ABSENCE OF OXIDATIVE STRESS AND SIRTUINS RECRUITMENT ON CARDIAC TISSUE POST STRESS

Stress has emerged as a factor associated with cardiovascular disease. Catecholamines released during the stress reaction by the sympathetic nerves and the adrenal medulla couple to β1-and β2-adrenoceptors in the cardiomyocytes membrane enhancing heart function in order to attend the organism demand. This might produce excessive reactive oxygen species what may culminate with oxidative stress and progression of several cardiac diseases. Sirtuins have been described as cardioprotective factors and important regulators of the cellular stress response in the heart. The aim of this work is to investigate the putative participation of oxidative stress and sirtuins in the heart of rats submitted to foot shock stress, an experimental model where there is up regulation of β2-adrenoceptors and downregulation of β1-adrenoceptors. The data have shown that in the myocardium of rats submitted to foot shock stress the H2O2 concentration, catalase and superoxide dismutase activity, NAD+/NADH ratio, as well as the protein expression of sirtuins 1 and 3 were not altered. Pharmacological blockade of the β2-adrenoceptors by ICI118,551, did not modify this scenario. It is concluded that foot shock stress does not cause disruptions in oxidative stress or redox state processes in the myocardium, and consequently, sirtuins are not recruited to stress response.

NERVOUS FACTORS OF ARTERIAL HYPERTENSION PROSPECTS FOR PREVENTION AND REHABILITATION

The article provides a theoretical analysis of the causes of arterial hypertension, describes a three-month observation of the initial stage of the development of hypertension and experiments on non-drug normalization of blood pressure on a group of volunteers. It has been shown that arterial hypertension is associated with spastic conditions of the intervertebral muscles in the lower thoracic spine, which lead to compression of the sympathetic nerves that control the transport of water through the kidneys and disturb the balance of fluid circulation through the circulatory system. The possibility of prevention of arterial hypertension and non-drug rehabilitation of patients with this disease has been shown.

PATHOPHYSIOLOGICAL COMPONENTS OF ARTERIAL HYPERTENSION. PROSPECTS FOR PREVENTION AND REHABILITATION

The article provides a theoretical analysis of the causes of arterial hypertension, describes a 3-month observation of the initial stage of the development of hypertension and experiments on non-drug normalization of blood pressure on a group of volunteers. We show that arterial hypertension is associated with spastic conditions of the intervertebral muscles in the lower thoracic spine, which leads to compression of sympathetic nerves that control the transport of water through the kidneys, which in turn upsets the balance of fluid circulation through the circulatory system.Theoretical analysis and experimental data made it possible to formulate a hypothesis about the dominant role of disorders in the activity of the sympathetic part of the nervous system in the development of primary and persistent arterial hypertension. The possibility of prevention of arterial hypertension and non-drug rehabilitation of patients with this disease has been shown.

Evidence of Ventricular Arrhythmogenicity and Cardiac Sympathetic Hyperinnervation in Early Cirrhotic Cardiomyopathy

Cirrhotic cardiomyopathy (CMP) is associated with altered cardiac electrophysiological (EP) properties, which leads to the risk of ventricular arrhythmias (VAs). We aimed to evaluate the EP properties, autonomic, and structural remodeling in a rabbit model with early liver cirrhosis (LC). Twelve rabbits were assigned to the sham and LC groups. The early-stage LC was induced by the ligation of the common bile duct. All rabbits received an EP study, VA inducibility test, myocardial, and liver histology staining. Western blot analyses of protein expression and tyrosine hydroxylase stain for sympathetic nerves were performed. The effective refractory period the LC group was significantly longer than the sham group [i.e., left ventricle (LV) 205.56 ± 40.30 vs. 131.36 ± 7.94 ms; right ventricle (RV) 206.78 ± 33.07 vs. 136.79 ± 15.15 ms; left atrium (LA) 140.56 ± 28.75 vs. 67.71 ± 14.29 ms; and right atrium (RA) 133.78 ± 40.58 vs. 65.43 ± 19.49 ms, all p < 0.01], respectively. The VA inducibility was elevated in the LC group when compared with the sham group (i.e., 21.53 ± 7.71 vs. 7.76 ± 2.44%, p = 0.013). Sympathetic innervation (102/μm2/mm2) was increased in all cardiac chambers of the LC group compared with the sham group (i.e., LV 9.11 ± 4.86 vs. 0.17 ± 0.15, p < 0.01; RV 4.36 ± 4.95 vs. 0.18 ± 0.12, p = 0.026; LA 6.79 ± 1.02 vs. 0.44 ± 0.20, p = 0.018; and RA 15.18 ± 5.12 vs. 0.10 ± 0.07, p = 0.014), respectively. Early LC is presented with an increased ventricular vulnerability, structural heterogeneity, and sympathetic innervation. Close monitoring for fatal arrhythmias is warranted in patients with early stages of LC.

