Atrial Natriuretic Peptide Levels Research Articles

Aldosterone, Hypertension, and Antihypertensive Therapy: Insights From a General Population

ObjectiveTo investigate the relationships among aldosterone level, use of antihypertensive (anti-HTN) medications, clinical profile, and atrial natriuretic peptide (ANP) level in individuals with HTN. Participants and MethodsIn a community-based cohort, we analyzed aldosterone plasma levels based on the presence (n=477) or absence (n=1073) of HTN. In individuals with HTN, we evaluated circulating aldosterone levels according to the number of anti-HTN drugs used, analyzed the associated clinical characteristics, and determined the relationship to the counterregulatory cardiac hormone ANP. Data were collected from August 25, 1997, through September 5, 2000. ResultsParticipants with HTN had higher serum aldosterone levels than those without HTN (6.4 vs 4.1 ng/dL [to convert to pmol/L, multiply by 27.74]; P<.001). When individuals with HTN were stratified according to the number of anti-HTN medications used, the increase in number of medications (0, 1, 2, and ≥3) was associated with higher aldosterone levels (4.8, 6.4, 7.10, and 7.9 ng/dL, respectively; P=.002), worse metabolic profile, and higher prevalence of cardiovascular, renal, and metabolic disease. In participants with HTN, ANP plasma levels were inversely related to aldosterone levels when the latter was divided into tertiles. ConclusionIn this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

An Acute Bout of Aquatic Treadmill Exercise Induces Greater Improvements in Endothelial Function and Postexercise Hypotension Than Land Treadmill Exercise: A Crossover Study.

The purpose of the study was to compare acute bouts of aquatic treadmill (ATM) and land treadmill (LTM) exercise on flow-mediated dilation, postexercise blood pressure, plasma nitrate/nitrite, and atrial natriuretic peptide in untrained, prehypertensive men. In a counterbalanced, crossover design, 19 untrained, prehypertensive men completed bouts of ATM and LTM on separate days. Flow-mediated dilation was measured pre-exercise and 1-hr postexercise. Blood samples were obtained pre-exercise and immediately postexercise and analyzed for plasma nitrate/nitrite and atrial natriuretic peptide. A magnitude-based inference approach to inference was used for statistical analysis. A possible clinically beneficial increase in flow-mediated dilation (1.2%, 90% confidence interval = -0.07% to 2.5%) was observed 1 hr after ATM. In contrast, a possible clinically harmful decrease in flow-mediated dilation (-1.3%, 90% confidence interval = -2.7% to 0.2%) was observed 1 hr after LTM. The magnitude of the postexercise systolic blood pressure reduction was greater after ATM (-4.9, SD = 2.9 mm Hg) than LTM (-2.6, SD = 2.5 mm Hg). Atrial natriuretic peptide increased 34.3 (SD = 47.0%) after ATM and decreased -9.0 (SD = 40.0%) after LTM. An acute bout of ATM induced a more favorable endothelial response and greater postexercise hypotensive response than LTM. These changes were associated with increased atrial natriuretic peptide levels after ATM.

Mechanistic implication of decreased plasma atrial natriuretic peptide level for transient rise in the atrial capture threshold early after ICD or CRT-D implantation.

Despite the use of steroid-eluting leads, a transient but not persistent rise in the atrial/ventricular capture threshold (TRACT/TRVCT) can occur early after pacemaker implantation in patients with sick sinus syndrome. This study aimed to assess the prevalence, predictors, and mechanisms of TRACT/TRVCT in patients with heart failure undergoing implantable cardioverter defibrillator (ICD) or cardiac resynchronization therapy (CRT) implantation. One hundred twenty consecutive patients underwent ICD (N = 70) or CRT (N = 50) implantation. Capture threshold was measured at implantation, 7-day, 1-month, and 6-month post-implantation. TRACT/TRVCT was defined as a threshold rise at 7days by more than twice the height of the threshold at implantation, with full recovery during follow-up. Atrial and brain natriuretic peptide (ANP and BNP) levels were measured before implantation. TRACT and TRVCT were observed in 13 (11%) and 10 (8%) patients, respectively. Patients with TRACT had lower ANP level (median 72 [42-105] vs. 99 [49-198] pg/mL, P = 0.06), lower ANP/BNP ratio (0.29 [0.20-0.36] vs. 0.50 [0.33-0.70], P < 0.01), lower atrial sensing amplitude (2.0 ± 0.8 vs. 2.7 ± 1.3mV, P = 0.02), and lower left ventricular ejection fraction (32 ± 12 vs. 40 ± 14%, P = 0.04) than those without TRACT. TRACT recovered within 1month, whereas TRVCT recovered within 6months. In multivariable analysis, ANP/BNP ratio was the only independent predictor of TRACT (OR, 0.018; 95% CI, 0.001-0.734; P = 0.034). Atrial degenerative change characterized by lower ANP/BNP ratio was associated with the occurrence of TRACT in patients with heart failure. TRVCT could also occur, but it required a longer recovery time than TRACT.

