Neural reflex regulation of arterial pressure in pathophysiological conditions : interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex

The maintenance of arterial pressure at levels adequate to perfuse the tissues is a basic requirement for the constancy of the internal environment and survival. The objective of the present review was to provide information about the basic reflex mechanisms that are responsible for the moment-to-moment regulation of the cardiovascular system. We demonstrate that this control is largely provided by the action of arterial and non-arterial reflexes that detect and correct changes in arterial pressure (baroreflex), blood volume or chemical composition (mechano- and chemosensitive cardiopulmonary reflexes), and changes in blood-gas composition (chemoreceptor reflex). The importance of the integration of these cardiovascular reflexes is well understood and it is clear that processing mainly occurs in the nucleus tractus solitarii, although the mechanism is poorly understood. There are several indications that the interactions of baroreflex, chemoreflex and Bezold-Jarisch reflex inputs, and the central nervous system control the activity of autonomic preganglionic neurons through parallel afferent and efferent pathways to achieve cardiovascular homeostasis. It is surprising that so little appears in the literature about the integration of these neural reflexes in cardiovascular function. Thus, our purpose was to review the interplay between peripheral neural reflex mechanisms of arterial blood pressure and blood volume regulation in physiological and pathophysiological states. Special emphasis is placed on the experimental model of arterial hypertension induced by N-nitro-L-arginine methyl ester (L-NAME) in which the interplay of these three reflexes is demonstrable

Oxidative Stress and Dementia in Alzheimer’s Patients: Effects of Synbiotic Supplementation

Alzheimer’s disease (AD) is the most common cause of dementia in elderly patients. Recently, several studies have shown that inflammation and oxidative stress precede the cardinal neuropathological manifestations of AD. In view of the proven antioxidant effects of probiotics, we proposed that continuous dietary supplementation with milk fermented with kefir grains might improve cognitive and metabolic and/or cellular disorders in the AD patients. Methods. This study was designed as an uncontrolled clinical investigation to test the effects of probiotic-fermented milk supplementation (2 mL/kg/daily) for 90 days in AD patients exhibiting cognitive deficit. Cognitive assessment, cytokine expression, systemic oxidative stress levels, and blood cell damage biomarkers were evaluated before (T0) and after (T90) kefir synbiotic supplementation. Results. When the patients were challenged to solve 8 classical tests, the majority exhibit a marked improvement in memory, visual-spatial/abstraction abilities, and executive/language functions. At the end of the treatment, the cytometric analysis showed an absolute/relative decrease in several cytokine markers of inflammation and oxidative stress markers (⋅ O2 – , H2O2, and ONOO− , ~30%) accompanied by an increase in NO bioavailability (100%). In agreement with the above findings by using the same technique, we observed in a similar magnitude an improvement of serum protein oxidation, mitochondrial dysfunction, DNA damage/repair, and apoptosis. Conclusion. In conclusion, we demonstrated that kefir improves cognitive deficits, which seems to be linked with three important factors of the AD—systemic inflammation, oxidative stress, and blood cell damage—and may be a promising adjuvant therapy against the AD progression.This study was supported by the National Council for Scientific and Technological Development (CNPq) and the State Agency for the Development of Science and Technology (FAPES) through the Edital 24/2018 -PRONEx #84321148, TO 569/2018S

Oral rapamycin attenuates atherosclerosis without affecting the arterial responsiveness of resistance vessels in apolipoprotein E-deficient mice

The objective of the present study was to assess the effects of the immunosuppressant rapamycin (Rapamune®, Sirolimus) on both resistance vessel responsiveness and atherosclerosis in apolipoprotein E-deficient 8-week-old male mice fed a normal rodent diet. Norepinephrine (NE)-induced vasoconstriction, acetylcholine (ACh)- and sodium nitroprusside (SNP)-induced vasorelaxation of isolated mesenteric bed, and atherosclerotic lesions were evaluated. After 12 weeks of orally administered rapamycin (5 mg·kg-1·day-1, N = 9) and compared with untreated (control, N = 9) animals, rapamycin treatment did not modify either NE-induced vasoconstriction (maximal response: 114 ± 4 vs 124 ± 10 mmHg, respectively) or ACh- (maximal response: 51 ± 8 vs 53 ± 5%, respectively) and SNP-induced vasorelaxation (maximal response: 73 ± 6 vs 74 ± 6%, respectively) of the isolated vascular mesenteric bed. Despite increased total cholesterol in treated mice (982 ± 59 vs 722 ± 49 mg/dL, P < 0.01), lipid deposition on the aorta wall vessel was significantly less in rapamycin-treated animals (37 ± 12 vs 68 ± 8 µm2 x 103). These results indicate that orally administered rapamycin is effective in attenuating the progression of atherosclerotic plaque without affecting the responsiveness of resistance vessels, supporting the idea that this immunosuppressant agent might be of potential benefit against atherosclerosis in patients undergoing therapy

