Blockade Of System Research Articles

Sodium-Glucose Cotransporter2 Inhibitors in Patients with Non-Diabetic Chronic Kidney Disease.

Sodium-glucose cotransporter2 (SGLT2) inhibitors can reduce cardiovascular morbidity and mortality in patients with type2 diabetes. Furthermore, recent clinical studies have revealed that SGLT2 inhibitors decrease the risk of renal function impairment in patients with type2 diabetes. However, the effects of SGLT2 inhibitors on non-diabetic chronic kidney disease (CKD) remains unclear. Regarding long-term clinical outcomes, the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial explicitly showed improvements in cardiovascular outcomes in patients presenting with heart failure, even in the absence of diabetes. The reduction in heart failure in patients without diabetes was confirmed following empagliflozin administration in the EMPagliflozin outcomE tRial in patients with chrOnic heart failure with Reduced ejection fraction (EMPEROR-Reduced) trial. A recent systematic review and meta-analysis of DAPA-HF and EMPEROR-Reduced showed improvements in the composite renal endpoint regardless of the presence of diabetes or baseline estimated glomerular filtration rate. The Dapagliflozin and Prevention of Adverse outcomes in Chronic Kidney Disease (DAPA-CKD) trial evaluated patients with CKD with or without type2 diabetes, irrespective of whether SGLT2 inhibitor dapagliflozin was added for renin-angiotensin system blockade as background renoprotective therapy. In this trial, dapagliflozin reduced the hazard ratio for a composite renal and cardiovascular death endpoint in patients with CKD attributed to various causes, with or without type2 diabetes.

RESISTANT HYPERTENSION ON TREATMENT (RESHYPOT) TRIAL: SEQUENTIAL NEPHRON BLOCKADE COMPARED TO DUAL BLOCKADE OF THE RENIN- ANGIOTENSIN-ALDOSTERONE SYSTEM PLUS BISOPROLOL

Objective: Resistant hypertension (RHTN) is a clinical entity, difficult to manage. To identify the contribution of the volume as well as the renin activity from the maintenance of blood pressure levels could individualize the treatment. Objectives : To demonstrate the efficacy of therapy of sequential nephron blocking (SNB) in relation to the double blockade of the renin-angiotensin system associated with beta-blockers (DBRAS) in patients with RHTN with > 85%-adherence rate after 20 weeks of treatment. Design and method: A prospective study was conducted, open, randomized, parallel comparison between two regimens for RHT: SNB versus DBRAS. SNB consists in a progressive increase of sodium depletion with thiazide, followed by a blockade of mineralocorticoid receptor, followed by progressive doses of loop diuretics and finally blocking sodium channels. DBRAS consists in reinforcing the effect of angiotensin receptor blocker (ARB) with an angiotensin converting enzyme inhibitors (ACEI), followed by betablockers to decrease the renin secretion. Seventy-two patients were randomized (35 to SNB 13 M/22F and 37 to RASDB 14 M/23F) coming from the tertiary outpatient clinic (HB-FAMERP). We used the criteria of the Brazilian VII Guidelines for Hypertension and V Guidelines for ABPM and HBPM. The BP was monitored with the SpaceLabs 90207. Results: Baseline clinical characteristics and laboratory parameters of the 72 RHTM randomized to SNB (n = 35) or DBRAS (n = 37) were similar across both study groups. At the end of the study, a significant reduction of the office pressure was observed (SBP and DBP) in both post-intervention groups (SNB group: initial SBP: 174.5 ± 21.08; final SBP: 127.0 ± 14.74; Initial DBP: 105.3 ± 15.5, final DBP: 78.11 ± 9.28 (p < 0.0001), RAASDB group: initial SBP: 178.4 ± 21.08, final SBP: 134.4 ± 23.25, initial DBP: 102.7 ± 11.07, final DBP: 77.33 ± 13.75 (p < 0.0001). No discontinuation due drug-related adverse events in both study groups. Conclusions: SNB and DBRAS associated with the beta-blocker in RHTN patients with full adherence to the treatment showed excellent therapeutic efficacy. However, the SNB group disclosed a greater absolute reduction of central blood pressure values.

