New Findings
What is the central question of this study?
This study was designed to investigate whether the Phox2b‐expressing neurons in the retrotrapezoid nucleus are important to breathing and ...chemoreflexes in conscious rats.
What is the main finding and its importance?
The high rate of destruction of a defined cell population (Phox2b+TH−) of the retrotrapezoid nucleus by the toxin suggests that the specialized connectivity of retrotrapezoid nucleus neurons, their glutamatergic nature and their relatively high sensitivity to CO2 are determinant factors in explaining their large contribution to the central and peripheral chemoreflexes.
Chemoreception is the classic mechanism by which the brain regulates breathing in response to changes in tissue CO2/H+. A brainstem region called the retrotrapezoid nucleus (RTN) contains a population of Phox2b‐expressing glutamatergic neurons that appear to function as important chemoreceptors. In the present study, we ask whether the destruction of a type of pH‐sensitive interneuron that expresses the transcription factor Phox2b and is non‐catecholaminergic (Phox2b+TH−) could affect breathing in conscious adult rats. The injection of substance P (1 nmol in a volume of 50 nl) into the RTN increased respiratory frequency, tidal volume, minute ventilation and mean arterial pressure. Bilateral injections of the toxin substance P conjugated with saporin (SSP–SAP) into the RTN destroyed Phox2b+TH− neurons but spared facial motoneurons, catecholaminergic and serotonergic neurons and the ventral respiratory column caudal to the facial motor nucleus. Bilateral inhibition of RTN neurons with SSP–SAP (0.6 ng in 30 nl) reduced resting ventilation and the increase in ventilation produced by hypercapnia (7% CO2) in conscious rats with or without peripheral chemoreceptors. In anaesthetized rats with bilateral lesions of around 90% of the Phox2b+TH− neurons, acute activation of the Bötzinger complex, the pre‐Bötzinger complex or the rostral ventral respiratory group with NMDA (5 pmol in 50 nl) elicited normal cardiorespiratory output. In conclusion, the destruction of the Phox2b+TH− neurons is a plausible cause of the respiratory deficits observed after injection of SSP–SAP into the RTN. Our results also suggest that RTN neurons activate facilitatory mechanisms important to the control of breathing in resting or hypercapnic conditions in conscious adult rats.
Borneol is a bicyclic monoterpene that has long been used in traditional Chinese medicine to increase blood-brain barrier permeability and has shown promising cardiovascular effects. The present ...study aimed to evaluate the effect of borneol on vascular tone, blood pressure, autonomic function, and baroreflex sensitivity in normotensive and hypertensive rats. A combination of in vitro and in vivo assays was performed in 2-kidneys-1-clip hypertensive rats (2K1C) and their controls (sham). We assessed the in vivo effect of oral treatment with borneol on blood pressure, heart rate, autonomic function, and baroreflex sensitivity in sham and 2K1C rats. Additionally, the vasorelaxant effect of borneol in the superior mesenteric artery isolated from rats and its mechanism of action were evaluated. Oral administration of borneol (125 mg/kg/day) reduced blood pressure, sympathetic vasomotor hyperactivity, and serum oxidative stress and improved baroreflex sensitivity in 2K1C rats. In vessel preparations, borneol induced endothelium-independent vasodilatation after precontraction with phenylephrine or KCl (60 mM). There was no difference in the vascular effect induced by borneol in either the 2K1C or the sham group. In addition, borneol antagonized the contractions induced by CaCl
and reversed (S)-(-)-Bay K 8644-induced contraction. These data suggest that borneol presents antihypertensive effects in 2K1C rats, which is associated with its ability to improve autonomic impairment and baroreflex dysfunction. The borneol-induced relaxation in the superior mesenteric artery involves L-type Ca
channel blockade. This vascular action associated with the antioxidant effect induced by borneol may be responsible, at least in part, for the in vivo effects induced by this monoterpene.
TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (AT
R), able to recruit β-arrestin 2 independently of G-proteins activation. β-arrestin activation in the central nervous ...system (CNS) was suggested to oppose the effects of Ang-II. The present study evaluates the effect of central infusion of TRV027 on arterial pressure (AP), autonomic function, baroreflex sensitivity (BRS), and peripheral vascular reactivity. Spontaneously hypertensive (SH) and Wistar Kyoto (WKY) rats were treated with TRV027 for 14 days (20 ng/h) delivered to the lateral ventricle via osmotic minipumps. Mechanistic studies were performed in HEK293T cells co-transfected with AT
R and Ang converting enzyme type 2 (ACE2) treated with TRV027 (100 nM) or Ang-II (100 nM). TRV027 infusion in SH rats (SHR) reduced AP (~20 mmHg,
<0.05), sympathetic vasomotor activity (ΔMAP = -47.2 ± 2.8 compared with -64 ± 5.1 mmHg,
<0.05) and low-frequency (LF) oscillations of AP (1.7 ± 0.2 compared with 5.8 ± 0.4 mmHg,
<0.05) compared with the SHR control group. TRV027 also increased vagal tone, improved BRS, reduced the reactivity of mesenteric arteries to Ang-II and increased vascular sensitivity to phenylephrine (Phe), acetylcholine, (ACh), and sodium nitroprusside (SNP).
