Is increased plasma TMAO a compensatory response to hydrostatic and osmotic stress in cardiovascular diseases?

Recent clinical studies show a positive correlation between elevated plasma TMAO and increased cardiovascular risk. However, the mechanism of the increase and biological effects of TMAO in the circulatory system are obscure. Plasma TMAO level depends mostly on the following three factors. First, the liver produces TMAO from TMA, a gut bacteria metabolite of dietary choline and carnitine. Second, plasma TMAO increases after ingestion of dietary TMAO from fish and seafood. Finally, plasma TMAO depends on TMAO and TMA excretion by the kidneys. Ample evidence highlights protective functions of TMAO, including the stabilization of proteins and cells exposed to hydrostatic and osmotic stresses, for example in fish exposed to hydrostatic stress (deep water) and osmotic stress (salty water). Osmotic stress and hydrostatic stresses are augmented in cardiovascular diseases such as hypertension. In hypertensive subjects a diastole-systole change in hydrostatic pressure in the heart may exceed 220 mmHg with a frequency of 60-220/min. This produces environment in which hydrostatic pressure changes over 100,000 times per 24 h. Furthermore, cardiovascular diseases are associated with disturbances in water-electrolyte balance which produce changes in plasma osmolarity. Perhaps, the increase in plasma TMAO in cardiovascular diseases is analogous to increased level of plasma natriuretic peptide B, which is both a cardiovascular risk marker and a compensatory response producing beneficial effects for pressure/volume overloaded heart. In this regard, there is some evidence that a moderate increase in plasma TMAO due to TMAO supplementation may be beneficial in animal model of hypertension-related heart failure. Finally, increased plasma TMAO is present in humans consuming seafood-rich diet which is thought to be health-beneficial. We hypothesize that increased plasma TMAO serves as a compensatory response mechanism which protects cells from hydrostatic and osmotic stresses.

Electrocardiography in rats: a comparison to human.

Electrocardiography (ECG) in rats is a widely applied experimental method in basic cardiovascular research. The technique of ECG recordings is simple; however, the interpretation of electrocardiographic parameters is challenging. This is because the analysis may be biased by experimental settings, such as the type of anesthesia, the strain or age of animals. Here, we aimed to review electrocardiographic parameters in rats, their normal range, as well as the effect of experimental settings on the parameters variation. Furthermore, differences and similarities between rat and human ECG are discussed in the context of translational cardiovascular research.

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.