Atrial natriuretic peptide in the prevention of acute renal dysfunction after heart transplantation-a randomized placebo-controlled double-blind trial.

BACKGROUND: Acute kidney injury (AKI) and renal dysfunction after heart transplantation are common and serious complications. Atrial natriuretic peptide (ANP) has been shown to increase glomerular filtration rate (GFR) and exert renoprotective effects when used for the prevention/treatment of AKI in cardiac surgery. We tested the hypothesis that intraoperative and postoperative administration of ANP could prevent a postoperative decrease in renal function early after heart transplantation. METHODS: Seventy patients were randomized to receive either ANP (50 ng/kg/min) (n = 33) or placebo (n = 37) starting after induction of anesthesia and continued for 4 days after heart transplantation or until treatment with dialysis was started. The primary end-point of the present study was measured GFR (mGFR) at day 4, assessed by plasma clearance of a renal filtration marker. Also, the incidence of postoperative AKI and dialysis were assessed. RESULTS: Median (IQR) mGFR at day 4 postoperatively was 60.0 (57.0) and 50.1 (36.3) ml/min/1.72 m2 for the placebo and ANP groups, respectively (p = .705). During ongoing ANP infusion, the need for dialysis was 21.6% and 9.1% for the placebo and ANP groups, respectively (p = .197). The incidences of AKI for the placebo and the ANP groups were 76.5% and 63.6%, respectively (p = .616). The incidences of AKI stage 1 were 32.4% and 21.2% for the placebo and ANP groups, respectively (p = .420) and for AKI stage 2 or 3, 37.8% and 42.4%, respectively (p = .808). CONCLUSION: The study failed to detect that ANP infusion attenuates renal dysfunction or decreases the incidence of AKI after heart transplantation.

Targeting and Modulation of the Natriuretic Peptide System in Covid-19: A Single or Double-Edged Effect?

Natriuretic peptide system (NPS) is a group of peptide hormones or paracrine factors, including atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and natriuretic peptide precursor C (NPC), that are structurally related. The physiological effects of NPS include natriuresis, increased glomerular filtration rate, inhibition release of renin, vasopressin, and aldosterone, sympathetic inhibition, vasodilatations, and prevents cardiac hypertrophy and remodeling. ANP has immunological effects, as it is produced locally from immune cells; it regulates innate and adaptive immune responses. Metabolism and degradation of ANP are achieved by neutral endopeptidase (NEP), also known as neprilysin. Coronavirus disease 2019 (Covid-19) pandemic may lead to acute lung injury (ALI) and/or respiratory distress syndrome (ARDS). The underlying causes of inflammatory and immunological disorders in patients with severe Covid-19 are connected to the immune over-stimulation with the subsequent release of pro-inflammatory cytokines. Covid-19 severity is linked with high ANP serum levels regardless of acute cardiac injury. Inflammatory stimuli appear to be linked with the release of NPs, which anti-inflammatory effects prevent the development of ALI/ARDS in Covid-19. Therefore, neprilysin inhibitors like sacubitril increase endogenous NPs and may reduce the risk of ALI in Covid-19 due to the potentiation of endogenous anti-inflammatory effects of NPs. However, sacubitril increases gastrin-releasing peptide, cathepsin G and release of pro-inflammatory cytokines that are inactivated by neprilysin. In conclusion, NPs and neprilysin have cardio-pulmonary protective effects against Covid-19-induced ALI/ARDS. Neprilysin inhibitor sacubitril has dual protective and harmful effects regarding metabolizing vasoactive peptides by neprilysin. These findings require potential reevaluation of the effect of neprilysin inhibitors in managing Covid-19.

Glipizide Combined with ANP Suppresses Breast Cancer Growth and Metastasis by Inhibiting Angiogenesis through VEGF/VEGFR2 Signaling.

