Marcin Ufnal

TMAO: A small molecule of great expectations

Trimethylamine N-oxide (TMAO) is a small organic compound whose concentration in blood increases after ingesting dietary l-carnitine and phosphatidylcholine. Recent clinical studies show a positive correlation between elevated plasma levels of TMAO and an increased risk for major adverse cardiovascular events defined as death, myocardial infarction, or stroke. Several experimental studies suggest a possible contribution of TMAO to the etiology of cardiovascular diseases by affecting lipid and hormonal homeostasis. On the other hand, TMAO-rich seafood, which is an important source of protein and vitamins in the Mediterranean diet, has been considered beneficial for the circulatory system. Although in humans TMAO is known mainly as a waste product of choline metabolism, a number of studies suggest an involvement of TMAO in important biological functions in numerous organisms, ranging from bacteria to mammals. For example, cells use TMAO to maintain cell volume under conditions of osmotic and hydrostatic pressure stresses. In this article, we reviewed well-established chemical and biological properties of TMAO and dietary sources of TMAO, as well as looked at the studies suggesting possible involvement of TMAO in the etiology of cardiovascular and other diseases, such as kidney failure, diabetes, and cancer.

Trimethylamine-N-oxide: a carnitine-derived metabolite that prolongs the hypertensive effect of angiotensin II in rats.

BACKGROUND Recent evidence suggests that an elevated plasma trimethylamine N-oxide (TMAO) level is associated with an increased risk of adverse cardiovascular events in humans; however, the mechanism is not clear. The aims of this study were to establish the plasma TMAO level in rats and to evaluate the effect of TMAO on arterial blood pressure (BP) and the hemodynamic effects of angiotensin II (Ang II). METHODS Twelve-week-old, Sprague-Dawley rats were implanted with telemetric transmitters, and continuous recordings of heart rate, systolic BP (SBP), and diastolic BP (DBP) were made for 7 days before and 14 days during osmotic minipump-driven subcutaneous infusion of saline (controls), TMAO, low-dose Ang II, or Ang II + TMAO. Plasma TMAO concentration was evaluated using liquid chromatography coupled with triple-quadrupole mass spectrometry. RESULTS The plasma TMAO concentration in controls was 0.57 μmol/L, whereas in TMAO-infused rats it was 58 μmol/L. Neither saline nor TMAO infusion affected SBP and DBP. Infusion of Ang II significantly increased SBP and DBP for the first 5 days of infusion only. In contrast, infusion of Ang II + TMAO produced a hypertensive response that lasted until the end of the experiment. TMAO infusions did not affect body weight and motor activity. CONCLUSIONS We showed that physiological plasma TMAO concentration in rats was approximately 10 times lower than that reported in humans. Furthermore, the new finding of the study is that TMAO does not affect BP in normotensive animals. However, it prolongs the hypertensive effect of Ang II.

Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs

Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure.

Gut Bacteria and Hydrogen Sulfide: The New Old Players in Circulatory System Homeostasis

Accumulating evidence suggests that gut bacteria play a role in homeostasis of the circulatory system in mammals. First, gut bacteria may affect the nervous control of the circulatory system via the sensory fibres of the enteric nervous system. Second, gut bacteria-derived metabolites may cross the gut-blood barrier and target blood vessels, the heart and other organs involved in the regulation of the circulatory system. A number of studies have shown that hydrogen sulfide (H2S) is an important biological mediator in the circulatory system. Thus far, research has focused on the effects of H2S enzymatically produced by cardiovascular tissues. However, some recent evidence indicates that H2S released in the colon may also contribute to the control of arterial blood pressure. Incidentally, sulfate-reducing bacteria are ubiquitous in mammalian colon, and H2S is just one among a number of molecules produced by the gut flora. Other gut bacteria-derived compounds that may affect the circulatory system include methane, nitric oxide, carbon monoxide, trimethylamine or indole. In this paper, we review studies that imply a role of gut microbiota and their metabolites, such as H2S, in circulatory system homeostasis.