Alamandine Protects the Heart Against Reperfusion Injury via the MrgD Receptor.

Alamandine differs from angiotensin-(1-7) in a single N-terminal alanine residue. The aim of this study was to investigate whether alamandine protects the heart against reperfusion injury. Methods and Results: After euthanizing Sprague-Dawley rats, hearts were perfused with Krebs-Henseleit buffer for a 20-min pre-ischemic period with or without alamandine, followed by 20 min global ischemia and 50 min reperfusion. Alamandine (0.1 mg/kg) improved the postischemic left ventricular developed pressure and ±dP/dt, decreased the infarct size, and decreased the lactate dehydrogenase levels in the effluent. Alamandine increased the coronary flow and the amount of atrial natriuretic peptide (ANP) in the coronary effluent, and it decreased the expression of apoptotic proteins and increased the expression of antioxidative proteins. Pretreatment with the MrgD receptor antagonist or PD123319, but not the angiotensin type 1 receptor antagonist, attenuated the cardioprotective effects of alamandine. A similar cardioprotective effect with alamandine was also observed with high plasma ANP levels in an in vivo study. Alamandine directly stimulated ANP secretion from isolated atria, which was completely blocked by pretreatment with the MrgD receptor antagonist and was partially blocked by PD123319. These results suggest that the cardioprotective effects of alamandine against I/R injury are, in part, related to the activation of antioxidant and antiapoptotic enzymes via the MrgD receptor.

Association of arginine vasopressin with low atrial natriuretic peptide levels, left ventricular remodelling, and outcomes in adults with and without heart failure.

AimsThe arginine vasopressin (AVP) pathway has been extensively studied in heart failure (HF) with reduced ejection fraction (HFrEF), but less is known about AVP in HF with preserved EF (HFpEF). Furthermore, the association between AVP and atrial natriuretic peptide (ANP, a well‐known inhibitor of AVP secretion) in HF is unknown.Methods and resultsWe studied subjects with HFpEF (n = 28) and HFrEF (n = 25) and without HF (n = 71). Left ventricular (LV) mass and left atrial (LA) volumes were measured with cardiac magnetic resonance imaging. Arginine vasopressin and ANP were measured with enzyme‐linked immunosorbent assay. Arginine vasopressin levels were significantly greater in HFpEF [0.96 pg/mL; 95% confidence interval (CI) = 0.83–1.1 pg/mL] compared with subjects without HF (0.69 pg/mL; 95% CI = 0.6–0.77 pg/mL; P = 0.0002). Heart failure with preserved ejection fraction (but not HFrEF) was a significant predictor of higher AVP after adjustment for potential confounders. Arginine vasopressin levels were independently associated with a greater LA volume and also paradoxically, with lower ANP levels. Key independent correlates of higher AVP were the presence of HFpEF (standardized β = 0.32; 95% CI = 0.09–0.56; P = 0.0073) and the ANP/LA volume ratio (standardized β = −0.23; 95% CI = −0.42 to −0.04; P = 0.0196). Arginine vasopressin levels were independently associated with LV mass (β = 0.26; 95% CI = 0.09–0.43; P = 0.003) and with an increased risk of death or HF admissions during follow‐up (hazard ratio = 1.61; 95% CI = 1.13–2.29; P = 0.008).ConclusionsArginine vasopressin is increased in HFpEF and is associated with LV hypertrophy and poor outcomes. Higher AVP is associated with the combination of LA enlargement and paradoxically low ANP levels. These findings may indicate that a relative deficiency of ANP (an inhibitor of AVP secretion) in the setting of chronically increased LA pressure may contribute to AVP excess.