BACKGROUND: Breast cancer is one of the most common cancers worldwide among women, and angiogenesis has an important effect on its growth and metastasis. Glipizide, which is a widely used drug for type 2 diabetes mellitus, has been reported to inhibit tumor growth and metastasis by upregulating the expression of natriuretic peptide receptor A (NPRA). Atrial natriuretic peptide (ANP), the receptor of NPRA, plays an important role in angiogenesis. The purpose of this study was to explore the effect of glipizide combined with ANP on breast cancer growth and metastasis. METHODS: This study aimed at investigating the effect of glipizide combined with ANP on breast cancer. Glipizide, ANP, or glipizide combined with ANP was intraperitoneally injected into MMTV-PyMT mice. To explore whether the anticancer efficacy of glipizide combined with ANP was correlated with angiogenesis, a tube formation assay was performed. RESULTS: Glipizide combined with ANP was found to inhibit breast cancer growth and metastasis in MMTV-PyMT mice, which spontaneously develop breast cancer. Furthermore, the inhibitory effect of ANP combined with glipizide was better than that of glipizide alone. ANP combined with glipizide significantly inhibited tube formation of human umbilical vein endothelial cells (HUVECs) by suppressing vascular endothelial growth factor (VEGF)/VEGFR2 (vascular endothelial growth factor receptor 2) signaling. CONCLUSION: These results demonstrate that glipizide combined with ANP has a greater potential than glipizide alone to be repurposed as an effective agent for the treatment of breast cancer by targeting tumor-induced angiogenesis.

Pharmacological interventions for the prevention of renal injury in surgical patients: a systematic literature review and meta-analysis.

BACKGROUND: The aim of this systematic review was to summarise the results of randomised controlled trials (RCTs) that have evaluated pharmacological interventions for renoprotection in people undergoing surgery. METHODS: Searches were conducted to update a previous review using the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE to August 23, 2019. RCTs evaluating the use of pharmacological interventions for renal protection in the perioperative period were included. The co-primary outcome measures were 30-day mortality and acute kidney injury (AKI). Pooled effect estimates were expressed as risk ratios (RRs) (95% confidence intervals). RESULTS: We included 228 trials enrolling 56 047 patients. Twenty-three trials were considered to be at low risk of bias across all domains. Atrial natriuretic peptides (14 trials; n=2207) reduced 30-day mortality (RR: 0.63 [0.41, 0.97]) and AKI events (RR: 0.43 [0.33, 0.56]) without heterogeneity. These effects were consistent across cardiac surgery and vascular surgery subgroups, and in sensitivity analyses restricted to studies at low risk of bias. Inodilators (13 trials; n=2941) reduced mortality (RR: 0.71 [0.53, 0.94]) and AKI events (RR: 0.65 [0.50, 0.85]) in the primary analysis and in cardiac surgery cohorts. Vasopressors (4 trials; n=1047) reduced AKI (RR: 0.56 [0.36, 0.86]). Nitric oxide donors, alpha-2-agonists, and calcium channel blockers reduced AKI in primary analyses, but not after exclusion of studies at risk of bias. Overall, assessment of the certainty of the effect estimates was low. CONCLUSIONS: There are multiple effective pharmacological renoprotective interventions for people undergoing surgery.

Cytokine storms caused by novel coronavirus 2019 and treatment for cardiac injury.

Since December 2019, an outbreak of a new coronavirus, COVID-19, infection has been taking place. At present, COVID-19 has spread to most countries worldwide. The latest evidence suggests that cytokine storm syndrome (CSS) is an important cause of the transition from mild to critical pneumonia and critically ill patients' death. The sudden exacerbation of COVID-19 may be related to a cytokine storm. Therefore, early identification and active treatment of CSS may play very important roles in improving the patients' prognosis, and these tasks are given attention in the current treatment of new Coronavirus pneumonia. However, there is still no specific medicine for this purpose. This article reviews cytokine storms and conducts an exploratory review of pharmacotherapy for cytokine storms to provide a reference for clinical treatment.

Human atrial natriuretic peptide for acute kidney injury in adult critically ill patients: A multicenter prospective observational study.

