Microglia and brain angiotensin type 1 receptors are involved in desensitising baroreflex by intracerebroventricular hypertonic saline in male Sprague-Dawley rats.

High salt diet alters cardiovascular control by increasing concentration of sodium ions (Na+) in cerebrospinal fluid (CSF) and is a risk factor for hypertension. Hypernatremic conditions activate microglia and upregulate renin-angiotensin system in the brain. Thus, we checked if chronic elevation of CSF Na+ affects neural control of circulatory system via microglia and brain angiotensin type 1 receptors (AT1Rs). Normotensive adult male Sprague-Dawley rats received two-week intracerebroventricular (ICV) infusion of either isoosmotic saline (0.9% NaCl); hyperosmotic saline (5% NaCl); 5% NaCl with minocycline - inhibitor of microglia; 5% NaCl with losartan - AT1R blocker. Fluid intake, urine output, and urinary Na+ excretion were measured before and during ICV infusions. At the end of ICV infusions, blood pressure and heart rate were recorded in awake rats at rest, in response to acute air jet stressor, during pharmacological evaluation of baroreflex, and after autonomic ganglia blockade. CSF and blood were collected for evaluation of Na+ concentration. Baroreflex was blunted in rats ICV infused with 5% NaCl. ICV treatment with losartan or minocycline prevented decrease in baroreflex sensitivity. Hemodynamic parameters at rest, in response to acute stressor and autonomic ganglia blockade were similar in all groups. Neither treatment affected water intake, urine output and urinary Na+ excretion. ICV infusion of 5% NaCl resulted in higher concentration of Na+ in CSF than in control group (0.9% NaCl) and in plasma. Our results indicate that chronic ICV infusion of hyperosmotic saline blunts baroreflex in normotensive rats and this desensitization is mediated by microglia and AT1Rs.

Tumour necrosis factor and interleukin 10 in blood pressure regulation in spontaneously hypertensive and normotensive rats.

INTRODUCTION: A growing body of evidence indicates that brain cytokines are involved in the control of the cardiovascular system. Tumour necrosis factor (TNF) is an archetypal cytokine, which exerts its proinflammatory actions via type 1 receptor (TNFR1). Interleukin 10 (IL-10) plays a critical anti-inflammatory role by binding to its receptor (IL-10Ra). The orchestrated inflammatory response is largely dependent on an intricate balance between proinflammatory and anti-inflammatory cytokines and expression of their receptors. AIM: In the study we evaluated the expression of the cytokines and their receptors in the brains of spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats, and how the cytokines affect arterial blood pressure. METHODS: In SH and WKY rats we recorded systolic blood pressure with tail cuff method and measured concentration of TNF, IL-10, TNFR1, and IL-10Ra in the serum, the brainstem, and the hypothalamus; we also measured serum concentrations of copeptin, a surrogate of vasopressin release, angiotensin II and norepinephrine. We immunostained brainstem sections for TNFR1, IL-10Ra, neurons, astrocytes and microglia for confocal imaging. In urethane anaesthetized SH and WKY rats, we invasively recorded blood pressure response to intracerebroventricular (IVC) infusion of TNF or IL-10. We also pharmacologically evaluated baroreflex with phenylephrine and chemoreflex with cyanide in SH and WKY rats. RESULTS: Compared to WKY rats, SH rats had: (1) higher blood pressure; (2) blunted baroreflex and augmented peripheral chemoreflex; (3) greater pressor response to ICV infused TNF and greater hypotensive response to ICV infused IL-10; (4) higher concentration of TNF in the ventral and dorsal aspects of the medulla oblongata; (5) higher expression of TNFR1 in the dorsal medulla; (6) higher concentration of IL-10 in both aspects of the medulla; (7) lower expression of IL-10Ra in the dorsal medulla. Confocal imaging showed co-localization of TNFR1 and IL-10Ra with neurons, astrocytes and microglia in both SH and WKY rats. The concentration of the cytokines and their receptors were significantly higher in the brain than in the serum. There were no significant differences in the concentration of the cytokines and their receptors in the hypothalamic region and in the serum between SH and WKY rats. Serum concentrations of norepinephrine, angiotensin II and copeptin were similar between SH and WKY rats. CONCLUSIONS: Taken together, these findings suggest the presence of a potent milieu for effective TNF signalling in the brainstem, which is associated with the hypertensive phenotype and enhanced hemodynamic response to intrabrain administration of the cytokines. In addition, we hypothesize that the increased IL-10 concentration in the brainstem is a compensatory mechanism for the upregulated TNF system.

Proinflammatory cytokines and ageing of the cardiovascular-renal system.

Cardiovascular health deteriorates with age, and age is one of the strongest risk factors for cardiovascular complications including myocardial infarction, heart failure, cardiac arrhythmias, and death related to heart diseases. In this review, we show that expression of proinflammatory cytokines (PICs) increases throughout the human lifespan, and this increase is correlated with cardiovascular health, morbidity, and mortality. We argue that increased concentrations of circulating PICs are not only markers of chronic low-grade inflammation, but they also serve as an important pathophysiological link between CV health and ageing. We discuss how PICs: 1) promote autonomic imbalance and sympathoexcitation; 2) enhance electrical instability of the myocardium, stimulate remodeling, and depress cardiac function; 3) prompt endothelial dysfunction, vasoconstriction, and progression of atherosclerosis; 4) impair renal function. All of these processes contribute to accelerated ageing of the CV system and increased susceptibility to CV morbidity and death.