Central Renin-angiotensin System Research Articles

Angiotensin-converting enzyme inhibition prevents l-dopa-induced dyskinesia in a 6-ohda-induced mouse model of Parkinson's disease

Parkinson's disease (PD) is characterised by severe movement defects and the degeneration of dopaminergic neurones in the midbrain. The symptoms of PD can be managed with dopamine replacement therapy using L-3, 4-dihydroxyphenylalanine (L-dopa), which is the gold standard therapy for PD. However, long-term treatment with L-dopa can lead to motor complications. The central renin–angiotensin system (RAS) is associated with the development of neurodegenerative diseases in the brain. However, the role of the RAS in dopamine replacement therapy for PD remains unclear. Here, we tested the co-treatment of the angiotensin-converting enzyme inhibitor (ACEI) with L-dopa altered L-dopa-induced dyskinesia (LID) in a 6-hydroxydopamine (6-OHDA)-lesioned mouse model of PD. Perindopril, captopril, and enalapril were used as ACEIs. The co-treatment of ACEI with L-dopa significantly decreased LID development in 6-OHDA-lesioned mice. In addition, the astrocyte and microglial transcripts involving Ccl2, C3, Cd44, and Iigp1 were reduced by co-treatment with ACEI and L-dopa in the 6-OHDA-lesioned striatum. In conclusion, co-treatment with ACEIs and L-dopa, such as perindopril, captopril, and enalapril, may mitigate the severity of L-DOPA-induced dyskinesia in a mouse model of PD.

Afferent renal denervation attenuates sympathetic over activation from the paraventricular nucleus in spontaneously hypertensive rats.

The effectiveness of Renal Denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central Renin-Angiotensin System (RAS) pathway. Ten-week-old Spontaneously Hypertensive Rats (SHR) were subjected to Selective Afferent Renal Denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of PVN in SHR. The experimental results show that ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the paraventricular nucleus of hypothalamus (PVN), and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway.

The central renin–angiotensin system: A genetic pathway, functional decoding, and selective target engagement characterization in humans

Accumulating evidence suggests that the brain renin angiotensin system (RAS) plays a pivotal role in the regulation of cognition and behavior as well as in the neuropathology of neurological and mental disorders. The angiotensin II type 1 receptor (AT1R) mediates most functional and neuropathology-relevant actions associated with the central RAS. However, an overarching comprehension to guide translation and utilize the therapeutic potential of the central RAS in humans is currently lacking. We conducted a comprehensive characterization of the RAS using an innovative combination of transcriptomic gene expression mapping, image-based behavioral decoding, and pre-registered randomized controlled discovery-replication pharmacological resting-state functional magnetic resonance imaging (fMRI) trials (N = 132) with a selective AT1R antagonist. The AT1R exhibited a particular dense expression in a subcortical network encompassing the thalamus, striatum, and amygdalo-hippocampal formation. Behavioral decoding of the AT1R gene expression brain map showed an association with memory, stress, reward, and motivational processes. Transient pharmacological blockade of the AT1R further decreased neural activity in subcortical systems characterized by a high AT1R expression, while increasing functional connectivity in the cortico-basal ganglia-thalamo-cortical circuitry. Effects of AT1R blockade on the network level were specifically associated with the transcriptomic signatures of the dopaminergic, opioid, acetylcholine, and corticotropin-releasing hormone signaling systems. The robustness of the results was supported in an independent pharmacological fMRI trial. These findings present a biologically informed comprehensive characterization of the central AT1R pathways and their functional relevance on the neural and behavioral level in humans.