PURPOSE: Acute kidney injury (AKI) is common in the intensive care unit (ICU). Selected clinical studies have implied human atrial natriuretic peptide (hANP) improves renal function; however, the treatment effects for AKI are unclear. METHODS: A multicenter prospective observational study in 13 Japanese ICUs. The effects of hANP were estimated by the standardized mortality ratio weighted analyses of generalized linear models using propensity scores. The primary outcome was renal replacement therapy (RRT) or death in the ICU. RESULTS: Of 904 patients with AKI, 63 received hANP as a treatment for AKI. The primary outcome occurred in 20.5% (185/904). HANP did not reduce the risk of RRT or death in the ICU (risk ratio 1.12, 95% confidence interval [CI] 0.74 to 1.69) and was associated with a lower mean arterial pressure (ß -3.8 mmHg, 95%CI -7.6 to -0.1), a longer hospital length of stay (ß 12.0 days, 95%CI 1.2 to 22.8) and a lower eGFR at hospital discharge (ß -10.4 mL/min/m2, 95%CI -19.1 to -1.7). No beneficial effect was observed in subgroups of cardiovascular surgery, sepsis, nor chronic kidney disease. CONCLUSIONS: In critically ill patients with AKI, the treatment effect of hANP was not evident on dialysis-free survival in the ICU.

Molecular mechanisms underlying the neuroprotective role of atrial natriuretic peptide in experimental acute ischemic stroke.

Along with its role in regulating blood pressure and fluid homeostasis, the natriuretic peptide system could be also part of an endogenous protective mechanism against brain damage. We aimed to assess the possibility that exogenous atrial natriuretic peptide (ANP) could protect against acute ischemic stroke, as well as the molecular mechanisms involved. Three groups of rats subjected to transient middle cerebral artery occlusion (tMCAO, intraluminal filament technique, 60 min) received intracerebroventricular vehicle, low-dose ANP (0.5 nmol) or high-dose ANP (2.5 nmol), at 30 min reperfusion. Neurofunctional condition, and brain infarct and edema volumes were measured at 24 h after tMCAO. Apoptotic cell death and expression of natriuretic peptide receptors (NPR-A and NPR-C), K+ channels (KATP, KV and BKCa), and PI3K/Akt and MAPK/ERK1/2 signaling pathways were analyzed. Significant improvement in neurofunctional status, associated to reduction in infarct and edema volumes, was shown in the high-dose ANP group. As to the molecular mechanisms analyzed, high-dose ANP: 1) reduced caspase-3-mediated apoptosis; 2) did not modify the expression of NPR-A and NPR-C, which had been downregulated by the ischemic insult; 3) induced a significant reversion of ischemia-downregulated KATP channel expression; and 4) induced a significant reversion of ischemia-upregulated pERK2/ERK2 expression ratio. In conclusion, ANP exerts a significant protective role in terms of both improvement of neurofunctional status and reduction in infarct volume. Modulation of ANP on some molecular mechanisms involved in ischemia-induced apoptotic cell death (KATP channels and MAPK/ERK1/2 signaling pathway) could account, at least in part, for its beneficial effect. Therefore, ANP should be considered as a potential adjunctive neuroprotective agent improving stroke outcome after successful reperfusion interventions.

New pulmonary hypertension model in conscious dogs to investigate pulmonary-selectivity of acute pharmacological interventions.

PURPOSE: Testing of investigational drugs in animal models is a critical step in drug development. Current models of pulmonary hypertension (PH) have limitations. The most relevant outcome parameters such as pulmonary artery pressure (PAP) are measured invasively which requires anesthesia of the animal. We developed a new canine PH model in which pulmonary vasodilators can be characterized in conscious dogs and lung selectivity can be assessed non-invasively. METHODS: Telemetry devices were implanted to measure relevant hemodynamic parameters in conscious dogs. A hypoxic chamber was constructed in which the animals were placed in a conscious state. By reducing the inspired oxygen fraction (FiO2) to 10%, a hypoxic pulmonary vasoconstriction was induced leading to PH. The PDE-5 inhibitor sildenafil, the current standard of care was compared to atrial natriuretic peptide (ANP). RESULTS: The new hypoxic chamber provided a stable hypoxic atmosphere during all experiments. The mean PAP under normoxic conditions was 15.8 ± 1.8 mmHg. Hypoxia caused a reliable increase in mean PAP (+ 12.2 ± 3.2 mmHg, p < 0.0001). Both, sildenafil (- 6.8 ± 4.4 mmHg) and ANP (- 6.4 ± 3.8 mmHg) significantly (p < 0.05) decreased PAP. Furthermore sildenafil and ANP showed similar effects on systemic hemodynamics. In subsequent studies, the in vitro effects and gene expression pattern of the two pathways were exemplified. CONCLUSIONS: By combining the hypoxic environment with the telemetric approach, we could successfully establish a new acute PH model. Sildenafil and ANP demonstrated equal effects regarding pulmonary selectivity. This non-invasive model could help to rapidly screen pulmonary vasodilators with decreased animal burden.

