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Increasing evidence suggests that hydrogen sulfide (H 2 S) is involved in brain mechanisms regulating the functions of the circulatory system. This appears to be mediated by cardiovascular centers located in the central nervous system. This chapter describes techniques of acute and chronic infusions into the brain cardiovascular centers in rats. Rats may be implanted either acutely or chronically with a cannula inserted into a selected cardiovascular center according to the stereotaxic coordinates. The cannula allows for the administration of the investigated compounds into a selected cardiovascular center.

In the eighties of the twentieth century nitric oxide (NO) was identified as the endothelium-derived relaxing factor. This discovery has triggered an interest in gaseous transmitters and their role in the regulation of the circulatory system. Recently, it has become evident that hydrogen sulfide (H2S) and carbon monoxide are also involved in physiological and pathological processes in the cardiovascular system. Nitrates that have been used for over a century and nebivolol, a third-generation b-blocker with vasodilating properties by increasing bioavailability of NO, provide convincing arguments that the compounds acting via NO pathway will remain an important class of cardiovascular drugs. A rapidly growing number of publications on functions of H2S in the circulatory system suggests that the gaseous transmitter may become a promising target for new treatment strategies in cardiovascular diseases. This review is focused on the role of gaseous transmitters in the regulation of the cardiovascular system and their pharmacotherapeutic potential.

Nitric oxide (NO) is one of the gaseous transmitters which play a very important role in the regulation of the circulatory system. Decreased NO availability is associated with hypertension, cardiovascular and kidney diseases. Endogenous NO is generated enzymatically by nitric oxide synthase (NOS) depending on the availability of the substrate, cofactors, or presence/absence of inhibitors, such as asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA). The objective of this study was to evaluate the potential relationship between NO level in rat tissues (heart and kidneys) and the concentrations of endogenous metabolites related to NO in plasma and urine. The experiment was carried out with 16- and 60-week-old male Wistar Kyoto (WKY) and age-matched male Spontaneously Hypertensive Rats (SHR). NO level in tissue homogenates was determined by the colorimetric method. RT-qPCR was used to verify the expression of the eNOS (endothelial NOS) gene. Plasma and urine concentrations of arginine, ornithine, citrulline, and dimethylarginines were examined by the UPLC-MS/MS method. 16-week-old WKY rats had the highest tissue NO and plasma citrulline levels. Furthermore, 16-week-old WKY rats showed higher urinary excretion of ADMA/SDMA compared to other experimental groups, however, plasma concentrations of arginine, ADMA, and SDMA were comparable between the groups. In conclusion, our research shows that hypertension and aging decrease tissue NO levels and are associated with reduced urinary excretion of NOS inhibitors, i.e., ADMA and SDMA. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that gut bacteria-derived metabolites interact with the cardiovascular system and alter blood pressure (BP) in mammals. Here, we evaluated the effect of indole-3-propionic acid (IPA), a gut bacteria-derived metabolite of tryptophan, on the circulatory system. Arterial BP, electrocardiographic, and echocardiographic (ECHO) parameters were recorded in male, anesthetized, 12-wk-old Wistar-Kyoto rats at baseline and after intravenous administration of either IPA or vehicle. In additional experiments, rats were pretreated with prazosin or pentolinium to evaluate the involvement of the autonomic nervous system in cardiovascular responses to IPA. IPA's concentrations were measured using ultra-high performance liquid chromatography tandem mass spectrometry. The reactivity of endothelium-intact and -denuded mesenteric resistance arteries was tested. Cells' viability and lactate dehydrogenase (LDH) cytotoxicity assays were performed on cultured cardiomyocytes. IPA increased BP with a concomitant bradycardic response but no significant change in QTc interval. The pretreatment with prazosin and pentolinium reduced the hypertensive response. ECHO showed increased contractility of the heart after the administration of IPA. Ex vivo, IPA constricted predilated and endothelium- denuded mesenteric resistance arteries and increased metabolic activity of cardiomyocytes. IPA increases BP via cardiac and vascular mechanisms in rats. Furthermore, IPA increases cardiac contractility and metabolic activity of cardiomyocytes. Our study suggests that IPA may act as a mediator between gut microbiota and the circulatory system. [ABSTRACT FROM AUTHOR]

Gut microbiota is a potent biological modulator of many physiological and pathological states. The renin-angiotensin system (RAS), including the local gastrointestinal RAS (GI RAS), emerges as a potential mediator of microbiota-related effects. The RAS is involved in cardiovascular system homeostasis, water-electrolyte balance, intestinal absorption, glycemic control, inflammation, carcinogenesis, and aging-related processes. Ample evidence suggests a bidirectional interaction between the microbiome and RAS. On the one hand, gut bacteria and their metabolites may modulate GI and systemic RAS. On the other hand, changes in the intestinal habitat caused by alterations in RAS may shape microbiota metabolic activity and composition. Notably, the pharmacodynamic effects of the RAS-targeted therapies may be in part mediated by the intestinal RAS and changes in the microbiome. This review summarizes studies on gut microbiota and RAS physiology. Expanding the research on this topic may lay the foundation for new therapeutic paradigms in gastrointestinal diseases and multiple systemic disorders. [ABSTRACT FROM AUTHOR]