Atrial natriuretic peptide and posterior pituitary neurohormone changes in patients with acute schizophrenia.

ObjectivesInteractions between neuropeptides and psychiatric disorders have been investigated for many years. The aim of this study was to evaluate oxytocin (OXT), arginine-vasopressin (AVP), and atrial natriuretic peptide (ANP) and assess their interactions with each other, as well as investigate these changes with the manifestations of schizophrenia.Participants and methodsThirty-four individuals having acute schizophrenia and 24 healthy individuals as the control group were included in the study. Positive and Negative Syndrome Scales, Global Assessment of Functionality score, and Clinical Global Impression (CGI) scores were measured. Serum hormone levels were analyzed using enzyme-linked immunosorbent assay and were compared with the clinical findings.ResultsOXT levels were significantly lower and AVP levels were significantly higher in patients having acute schizophrenia than the control group. OXT was negatively correlated with Positive and Negative Syndrome Scales positive score and CGI score, while it was positively correlated with Global Assessment of Functionality score. AVP was negatively correlated with CGI score. ANP levels of the patients having schizophrenia were lower than the control group; however, there was no significant correlation with clinical findings.ConclusionThe obtained data indicate that the AVP level was higher, but OXT and ANP levels were lower in the patients having acute schizophrenia. Specifically OXT is related with reduced disease severity and increased functionality.

Diagnostic accuracy of plasma atrial natriuretic peptide concentrations in cats with and without cardiomyopathies

ObjectivesPlasma atrial natriuretic peptide (ANP) levels have been reported to be elevated in cats with cardiomyopathy. We investigated the diagnostic accuracy of plasma ANP concentration as an indicator of the severity of cardiomyopathies. AnimalsThis study included 78 control cats and 83 cats with various types of cardiomyopathy. MethodsThis was a prospective multicentre study. Control cats were determined to have a normal heart, and diseased cats were diagnosed by echocardiography. Diseased cats were divided into asymptomatic cats without left atrial dilation (LAD), asymptomatic cats with LAD, and cats with heart failure. Plasma C-terminal ANP concentrations were measured using chemiluminescence. ResultsThe median plasma ANP concentration in controls was 43.3 (interquartile range, 33.0–56.3) pg/mL. Plasma ANP values were significantly higher in the cardiomyopathic cats with LAD and heart failure, but the values in cats without LAD were comparable to those in control cats. To distinguish cats with cardiomyopathy from controls, a plasma ANP concentration >77.5 pg/mL afforded sensitivity of 66.3% and specificity of 84.6%. Use of plasma ANP concentration >110.9 pg/mL to identify cats with LAD had a sensitivity of 73.6% and specificity of 93.5%. The areas under the receiver-operating characteristic curve were 0.80 and 0.86. ConclusionsPlasma ANP concentrations were higher in cats with more advanced cardiomyopathy. Although assaying the ANP concentration alone may not help to diagnose cardiac disease, measuring provides additional information that is useful for assessing the severity of cardiomyopathies.

Serum atrial natriuretic peptide levels among clomiphene citrate resistant polycystic ovarian syndrome patients

Abstract Aim To investigate whether atrial natriuretic peptide (ANP) level is altered in polycystic ovarian syndrome (PCOS) patients with clomiphene citrate (CC) resistant and whether it correlates with insulin sensitivity markers. Methods Serum ANP, insulin and glucose levels and the homeostasis model assessment for insulin resistance index (HOMA-IR) were evaluated among a group of PCOS women with CC resistance (n = 40). A control group (n = 30) was selected from healthy women with regular menstrual cycles. Results Serum ANP level was significantly lower in the study group than in the control group (0.74 ± 1.1 ng/ml vs 3.17 ± 1.9 ng/ml; P Conclusion The PCOS patients with CC resistant have reduced plasma ANP level and increases HOMA-IR index compared with healthy regular menstruating women. Low serum ANP level may be involved in the metabolic features of CC resistant PCOS.

Intermittent versus constant aerobic exercise in middle-aged males: acute effects on arterial stiffness and factors influencing the changes.