A narrative review of new treatment options for chronic kidney disease in type 2 diabetes.

Diabetic kidney disease is a frequent and costly complication to type 2 diabetes. After many years with a lack of successful trials there are now significant developments that will change treatment, guidelines and future outcome. Since the last two decades blockade of the renin-angiotensin system (RAS) is standard treatment, but new antidiabetic treatments have shown potential for kidney protection. After cardiovascular outcome studies with glucagon-like peptide (GLP-1) receptor agonists it is evident that drugs like liraglutide, semaglutide and dulaglutide can reduce albuminuria levels and progression to macroalbuminuria. At present, a renal outcome trial with semaglutide is ongoing which will provide more evidence on the drug class in the future. The sodium glucose co-transporter 2 (SGLT2) inhibitor class has also demonstrated effects beyond glucose-lowering, as the drugs can reduce blood pressure, albuminuria and loss of renal function. In the first renal outcome study the SGLT2 inhibitor canagliflozin was found to reduce the risk of hard renal outcome with 30%. SGLT2 inhibition is now recommended in type 2 diabetes with chronic kidney disease. Renal outcome studies testing additional SGLT2 inhibitors and the GLP-1 receptor agonist semaglutide will report in the coming future potentially providing more and much needed options for treatment.

EFFECT OF SEQUENTIAL NEPHRON BLOCKING IN COMPARISON WITH THE DOUBLE BLOCKADE OF THE RENIN- ANGIOTENSIN SYSTEM + BISOPROLOL ON CENTRAL SYSTOLIC BLOOD PRESSURE AND ARTERIAL STIFFNESS

Objective: The different classes of drugs routinely used in anti-hypertensive therapy promote different effects on markers of arterial stiffness and, consequently, on the central blood pressure. Arterial stiffness is the main determinant for the increase of the central blood pressure and considered an important predictor for myocardial infarction, stroke and congestive heart failure. Objective: The objective of this study was to compare the effect on the systolic central blood pressure and arterial stiffness in resistant hypertensive patients submitted to sequential nephron blockade (SNB) against double blockade of the renin-angiotensin-aldosterone system (DBRAS) plus Bisoprolol. Design and method: Fifty-five resistant hypertensive patients were recruited in the Hypertension Outpatient Clinic of FAMERP, twenty-nine in the SNB group (18F/11 M) and twenty-six in the DBRAS group (22F/4 M). Central systolic blood pressure (cSBP), incrementing index (AI) and AI75 were measured with Omron HEM9000-A. (Japan). Results: The main result showed significant reduction of the central systolic blood pressure in patients submitted to sequential blockade nephron treatment when compared with the double blockade of the renin-angiotensin system plus Bisoprolol group (128.8 ± 22.1 vs. 117.4 ± 17.9 mmHg - P = 0.03). Figure 1 Conclusions: The sequential nephron blockade group, when compared with the double blockade of the renin-angiotensin-aldosterone system plus Bisoprolol, promotes significant higher reduction of the central systolic blood pressure in resistant hypertensive patients.

POS-830 NEFECON FOR THE TREATMENT OF IgA NEPHROPATHY IN PATIENTS AT RISK OF PROGRESSING TO END-STAGE RENAL DISEASE: THE NEFIGARD PHASE 3 TRIAL RESULTS