Valporic acid enhances the Atrial Natriuretic Peptide (ANP) mediated anti-hypertrophic activity by modulating the Npr1 gene transcription in H9c2 cells in vitro.

The present study was aimed to determine whether stimulating Npr1 gene activity using Valporic acid (VA), a small short chain fatty acid molecule can enhance ANP mediated anti-hypertrophic activity in isoproterenol (ISO) - treated H9c2 cells in vitro. H9c2 cells were treated with ISO (10-5 M) and co-treated with VA (10-5 M) in the presence and absence of ANP (10-8M), for 48h. ATRA (10-5 M) was used as a positive inducer of Npr1 gene transcription. The mRNA expression of Npr1 and PKG-I genes, proto-oncogenes (c-fos, c-jun and c-myc) and hypertrophic markers (ANP, BNP, α-sk and ß-MyHC), genes were determined by quantitative PCR (qPCR). The protein profiling of NPR-A, PKG-I and cGMP were evaluated by Western blot, immunofluorescence and ELISA respectively. A marked reduction in the level of expression of Npr1 (3- fold) and PKG-I (2.5-fold) genes and increased expression of proto-oncogenes (p< 0.001, respectively) and hypertrophic marker genes (p<0.001, respectively) were noticed in the ISO-treated H9c2 cells as compared with control cells. In contrast, the VA treated cells showed maximal Npr1 gene expression (3.5-fold) as compared with ATRA treated cells (2 fold), which is well correlated with the intracellular cGMP levels (80% vs 60%) and reduced (2.5-fold) HDAC -1&-2 mRNA expression. Furthermore, VA or ATRA treatment effectively reversed the ISO-induced altered expression of Npr1 and PKG-I genes, proto-oncogenes, and hypertrophic markers genes. Interestingly, the results of the present study suggest that ANP mediated anti-hypertrophic activity was enhanced with either VA (p<0.001) or ATRA (p<0.01) co-treatment. Together, we conclude that VA in combination with ANP can be a novel therapeutical approach for the treatment and management of left ventricular cardiac hypertrophy.

Atrial Natriuretic Peptide　- Old But New Therapeutic in Cardiovascular Diseases.

With the discovery of atrial natriuretic peptide (ANP), the heart as an endocrine organ was established. Basic science revealed that ANP, through the particulate guanylyl cyclase A receptor and cGMP, plays a fundamental role in cardiorenal biology. This work has led to the development of ANP as a therapeutic, especially in heart failure (HF). Human genomics has strengthened our understanding of ANP, revealing specific ANP gene variants that may be associated with biological dysfunction, but also may mediate protective properties, including in metabolic syndrome. Advances in understanding the processing and degradation of ANP molecular forms have resulted in therapeutic breakthroughs, especially inhibition of ANP degradation by neprilysin inhibitors. Although ANP is administered intravenously for acute HF, a novel therapeutic strategy is its chronic delivery by subcutaneous injection. An innovative therapeutic development is engineering to develop ANP-based peptides for chronic use. These interconnected topics of ANP biology and therapeutics will be reviewed in detail.

Suppression of Graft Spasm by the Particulate Guanylyl Cyclase Activator in Coronary Bypass Surgery.