Both constant and intermittent acute aerobic exercises have been found to decrease arterial stiffness. However, direct comparisons of these two types of exercise are sparse. It is not known which type of exercise has the greatest effect. We evaluated the haemodynamic responses in 15 males (age 48.5 ± 1.3 years; BMI 27.5 ± 0.8kgm-2) following acute constant (CE) and intermittent cycling exercise (IE). Duration and heart rate were matched during both exercises (131.8 ± 3.2bpm for CE and 132.0 ± 3.1bpm for IE). Central and peripheral arterial stiffness was assessed through pulse wave velocity (PWV). Plasma concentrations of nitric oxide (NO), atrial natriuretic peptide (ANP), blood lactate, noradrenaline, and adrenaline were measured before and after each exercise. Central (+ 1.8 ± 7.4 and - 6.5 ± 6.8% for CE and IE) and upper limb PWV (+ 2.7 ± 6.2 and - 8 ± 4.6% for CE and IE) were not significantly altered although a small decrease (small effect size) was observed after IE. However, lower limb PWV significantly decreased after exercises (- 7.3 ± 5.7 and - 15.9 ± 4% after CE and IE), with a larger effect after IE. Greater decrease in lower limb PWV occurred after IE despite greater heart rate. This may be due to the higher blood levels of lactate during IE, while NO, ANP, noradrenaline, and adrenaline levels remained not statistically different from CE. These results underlined the importance of lactate in triggering the post-exercise vascular response to exercise, as well as its regional characteristic.

Long noncoding RNA myocardial infarction‑associated transcript is associated with the microRNA‑150‑5p/P300 pathway in cardiac hypertrophy.

In numerous diseases, abnormal expression of myocardial infarction-associated transcript (MIAT) has been reported to be involved in cell proliferation, apoptosis and migration. However, whether this long non-coding RNA MIAT has a regulatory effect on heart hypertrophy requires further investigation. To this end, the present study evaluated MIAT in hypertrophic cardiomyocytes in vitro and in vivo. Neonatal rat ventricular myocytes (NRVMs) were induced by isoproterenol (ISO) to create a cell hypertrophy model, and mice were intraperitoneally injected with ISO to establish an animal model. Echocardiography, immunofluorescence staining, western blot analysis, RNA isolation and reverse transcription-polymerase chain reaction were applied to test the involvement of MIAT in cardiac hypertrophy. The results revealed that MIAT was upregulated under ISO stimulation at the mRNA level both in vivo and in vitro. Silencing of MIAT resulted in decreased expression levels of atrial natriuretic peptide and brain natriuretic peptide in ISO-treated NRVM cardiomyocytes, confirming the connection between MIAT and hypertrophy. Furthermore, MIAT small interfering RNA significantly increased microRNA (miR)-150 and decreased P300 expression in NRVMs. In conclusion, the MIAT/miR-150-5p axis targets P300 as a positive regulator of cardiomyocyte hypertrophy.

Alamandine attenuates hypertension and cardiac hypertrophy in hypertensive rats

Oral administration of the peptide alamandine has antihypertensive and anti-fibrotic effects in rats. This work aimed to determine whether subcutaneous alamandine injection would attenuate hypertension and cardiac hypertrophy, and improve the function of a major target of hypertension-related damage, the left ventricle (LV), in spontaneously hypertensive rats (SHRs). This was examined in vivo in SHRs and normotensive rats subjected to 6-week subcutaneous infusion of alamandine or saline control, and in vitro in H9C2-derived and primary neonatal rat cardiomyocytes treated with angiotensin (Ang) II to model cardiac hypertrophy. Tail artery blood pressure measurement and transthoracic echocardiography showed that hypertension and impaired LV function in SHRs were ameliorated upon alamandine infusion. Alamandine administration also decreased the mass gains of heart and lung in SHRs, suppressed cardiomyocyte cross-sectional area expansion, and inhibited the mRNA levels of atrial natriuretic peptide and brain natriuretic peptide. The expression of alamandine receptor Mas-related G protein-coupled receptor, member D was increased in SHR hearts and in cardiomyocytes treated with Ang II. Alamandine inhibited the increases of protein kinase A (PKA) levels in the heart in SHRs and in cardiomyocytes treated with Ang II. In conclusion, the present study showed that alamandine administration attenuates hypertension, alleviates cardiac hypertrophy, and improves LV function. PKA signaling may be involved in the mechanisms underlying these effects.