Peyer’s patches located within the gut-associated lymphoid tissue have been identified as a major source of poorly O-galactosylated immunoglobulin A (IgA)1, which triggers the formation of nephritogenic immune complexes in IgA nephropathy (IgAN). The therapeutic potential of targeting Peyer’s patches in patients with IgAN was demonstrated in the Phase 2 NEFIGAN trial, which assessed the safety and efficacy of a novel targeted-release formulation of budesonide (NEFECON), designed to deliver budesonide to the Peyer’s patches in the ileum. Patients treated for 9 months with NEFECON 16 mg/day demonstrated a significant (~30%) reduction in urine protein-to-creatinine ratio (UPCR) compared with placebo, and stabilization of estimated glomerular filtration rate (eGFR). Based on these data, the Phase 3 NefIgArd trial is a two-part design: Part A evaluates proteinuria reduction as a surrogate of the effect of NEFECON on long-term kidney function preservation. NefIgArd is a randomized, double-blind, placebo-controlled clinical trial recruiting a total of 360 patients across 155 nephrology clinics in 20 countries. Patients must be aged ≥18 years with biopsy-confirmed primary IgAN, proteinuria >1 g/24 h and eGFR 35–90 mL/min/1.73 m2 despite optimized renin–angiotensin system blockade. Patients are randomized on a 1:1 ratio to NEFECON 16 mg/day or placebo. The primary endpoint, based on the first 199 patients, is the percentage decrease in proteinuria (UPCR) after 9 months of treatment. The secondary objectives include the difference in kidney function between NEFECON-treated subjects and those on placebo, as measured using eGFR, and the urine albumin-to-creatinine ratio (UACR) at 9 months compared with baseline. Between September 2018 and October 2020, 657 subjects were screened. Of these, 306 patients were randomized and 199 with 9 months of follow-up were included in the efficacy analyses of Part A of the study. At 9 months, the geometric mean UPCR was reduced by 27% in the NEFECON group compared with the placebo group (p=0.0005). At 9 months, the NEFECON group provided a statistically significant 7% (3.87 mL/min/1.73m2) treatment benefit on eGFR (p=0.0029), compared with placebo. There was a similar overall incidence of adverse events in the two treatment groups. The NefIgArd study met its primary endpoint and demonstrated a favorable safety profile. These results are indicative of a clinically meaningful reduced risk of future progression to end-stage renal disease in patients with IgAN treated with NEFECON. This trial will continue in order to validate UPCR reduction as a surrogate of long-term renal function preservation.

Back off to better blow up: acute GFR decrease at SGLT-2 inhibitor initiation

The drop in glomerular filtration rate often observed in the first weeks of nephroprotective treatment, whether because of protein restriction or renin-angiotensin system blockade, can be interpreted as a marker of the relationship between the intensity of baseline glomerular anomalies and the potential treatment benefit. In this issue, Oshima etal. reported a post hoc analysis of the Canagliflozin and Renal Events in Diabetes With Established Nephropathy Clinical Evaluation (CREDENCE) study, the results of which confirm that such a relationship is also observed under sodium-glucose cotransporter 2 inhibition in diabetic patients with chronic kidney disease.

Renin-angiotensin system blockade in patients with chronic kidney disease: benefits, problems in everyday clinical use, and open questions for advanced renal dysfunction.

Management of hypertension and albuminuria are considered among the primary goals of treatment to slow the progression of chronic kidney disease (CKD). Renin-angiotensin system (RAS) blockers, i.e., angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are the main drugs to achieve these goals. Seminal studies have showed that RAS blockers present significant renoprotective effects in CKD patients with very high albuminuria. In post hoc analyses of such trials, these renoprotective effects appeared more robust in patients with more advanced CKD. However, randomized trials specifically addressing whether RAS blockers should be initiated or maintained in patients with advanced CKD are scarce and do not include subjects with normoalbuminuria, thus, many clinicians are unconvinced for the beneficial effects of RAS blockade in these patients. Further, the fear of hyperkalemia or acute renal decline is another factor due to which RAS blockers are usually underprescribed and are easily discontinued in patients with more advanced CKD; i.e., those in Stages 4 and 5. This review summarizes evidence from the literature regarding the use of RAS blockers in patients with advanced CKD.