Protective effects of kefir in the angiotensin II-dependent hypertension

Recently, we have reported cardiovascular protective effects of the probiotic kefir in a model of primary hypertension. Now, we evaluated the beneficial effects of kefir in a model of secondary hypertension under hyperactivation of the renin-angiotensin-system by partially clipping one kidney artery (2K1C) for 60 days and compared with Sham rats. Maximum levels of arterial pressure were reached 7–14 days post-clipping in both 2K1C and 2K1C-Kefir, but after that time the values were approximately 20% lower in 2K1C-Kefir rats. Also, kefir attenuated the angiotensin converting enzyme activity (intrarenal-40%/plasma-25%) preventing the increase of angiotensin II in both samples. Isolated aortic rings showed an impaired relaxation to acetylcholine in 2K1C (-38%) compared to the Sham group and this difference was attenuated in 2K1C-Kefir rats (~15%). Additional analysis revealed that kefir protected kidney and vascular endothelium against the synergistic oxidative stress/angiotensin II-axis. Thus, kefir is an effective nutraceutical therapy for prevention/treatment of hypertensionThis work was supported by the CNPq/FAPES -Brazil (PRONEX CNPq # 24/2018; Termo Outorga 569/2018); FAPES-Universal (# 21/2018, Termo Outorga 120/2019); FAPES (BPC 552/2018;120/2019) and CNPq (BVN 160990/2019-0; SSM 312056/2018-5, TMCP 309277/2019-1 and ECV 305740/2019-9)S

Coadjuvants in the Diabetic Complications: Nutraceuticals and Drugs with Pleiotropic Effects

Because diabetes mellitus (DM) is a multifactorial metabolic disease, its prevention and treatment has been a constant challenge for basic and clinical investigators focused on translating their discoveries into clinical treatment of this complex disorder. In this review, we highlight recent experimental and clinical evidences of potential coadjuvants in the management of DM, such as polyphenols (quercetin, resveratrol and silymarin), cultured probiotic microorganisms and drugs acting through direct/indirect or pleiotropic effects on glycemic control in DM. Among several options, we highlight new promising therapeutic coadjuvants, including chemical scavengers, the probiotic kefir and the phosphodiesterase 5 inhibitors, which besides the reduction of hyperglycemia and ameliorate insulin resistance, they reduce oxidative stress and improve endothelial dysfunction in the systemic vascular circulation. In the near future, experimental studies are expected to clear the intracellular pathways involving coadjuvants. The design of clinical trials may also contribute to new strategies with coadjuvants against the harmful effects of diabetic complications

The Protective Effects of Oral Low-dose Quercetin on Diabetic Nephropathy in Hypercholesterolemic Mice

Aims: Diabetic nephropathy (DN) is one of the major causes of end-stage renal disease, and the incidence of DN is increasing worldwide. Considering our previous report indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated renoprotective, anti-oxidative and anti-apoptotic effects in the C57BL/6J model of diabetic nephropathy, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE-/-). Methods: DN was induced by streptozotocin (100 mg/kg/day, for 3 days) in adult apoE-/-mice. Six weeks later, the mice were divided into the following groups: diabetic apoE-/- mice treated with quercetin (DQ, 10 mg/kg/day, 4 weeks), diabetic ApoE-/- mice treated with vehicle (DV) and non-treated non-diabetic (ND) mice.Results: Quercetin treatment caused a reduction in polyuria (~30%), glycemia (~25%), abolished the hypertriglyceridemia and had significant effects on renal function, including decreased proteinuria (~15%) and creatininemia (~30%), which were accompanied by beneficial effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight.Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical and morphological modifications. Thus, this translational study highlights the importance of quercetin as a potential nutraceutical for the management of DN, including in diabetes associated with dyslipidemia

Increased Blood Pressure Variability Prior to Chronic Kidney Disease Exacerbates Renal Dysfunction in Rats

Increased blood pressure variability (BPV), which can be experimentally induced by sinoaortic denervation (SAD), has emerged as a new marker of the prognosis of cardiovascular and renal outcomes. Considering that increased BPV can lead to organ-damage, the goal of the present study was to evaluate the effects of SAD on renal function in an experimental model of chronic kidney disease (CKD). SAD was performed in male Wistar rats 2 weeks before 5/6 nephrectomy and the animals were evaluated 4 weeks after the induction of CKD. Our data demonstrated that BPV was increased in SAD and CKD animals and that the combination of both conditions (SAD+CKD) exacerbated BPV. The baroreflex sensitivity index was diminished in the SAD and CKD groups; this reduction was more pronounced when SAD and CKD were performed together. 5/6 nephrectomy led to hypertension, which was higher in SAD+CKD animals. Regarding renal function, the combination of SAD and CKD resulted in reduced renal plasma and blood flow, increased renal vascular resistance and augmented uraemia when compared to CKD animals. Glomerular filtration rate and BPV were negatively correlated in SAD, CKD and SAD+CKD animals. Moreover, SAD+CKD animals presented a higher level of glomerulosclerosis when compared to all other groups. Cardiac and renal hypertrophy, as well as oxidative stress, was also further increased when SAD and CKD were combined. These results show that SAD prior to 5/6 nephrectomy exacerbates renal dysfunction, suggesting that previous augmented BPV should be considered as an important factor to the progression of renal diseases