Ambulatory Blood Pressure Lower Following Aquatic Exercise than Land Treadmill Exercise

Blood pressure (BP) is an important marker of cardiovascular (CV) health. Aquatic (AQ) exercise training has been shown to reduce BP reactivity to exercise to a greater degree than land treadmill (LT) training. Furthermore, an acute bout of AQ exercise tended to elicit a greater post-exercise hypotensive response and augmentation in flow-mediated dilation (FMD). However, it is unclear how long the post-exercise hypotensive benefits last following an acute bout of AQ exercise. PURPOSE: To determine the effects of acute bouts of deep water aqua-jogging and land treadmill exercise on daytime ambulatory BP (AMBP) in pre-hypertensive, physically untrained men and women. METHODS: Following resting BP screening, 12 subjects (9 male, 29 ± 13 years, 30.4 ± 6.1 kg·m-2, 127 ± 8/ 82 ± 8 mmHg) completed acute bouts of both AQ and LT exercise at 55% heart rate reserve for a duration of 30 minutes. Exercise sessions began at 0700 hours. Immediately following the exercise bout, subjects wore an AMBP device (Oscar 2, Suntech Medical), which was programmed to take measurements every 15 minutes throughout the day until 1600 hours. Sessions occurred on separate days with 2-7 days off between sessions. The order that the modes were performed was counterbalanced among the subjects. Subjects were required to abstain from alcohol, caffeine, nicotine, and exercise on the day of the session and 24 hours prior. Comparisons between modes were made by a dependent sample t-test. RESULTS: All results are displayed in Table 1. CONCLUSION: Daytime AMBP was significantly lower following AQ than LT exercise. This is consistent with previous findings of a greater post-exercise hypotensive response in the 1-2 hours post AQ exercise. Previous research also demonstrated improved FMD and increased atrial natriuretic peptide levels following AQ exercise, which could potentially explain the reduced BP findings. These data further support the efficacy of AQ exercise for the promotion of CV health and BP regulation.Table 1: Ambulatory Blood Pressure Response

Long non-coding RNA CHRF facilitates cardiac hypertrophy through regulating Akt3 via miR-93.

Non-coding RNAs, including long non-coding RNAs (lncRNAs) and microRNAs (miRNAs), have been demonstrated as central mediators in cardiac hypertrophy responses. LncRNA cardiac hypertrophy related factor (CHRF) has been reported to be implicated in cardiac hypertrophy. However, the underlying mechanisms of CHRF have not been thoroughly elucidated. Expressions of CHRF and microRNA-93 (miR-93) in heart tissues and cardiomyocytes were detected by RT-qPCR assay. Cell surface area, protein/DNA ratio, atrial natriuretic peptide (ANP) and β-myosin heavy chain (β-MHC) levels were examined as the indicators of cardiac hypertrophy responses. Luciferase reporter assay was used to validate the direct binding between miR-93 and CHRF or Akt3 3'UTR. RIP assay was performed to demonstrate the potential interaction between CHRF and miR-93. Akt3 protein level was determined by western blot assay. CHRF expression was up-regulated and miR-93 expression was down-regulated in mice and cellular models of cardiac hypertrophy. CHRF knockdown attenuated isoproterenol (Iso)-induced hypertrophy responses through up-regulating miR-93 expression in cardiomyocytes. Moreover, CHRF acted as a competing endogenous RNA of miR-93 to sequester miR-93 from Akt3, resulting in the increase of Akt3 expression. Furthermore, miR-93 suppressed cardiac hypertrophy responses by targeting Akt3 in Iso-stimulated cardiomyocytes. CHRF induced cardiac hypertrophy by regulating miR-93/Akt3 axis in Iso-stimulated cardiomyocytes, deepening our understanding of the molecular mechanisms of lncRNAs in cardiac hypertrophy and providing a potential therapy target for cardiac hypertrophy.