Blockade of Opiodergic System During Early Weaning Reverts Feeding Behavior Altered Patterns

Adverse experiences that occur during the early stages of life can have permanent repercussions in adulthood. Among these experiences, early weaning is one that can alter the molecular, cellular, and behavior patterns in later life. Centered on this fact, the objective of the current study was to evaluate the effect of early weaning at 15 days of life of Wistar rats on their feeding behavior and if the opioidergic system blockade would cause a reversal of these outcomes. Experimental groups were formed based on the weaning period of each litter. On postnatal day 15, the group D15 was weaned and, on postnatal day 30 (natural weaning), the group D30 was weaned. The rats weaned on postnatal day 15, and administered subcutaneous Naltrexone (3 mg/kg) were from group D15 + NTX. Those weaned at 15 days of age exhibited higher depressive-like behavior, lesser reactivity time to sucrose, and higher intake of palatable food than the control group. The Naltrexone administration was observed to reverse some outcomes, such as increasing the reactivity time to sucrose and decreasing the quantity of palatable food consumed, to levels similar to those of the control group. Together, the findings of the present study are indicative of the vital role played by the opioidergic system in inducing the changes noted in the eating behavior patterns during adulthood, post early weaning.

Supportive Management of IgA Nephropathy With Renin-Angiotensin Blockade, the AIIMS Primary IgA Nephropathy Cohort (APPROACH) Study

IntroductionRenin−angiotensin system (RAS) blockade using angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB) is first-line therapy for IgA nephropathy (IgAN). There is a paucity of information on the predictors and magnitude of response to this treatment.MethodsIn a prospective study, treatment-naive patients with IgAN with urinary protein ≥ 1 g/d and estimated glomerular filtration rate (eGFR) ≥ 30 ml/min per 1.73 m2 received supportive treatment including ACEi (ramipril) or ARB (losartan) in patients intolerant to ACEi, and optimal blood pressure (BP) control to ≤130/80 mm Hg, with a follow-up of 6 months. The primary outcome was remission of proteinuria. Complete remission (CR) was defined as proteinuria < 0.5 g/d and partial remission (PR) as proteinuria < 1g/d with at least a 50% decline from the baseline with stable renal function (≤ 25% reduction in eGFR).ResultsA total of 96 patients were analyzed, with a mean age of 33.3 ± 10.2 years, baseline eGFR 74.0 ± 30.9 ml/min per 1.73 m2, and urinary protein 2.6 ± 1.2 g/d. In all, 71.9% patients received ≥ 75% of the maximum approved dose of ACEi/ARB. Remission was observed in 36.5% (CR, 6.3%) patients at 3 months and in 55.2% (CR, 31.3%) at 6 months. Patients who failed to achieve remission had lower baseline eGFR (P = 0.002) and serum albumin levels (P< 0.001), asymptomatic hyperuricemia (P < 0.001), and higher proteinuria (P = 0.076). E1 (P= 0.053) and T1/T2 (P = 0.009) lesions were more frequent on histology. The ACEi/ARB had to be discontinued in 17 (17.7%) patients. These patients were older (P= 0.085) with lower eGFR (P < 0.002) and serum albumin levels (P = 0.001) and more E1 (P = 0.012) and T1/T2 (P = 0.001) lesions on histology.ConclusionMeticulous supportive therapy with optimal use of ACEi/ARB achieved remission in half of IgAN patients in this study. Increasing the treatment duration to 6 months improved remission rates. Patients with severe clinical and histological disease were less likely to tolerate and respond to treatment with RAS blockade.

Angiotensin receptor blockers use and changes in frailty, muscle mass, and function indexes: Singapore Longitudinal Ageing Study

