natriuretic-peptide--brain and Reperfusion-Injury

Atrial natriuretic peptide (ANP) is a cardiac hormone belonging to the family of natriuretic peptides (NPs). ANP exerts diuretic, natriuretic, and vasodilatory effects that contribute to maintain water-salt balance and regulate blood pressure. Besides these systemic properties, ANP displays important pleiotropic effects in the heart and in the vascular system that are independent of blood pressure regulation. These functions occur through autocrine and paracrine mechanisms. Previous works examining the cardiac phenotype of loss-of-function mouse models of ANP signaling showed that both mice with gene deletion of ANP or its receptor natriuretic peptide receptor A (NPR-A) developed cardiac hypertrophy and dysfunction in response to pressure overload and chronic ischemic remodeling. Conversely, ANP administration has been shown to improve cardiac function in response to remodeling and reduces ischemia-reperfusion (I/R) injury. ANP also acts as a pro-angiogenetic, anti-inflammatory, and anti-atherosclerotic factor in the vascular system. Pleiotropic effects regarding brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) were also reported. In this review, we discuss the current evidence underlying the pleiotropic effects of NPs, underlying their importance in cardiovascular homeostasis.

Topics: Animals; Cardiovascular System; Humans; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptides; Reperfusion Injury; Vascular Remodeling; Ventricular Remodeling

Natriuretic peptides elicit vasodilation, increased sodium excretion and concomitant diuresis, and counteract the RAAS. In the heart itself, natriuretic peptides may also act anti-inflammatory and antifibrotic. This has led to the pursuit of natriuretic peptides and chemically modified peptides as adjunctive therapy in myocardial ischaemia. However, natriuretic peptide infusion may also influence the endogenous natriuretic peptide response and lipid accumulation. We hypothesised that a) natriuretic peptide infusion (BNP and CD-NP) is cardiomyocyte protective, b) affects the endogenous response, and c) facilitate cardiac lipid accumulation. We examined these effects in a minimally invasive porcine model of regional cardiac ischaemia and reperfusion. The studies were supplemented by a 48-hour porcine model of ischemia and reperfusion as well as an in vitro study of BNP administered in a HL-1 cell model of "ischaemia/reperfusion". Infarct size was determined by TTC staining, plasma troponin T release, and total RNA integrity in cardiac tissue samples. The endogenous response was assessed by a processing-independent proANP immunoassay and mRNA quantitation. Lipids in plasma and myocardial tissue were determined by TLC. The studies show that natriuretic peptides decrease cardiomyocyte damage, possibly partly through indirect mechanisms. Furthermore, BNP infusion completely inverts the endogenous response, whereas CD-NP infusion does not. Finally, both natriuretic peptides increase plasma free fatty acids, which is associated with an increased cardiac lipid accumulation in non-ischaemic myocardium. In conclusion, the studies suggest that natriuretic peptides are beneficial in terms of reduced cardiac injury. In addition, the endogenous natriuretic peptide response is inverted. The results advocate for pursuing natriuretic peptide treatment in ischaemia/reperfusion damage. However, the metabolic consequences in a cardiac tissue challenged by ischaemia should be pursued before testing the peptides in patients.

Topics: Animals; Blood Pressure; Caspase 1; Cholesterol; Cyclic GMP; Diuresis; Fatty Acids, Nonesterified; Female; Glycerol; Mice; Myocardial Infarction; Myocardial Ischemia; Myocytes, Cardiac; Natriuretic Peptide, Brain; Natriuretic Peptide, C-Type; Natriuretic Peptides; Reperfusion Injury; RNA, Messenger; Swine; Triglycerides; Troponin T; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A

The main aim of this study was to evaluate the effect of remote ischaemic preconditioning (RIPC) on preventing the leakage of cardiac damage biomarkers in patients undergoing vascular surgery.. This is a randomised, sham-controlled, double-blinded, single-centre study. Patients undergoing open abdominal aortic aneurysm repair, surgical lower limb revascularisation surgery or carotid endarterectomy were recruited non-consecutively. The RIPC protocol consisting of 4 cycles of 5 minutes of ischaemia, followed by 5 minutes of reperfusion, was applied. A RIPC or a sham procedure was performed noninvasively along with preparation for anaesthesia. High sensitivity troponin T level was measured preoperatively and 2, 8 and 24 hours after surgery and pro b-type natriuretic peptide was measured preoperatively and 24 hours after surgery.. There was significantly higher leakage of high sensitivity troponin T (peak change median 2 ng/L, IQR 0.9-6.2 ng/L vs 0.6 ng/L, IQR 0.7-2.1 ng/L, p = .0002) and pro b-type natriuretic peptide (change median 144 pg/mL, IQR 17-318 pg/mL vs 51 pg/mL, IQR 12-196 pg/mL, p = .02) in the sham group compared to the RIPC group.. RIPC reduces the leakage of high sensitivity troponin T and pro b-type natriuretic peptide. Therefore, it may offer cardioprotection in patients undergoing non-cardiac vascular surgery. The clinical significance of RIPC has to be evaluated in larger studies excluding the factors known to influence its effect.