BACKGROUND: Spasm of arterial grafts is still a clinical problem in coronary artery bypass surgery. The present study was designed to examine the effect of particulate guanylyl cyclase activator (carperitide) as an antispastic agent in internal thoracic artery and gastroepiploic artery grafts. METHODS: Isolated arterial grafts taken during surgery were studied in organ bath in three ways: the relaxing effect of carperitide on vasoconstrictor-induced precontraction; the inhibitory effect of pretreatment with carperitide on subsequent vasoconstrictor-induced contraction; and the effect of carperitide and nitroglycerin on increase of intracellular cyclic guanosine monophosphate levels. RESULTS: Carperitide produced a concentration-related, endothelium-independent relaxation contracted with potassium chloride, phenylephrine, prostaglandin F2α, or endothelin-1. Carperitide showed significantly higher potency and efficacy than nitroglycerin and nifedipine. Pretreatment with carperitide significantly attenuated the subsequent vasoconstrictor-induced contraction. Carperitide produced more cyclic guanosine monophosphate than nitroglycerin. CONCLUSIONS: Carperitide has a potent inhibitory effect on the vasoconstriction mediated by different vasoconstrictors in human internal thoracic artery and gastroepiploic artery grafts. The use of carperitide in patients during and after coronary artery bypass surgery is favored for the prevention and reversal of graft spasm.

Progress in Therapies for Myocardial Ischemia Reperfusion Injury.

BACKGROUND: Experimental studies of acute myocardial infarction have revealed that up to half of the final infarct size may be due to reperfusion injury rather than the initial ischemic incident. Research over the past three decades has deepened our understanding of the molecular mechanisms underlying ischemic reperfusion injury and several therapeutic strategies to decrease the incidence and severity of reperfusion injury have been explored. OBJECTIVE: To discuss the promising therapies and future perspectives on methods to attenuate myocardial reperfusion injury. RESULTS: Existing therapies that address reperfusion can be divided into two major groups comprising nonpharmacological and pharmacological interventions. Myriad pharmacological and nonpharmacological approaches to reduce lethal reperfusion injury have been employed. Although many initial clinical studies were negative, more recent proof-of-concept clinical trials are promising. To date, the most encouraging results are with ischemic postconditioning, remote ischemic preconditioning, ANP, adenosine, cyclosporine and exenatide. CONCLUSION: Studies demonstrate that nonpharmacological and pharmacological conditioning can be used together as part of a multifaceted approach to improve clinical outcomes in patients with ischemic heart disease.

Therapy of acute kidney injury in the perioperative setting.

PURPOSE OF REVIEW: The current review analyzes the current pharmacologic approaches in cardiac surgery-associated acute kidney injury and renal replacement/support therapies. RECENT FINDINGS: Hemodynamic management and promising therapies, including atrial natriuretic peptide, calcium sensitizer inodilators, and mesenchymal stem cells have been discussed. Encouraging results from pre-emptive renal replacement therapies have been also addressed. SUMMARY: Cardiac surgery is responsible for the highest risk of renal dysfunction with respect to other surgical settings. A number of different and coacting insults, including toxins, renal hypoperfusion, ischemia-reperfusion injury, and systemic inflammation, are leading causes of this frequent complication. Intense research is ongoing on the treatment of established cardiac surgery-associated acute kidney injury and, in this view, a holistic approach including preoperative data, risk stratification, prevention, timely diagnosis, and aggressive intervention can limit the burdening consequences of renal dysfunction in these patients. Although no specific pharmacologic and nonpharmacologic strategy can be currently recommended outside clinical research, the prompt identification of renal dysfunction and the application of multimodal treatments are fundamental aspects. Right ventricular dysfunction and increased central venous pressure, frequently affecting cardiac surgery patients, potentially lead to congestive renal dysfunction. Hemodynamic management covers a central role in these cases.

Silent disease progression in clinically stable heart failure.