The role of mitofilin in left ventricular hypertrophy in hemodialysis patients

Left ventricular hypertrophy (LVH) is a common abnormality in hemodialysis (HD) patients. Mitochondrial dysfunction contributes to the progression of LVH. As an inner mitochondrial membrane structural protein, mitofilin plays a key role in maintaining mitochondrial structure and function. The aim of this study was to investigate the relationship between mitofilin and LVH in HD patients. A total of 98 HD patients and 32 healthy controls were included in the study. Serum N-terminal proBNP (NT-proBNP), endothelin-1 (ET-1), and atrial natriuretic peptide (ANP) were examined. The protein level of mitofilin and the mitochondrial DNA (mtDNA) copy number were estimated in peripheral blood mononuclear cells (PBMCs). The left ventricle mass index (LVMI) was evaluated in all participants, and the interaction between these variables and the LVMI was assessed. The LVMI was positively correlated with the NT-proBNP, ET-1, and ANP levels, and it was negatively correlated with mtDNA copy number and mitofilin levels. Multiple regression analysis showed that the NT-proBNP, ET-1, and ANP levels as well as mitofilin levels and mtDNA copy number were associated with the LVMI. Although further research of these associations is needed, this result suggests that LVH may affect the levels of mitofilin in HD patients.

Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice

Pathological cardiac hypertrophy is associated with the accumulation of lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein in the heart. These aldehydes are metabolized via several pathways, of which aldose reductase (AR) represents a broad-specificity route for their elimination. We tested the hypothesis that by preventing aldehyde removal, AR deficiency accentuates the pathological effects of transverse aortic constriction (TAC). We found that the levels of AR in the heart were increased in mice subjected to TAC for 2 weeks. In comparison with wild-type (WT), AR-null mice showed lower ejection fraction, which was exacerbated 2 weeks after TAC. Levels of atrial natriuretic peptide and myosin heavy chain were higher in AR-null than in WT TAC hearts. Deficiency of AR decreased urinary levels of the acrolein metabolite, 3-hydroxypropylmercapturic acid. Deletion of AR did not affect the levels of the other aldehyde-metabolizing enzyme - aldehyde dehydrogenase 2 in the heart, or its urinary product - (N-Acetyl-S-(2-carboxyethyl)-l-cystiene). AR-null hearts subjected to TAC showed increased accumulation of HNE- and acrolein-modified proteins, as well as increased AMPK phosphorylation and autophagy. Superfusion with HNE led to a greater increase in p62, LC3II formation, and GFP-LC3-II punctae formation in AR-null than WT cardiac myocytes. Pharmacological inactivation of JNK decreased HNE-induced autophagy in AR-null cardiac myocytes. Collectively, these results suggest that during hypertrophy the accumulation of lipid peroxidation derived aldehydes promotes pathological remodeling via excessive autophagy, and that metabolic detoxification of these aldehydes by AR may be essential for maintaining cardiac function during early stages of pressure overload.

Deficiency of Prostaglandin E2 Receptor Subtype 4 Exacerbates Left Ventricular Remodeling and Myocardial Fibrosis in Diet‐induced Mice