Autonomic Regulation of Kidney Function

A potential role for the renal innervation was first described in 1859 by Claude Bernard, who observed an increase in urine flow following section of the greater splanchnic nerve, which included the renal nerves. Subsequent studies provided little further clarity, leading Homer Smith in 1951 to declare that the renal innervation had little or no significance in controlling kidney hemodynamic or excretory function. However, since the 1960s, there has been increased attention to how the renal nerves may contribute to the deranged control of blood pressure and heart function cardiovascular diseases. The efferent (sympathetic) nerves have neuroeffector junctions which provide close contact with all vascular and tubular elements of the kidney. Activation of the sympathetic nerves at the resistance vessels, that is, the interlobular arteries afferent and even arterioles, modulates both renal blood flow and glomerular filtration rate; at the juxtaglomerular granular cells, they cause renin release and subsequent angiotensin II generation, and at the tubules there is a neurally stimulated increase in epithelial cell sodium transport. Less is known of the role of the afferent nerves, which primarily innervate the renal pelvis, and to a lesser degree the cortex and medulla. Their role is uncertain but sensory information passing to the brain can influence renal efferent nerve activity, forming the basis of both inhibitory and excitatory reno-renal reflexes. Increasingly, it is perceived that in a range of cardiovascular diseases such as cardiac failure, chronic renal disease, and hypertension, there is an inappropriate sympatho-excitation related to alterations in afferent renal nerve activity, which exacerbates the disease progression. The importance of the renal innervation in these disease processes has been emphasized in clinical studies where renal denervation in humans has been found to reduce blood pressure in resistant hypertensive patients and to ameliorate the progression of cardiac and kidney diseases, diabetes, and obesity and hypertension. The importance of both systemic and renal inflammatory responses in activating the neurohumoral control of the kidney is a continuing source of investigation.

Pathophysiological significance of increased α-synuclein deposition in sympathetic nerves in Parkinson disease: A post-mortem observational study

Background: Parkinson disease (PD) is characterized by intra-neuronal deposition of the protein α-synuclein (α-syn) and by deficiencies of the catecholamines dopamine and norepinephrine (NE) in the brain and heart. Accumulation of α-syn in sympathetic noradrenergic nerves may provide a useful PD biomarker; however, whether α-syn buildup is pathophysiological has been unclear. If it were, one would expect associations of intra-neuronal α-syn deposition with catecholaminergic denervation and with decreased NE contents in the same samples. Methods: We assayed immunoreactive α-syn and tyrosine hydroxylase (TH, a marker of catecholaminergic innervation) concurrently with catecholamines in coded post-mortem scalp skin, submandibular gland (SMG), and apical left ventricular myocardial tissue samples from 14 patients with autopsy-proven PD and 12 age-matched control (CTRL) subjects who did not have a neurodegenerative disease. Results: PD patients had increased α-syn in sympathetic noradrenergically innervated arrector pili muscles (5.7 times CTRL, p<0.0001), SMG (35 times CTRL, p=0.0011), and myocardium (11 times CTRL, p=0.0011). Myocardial TH in the PD group was decreased from CTRL by 65% (p=0.0008), whereas the groups did not differ in TH in either arrector pili muscles or SMG. Similarly, myocardial NE was decreased by 92% in the PD group (p<0.0001), but the groups did not differ in NE in either scalp skin or SMG. Conclusions: PD entails increased α-syn in skin, SMG, and myocardial tissues. In skin and SMG augmented α-syn deposition in sympathetic nerves does not seem to be pathogenic. The pathophysiological significance of intra-neuronal α-syn deposition appears to be organ-selective and prominent in the heart.

Role of Renal Sympathetic Nerves in GLP‐1 (Glucagon‐Like Peptide‐1) Receptor Agonist Exendin‐4‐Mediated Diuresis and Natriuresis in Diet‐Induced Obese Rats

Background The gut‐derived hormone GLP‐1 (glucagon‐like peptide‐1) exerts beneficial effects against established risk factors for chronic kidney disease. GLP‐1 influences renal function by stimulating diuresis and natriuresis and thus lowering arterial blood pressure. The role of the sympathetic nervous system has been implicated as an important link between obesity with elevated arterial pressure and chronic kidney disease. The primary aim of this study was to determine the contribution of renal sympathetic nerves on intrapelvic GLP‐1‐mediated diuresis and natriuresis in high‐fat diet (HFD)‐induced obese rats. Methods and Results Obesity was induced in rats by HFD for 12 weeks, followed by either surgical bilateral renal denervation or chronic subcutaneous endopeptidase neprilysin inhibition by sacubitril for a week. Diuretic and natriuretic responses to intrapelvic administration of the GLP‐1R (GLP‐1 receptor) agonist exendin‐4 were monitored in anesthetized control and HFD rats. Renal GLP‐1R expression and neprilysin expression and activity were measured. The effects of norepinephrine on the expression of GLP‐1R and neprilysin in kidney epithelial LLC‐PK1 cells were also examined. We found that diuretic and natriuretic responses to exendin‐4 were significantly reduced in the HFD obese rats compared with the control rats (cumulative urine flow at 40 minutes, 387±32 versus 650±65 µL/gkw; cumulative sodium excretion at 40 minutes, 42±5 versus 75±10 µEq/gkw, P <0.05). These responses in the HFD rats were restored after ablation of renal nerves (cumulative urine flow at 40 minutes, 625±62 versus 387±32 µL/gkw; cumulative sodium excretion at 40 minutes, 70±9 versus 42±5 µEq/gkw, P <0.05). Renal denervation induced significant reductions in arterial pressure and heart rate responses to intrapelvic GLP‐1 in the HFD rats. Renal denervation also significantly increased the GLP‐1R expression and reduced neprilysin expression and activity in renal tissues from the HFD rats. Chronic subcutaneous neprilysin inhibition by sacubitril increased GLP‐1–induced diuretic and natriuretic effects in the HFD rats. Finally, exposure of the renal epithelial cells to norepinephrine in vitro led to downregulation of GLP‐1R expression but upregulation of neprilysin expression and activity. Conclusions These results suggest that renal sympathetic nerve activation contributes to the blunted diuretic and natriuretic effects of GLP‐1 in HFD obese rats. This study provides significant novel insight into the potential renal nerve–neprilysin–GLP‐1 pathway involved in renal dysfunction during obesity that leads to hypertension.