Butyric acid (BA) is a short-chain fatty acid (SCFA) produced by gut bacteria in the colon. We hypothesized that colon-derived BA may affect hemodynamics. Arterial blood pressure (BP) and heart rate (HR) were recorded in anesthetized, male, 14-week-old Wistar rats. A vehicle, BA, or 3-hydroxybutyrate, an antagonist of SCFA receptors GPR41/43 (ANT) were administered intravenously (IV) or into the colon (IC). Reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries was tested ex vivo. The concentration of BA in stools, urine, portal, and systemic blood was measured with liquid chromatography coupled with mass spectrometry. BA administered IV decreased BP with no significant effect on HR. The ANT reduced, whereas L-NAME, a nitric oxide synthase inhibitor, did not affect the hypotensive effect of BA. In comparison to BA administered intravenously, BA administered into the colon produced a significantly longer decrease in BP and a decrease in HR, which was associated with a 2–3-fold increase in BA colon content. Subphrenic vagotomy and IC pretreatment with the ANT significantly reduced the hypotensive effect. Ex vivo, BA dilated MA and GMA. In conclusion, an increase in the concentration of BA in the colon produces a significant hypotensive effect which depends on the afferent colonic vagus nerve signaling and GPR41/43 receptors. BA seems to be one of mediators between gut microbiota and the circulatory system. [ABSTRACT FROM AUTHOR]

Accumulating evidence suggests that the brain renin-angiotensin system and proinflammatory cytokines, such as TNF-α, play a key role in the neurohormonal activation in chronic heart failure (HF). In this study we tested the involvement of TNF-α and angiotensin type 1 receptors (AT1Rs) in the central control of the cardiovascular system in HF rats. Methods: we carried out the study on male Sprague–Dawley rats subjected to the left coronary artery ligation (HF rats) or to sham surgery (sham-operated rats). The rats were pretreated for four weeks with intracerebroventricular (ICV) infusion of either saline (0.25 μl/h) or TNF-α inhibitor etanercept (0.25 μg/0.25 μl/h). At the end of the pretreatment period, we measured mean arterial blood pressure (MABP) and heart rate (HR) at baseline and during 60 min of ICV administration of either saline (5 μl/h) or AT1Rs antagonist losartan (10 μg/5 μl/h). After the experiments, we measured the left ventricle end-diastolic pressure (LVEDP) and the size of myocardial scar. Results: MABP and HR of sham-operated and HF rats were not affected by pretreatments with etanercept or saline alone. In sham-operated rats the ICV infusion of losartan did not affect MABP either in saline or in etanercept pretreated rats. In contrast, in HF rats the ICV infusion of losartan significantly decreased MABP in rats pretreated with saline, but not in those pretreated with etanercept. LVEDP was significantly elevated in HF rats but not in sham-operated ones. Surface of the infarct scar exceeded 30% of the left ventricle in HF groups, whereas sham-operated rats did not manifest evidence of cardiac scarring. Conclusions: our study provides evidence that in rats with post-infarction heart failure the regulation of blood pressure by AT1Rs depends on centrally acting endogenous TNF-α. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Abstract: Hypertension is a chronic medical condition in which systemic arterial blood pressure is elevated. About 80–90% of diagnosed hypertension is considered essential (idiopathic), which means there is no obvious cause of the increase in blood pressure. My hypothesis states that part of idiopathic hypertension results from erroneous information that the brain receives from receptors involved in the regulation of arterial blood pressure, i.e. if, despite high systemic blood pressure, the brain receives false “low-arterial pressure input” from cardiovascular receptors. As a result the brain centres which control blood pressure reset and produce an inappropriate output to the effectors (heart, blood vessels, kidneys and glands). The information errors may result from: (i) structural and/or functional impairment of cardiovascular receptors, (ii) changes in cardiovascular receptors activity, which are caused by other factors than changes in blood pressure, and (iii) impaired transmission in afferent fibres. I assume that in contrast to the lack of input from damaged or denervated cardiovascular receptors, an erroneous input will impair the control of arterial blood pressure. This will apply especially to false input which imitates “low-arterial pressure input”. Higher priority of “low-arterial pressure input” over “high-arterial pressure input” or none input may be explained by the evolutionary adaptation, i.e. low blood pressure, mostly due to haemorrhage, used to be a more common condition than high blood pressure and constitute a major threat to humans. [Copyright &y& Elsevier]

Abstract: 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-1β) 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. [Copyright &y& Elsevier]