, TRV027 prevented the Ang-II-induced up-regulation of ADAM17 and in contrast with Ang-II, had no effects on ACE2 activity and expression levels. Furthermore, TRV027 induced lesser interactions between AT
R and ACE2 compared with Ang-II. Together, these data suggest that due to its biased activity for the β-arrestin pathway, TRV027 has beneficial effects within the CNS on hypertension, autonomic and vascular function, possibly through preserving ACE2 compensatory activity in neurones.
Nitric oxide (NO) is a key signalling molecule in the regulation of cardiometabolic function and impaired bioactivity is considered to play an important role in the onset and progression of ...cardiovascular and metabolic disease. Research has revealed an alternative NO-generating pathway, independent of NO synthase (NOS), in which the inorganic anions nitrate (NO3-) and nitrite (NO2-) are serially reduced to form NO.
This work specifically aimed at investigating the role of commensal bacteria in bioactivation of dietary nitrate and its protective effects in a model of cardiovascular and metabolic disease.
In a two-hit model, germ-free and conventional male mice were fed a western diet and the NOS inhibitor l-NAME in combination with sodium nitrate (NaNO3) or placebo (NaCl) in the drinking water. Cardiometabolic parameters including blood pressure, glucose tolerance and body composition were measured after six weeks treatment.
Mice in both placebo groups showed increased body weight and fat mass, reduced lean mass, impaired glucose tolerance and elevated blood pressure. In conventional mice, nitrate treatment partly prevented the cardiometabolic disturbances induced by a western diet and l-NAME. In contrast, in germ-free mice nitrate had no such beneficial effects. In separate cardiovascular experiments, using conventional and germ-free animals, we assessed NO-like signalling downstream of nitrate by administration of sodium nitrite (NaNO2) via gavage. In this acute experimental setting, nitrite lowered blood pressure to a similar degree in both groups. Likewise, isolated vessels from germ-free mice robustly dilated in response to the NO donor sodium nitroprusside.
In conclusion, our findings demonstrate the obligatory role of host-microbiota in bioactivation of dietary nitrate, thus contributing to its favourable cardiometabolic effects.
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•Dietary nitrate has salutary effects on cardiometabolic function in a mouse model of metabolic syndrome.•These effects are absent in germ free mice.•Host bacteria are essential for bioactivation of dietary nitrate.
High-fat (HF) diet consumption has been associated with gut dysbiosis and increased risk of dyslipidemia, type 2 diabetes mellitus and hypertension. Probiotic administration has been suggested as a ...safe therapeutic strategy for the treatment of cardiometabolic disorders. This study was designed to assess the effects of probiotic Lactobacillus (L.) fermentum 296, a fruit-derived bacteria strain, against cardiometabolic disorders induced by HF diet.
Male Wistar rats were divided into control diet (CTL); HF diet; and HF diet treated with Lactobacillus fermentum 296 (HF + Lf 296). The L. fermentum 296 strain at 1 × 109 colony forming units (CFU)/ml were daily administered by oral gavage for 4 weeks. The results showed that rats fed with HF diet displayed insulin resistance, reduced Lactobacillus spp. counts in feces, serum lipids, and oxidative profile. Rats fed on HF diet also demonstrated augmented blood pressure associated with sympathetic hyperactivity and impaired baroreflex control. The administration of L. fermentum 296 for 4 weeks recovered fecal Lactobacillus sp. counts and alleviated hyperlipidemia, sympathetic hyperactivity, and reduced systolic blood pressure in HF rats without affecting baroreflex sensibility.
Our results suggest the ability of L. fermentum 296 improve biochemical and cardiovascular parameters altered in cardiometabolic disorders.
•High fat consumption is a risk factor for dysbiosis, dyslipidemias and hypertension.•L. fermentum 296 recovered fecal Lactobacillus counts and alleviated hyperlipidemia in high fat diet-treated rats.•L. fermentum 296 reduced sympathetic hyperactivity and systolic blood pressure in high fat diet treated rats.•L. fermentum 296 exhibit qualities to be translated into nutritional approaches to prevent or treat cardiometabolic disease.