Left ventricular (LV) remodeling is closely associated with the development of congestive heart failure. Obese populations have a high prevalence to promote LV remodeling, however the mechanism remains unexplored. Although prostaglandin E2 receptor subtype 4 (EP4) affects cardiac function, no available information focuses on its role in LV remodeling. The aim of this study was to investigate the role of EP4 in LV remodeling under high‐fat condition. Six‐week old male EP4 wildtype and knockout mice were fed with standard chow or high‐fat diet (HFD, 20% protein, 60% fat and 20% carbohydrate) for eight weeks. The effects of EP4 deficiency on cardiac function, cardiomyocytes remodeling and myocardial fibrosis in mice were studied. The possible regulatory mechanisms were further investigated. Echocardiography showed that there is no differ in cardiac function in EP4 wildtype and knockout mice under normal diet feeding. Heart from HFD‐fed EP4 knockout mice had a 54% increase in relative wall thickness and a 38.1% reduction in LV diastolic volume, but preserved LV mass as compared to that from wild type littermates, suggesting EP4 knockout mice were having worse LV concentric remodeling under high‐fat feeding. HFD fed‐EP4 knockout mice also developed cardiac hypertrophy, as showed by an increased ratio of heart‐to‐body weight and an enlarged cardiomyocytes size. Such conclusion was further reinforced by studies where EP4 deficiency elevated mRNA expression of cardiac hypertrophy markers, atrial natriuretic peptide (ANP) (by 68.8%) and brain natriuretic peptide (BNP) (by 241.7%). The absence of EP4 also induced severe myocardial fibrosis, as showed by elevated mRNA expression of collagen synthetic genes (collagen I, collagen III, transforming growth factor beta 1) and suppressed degradation of matrix collagen genes (matrix metalloproteinase‐2, decorin). Such results were confirmed by staining collagen in cardiac tissue and there was an increased collagen content in EP4 knockout mice. The phosphorylation of extracellular signal‐regulated kinase 1/2 (ERK1/2), a protein that promotes concentric remodeling and hypertrophy, was increased in cardiac tissue of high‐fat treated EP4 knockout mice. Lastly, in high‐glucose treated rat origin cardiomyocytes (H9C2), treatment with EP4 antagonist (L161,982) increased gene level of ANP, BNP, collagen I and collagen III, and protein presence of ERK1/2, while such increase was reversed with ERK inhibitors U0126 and PD98059 pretreatment. In summary, EP4 deficiency induced LV concentric remodeling, cardiomyocyte hypertrophy and myocardial fibrosis, which may be through activated ERK1/2 signaling. These findings collectively showed that EP4 plays an essential role in regulation of LV remodeling and myocardial fibrosis through ERK1/2 signaling axis under high‐fat condition.Support or Funding InformationThis work is supported by Health and Medical Research Fund (HMRF) Project Code: 04151816.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Serum nitric oxide level correlates with serum brain natriuretic peptide and whole blood viscosity in hemodialysis patients

BackgroundNitric oxide (NO) is tonically synthesized by the vascular endothelium and known as a marker of vasodilatation and blood flow. As NO has a critical role in hemodynamics, NO may be associated with other hemodynamics-related factors including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP) and whole blood viscosity (WBV). It has been reported that serum NO level increased in patients undergoing hemodialysis. However, there are few reports about the relationship between NO and hemodynamic parameters in hemodialysis patients. ObjectiveWe investigated the associations between serum levels of NO and other hemodynamics-related factors such as ANP, BNP and WBV in patients with hemodialysis. MethodsNO, ANP, and BNP levels before hemodialysis were measured using ELISA method. We measured WBV in pre- and post-dialysis. ResultsMean serum levels of NO, ANP, and BNP were 13.97 ± 10.34 μg/mL, 198.85 ± 61.56 pg/mL, and 1233.32 ± 280.81 pg/mL, respectively in patients with hemodialysis. The mean WBV values at shear rates of 1, 5, and 300 s−1 for pre-dialyses were 168.5 ± 62.5, 76.9 ± 20.6, and 33.3 ± 3.8 mP, respectively. Serum NO level was positively correlated with WBV at shear rates of 1, 5, and 300 s−1 at pre- and post-hemodialysis. There is a correlation between serum nitrite levels and the change of SBV during hemodialysis. Serum nitrite levels correlated with the serum BNP levels. ANP levels have a negative correlation with pre-dialytic WBV. However, BNP levels did not correlate with WBV during hemodialysis. ConclusionsWBV is linked to an imbalance in serum vasoactive substances in hemodialysis patients and can cause significant hemodynamic disturbance.

Genetic ablation of TRPV1 exacerbates pressure overload-induced cardiac hypertrophy