AbstractBackgroundPre‐clinical studies suggest that renin–angiotensin system blockade may improve muscle function. Clinical reports of the effect of angiotensin converting enzyme inhibitors (ACEIs) on physical functioning are inconsistent. There are no reports of the effect of angiotensin receptor blockers (ARBs) treatment in older adults.MethodsWe analysed data of 1268 participants in the Singapore Longitudinal Ageing Study (SLAS‐2) who provided information on the use of ACEI, ARB, and other antihypertensive drugs at baseline and follow‐up (mean 4.5 years later). Baseline and follow‐up outcome measures were cumulated deficits frailty index (CD‐FI), physical phenotype frailty index (PP‐FI), calf circumference (CC), knee extension strength, composite muscle mass and strength (MMS) z‐score, and gait speed (GS). In primary analyses, we compared the use and non‐use of an anti‐hypertensive drug class among participants with hypertensive and cardiac disease, and secondarily with participants having other chronic diseases, and those who reported no chronic diseases. Multi‐variable analyses adjusted for socioeconomic status, body mass index ≥30, ≥5 comorbidities, ≥5 drugs use, other non‐ARB or non‐ACEI drugs (calcium channel blockers, beta blockers, or hydrochlorothiazide), MMSE &lt;23, Geriatric Depression Scale score, Nutrition Screening Initiative nutritional risk, physical activities, baseline frailty, and physical performance.ResultsAmong study participants, 7.8% (N = 99) were ARB users (62% used losartan), 11.7% (N = 148) were ACEI users (53% used enalapril), and 34.2% (N = 434) were users of other anti‐hypertensive drug classes. The cohort participants overall showed increases in the mean levels and changes in CD‐FI and PP‐FI and decreases in knee extension strength, GS, CC, and MMS. However, among groups, ARB users showed decreasing trends in CD‐FI and increasing trends of CC and MMS. Among participants with hypertensive and cardiovascular disease, there were significant differences in CD‐FI and PP‐FI changes, adjusted for confounding variables: ARB users compared with non‐users showed lesser declines in CD‐FI (0.013 vs. 0.028, P = 0.018) and PP‐FI (0.924 vs. 1.170, P = 0.017). ARB users also showed statistically significantly greater gains in MMS z‐scores: 0.329 vs. 0.076, P = 0.022. There was no association of ACEI or other anti‐hypertensive class use with changes in frailty, MMS, or GS.ConclusionsThe use of ARBs is associated with a reduction in frailty and age‐related loss of muscle mass and strength.

Role of traditional medicines as a challenge for Coronavirus (Covid-19)

The most countries in the World are facing the problem of disease caused by Noval coronavirus (covid-19) with symptoms of higher grade flu like symptoms or with no symptom. The infection is spreading through contact with the person suffered from coronavirus symptoms like sneezing, high fever, cough and ultimately blockade of respiratory system. Sometimes symptoms of diarrhea and dysentery were also detected at advanced stage of the disease. Till now any effective medicine or vaccine could not be developed for the prevention and getting relief. Only trial and error by applying some antimalarial drugs chloroquine hydroxide alongwith some other antiviral infections is used and up to 38% are being recovered in India as well as other countries. Under such circumstances strengthening immune system becomes only option for preventing from this viral disease and our traditional medicines are playing vital role for immunity strengthening. Accordingly, some herbs either singly or in combination form have been suggested as preventive measure for coronavirus through this communication.

Renin-Angiotensin-Aldosterone System Blockers Prior to Hospitalization and Their Association With Clinical Outcomes in Coronavirus Disease 2019 (COVID-19).

Objective: To determine the effect of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) use prior to hospitalization on clinical outcomes in coronavirus disease 2019 (COVID-19) patients.Design: An observational retrospective cohort study from 178 hospitals from a large health system across the United States. Patient population: Hospitalized patients (n=2726) with confirmed COVID-19 between January 1, 2020, and April 1, 2020.Main outcome(s) and measure(s): Outcomes during hospitalization, including disease severity by level of care, intensive care unit (ICU) admission, mechanical ventilator (MV) use, hospital length of stay, and in-hospital death. Patient demographics and comorbidities were also recorded.Results: A total of 2,726 patients were included in the analysis. Three hundred ninety-eight (14.6%) patients were taking an ACEI, while 352 (12.9%) patients were taking an ARB prior to hospitalization. After adjusting for comorbidities, age, renal function, and severity of illness based on level of care, ACEI prior to admission was independently associated with decreased need for MV (odds ratio [OR] 0.56, p value 0.003) and mortality (OR 0.45, p value <0.001). Similarly, patients who took ARBs were less likely to require MV when compared to the non-renin-angiotensin-aldosterone system blockade (RAASb) group (7.4% vs 12.2%, p value 0.009, respectively). ARB prior to admission was also independently associated with decreased need for MV (OR 0.46, p value 0.001) and mortality (OR 0.66, p value 0.017) compared to the non-RAASb group.Conclusion: Taking ACEIs and ARBs prior to admission for COVID-19 was independently associated with decreased need for mechanical ventilation and in-hospital mortality.