The purpose of the present study was to elucidate if rats with myocardial infarction manifest altered responsiveness to central cardiovascular effects of low doses of angiotensin II (ANG II), and if ANG II and vasopressin (VP) cooperate in the central regulation of cardiovascular functions at rest and during stress. Conscious Sprague-Dawley rats with myocardial infarction induced by left coronary artery ligation, or sham-ligated (SL) controls were infused intracerebroventricularly with artificial cerebrospinal fluid (aCSF), ANG II, ANG II + VP or ANG II + V1a receptor antagonist (V1ANT) 4 weeks after cardiac surgery. In the infarcted but not in the SL rats, the resting mean arterial blood pressure (MABP) was significantly elevated by infusions of ANG II and ANG II + VP, while infusion of ANG II + V1ANT was not effective. During administration of aCSF, the pressor, and tachycardic responses to an air-jet stressor were significantly greater in the infarcted than in the SL rats. In the SL rats, the pressor responses to the stressor were significantly greater during infusions of ANG II, ANG II + VP and ANG II + V1ANT than during infusion of aCSF. The tachycardic response in the SL rats was enhanced only by the combined infusion of ANG II + VP. In the infarcted rats, the pressor and the tachycardic responses to the stressor were similar in all groups. It is concluded that: (1) under resting conditions the infarcted rats manifest sensitisation to the central pressor effect of ANG II and that this effect depends on concomitant stimulation of V1a VP receptors, (2) central ANG II may enhance the pressor response to an alarming stressor in the SL rats through an action which does not depend on the concomitant stimulation of V1a receptors, (3) the cooperative action of ANG II and VP is required for intensification of the tachycardic response to the alarming stressor in the SL rats and (4) exaggeration of the cardiovascular responses to the alarming stressor in the infarcted rats cannot be further augmented by an additional stimulation of central ANG II receptors or combined stimulation of ANG II and VP receptors. [ABSTRACT FROM AUTHOR]

The prevalence of hypertension increases with age, but the mechanisms linking this phenomenon are not well understood. Hydrogen sulfide (H 2 S) may be involved in this process, as it plays a role in the cardiovascular system, affecting blood pressure and heart and kidney functions. The aim of this study was to evaluate the influence of hypertension and aging on sulfur-containing compounds metabolism in the hearts and kidneys of Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR) of different age groups. We determined the expression and activity of four enzymes participating in H 2 S production: cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CTH), 3-mercaptopyruvate sulfurtransferase (MPST), and thiosulfate sulfurtransferase (TST). The levels of reduced/oxidized glutathione, cysteine, cystine, and cystathionine, and the ability of tissues to form hydrogen sulfide were also investigated. Tissues obtained from younger WKY rats produced the highest amounts of H 2 S. The effect of hypertension on the metabolism of sulfur-containing compounds was manifested by a decrease in sulfane sulfur concentrations in heart homogenates and a decrease in CTH activity in the kidneys. The hearts and kidneys of older WKY rats were characterized by lower MPST or CTH gene expression, respectively, compared to younger animals. Our study demonstrates that hypertension and aging influence cardiac and renal sulfur-containing compounds metabolism and reduce H 2 S production. Furthermore, we showed that MPST plays a major role in the production of hydrogen sulfide in the heart and CTH in the kidneys of rats. • Hypertension and aging affect cardiac and renal sulfur metabolism in rats. • H 2 S production is decreased in heart and kidneys of hypertensive and older rats. • 3-mercaptopyruvate sulfurtransferase is responsible for H 2 S generation in rat heart. • Cystathionine gamma-lyase plays a major role in H 2 S formation in rat kidneys. [ABSTRACT FROM AUTHOR]

Valeric acid (VA) is a short-chain fatty acid produced by microbiota and herbs such as Valeriana officinalis. Moreover, VA is released from medicines such as estradiol valerate by esterases. We evaluated the concentrations of endogenous VA in male, 14-week-old rats in the liver, heart, brain, kidneys, lungs, blood and in the colon, a major site of microbiota metabolism, using liquid chromatography coupled with mass spectrometry. In addition, the tissue distribution of VA D9-isotope (VA-D9) administered into the colon was assessed. Finally, we investigated the effect of exogenous VA on arterial blood pressure (BP) and heart rate (HR) in anesthetized rats, and the reactivity of mesenteric (MA) and gracilis muscle (GMA) arteries ex vivo. Physiological concentration of VA in the colon content was ≈650 μM, ≈ 0.1–1 μM in the investigated tissues, and ≈0.4 μM in systemic blood. VA-D9 was detected in the tissues 5 min after the administration into the colon. The vehicle did not affect BP and HR. VA produced a dose-dependent decrease in BP, and at higher doses lowered HR. The hypotensive effect of VA was inhibited by 3-hydroxybutyrate, an antagonist of GPR41/43-receptors but not by the subphrenic vagotomy. Hexamethonium prolonged the hypotensive effect of VA while atropine did not influence the hypotensive effect. VA dilated GMA and MA. In conclusion, the exogenous VA produces vasodilation and lowers BP. The colon-derived VA rapidly penetrates to tissues involved in the control of BP. Further studies are needed to evaluate the effects of endogenous and exogenous VA on the circulatory system. [ABSTRACT FROM AUTHOR]