Transient receptor potential vanilloid 1 (TRPV1) channels expressed in sensory nerves may regulate vascular tone and cardiovascular function via their anti-inflammatory effects by releasing neuropeptide calcitonin gene-related peptide (CGRP). Inflammation plays a role in the progression of cardiac hypertrophy and TRPV1 activation may be key to cardiac inflammatory processes. The aim of this study was to test the hypothesis that TRPV1 modulates inflammatory processes to protect the heart from pressure overload-induced hypertrophy and inflammatory responses. Trpv1 knockout (Trpv1−/−) and wild-type (WT) mice were subjected to transverse aortic constriction (TAC) or sham operation. Four weeks after TAC, WT and Trpv1-/- mice had developed left ventricular (LV) hypertrophy with increased LV mass, fibrosis and infiltration of macrophages as well as increased secretion of tumor necrosis factor α, interleukin-6 from cardiac tissue (all P < 0.05), those were higher in Trpv1-/- than in WT mice with TAC (all P < 0.05). In addition, decreases of LV ejection fraction and fractional shortening were greater in Trpv1-/- than in WT mice (both P < 0.05). Moreover, atrial natriuretic peptide level was greater in Trpv1-/- than in WT mice with TAC (P < 0.05). Compared to sham control, TAC procedure significantly increased cardiac TRPV1 expression and CGRP release in WT mice (both P < 0.05), but not in Trpv1-/- mice. These results demonstrate that Trpv1 gene deletion results in excessive inflammation, exaggerates cardiac hypertrophy, and deteriorates cardiac function after TAC, which may be due to abnormal cardiac remodeling and decreased CGRP in the absence of TRPV1.

Neprilysin inhibition and endothelin-1 elevation: Focus on the kidney

Increasing the degree of renin-angiotensin system (RAS) blockade by combining ≥2 RAS blockers marginally increases efficacy, but results in more side effects. Hence, interference with other systems is currently being investigated, like potentiation of natriuretic peptides with neprilysin inhibitors. However, the neprilysin inhibitor thiorphan was recently found to increase endothelin-1 when administered to TGR(mREN2)27 (Ren2) rats on top of RAS blockade. Here we investigated whether this effect is thiorphan-specific, by comparing the neprilysin inhibitors thiorphan and sacubitril, administered by osmotic minipumps at a low or high dose for 7 days, in Ren2 rats. Plasma and urinary levels of endothelin-1, atrial and brain natriuretic peptide (ANP, BNP) and their second messenger cyclic guanosine 3′5′ monophosphate (cGMP) were monitored. No significant differences were found in the plasma concentrations of endothelin-1, cGMP, ANP and BNP after treatment, although plasma ANP tended to be higher in the high-dose thiorphan treatment group and the low- and high-dose sacubitril treatment groups, compared with vehicle. Urinary endothelin-1 increased in the low-dose thiorphan and high-dose sacubitril groups, compared with baseline, although significance was reached for the former only. Urinary cGMP rose significantly in the high-dose sacubitril treatment group compared with baseline. Both urinary endothelin-1 and cGMP were significantly higher in the high-dose sacubitril group compared with the low-dose sacubitril group. In conclusion, endothelin-1 upregulation occurs with both thiorphan and sacubitril, and is particularly apparent in neprilysin-rich organs like the kidney. High renal neprilysin levels most likely also explain why sacubitril increased cGMP in urine only.

Protective effect of Dendrobium candidum on isoproterenol induced cardiac hypertrophy in rats

To study the effect and mechanism of Dendrobium candidum on isoproterenol-induced myocardial hypertrophy in rats, 60 healthy SD rats(30 males and 30 females) were randomly divided into 5 groups(12 in each group): normal group, model group, three D. candidum preventive administration groups(0.09, 0.18, 1.1 g·kg⁻¹). Except for the normal group, rats of other groups were injected back subcutaneously with ISO(5 mg·kg⁻¹) for 10 consecutive days. At the same time, preventive administration groups began to give different doses of the sample for 30 days and model group began to give normal saline. Left ventricular systolic pressure(LVSP) was measured in each group by common carotid artery cannulation, and the left ventricle(LW)/tibia length, heart weight index(HWI) and myocardial hydroxyproline(Hydro) content were calculated. Myocardial tissue HE staining and Masson staining were used to observe the myocardial structure and the degree of myocardial fibrosis respectively. Atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP), and cardiac troponin I(cTN-I) concentration were measured by enzyme-linked immunosorbent assay(ELISA). The results showed that as compared with the normal group, the levels of ANP, BNP and cTN-I in plasma were significantly increased in ISO-induced hypertrophic rats; as compared with the model group, D. candidumcan inhibit ISO-induced ventricular pressure and ventricular hypertrophy, reduce myocardial collagen synthesis, improve myocardial fibrosis and ventricular remodeling, and significantly down-regulate ANP, BNP and cTN-I levels in plasma. This study shows that D. candidum has a protective effect on isoproterenol-induced cardiac hypertrophy.