabinoids, and some other compounds involved in regulation of neuroendocrine, sympatho-adrenal and parasympathetic nervous systems. Special attention is drawn to those factors which play a role in immunology and inflammatory processes. Interaction between various neurotransmitter/neuromodulatory systems which may be involved in integration of metabolic and cardiovascular functions is analyzed. The survey gives evidence for significant disturbances in release or action of the same mediators in hypertension heart failure, obesity, diabetes mellitus, metabolic syndrome, starvation, chronic stress, depression and other psychiatric disorders. With regard to the pathogenic background of the cardiovascular diseases especially valuable are the studies showing inappropriate function of angiotensin peptides, vasopressin, CRH, apelin, cytokines and orexins in chronic stress, cardiovascular and metabolic diseases. The studies surveyed in this review suggest that multiple brain mechanisms interact together sharing the same neural circuits responsible for adjustment of function of the cardiovascular system and metabolism to current needs.

Central TNF-alpha elevates blood pressure and sensitizes to central pressor action of angiotensin II in the infarcted rats.

In patients with chronic heart failure (CHF) concentration of TNF-alpha is elevated. Enhanced synthesis of TNF-alpha was also found in the hypothalamus of rats shortly after induction of the myocardial infarct. Available evidence indicates that TNF-alpha increases sympathetic activity and enhances function of the renin-angiotensin-aldosterone system in peripheral tissues. The role of TNF-alpha in regulation of the cardiovascular system and its interactions with brain angiotensin II (ANGII) in CHF was evaluated in the following study. Fourteen Sprague-Dawley rats underwent left coronary artery ligation, implantation of lateral cerebral ventricle cannula and insertion of femoral artery catheter. Post-infarct CHF was confirmed by increased left ventricle end-diastolic pressure. Mean arterial blood pressure (MABP) and heart rate (HR) were recorded during 60 min of intracerebroventricular (i.c.v.) infusion of 0.9% NaCl (5 microl/hr) (control group, n = 7) or TNF-alpha (100 ng/5 microl/hr) (experimental group, n = 7). This was followed by i.c.v. injection of subpressor dose of ANGII (5 ng/2 microl/30 sec) and measurements were continued for 20 min. Infusion of TNF-alpha resulted in the increase of MABP without changes in HR. Administration of ANGII elicited significantly greater increase of MABP in rats pretreated with TNF-alpha. Present results indicate that TNF-alpha increases MABP in CHF and sensitizes to pressor effect of centrally administered ANGII.