Organic nitrates: past, present and future França-Silva, Maria S; Balarini, Camille M; Cruz, Josiane C ...
Molecules,
09/2014, Volume:
19, Issue:
9
Journal Article, Book Review
Peer reviewed
Open access
Nitric oxide (NO) is one of the most important vasodilator molecules produced by the endothelium. It has already been established that NO/cGMP signaling pathway deficiencies are involved in the ...pathophysiological mechanisms of many cardiovascular diseases. In this context, the development of NO-releasing drugs for therapeutic use appears to be an effective alternative to replace the deficient endogenous NO and mimic the role of this molecule in the body. Organic nitrates represent the oldest class of NO donors that have been clinically used. Considering that tolerance can occur when these drugs are applied chronically, the search for new compounds of this class with lower tolerance potential is increasing. Here, we briefly discuss the mechanisms involved in nitrate tolerance and highlight some achievements from our group in the development of new organic nitrates and their preclinical application in cardiovascular disorders.
ADAM17 is a metalloprotease and disintegrin that lodges in the plasmatic membrane of several cell types and is able to cleave a wide variety of cell surface proteins. It is somatically expressed in ...mammalian organisms and its proteolytic action influences several physiological and pathological processes. This review focuses on the structure of ADAM17, its signaling in the cardiovascular system and its participation in certain disorders involving the heart, blood vessels, and neural regulation of autonomic and cardiovascular modulation.
The paraventricular nucleus of the hypothalamus (PVN) contains heterogeneous populations of neurons involved in autonomic and neuroendocrine regulation. The PVN plays an important role in the ...sympathoexcitatory response to increasing circulating levels of angiotensin II (Ang-II), which activates AT1 receptors in the circumventricular organs (OCVs), mainly in the subfornical organ (SFO). Circulating Ang-II induces a de novo synthesis of Ang-II in SFO neurons projecting to pre-autonomic PVN neurons. Activation of AT1 receptors induces intracellular increases in reactive oxygen species (ROS), leading to increases in sympathetic nerve activity (SNA). Chronic sympathetic nerve activation promotes a series of metabolic disorders that characterizes the metabolic syndrome (MetS): dyslipidemia, hyperinsulinemia, glucose intolerance, hyperleptinemia and elevated plasma hormone levels, such as noradrenaline, glucocorticoids, leptin, insulin, and Ang-II. This review will discuss the contribution of our laboratory and others regarding the sympathoexcitation caused by peripheral Ang-II-induced reactive oxygen species along the subfornical organ and paraventricular nucleus of the hypothalamus. We hypothesize that this mechanism could be involved in metabolic disorders underlying MetS.
This study was designed to investigate the effects of a newly synthesized carboxymethyl-glucan (CM-G) on blood pressure (BP), baroreflex sensitivity (BRS) and sympathetic vascular modulation in ...renovascular hypertensive rats. Male Wistar rats were divided into four groups: Sham (
= 10); 2K1C (subjected to renal artery clipping to induce renovascular hypertension,
= 10); Sham + CM-G (treated with CM-G,
= 7) and 2K1C + CM-G (treated with CM-G,
= 7). The daily treatment with CM-G (40 mg/kg) was performed for 2 weeks. Blood pressure, heart rate (HR), systolic BP variability, baroreflex sensitivity (BRS) and sympathetic vascular tone were evaluated. After six weeks of renal artery clipping, 2K1C rats exhibited arterial hypertension (171 ± 11 vs. 118 ± 4 mmHg, p < 0.05), impaired BRS (-1.30 ± 0.10 vs. -2.59 ± 0.17 bpm.mmHg-1, p < 0.05) and enhanced sympathetic activity as shown by the hexamethonium test (-60 ± 5 vs. -33 ± 2 ΔmmHg, p < 0.05) when compared to sham rats. Oral administration of CM-G in renovascular hypertensive rats reduced hypertension (126 ± 4 vs. 171 ± 11 mmHg, p < 0.05) and improved the BRS (-2.03 ± 0.16 vs. -1.30 ± 0.10 bpm.mmHg
, p < 0.05) in 2K1C rats when compared to placebo. Those effects seem to be caused by a reduction in sympathetic activity. The present study revealed for the first time that CM-G treatment reduces arterial hypertension and restores arterial baroreflex sensitivity via a reduction in the sympathetic tone in conscious renovascular hypertensive rats.
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