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria. Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose-lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.

Peptidoglycan Switches Off the TLR2-Mediated Sperm Recognition and Triggers Sperm Localization in the Bovine Endometrium.

In mammals, the uterine mucosal immune system simultaneously recognizes and reacts to most bacteria as well as allogenic sperm mainly through the Toll-like receptors (TLR)2/4 signaling pathway. Here, we characterized the impact of pathogen-derived TLR2/4 ligands (peptidoglycan (PGN)/lipopolysaccharide (LPS)) on the immune crosstalk of sperm with the bovine endometrial epithelium. The real-time PCR analysis showed that the presence of low levels of PGN, but not LPS, blocked the sperm-induced inflammatory responses in bovine endometrial epithelial cells (BEECs) in vitro. Immunoblotting analysis revealed that PGN prevented the sperm-induced phosphorylation of JNK in BEECs. Activation or blockade of the TLR2 system in the endometrial epithelium verified that TLR2 signaling acts as a commonly-shared pathway for PGN and sperm recognition. The impairment of endometrial sperm recognition, induced by PGN, subsequently inhibited sperm phagocytosis by polymorphonuclear neutrophils (PMNs). Moreover, using an ex vivo endometrial explant that more closely resembles those in vivo conditions, showed that sperm provoked a mild and reversible endometrial tissue injury and triggered PMN recruitment into uterine glands, while PGN inhibited these events. Of note, PGN markedly increased the sperm attachment to uterine glands, and relatively so in the surface epithelium. However, addition of the anti-CD44 antibody into a PGN-sperm-explant co-culture completely blocked sperm attachment into glands and surface epithelia, indicating that the CD44 adhesion molecule is involved in the PGN-triggered sperm attachment to the endometrial epithelium. Together, these findings demonstrate that, the presence of PGN residues disrupts sperm immune recognition and prevents the physiological inflammation induced by sperm in the endometrial epithelium via the MyD88-dependent pathway of TLR2 signaling, possibly leading to impairment of uterine clearance and subsequent embryo receptivity.

Heartbeat: higher risk of COVID-19 infection in younger patients with cardiovascular disease

Cardiovascular disease (CVD) is a major risk factor for adverse outcomes with COVID-19 infection. Concerns raised early in the pandemic that renin-angiotensin system (RAS) blockade by treatment with angiotensin converting...

Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial

Management of Renin-Angiotensin-Aldosterone System blockade in patients admitted to hospital with confirmed coronavirus disease (COVID-19) infection (The McGill RAAS-COVID- 19): A structured summary of a study protocol for a randomized controlled trial

Renin-angiotensin system blockade in the COVID-19 pandemic.

In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin–angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships.

Acetylcholine and spinal locomotor networks: The insider.

This article aims to review studies that have investigated the role of neurons that use the transmitter acetylcholine (ACh) in controlling the operation of locomotor neural networks within the spinal cord. This cholinergic system has the particularity of being completely intraspinal. We describe the different effects exerted by spinal cholinergic neurons on locomotor circuitry by the pharmacological activation or blockade of this propriospinal system, as well as describing its different cellular and subcellular targets. Through the activation of one ionotropic receptor, the nicotinic receptor, and five metabotropic receptors, the M1 to M5 muscarinic receptors, the cholinergic system exerts a powerful control both on synaptic transmission and locomotor network neuron excitability. Although tremendous advances have been made in our understanding of the spinal cholinergic system's involvement in the physiology and pathophysiology of locomotor networks, gaps still remain, including the precise role of the different subtypes of cholinergic neurons as well as their pre‐ and postsynaptic partners. Improving our knowledge of the propriospinal cholinergic system is of major relevance to finding new cellular targets and therapeutics in countering the debilitating effects of neurodegenerative diseases and restoring motor functions after spinal cord injury.