Simulating of human physiological supersystems: modeling of kidney and bladder functions

A quantitative model describing the functions of human kidney and bladder is created. The model is realized and tested as an autonomous C# software module (SM) functioning under given dynamic input characteristics. Finally, SM will be incorporated into our specialized general software capable of simulating the main modes of human integrative physiology, namely, interactions of physiological super-system (PSS). The model of the kidney describes mechanisms of blood filtration in Bowman’s capsule, reabsorption in collecting tubules, as well as the central renin-angiotensin system mechanism. The model of the bladder describes the dynamics of its filling and periodic emptying. Each act of bladder emptying is initiated by a signal generated by the brain in response to afferent impulse patterns from the bladder’s mechanoreceptors. Models have been tested using algorithms that design scenarios, including simulation of either short-time or long-time (hours or days) observations. Input data include different combinations of pressure in renal afferent arterioles, osmotic, and oncotic blood pressures. Output data includes dynamics of primary urine, final urine, bladder volume, urine pressure, mechanoreceptors’ activity, renin production velocity, blood renin concentration, angiotensin2 production velocity, and blood angiotensin2 concentration, as well as blood albumin and sodium concentrations. Both student-medics and physiologists interested in providing theoretical research can be users of SM.

Role of brain renin-angiotensin system in depression: A new perspective.

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin-angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS-induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain-derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non-classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation.

Activation of Angiotensin-converting Enzyme 2 Protects Against Lipopolysaccharide-induced Glial Activation by Modulating Angiotensin-converting Enzyme 2/Angiotensin (1-7)/Mas Receptor Axis.

Neuroinflammation is associated with activation of glial cells and pro-inflammatory arm of the central Renin Angiotensin System (RAS) namely, Angiotensin-Converting Enzyme/Angiotensin II/Angiotensin Type 1 Receptor (ACE/Ang II/AT1R) axis. Apart from this, another axis of RAS also exists, Angiotensin-Converting Enzyme 2/Angiotensin (1-7)/Mas Receptor (ACE2/Ang (1-7)/MasR), which counters ACE/Ang II/AT1R axis by showing anti-inflammatory properties. However, the role of ACE2/Ang (1-7)/MasR axis has not been explored in glial activation and neuroinflammation. Hence, the present study tries to unveil the role of ACE2/Ang (1-7)/MasR axis in lipopolysaccharide (LPS)-induced neuroinflammation using diminazene aceturate (DIZE), an ACE2 activator, in astroglial (C6) and microglial (BV2) cells as well as male SD rats. We found that ACE2 activation efficiently prevented LPS-induced changes by decreasing glial activation, inflammatory signaling, cell migration, ROS generation via upregulation of ACE2/Ang (1-7)/MasR signaling. In addition, activation of ACE2/Ang (1-7)/MasR axis by DIZE significantly suppressed the pro-inflammatory ACE/Ang II/AT1R axis by reducing Ang II level in neuroinflammatory conditions induced by LPS in both in vitro and in vivo. ACE2/Ang (1-7)/MasR axis activation further decreased mitochondrial depolarization and apoptosis, hence providing neuroprotection. Furthermore, to validate that the beneficial effect of the ACE2 activator was indeed through MasR, a selective MasR antagonist (A779) was used that significantly blocked the anti-inflammatory effect of ACE2 activation by DIZE. Hence, our study demonstrated that ACE2 activation imparted neuroprotection by enhancing ACE2/Ang (1-7)/MasR signaling which in turn decreased glial activation, neuroinflammation, and apoptosis and improved mitochondrial health.

Angiotensin II As A Natural Suppressor On Cardiac Natriuretic Peptide System: Molecular Insights And Novel Therapeutic Design