Exogenous hydrogen sulfide causes different hemodynamic effects in normotensive and hypertensive rats via neurogenic mechanisms

BACKGROUND Increasing evidence suggests that disturbances in H2S homeostasis may participate in the development of hypertension. In this study we compared hemodynamic responses to intracerebroventricular (ICV) infusions of sodium hydrosulfide (NaHS), a H2S donor, between normotensive rats (WKY), spontaneously hypertensive rats (SHR) and angiotensin II - induced hypertensive rats (WKY-Ang II). METHODS We tested the effects of NaHS on mean arterial blood pressure (MABP) and heart rate (HR) in 12-14-week-old, male rats. MABP and HR were continuously recorded at baseline and during ICV infusion of either vehicle (Krebs-Henseleit buffer) or NaHS. RESULTS ICV infusions of the vehicle did not affect MABP and HR. WKY rats infused with 30 nmol/h of NaHS showed a mild decrease in MABP and HR. ICV infusion of 100 nmol/h produced a biphasic response i.e. mild hypotension and bradycardia followed by an increase in MABP and HR, whereas, the infusion of 300 nmol/h of the H2S donor caused a monophasic increases in MABP and HR. In contrast, SHR rats as well as WKY-Ang II rats showed a decrease in MABP and HR during ICV infusions of NaHS. CONCLUSIONS The results provide further evidence for the involvement of H2S in the neurogenic regulation of the circulatory system and suggest that alterations in H2S signaling in the brain could be associated with hypertension.

Statins, the renin–angiotensin–aldosterone system and hypertension – a tale of another beneficial effect of statins

Background: Statins, a class of lipid lowering drugs, decrease mortality associated with cardiovascular events. As hypercholesterolemia is often accompanied by hypertension, a large number of patients receive therapy with statins and antihypertensive drugs which act via the renin–angiotensin–aldosterone system (RAAS). New guidelines published by the American Heart Association and American College of Cardiology on the treatment of dyslipidaemia and the reduction of atherosclerotic cardiovascular risk, which use a risk prediction algorithm based on risk factors such as hypertension but not low-density lipoprotein (LDL) level, may even further increase the number of patients receiving such concomitant therapy. Method: In this paper we review studies on an interaction between statins, the RAAS and antihypertensive drugs acting via the RAAS. Result: Accumulating evidence suggests that the combination of statins and drugs affecting the RAAS exerts a synergistic effect on the circulatory system. For example, statins may lower arterial blood pressure and augment the effect of antihypertensive drugs acting via the RAAS. Statins may interact with the RAAS in a number of ways i.e. to decrease the expression of receptors for angiotensin II (Ang II), inhibit the Ang II-dependent intracellular signalling, reduce the RAAS-dependent oxidative stress and inflammation as well as inhibit the synthesis of Ang II and aldosterone. Conclusion: Although statins given either alone or together with antihypertensive drugs acting via the RAAS may lower arterial blood pressure, further research is needed to evaluate the mechanisms and their therapeutic significance.

The role of brain gaseous transmitters in the regulation of the circulatory system.

A number of neurotransmitters, including biologically active gases namely, nitric oxide (NO), hydrogen sulfide (H2S) and carbon monoxide (CO) have been postulated to play an important role in the control of the cardiovascular system by the brain. The attention of researchers has been focused on NO in particular. It has been shown that pharmacological manipulation of NO concentration in the brain produces significant changes in circulatory parameters. Furthermore, significant alterations in the brain NO system have been found in animal models of human cardiovascular diseases. These findings imply that NO in the brain may become a promising target for new treatment strategies. Although H2S and CO have also been proved to serve as transmitters in the central nervous system, their role in the neurogenic regulation of the cardiovascular system remains more obscure. Interestingly, increased synthesis of NO, H2S and CO is found in inflammation and it appears that the gases mediate some of the circulatory responses to inflammatory stimuli. In this review we discuss the role of brain gaseous transmitters in the control of the circulatory system in health and disease.

