A novel model of cardiovascular-kidney-metabolic syndrome combining unilateral nephrectomy and high-salt-sugar-fat diet in mice.

The aim of this study was to explore biological interaction and pathophysiology mechanisms in a new mouse model of cardiovascular-kidney-metabolic (CKM) syndrome, induced by chronic moderate renal failure in combination with consumption of a customized Western diet rich in carbohydrates, fat and salt. Male C57BL/6J mice were subjected to unilateral nephrectomy, fed a customized Western diet rich not only in sugar and fat but also in salt, and followed for 12 weeks or 20 weeks. Sham-operated mice on a standard chow served as healthy controls.

Specific NOX4 Inhibition Preserves Mitochondrial Function and Dampens Kidney Dysfunction Following Ischemia-Reperfusion-Induced Kidney Injury.

: Acute kidney injury (AKI) is a sudden episode of kidney failure which is frequently observed at intensive care units and related to high morbidity/mortality. Although AKI can have many different causes, ischemia-reperfusion (IR) injury is the main cause of AKI. Mechanistically, NADPH oxidases (NOXs) are involved in the pathophysiology contributing to oxidative stress following IR.

Dimethyl malonate preserves renal and mitochondrial functions following ischemia-reperfusion via inhibition of succinate dehydrogenase.

Background: Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main causative factor. Succinate accumulation during ischemia contributes to the excessive generation of reactive oxygen species at reperfusion. Inhibition of succinate dehydrogenase has been associated with protective outcome in cardiac ischemia-reperfusion after 24h, but the effects on kidney and mitochondrial functions are less well studied.

NO-ferroheme is a signaling entity in the vasculature.

Despite wide appreciation of the biological role of nitric oxide (NO) synthase (NOS) signaling, questions remain about the chemical nature of NOS-derived bioactivity. Here we show that NO-like bioactivity can be efficiently transduced by mobile NO-ferroheme species, which can transfer between proteins, partition into a hydrophobic phase and directly activate the sGC-cGMP-PKG pathway without intermediacy of free NO. The NO-ferroheme species (with or without a protein carrier) efficiently relax isolated blood vessels and induce hypotension in rodents, which is greatly potentiated after the blockade of NOS activity.

Effects of chronic dietary nitrate supplementation on longevity, vascular function and cancer incidence in rats.

Rationale: Dietary nitrate and nitrite have a notoriously bad reputation because of their proposed association with disease, in particular cancer. However, more recent lines of research have challenged this dogma suggesting that intake of these anions also possess beneficial effects after in vivo conversion to the vital signaling molecule nitric oxide. Such effects include improvement in cardiovascular, renal and metabolic function, which is partly mediated via reduction of oxidative stress.

Renovascular effects of inorganic nitrate following ischemia-reperfusion of the kidney.

Background: Renal ischemia-reperfusion (IR) injury is a common cause of acute kidney injury (AKI), which is associated with oxidative stress and reduced nitric oxide (NO) bioactivity and increased risk of developing chronic kidney disease (CKD) and cardiovascular disease (CVD). New strategies that restore redox balance may have therapeutic implications during AKI and associated complications.

Aim: To investigate the therapeutic value of boosting the nitrate-nitrite-NO pathway during development of IR-induced renal and cardiovascular dysfunction.

Head-to-head comparison of inorganic nitrate and metformin in a mouse model of cardiometabolic disease.

Background/purpose: Unhealthy dietary habits contribute to the increasing incidence of metabolic syndrome and type 2 diabetes (T2D), which is accompanied by oxidative stress, compromised nitric oxide (NO) bioavailability and increased cardiovascular risk. Apart from lifestyle changes, biguanides such as metformin are the first-line pharmacological treatment for T2D. Favourable cardiometabolic effects have been demonstrated following dietary nitrate supplementation to boost the nitrate-nitrite-NO pathway.

The obligatory role of host microbiota in bioactivation of dietary nitrate.

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 (NO) and nitrite (NO) 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.

Central Inhibition of Tumor Necrosis Factor Alpha Reduces Hypertension by Attenuating Oxidative Stress in the Rostral Ventrolateral Medulla in Renovascular Hypertensive Rats.

Inflammation in the central nervous system is being considered a key player linked to neurogenic hypertension. Using combined and approaches, we investigated the effects of central inhibition of TNF-α on blood pressure, sympathetic tone, baroreflex sensitivity, and oxidative stress in the rostral ventrolateral medulla (RVLM) of rats with 2-kidney-1-clip (2K1C) renovascular hypertension. Continuous infusion of pentoxifylline, a TNF-α inhibitor, into the lateral ventricle of the brain for 14 consecutive days reduced blood pressure and improved baroreflex sensitivity in renovascular hypertensive rats.

Dietary Nitrate Reduces Blood Pressure in Rats With Angiotensin II-Induced Hypertension via Mechanisms That Involve Reduction of Sympathetic Hyperactivity.

Several experimental and clinical studies have shown that dietary nitrate supplementation can increase nitric oxide bioavailability. In the oral cavity, commensal bacteria reduce nitrate to nitrite, which is subsequently absorbed into the circulation where reduction to nitric oxide by enzymatic systems occur. Although it is well-known that boosting the nitrate-nitrite-nitric oxide pathway can improve cardiovascular, renal, and metabolic functions and that sympathoexcitation contributes to the development of the same disorders, the potential effects of dietary nitrate on sympathetic activity remain to be elucidated.

Central administration of TRV027 improves baroreflex sensitivity and vascular reactivity in spontaneously hypertensive rats.

TRV027 is a biased agonist for the Angiotensin (Ang)-II type 1 receptor (ATR), 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.

Ondansetron and promethazine have differential effects on hypothermic responses to lithium chloride administration and to provocative motion in rats.

We recently reported that provocative motion (rotation in a home cage) causes hypothermic responses in rats, similar to the hypothermic responses associated with motion sickness in humans. Many stimuli inducing emesis in species with an emetic reflex also provoke hypothermia in the rat, therefore we hypothesized that a fall in body temperature may reflect a "nausea-like" state in these animals. As rats do not possess an emetic reflex, we employed a pharmacological approach to test this hypothesis.

Cardiorespiratory effects induced by 2-nitrate-1,3-dibuthoxypropan are reduced by nitric oxide scavenger in rats.

The search for new nitric oxide donors is warranted by the limitations of organic nitrates currently used in cardiology. The new organic nitrate 2-nitrate-1,3-dibuthoxypropan (NDBP) exhibited promising cardiovascular activities in previous studies. The aim of this study was to investigate the cardiorespiratory responses evoked by NDBP and to compare them to the clinically used organic nitrate nitroglycerine (NTG).

α-lipoic acid reduces hypertension and increases baroreflex sensitivity in renovascular hypertensive rats.

Renovascular hypertension has robust effects on control of blood pressure, including an impairment in baroreflex mechanisms, which involves oxidative stress. Although α-lipoic acid (LA) has been described as a potent antioxidant, its effect on renovascular hypertension and baroreflex sensitivity (BRS) has not been investigated. In the present study we analyzed the effects caused by chronic treatment with LA on blood pressure, heart rate and baroreflex sensitivity (sympathetic and parasympathetic components) in renovascular hypertensive rats.