<h3>Introduction</h3> Therapeutic strategies harnessing both renin-angiotensin system (RAS) and natriuretic peptide system (NPS) mediated effects, such as Sacubitril/Valsartan, has been proven to be promising in treating human heart failure (HF). However, molecular understanding of the interaction between RAS and NPS remains to be fully elucidated. While angiotensin II (ANGII), the central RAS hormone, is thought to interact with NPS at multiple levels, whether and how it may influence the actions of particulate guanylyl cyclase A (pGC-A), the only functional receptor for both atrial and b-type natriuretic peptide (ANP and BNP), has not been investigated. <h3>Hypothesis</h3> We hypothesize that ANGII naturally suppresses pGC-A and the inhibition of this crosstalk would be a novel therapeutic strategy to combat cardiovascular disease (CVD) of which RAS hyperactivation is a hallmark feature. <h3>Methods</h3> Plasma ANP, BNP, cGMP, and ANGII were measured in 128 healthy humans to define the balance between ANGII and NPS. cGMP responses to acute infusion of ANP alone and in the presence of ANGII was characterized in normal rats. The molecular mechanisms including involvement of ANGII type I receptor (AT1R) and its downstream target protein kinase C (PKC) were investigated in HEK293 cell overexpressing pGC-A and together with AT1R. CRRL-58, an innovative dual-functional peptide was designed to activate pGC-A and inhibit PKC, and tested for cGMP generation in HEK293 cells. <h3>Results</h3> In healthy human, plasma cGMP was positively associated with ANP or BNP only in low (≤ 4.5 pg/mL) but not those with high (> 4.5 pg/mL) ANGII levels (see Figure). Infusion of ANP (300 pmol/kg/min) in normal rats increased plasma and urinary cGMP, however ANP mediated cGMP generation was reduced in the presence of ANGII (50 pmol/kg/min). Notably, the suppressive effect of ANGII on pGC-A was recapitulated in HEK293 cell overexpressing both pGC-A and AT1R, but not in HEK293 cell overexpressing pGC-A alone. Meanwhile, we found PKC, a well-established downstream target of AT1R, was a key mediator for this observed crosstalk, as the suppression effect of ANGII was largely ablated by Go6983, a pan PKC inhibitor. Notably, CRRL-58 had superior potency in cGMP generation compared to the currently best-in-class ANP-analog, MANP, in vitro. <h3>Conclusions</h3> Our human and experimental data demonstrate that ANGII is a natural suppressor of pGC-A activation via AT1R and PKC signaling, but not via pGC-A per se. Moreover, we report for the first time that CRRL-58, an innovative bioengineered peptide that activates pGC-A receptor while inhibiting PKC signaling, potently generates cGMP. Together, our study provides new insights into the interaction between RAS and NPS, and highlights a novel and mechanism-based therapeutic avenue for treating HF and other CVDs.

New Insights Into the Role of Inflammation in the Brain in Heart Failure.

Heart failure is a growing medical problem. Although the underlying aetiology of heart failure differs according to the phenotype, there are some common characteristics observed in patients with heart failure. These include an increased sympathetic nerve activity, an activated renin–angiotensin system, and inflammation. The mechanisms mediating the increased sympathetic activity are not completely understood but the central nervous system plays a major role. Activation of the renin–angiotensin system plays an active role in the remodelling of the heart and in fluid and electrolyte imbalance. The presence of a central renin–angiotensin system means that locally produced angiotensin in the brain may also play a key role in autonomic dysfunction seen in heart failure. Markers of inflammation in the heart and in the circulation are observed in patients diagnosed with heart failure. Circulating pro-inflammatory cytokines can also influence cardiac function further afield than just locally in the heart including actions within the brain to activate the sympathetic nervous system. Preclinical evidence suggests that targeting the pro-inflammatory cytokines would be a useful therapy to treat heart failure. Most clinical studies have been disappointing. This mini-review suggests that pro-inflammatory cytokines in the brain play a key role and there is a problem associated with access of effective doses of the drugs to the site of action in the brain. The recent advances in nanotechnology delivery techniques may provide exciting future technology to investigate the role of specific pro-inflammatory mediators as novel targets within the brain in the treatment of heart failure.

Drugs Modulating Renin-Angiotensin System in COVID-19 Treatment.