Differential Roles of Calcium-Activated and Calcium-Inhibited Adenylyl Cyclase Isoforms in the Regulation of SAN Automaticity

Sinoatrial node (SAN) is the primary pacemaker of the heart and is tightly regulated by β-adrenergic receptor (β-AR) signaling. Adenylyl cyclase (AC) is a key enzyme in the β-AR pathway that catalyzes the production of cAMP from ATP, leading to the activation of a cascade of downstream effectors. There are 10 known isoforms of AC, but their relative expression and distribution vary considerably among different regions of the heart. Additionally, a knowledge gap exists regarding their contribution to SAN automaticity. We hypothesize that Ca2+-activated AC isoforms play important regulatory roles in SAN automaticity. To determine regional distribution of AC isoforms in the heart, single-cell RT-PCR was performed. Global knockout (KO) of AC isoforms and WT C57Bl/6 mice were utilized to assess the role of AC in the SAN at basal and after β-AR stimulation with isoproterenol (ISO). Cardiac structure and function were assessed by echocardiography as well as hemodynamic measurements. Ambulatory electrocardiography was used to determine in vivo SAN function during basal condition, after β-AR stimulation, and after autonomic nervous system blockade. Pacemaker and Ca2+ currents, as well as local Ca2+ release, were performed in isolated SAN cells using conventional patch-clamp techniques and confocal microscopy. cAMP biosensors were used to directly evaluate compartmentalization of the different isoforms. Indeed, we found distinct regulation of SAN automaticity by different isoforms of ACs. Differential compartmentalization of AC isoforms with the Ca2+vs. membrane clocks further validated these findings. Localization and contribution to SAN automaticity vary with different isoforms of ACs due to their distinct compartmentalization with the Ca2+vs. membrane clocks. The findings have broad therapeutic ramifications. Embedded in these findings are novel insights that can be exploited in developing successful therapeutics for SAN dysfunction.

Chronic Naltrexone Therapy Is Associated with Improved Cardiac Function in Volume Overloaded Rats

PurposeMyocardial opioid receptors were demonstrated in animals and humans and seem to colocalize with membranous and sarcolemmal calcium channels of the excitation–contraction coupling in the left ventricle (LV). Therefore, this study investigated whether blockade of the cardiac opioid system by naltrexone would affect cardiac function and neurohumoral parameters in Wistar rats with volume overload-induced heart failure.MethodsVolume overload in Wistar rats was induced by an aortocaval fistula (ACF). Left ventricular cardiac opioid receptors were identified by immunohistochemistry and their messenger ribonucleic acid (mRNA) as well as their endogenous ligand mRNA quantified by real-time polymerase chain reaction (RT-PCR). Following continuous delivery of either the opioid receptor antagonist naltrexone or vehicle via minipumps (n = 5 rats each), hemodynamic and humoral parameters were assessed 28 days after ACF induction. Sham-operated animals served as controls.ResultsIn ACF rats mu-, delta-, and kappa-opioid receptors colocalized with voltage-gated L-type Ca2+ channels in left ventricular cardiomyocytes. Chronic naltrexone treatment of ACF rats reduced central venous pressure (CVP) and left ventricular end-diastolic pressure (LVEDP), and improved systolic and diastolic left ventricular functions. Concomitantly, rat brain natriuretic peptide (rBNP-45) and angiotensin-2 plasma concentrations which were elevated during ACF were significantly diminished following naltrexone treatment. In parallel, chronic naltrexone significantly reduced mu-, delta-, and kappa-opioid receptor mRNA, while it increased the endogenous opioid peptide mRNA compared to controls.ConclusionOpioid receptor blockade by naltrexone leads to improved LV function and decreases in rBNP-45 and angiotensin-2 plasma levels. In parallel, naltrexone resulted in opioid receptor mRNA downregulation and an elevated intrinsic tone of endogenous opioid peptides possibly reflecting a potentially cardiodepressant effect of the cardiac opioid system during volume overload.