Blockade of angiotensin II AT1 receptors inhibits pressor action of centrally administered interleukin-1β in Sprague Dawley rats

The aim of the present study was to evaluate the influence of intraventricular administration of recombinant rat interleukin-1beta (IL-1beta) on regulation of resting blood pressure and heart rate and to test the hypothesis that the brain angiotensinergic system is involved in regulation of hemodynamic parameters by centrally applied IL-1beta. The experiments were performed on Sprague Dawley rats, assigned to three series of experiments. In series 1 (control, n = 6), mean arterial pressure (MAP) and heart rate (HR) were recorded for 15 min under baseline conditions. This was followed by infusion of saline (0.9% sterile NaCl 5 microL/h) into the left cerebral ventricle (LCV). Measurements were continued during the next 60 min. In series 2 (n = 6) and 3 (n = 6) the experimental design was similar, except that in series 2 the animals were LCV infused with saline containing IL-1beta (100 ng/h) and in series 3 with saline containing IL-1beta (100 ng/h) and angiotensin type 1 (AT1) receptors antagonist (Losartan, 10 microg/h). LCV infusion of saline alone did not influence MAP and HR while administration of IL-1beta elicited significant increase in MAP, but not in HR. The pressor effect was absent during combined infusion of IL-1beta and Losartan. Results of the study provide evidence that centrally administered IL-1beta exerts pressor effect, and reveal that this effect is mediated by stimulation of the brain angiotensin system and requires activation of AT1 receptors.

Interleukin-1 receptor antagonist reduces the magnitude of the pressor response to acute stress

The purpose of the present study was to establish the effect of chronic central interleukin-1 receptors blockade and central chronic infusion of interleukin-1 beta (IL-1beta) on cardiovascular response to an acute stressor. The experiments were performed on 12-14-week-old, male WKY rats, divided into three experimental groups. Each group was subjected to chronic intracerebroventricular (ICV) infusion of one of the following compounds: saline (control, group C), recombinant rat IL-1 receptor antagonist (IL-ANT group) or interleukin-1 beta (IL-1B group). After 5 days of the ICV infusions mean arterial blood pressure (MABP) and heart rate (HR) were recorded continuously under baseline conditions and after the application of an air jet stressor. The stressor was applied three times with 10-min intervals. There were no significant differences in MABP and HR between groups under baseline conditions and immediately before the application of the three consecutive air jets. After the first stressor the IL-ANT group responded with a significantly lower increase in blood pressure than the control and IL-1B group. After the application of the two following air jets only the trend for an intergroup difference was present. The results of the present study provide further evidence that cytokines play an important role in the regulation of the circulatory system. The most important new finding is that the magnitude of the pressor response to the alarming stress is strongly influenced by IL-1 receptors in the brain.

The gut-blood barrier permeability – A new marker in cardiovascular and metabolic diseases?

Recent studies suggest that blood-borne metabolites of gut microbiota, such as trimethylamine N-oxide (TMAO) are involved in the aetiology of cardiovascular diseases and may serve as markers of cardiovascular risk. To enter the bloodstream the microbiota-derived molecules need to pass the gut-blood barrier (GBB). The GBB plays an important role in maintaining organism homeostasis. It is a complex multi-layer system which determines the absorption of nutrients, water and many other substances. The integrity and permeability of the GBB may be impaired in numerous diseases including gastrointestinal, metabolic and cardiovascular diseases. Here, we propose that the evaluation of the GBB permeability may have a significant diagnostic potential in cardiovascular and metabolic diseases. Second, we suggest that the GBB permeability is a variable that confounds diagnostic value of new gut microbiota-derived biomarkers such as TMAO. Therefore, cardiovascular risk assessment requires the evaluation of both TMAO and the GBB permeability.