A massive worldwide vaccination campaign constitutes the main tool against the COVID-19 pandemic. However, drug treatments are also necessary. Antivirals are the most frequently considered treatments. However, strategies targeting mechanisms involved in disease aggravation may also be effective. A major role of the tissue renin-angiotensin system (RAS) in the pathophysiology and severity of COVID-19 has been suggested. The main link between RAS and COVID-19 is angiotensin-converting enzyme 2 (ACE2), a central RAS component and the primary binding site for SARS-CoV-2 that facilitates the virus entry into host cells. An initial suggestion that the susceptibility to infection and disease severity may be enhanced by angiotensin type-1 receptor blockers (ARBs) and ACE inhibitors (ACEIs) because they increase ACE2 levels, led to the consideration of discontinuing treatments in thousands of patients. More recent experimental and clinical data indicate that ACEIs and, particularly, ARBs can be beneficial for COVID-19 outcome, both by reducing inflammatory responses and by triggering mechanisms (such as ADAM17 inhibition) counteracting viral entry. Strategies directly activating RAS anti-inflammatory components such as soluble ACE2, Angiotensin 1-7 analogues, and Mas or AT2 receptor agonists may also be beneficial. However, while ACEIs and ARBs are cheap and widely used, the second type of strategies are currently under study.

Controlled Hemorrhage Sensitizes Angiotensin II-Elicited Hypertension through Activation of the Brain Renin-Angiotensin System Independently of Endoplasmic Reticulum Stress.

Hemorrhagic shock is associated with activation of renin-angiotensin system (RAS) and endoplasmic reticulum stress (ERS). Previous studies demonstrated that central RAS activation produced by various challenges sensitizes angiotensin (Ang) II-elicited hypertension and that ERS contributes to the development of neurogenic hypertension. The present study investigated whether controlled hemorrhage could sensitize Ang II-elicited hypertension and whether the brain RAS and ERS mediate this sensitization. Results showed that hemorrhaged (HEM) rats had a significantly enhanced hypertensive response to a slow-pressor infusion of Ang II when compared to sham HEM rats. Treatment with either angiotensin-converting enzyme (ACE) 1 inhibitor, captopril, or ACE2 activator, diminazene, abolished the HEM-induced sensitization of hypertension. Treatment with the ERS agonist, tunicamycin, in sham HEM rats also sensitized Ang II-elicited hypertension. However, blockade of ERS with 4-phenylbutyric acid in HEM rats did not alter HEM-elicited sensitization of hypertension. Either HEM or ERS activation produced a greater reduction in BP after ganglionic blockade, upregulated mRNA and protein expression of ACE1 in the hypothalamic paraventricular nucleus (PVN), and elevated plasma levels of Ang II but reduced mRNA expression of the Ang-(1-7) receptor, Mas-R, and did not alter plasma levels of Ang-(1-7). Treatment with captopril or diminazene, but not phenylbutyric acid, reversed these changes. No treatments had effects on PVN protein expression of the ERS marker glucose-regulated protein 78. The results indicate that controlled hemorrhage sensitizes Ang II-elicited hypertension by augmenting RAS prohypertensive actions and reducing RAS antihypertensive effects in the brain, which is independent of ERS mechanism.

Abstract 10303: CRRL290: A Novel and Mechanism-Based Therapeutic Peptide Targeting the Crosstalk Between Angiotensin II and the Natriuretic Peptide System for Cardiorenal Disease

Introduction: Therapeutic strategies dual-targeting renin-angiotensin system (RAS) and natriuretic peptide system (NPS), such as Sacubitril/Valsartan, have been proven promising in treating cardiorenal disease (CRD). However, mechanisms behind the crosstalk between RAS and NPS remain to be fully elucidated. While angiotensin II (ANGII), the central RAS hormone, is thought to interact with NPS at multiple levels, whether and how it may influence the actions of particulate guanylyl cyclase A (pGC-A), the receptor activated by ANP and BNP to increase its second messenger cGMP, has not been investigated. Hypothesis: We hypothesize ANGII naturally suppresses pGC-A activity and inhibition of this ANGII mediated action can be a new strategy to combat CRD. Methods: Studies consist of biomarker analyses in plasma from healthy humans, drug infusions in normal rats, molecular characterization in human HEK293 cells, and in vitro assessment of CRRL290, an innovative dual-functional peptide designed to activate pGC-A and inhibit protein kinase C (PKC). Results: In 128 healthy humans, plasma cGMP was positively associated with ANP or BNP in low (≤ 4.5 pg/mL) but not those with high (&gt; 4.5 pg/mL) ANGII levels. Infusion of ANP (300 pmol/kg/min) in normal rats increased plasma and urinary cGMP, however ANP mediated cGMP generation was reduced in the presence of ANGII. Interestingly, suppression effect of ANGII on pGC-A was only recapitulated in HEK293 cell overexpressing both pGC-A and AT1R, but not in HEK293 cell overexpressing pGC-A alone. We also found PKC, a known downstream target of AT1R, was a key mediator as the suppression effect of ANGII was largely ablated by Go6983, a pan PKC inhibitor. Accordingly, we designed and synthesized CRRL290. Notably, CRRL290 had superior potency in cGMP generation compared to the currently best-in-class ANP-analog, MANP, in HEK293 cells. Conclusions: We demonstrate that ANGII is a natural suppressor of pGC-A via AT1R and PKC signaling. We also report for the first time that CRRL290, a novel bioengineered peptide that activates pGC-A receptor while inhibiting PKC signaling, potently generates cGMP. Our study provides new insights into the RAS-NPS interaction, and highlights a novel and mechanism-based therapeutic avenue for treating CRD.