Heart failure with reduced ejection fraction (HFrEF) is a progressive disorder whereby cardiac structure and function continue to deteriorate, often despite the absence of clinically apparent signs and symptoms of a worsening disease state. This silent yet progressive nature of HFrEF can contribute to the increased risk of death-even in patients who are 'clinically stable', or who are asymptomatic or only mildly symptomatic-because it often goes undetected and/or undertreated. Current therapies are aimed at improving clinical symptoms, and several agents more directly target the underlying causes of disease; however, new therapies are needed that can more fully address factors responsible for underlying progressive cardiac dysfunction. In this review, mechanisms that drive HFrEF, including ongoing cardiomyocyte loss, mitochondrial abnormalities, impaired calcium cycling, elevated LV wall stress, reactive interstitial fibrosis, and cardiomyocyte hypertrophy, are discussed. Additionally, limitations of current HF therapies are reviewed, with a focus on how these therapies are designed to counteract the deleterious effects of compensatory neurohumoral activation but do not fully prevent disease progression. Finally, new investigational therapies that may improve the underlying molecular, cellular, and structural abnormalities associated with HF progression are reviewed.

Natriuretic peptides and their therapeutic potential in heart failure treatment: An updated review.

Brain natriuretic peptide (BNP), also known as a B-type natriuretic peptide, is one of the important biomarkers with a proven role in the diagnosis of congestive heart failure (CHF). Researchers from the different clinical field have researched into the performance features of BNP testing in the acute care set-up to assist and improve in diagnosing CHF and in predicting future morbidity and mortality rates. The potency of BNP has also been researched into in cases like myocardial ischemia and infarction, cor pulmonale, and acute pulmonary embolism (PE). Based on their vaso-dilatory and diuretic properties and ability to inhibit renin-angiotensin-aldosterone system, natriuretic peptides are able to provide an efficient technique and mechanism of action in the pathophysiologic framework for CHF treatment and management. Recent clinical studies reported that ularitide, a synthetic form of urodilatin, secreted by kidney may be effective in managing and treatment of decompensated heart failure. It has also been reported that Nesiritide, a recombinant natriuretic peptide has been proven to improve dyspnea and hemodynamic parameters in heart failure patients. This review provides an update on natriuretic peptides and their therapeutic potential in CHF treatment.

An evidence-based review of recent advances in therapy for heart failure with reduced ejection fraction (HFrEF).

An estimated 5.1 million Americans have chronic heart failure and this is expected to increase 25% by 2030. Heart failure is a clinical syndrome that evolves from either functional or structural changes to the ventricles that lead to filling or ejection abnormalities. Thus far, pharmacotherapy has been show to be beneficial in patients only with reduced ejection fraction; however, new therapies have been developed in hopes of reducing the burden of heart failure. In this review, we will discuss current pharmacotherapies recommended in American College of Cardiology/American Heart Association guidelines, the evidence behind these recommendations as well as new and emerging therapies that have been developed.

Renin-Angiotensin System Control for Chronic Kidney Disease Patients Undergoing Coronary Surgery.

PURPOSE: We investigated the effectiveness of active renin-angiotensin-aldosterone system (RAAS) control with human atrial natriuretic peptide (hANP) and an angiotensin II receptor blocker (ARB) in patients with chronic kidney disease (CKD) undergoing coronary artery bypass grafting (CABG). METHODS: A total of 286 consecutive patients with CKD undergoing CABG were divided into three groups: Group C (n = 50) receiving placebo, the hANP group (n = 60) receiving hANP, and the active RAAS control therapy (ARC) group (n = 56) receiving hANP plus an ARB. Renal function, brain natriuretic peptide (BNP) and RAAS parameters were analyzed. RESULTS: After 1 year, renal function parameters were better in the hANP and ARC groups compared with group C, and the dialysis rate was significantly lower (group C: 12%, hANP group: 1.7%, ARC group: 1.8%, p = 0.018) in the hANP and ARC groups. BNP levels were significantly lower in the hANP and ARC groups compared with group C (p = 0.001). There was also a significant difference of aldosterone among the groups (p = 0.023), as well as a significant difference between group C and the ARC group (p = 0.017). CONCLUSIONS: The present study showed that active RAAS control preserved renal function in patients with CKD undergoing CABG. The improved early postoperative outcome with RAAS control may lead to long-term inhibition of cardiovascular events.