Both central sympathoexcitation and peripheral angiotensin II-dependent vasoconstriction contribute to hypertension development in immature heterozygous Ren-2 transgenic rats.

Recently, we demonstrated that chronic blockade of the renin-angiotensin system (RAS) lowered the blood pressure (BP) of adult Ren-2 transgenic rats (TGR) mainly through the attenuation of central sympathoexcitation. However, the participation of central and peripheral mechanisms in the development of high BP in immature TGR remains unclear. In the present study, 6-week-old heterozygous TGR males were chronically treated with intracerebroventricular (ICV) or intraperitoneal (IP) infusions of the AT1 receptor inhibitor losartan (1 or 2 mg/kg/day) for 4 weeks. The influence of these treatments on sympathetic- and angiotensin II-dependent BP components (BP response to pentolinium or captopril, respectively) as well as on BP response to exogenous angiotensin II were determined to evaluate the participation of central and peripheral RAS in hypertension development. Chronic IP losartan administration (1 or 2 mg/kg/day) lowered the BP of immature TGR by reducing both sympathetic and angiotensin II-dependent BP components. The central action of IP-administered losartan was indicated by a reduced BP response to acute ICV angiotensin II injection. Chronic ICV administration of a lower losartan dose (1 mg/kg/day) reduced only the sympathetic BP component, whereas a higher ICV administered dose (2 mg/kg/day) was required to influence the angiotensin II-dependent BP component. Accordingly, chronic ICV losartan administration of 2 mg/kg/day (but not 1 mg/kg/day) attenuated the BP response to acute intravenous angiotensin II application. In conclusion, central sympathoexcitation seems to play an important role in hypertension development in immature TGR. Central sympathoexcitation is highly susceptible to inhibition by low doses of RAS-blocking agents, whereas higher doses also affect peripheral angiotensin II-dependent vasoconstriction.

Activation of the Central Renin-Angiotensin System Causes Local Cerebrovascular Dysfunction.

Hypertension is a leading risk factor for cerebrovascular disease and loss of brain health. While the brain renin-angiotensin system (RAS) contributes to hypertension, its potential impact on the local vasculature is unclear. We tested the hypothesis that activation of the brain RAS would alter the local vasculature using a modified deoxycorticosterone acetate (DOCA) model. C57BL/6 mice treated with DOCA (50 mg SQ; or shams) were given tap H2O and H2O with 0.9% NaCl for 1 to 3 weeks. In isolated cerebral arteries and parenchymal arterioles from DOCA-treated male mice, endothelium- and nitric oxide-dependent dilation was progressively impaired, while mesenteric arteries were unaffected. In contrast, cerebral endothelial function was not significantly affected in female mice treated with DOCA. In males, mRNA expression of renal Ren1 was markedly reduced while RAS components (eg, Agt and Ace) were increased in both brain and cerebral arteries with central RAS activation. In NZ44 reporter mice expressing GFP (green fluorescent protein) driven by the angiotensin II type 1A receptor (Agtr1a) promoter, DOCA increased GFP expression ≈3-fold in cerebral arteries. Impaired endothelial responses were restored to normal by losartan, an AT1R (angiotensin II type 1 receptor) antagonist. Last, DOCA treatment produced inward remodeling of parenchymal arterioles. These findings suggest activation of the central and cerebrovascular RAS impairs endothelial (nitric oxide dependent) signaling in brain through expression and activation of AT1R and sex-dependent effects. The central RAS may be a key contributor to vascular dysfunction in brain in a preclinical (low renin) model of hypertension. Because the brain RAS is also activated during aging and other diseases, a common mechanism may promote loss of endothelial and brain health despite diverse cause.

Dynamic Regulation of Brain Renin Angiotensin System During Fear Memory Reconsolidation

Background Dysregulation of the renin angiotensin system (RAS) has been linked to autonomic dysfunction, fear -related disorders (i.e., PTSD) and increased cardiovascular disease (CVD) risk. We recently demonstrated that following reactivation of a fear memory, the peripheral administration of losartan, an angiotensin type 1 receptor blocker (Agtr1) blocker, disrupted long term cue-dependent fear memory. In order to further analyze the role of brain RAS in fear memory processes, here we examined brain RAS gene expression patterns in the basolateral amygdala (BLA), a brain region essential for fear or threat related memory. We hypothesized that peripheral losartan administration would interfere with the reconsolidation of memory by altering the expression of central RAS and other downstream signaling genes involved in fear memory. Methods Pavlovian auditory fear conditioning, whole-genome RNA-sequencing and RT-qPCR on brain tissue punches were combined to analyze gene expression patterns at early (40mins) and late (4hr) phases of reconsolidation and also after acute losartan treatment (10mg/kg, i.p). Results Following auditory cued fear memory retrieval, mRNA expression of immediate early genes (IEGs) - fos, Egr-1 and Arc in the BLA were rapidly increased at 40mins (2-3-fold, p<0.001; n=8) and returned to baseline at 4hrs. At these same early (40 min) activation and late (4hrs) time-points, RAS gene expression (mRNA) patterns in the BLA and synaptic plasticity genes were also dynamically regulated in a time-dependent manner. Compared to our control (non-retrieval group), at 40 min, we observed 2-3-fold mRNA changes in levels of the angiotensin peptide pre-cursor angiotensinogen - Agt (3-fold p<0.025, n=6) and the angiotensin II converting to angiotensin 1-7 cleaving enzyme - Ace2 (2-fold, p<0.05, n=8) which both returned to control levels at 4 hours. In contrast, at the receptor level, the angiotensin II type 1 receptor (Agtr1) was increased at 4 hours, but not 40 min while the type 2 receptor (Agtr2) was increased at both time points. The mRNA level of brain derived neurotrophic factor (Bdnf), an important synaptic plasticity modulator and downstream to angiotensin II signaling, was also elevated (1-fold, p<0.005, n=8) at 40mins. These gene expression patterns were distinct only for BLA as other brain regions of CA1, PVN and PFC showed no significant change. Finally, we determined whether post-retrieval losartan effects RAS genes in the BLA. We found that losartan prevented the rapid increase in Agt expression (p<0.05, n=8) and further increased Ace2 levels (p<0.01, n=8). Conclusion These results demonstrate that following retrieval of a fear memory, brain Agt expression is dynamically regulated in the basolateral amygdala and its expression is also influenced by losartan administration. These results contribute to further understanding the role of brain RAS in modulating central fear memory processes which may have important translational implications for advancing novel therapeutics for PTSD.