Atrial natriuretic peptide attenuation of renal ischemia-reperfusion injury after major surgery.

BACKGROUND: Ischemia-reperfusion (I/R) injury is one of the most important pathologic processes causing acute kidney injury. Human atrial natriuretic peptide (hANP) has various effects, including renal protection. The purpose of the present work was to study the effects of intrarenal angiotensin II (Ang II) and investigate the potential of hANP to prevent kidney injury. MATERIALS AND METHODS: Male Sprague-Dawley rats were divided into three groups as follows: (1) sham; (2) I/R (30 min of bilateral renal ischemia followed by 6 h reperfusion); and (3) I/R + hANP (I/R injury + continuous intravenous infusion of hANP at 0.025 µg/kg/min). After 6 h of reperfusion, both renal and plasma Ang II concentrations were measured. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin were measured before ischemia and 2, 4, and 6 h after reperfusion. To evaluate the renal-protective effects of hANP, serum creatinine was determined 6 and 24 h after reperfusion. In addition, mitochondrial oxygen consumption in kidney cortex was measured in the presence of Ang II and hANP. RESULTS: Renal Ang II concentrations were 24.5 ± 3.9 and 14.2 ± 3.4 pg/mg renal weight in the I/R and I/R + hANP groups, respectively. Urinary angiotensinogen and neutrophil gelatinase-associated lipocalin excretions were elevated after I/R injury. Treatment with hANP significantly attenuated this effect after 4 and 6 h. Oxygen consumption in renal mitochondria increased with the addition of Ang II, which was also attenuated by hANP. CONCLUSIONS: Production of intrarenal Ang II was attenuated by hANP, indicating a potential to diminish renal I/R injury.

Natriuretic peptides for perioperative management of cardiac surgery.

Atrial natriuretic peptide (carperitide) is used to treat heart failure in Japan, while brain natriuretic peptide (nesiritide) is employed in Europe/USA. Patients undergoing cardiac surgery have a complex underlying pathologic state that features increased levels of neurohumoral factors due to activation of the renin-angiotensin-aldosterone system and/or increased sympathetic activity. We considered that perioperative administration of carperitide could be beneficial for cardiac surgery patients, and we have conducted clinical investigations of its use. This article reviews the effects of natriuretic peptides in cardiac surgery patients based on our experience and on previous reports about perioperative management with carperitide or nesiritide.

Atrial natriuretic peptide protects against cisplatin-induced acute kidney injury.

PURPOSE: Cisplatin is an effective chemotherapeutic agent used in the treatment of a wide variety of malignancies. Acute kidney injury (AKI) is the major toxicity associated with cisplatin and sometimes necessitates a reduction in dose or discontinuation of treatment. Atrial natriuretic peptide (ANP) is secreted by the heart and exerts a wide range of renoprotective effects, including anti-inflammatory activity. The objective of this study was to investigate the protective effects of ANP on cisplatin-induced AKI in mice. METHODS: Mice were randomly divided into three groups: control, cisplatin (20 mg/kg, intraperitoneal)/vehicle treatment, and cisplatin/ANP (1.5 µg/kg/min via osmotic-pump, subcutaneous) treatment. At 72 h after cisplatin injection, serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of mRNAs encoding tumor necrosis factor-α, interleukin (IL)-1ß, IL-6, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and transforming growth factor (TGF)-ß were measured using real-time polymerase chain reaction. Histological changes were also evaluated. RESULTS: ANP treatment significantly attenuated cisplatin-induced increases in serum blood urea nitrogen and creatinine, urine albumin/creatinine, and renal expression of IL-1ß, IL-6, intercellular adhesion molecule-1, and monocyte chemoattractant protein-1 mRNAs. Cisplatin-induced renal dysfunction and renal tubular necrosis were thus attenuated by ANP treatment. CONCLUSIONS: Our results indicate that ANP exhibits a protective effect against cisplatin-induced AKI in mice. ANP may thus be of value in prophylactic strategies aimed at mitigating the adverse effects associated with chemotherapy agents, including cisplatin.