Inhibition of PLCβ1 signaling pathway regulates methamphetamine self-administration and neurotoxicity in rats

Studies have shown that the central renin–angiotensin system is involved in neurological disorders. Our previous studies have demonstrated that angiotensin II receptor type 1 (AT1R) in the brain could be a potential target against methamphetamine (METH) use disorder. The present study was designed to investigate the underlying mechanisms of the inhibitory effect of AT1R on various behavioural effects of METH. We first examined the effect of AT1R antagonist, candesartan cilexetil (CAN), on behavioural and neurotoxic effects of METH. Furthermore, we studied the role of phospholipase C beta 1 (PLCβ1) blockade behavioural and neurotoxic effects of METH. The results showed that CAN significantly attenuated METH-induced behavioral disorders and neurotoxicity associated with increased oxidative stress. AT1R and PLCβ1 were significantly upregulated in vivo and in vitro. Inhibition of PLCβ1 effectively alleviated METH-induced neurotoxicity and METH self-administration (SA) by central blockade of the PLCβ1 involved signalling pathway. PLCβ1 blockade significantly decreased the reinforcing and motivation effects of METH. PLCβ1 involved signalling pathway, as well as a more specific role of PLCβ1, involved the inhibitory effects of CAN on METH-induced behavioural dysfunction and neurotoxicity. Collectively, our findings reveal a novel role of PLCβ1 in METH-induced neurotoxicity and METH use disorder.

The Level and Significance of Circulating Angiotensin-III in Patients with Coronary Atherosclerosis.

Objective Angiotensin-III (Ang-III) is the downstream product of angiotensin-II (Ang-II) metabolized by aminopeptidase A (APA). At present, the research of Ang-III mainly concentrates on hypertension and the central renin-angiotensin system (RAS). However, few studies have focused on the relationship between Ang-III and coronary atherosclerosis (CAS). Methods and Results Plasma Ang-III and APA levels were measured by the enzyme-linked immunosorbent assay (ELISA) in 44 normal subjects and 84 patients confirmed as having CAS by coronary angiography. Circulating Ang-III levels were significantly lower in patients with CAS than in normal controls (P = 0.013). APA levels were slightly lower in the CAS group (P = 0.324). According to the severity of atherosclerosis, CAS patients were divided into two groups. Compared with the controls, the APA and Ang-III levels were lower in the high scoring group and APA decreased significantly. Conclusions Circulating Ang-III levels were reduced in patients with CAS, and the possible reason may be related to the decrease in the APA level.

Angiotensin receptors and neuropathic pain.

Growing evidence implicates the renin–angiotensin system (RAS) in multiple facets of neuropathic pain (NP). This narrative review focuses primarily on the major bioactive RAS peptide, Angiotensin II (Ang II), and its receptors, namely type 1 (AT1R) and type 2 (AT2R). Both receptors are involved in the development of NP and represent potential therapeutic targets. We first discuss the potential role of Ang II receptors in modulation of NP in the central nervous system. Ang II receptor expression is widespread in circuits associated with the perception and modulation of pain, but more studies are required to fully characterize receptor distribution, downstream signaling, and therapeutic potential of targeting the central nervous system RAS in NP. We then describe the peripheral neuronal and nonneuronal distribution of the RAS, and its contribution to NP. Other RAS modulators (such as Ang (1-7)) are briefly reviewed as well. AT1R antagonists are analgesic across different pain models, including NP. Several studies show neuronal protection and outgrowth downstream of AT2R activation, which may lead to the use of AT2R agonists in NP. However, blockade of AT2R results in analgesia. Furthermore, expression of the RAS in the immune system and a growing appreciation of neuroimmune crosstalk in NP add another layer of complexity and therapeutic potential of targeting this pathway. A growing number of human studies also hint at the analgesic potential of targeting Ang II signaling. Altogether, Ang II receptor signaling represents a promising, far-reaching, and novel strategy to treat NP.

The anti-Alzheimer effect of telmisartan in a hyperglycemic ovariectomized rat model; role of central angiotensin and estrogen receptors

The central renin angiotensin system (RAS) is implicated in Alzheimer's disease (AD). Here, induction of experimental AD simulation was performed by D-galactose (D-Gal) injection to ovariectomized (OVX) rats fed on high fat high fructose diet (HFFD). Telmisartan administration to OVX/HFFD/D-Gal rats lowered the expression of hippocampal angiotensin 1 and 2 receptors and glucose transporter 2 in addition to lowering of the peripheral and central glucose levels. Furthermore, it improved cognitive impairment and suppressed hippocampal amyloidogenic markers including amyloid-beta level, phosphorylated tau protein and beta site amyloid precursor protein cleaving enzyme 1 expression, while elevated levels of insulin degrading enzyme and recovered permeability of blood brain barrier (BBB). In addition, it inhibited hippocampal oxido-nitrosative stress as well as neuroinflammatory and apoptotic biomarkers. Telmisartan improved memory and cognitive impairment as shown in the behavioral Morris water maze, Y-maze, novel object recognition and open field tests in addition to amelioration of depressive like behavior as shown in forced swimming test. Histopathological examination of brain and immune expression of glial fibrillary acidic protein were also improved together with astrogliosis improvement. In conclusion, telmisartan improved memory and cognitive impairment, recovered amyloidogenesis-hyperglycemic axis, astrogliosis, integrity of BBB, memory deficit and oxidonitrosative stress induced in OVX/HFFD/D-Gal rats.

The Impact of Renal Denervation on the Progression of Heart Failure in a Canine Model Induced by Right Ventricular Rapid Pacing

Heart failure (HF) has been proposed as a potential indication of renal denervation (RDN). However, the mechanisms enabling RDN to attenuate HF are not well understood, especially the central effects of RDN. The aim of this study was to decipher the mode of operation of RDN in the treatment of HF using a canine model of right ventricular rapid pacing-induced HF. Accordingly, 24 Chinese Kunming dogs were randomly grouped to receive sham procedure (sham-operated group), bilateral RDN (RDN group), rapid pacing to induce HF (HF-control group), and bilateral RDN plus rapid pacing (RDN + HF group). Echocardiography, plasma brain natriuretic peptide (BNP), and norepinephrine (NE) concentrations of randomized dogs were measured at baseline and 4 weeks after interventions, followed by histological and molecular analyses. Twenty dogs completed the research successfully and were enrolled for data analyses. Results showed that the average optical density of renal efferent and afferent nerves were significantly lower in the RDN and RDN + HF groups than in the sham-operated group, with a significant reduction of renal NE concentration. Rapid pacing in the RDN + HF and HF-control groups, compared with the sham-operated group, induced a significant increase in left ventricular end-diastolic volume and decrease in left ventricular ejection fraction and correspondingly resulted in cardiac fibrosis and dysfunction. Cardiac fibrosis evaluated by Masson’s trichrome staining and the expression of transforming growth factor-β1 (TGF-β1) were significantly higher in the HF-control group than in the sham-operated group, which were remarkably attenuated by the application of the RDN technique in the RDN + HF group. In terms of central renin–angiotensin system (RAS), the expression of angiotensin II (AngII)/angiotensin-converting enzyme (ACE)/AngII type 1 receptor (AT1R) in the hypothalamus of dogs in the HF-control group, compared with the sham-operated group, was upregulated and that of the angiotensin-(1-7) [Ang-(1-7)]/ACE2 was downregulated. Furthermore, both of them were significantly attenuated by the RDN therapy in the RDN + HF group. In conclusion, the RDN technique could damage renal nerves and suppress the cardiac remodeling procedure in canine with HF while concomitantly attenuating the overactivity of central RAS in the hypothalamus.

Программный симулятор механизмов долговременной регуляции гемодинами-ки человека

A computer simulator (CS) of the physiological mechanisms of long-term control of the state of human cardiovascular system (CVS) is developed. The bases of CS are quantitative mathematical models (MM) describing: a) the effects of the central renin-angiotensin system on the characteristics of the CVS; b) the dynamics of the total blood volume. Test studies of MM in offline mode showed the adequacy of the models. It is planned to combine this model with the previously created model simulating the urgent regulation of CVS. Based on the integrated model, specialized software technology will be developed to support computer simulations on various aspects of the physiology of the healthy person’s blood circulation. A special simulation study should identify the causes of different scenarios for the development of hypertension. The program is written in C ++17. Problems in programming 2019; 4: 111-120