Topics: Aged; Biomarkers; Female; Humans; Ischemic Preconditioning; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Reperfusion Injury; Time Factors; Treatment Outcome; Troponin T; Vascular Surgical Procedures

We aimed to evaluate the clinical performance of early administration of recombinant human B-type natriuretic peptide (rhBNP) to ST-elevation myocardial infarction (STEMI) patients receiving percutaneous coronary intervention (PCI) treatment.. In total, 185 patients diagnosed with STEMI were enrolled and randomised into either the placebo-treated (n = 88) or rhBNP-treated (n = 97) group. Patients were given either saline or rhBNP ten minutes before PCI and monitored with various cardiac parameters, including accelerated idioventricular rhythm, frequent ventricular premature beat (FVPB), ventricular tachycardia, systolic blood pressure, thrombolysis in myocardial infarction (TIMI) 3 gradation, corrected TIMI frame count (cTFC) and myocardial blush grade (MBG) 3 classification.. Our results revealed no difference in accelerated idioventricular rhythm between the two groups. However, FVPB and ventricular tachycardia were significantly decreased in rhBNP-treated patients compared to placebo-treated patients (p < 0.05). Moreover, the occurrence ratio of reperfusion-associated low blood pressure in rhBNP-treated patients was lower than in placebo-treated patients (p = 0.03), while no difference was observed in infarction-related arteries TIMI 3 blood flow between the two groups (p = 0.23). Importantly, measurement of post-reperfusion blood flow velocity via cTFC suggested that rhBNP treatment could significantly increase blood circulation (p = 0.003). After stent implantation, the acquisition rate of MBG 3 was higher in rhBNP-treated patients compared to placebo-treated patients (p = 0.071), although the difference was not significant.. We concluded that early administration of rhBNP can ameliorate the severity of reperfusion injury for STEMI patients receiving PCI treatment.

Topics: Aged; Arrhythmias, Cardiac; Coronary Circulation; Electrocardiography; Female; Humans; Hypotension; Male; Middle Aged; Natriuretic Peptide, Brain; Percutaneous Coronary Intervention; Recombinant Proteins; Reperfusion Injury; ST Elevation Myocardial Infarction; Stents; Tachycardia, Ventricular; Treatment Outcome

The purpose of this study was to investigate the clinical outcome, inflammatory response and myocardial function in high-risk patients undergoing three different leukocyte depletion strategies. Over a four-month period, forty patients (EuroSCORE 6+) undergoing coronary revascularization were prospectively randomized to one of the four perfusion protocols: Group 1 (N=10): Conventional circuits (ECC) + two leukocyte filters (LG6B, Pall, USA) with the method of two-phase (continuous + strategic) leukofiltration; Group 2 (N=10): ECC + single leukocyte filter with the method of continuous leukofiltration; Group 3 (N=10): ECC + single leukocyte filter with the method of strategic leukofiltration; Group 4 (N=10) CONTROL: ECC without leukocyte filtration. Blood samples were collected at T1: Baseline, T2: On CPB, T3: X-Clamp, T4: Off CPB, T5: ICU24 and T6: ICU48. Perioperative follow-up was thoroughly monitored. Leukocyte counts in double filter and strategic filtration groups demonstrated significant differences at T4 (p < .05 vs. control). TNFalpha levels were significantly lower in Group 1 at T4 and procalcitonin levels at T5 and T6 (p < .05 vs. control). CKMB levels demonstrated well preserved myocardium in double filter group (p < .05 vs. control). Brain natriuretic peptide levels in double filter group were significantly lower at T5 and T6 with respect to Group 2 (p <.05) and control (p <.001). Matrixmetallopeptidase 9 and D-Dimer levels in double filter group were significantly lower at T5 and T6 (p <.05 vs. control).Two-phase leukofiltration is associated with some compound benefit over continuous deployment in high-risk patients. A larger more powerful study than this pilot one is warranted for further evaluation.

Topics: Aged; Cardiopulmonary Bypass; Coronary Artery Bypass; Creatine Kinase, MB Form; Female; Fibrin Fibrinogen Degradation Products; Humans; Leukapheresis; Leukocyte Reduction Procedures; Male; Matrix Metalloproteinase 9; Middle Aged; Natriuretic Peptide, Brain; Reperfusion Injury

The aim of the present study was to evaluate the efficacy of alpha-human atrial natriuretic peptide (hANP) in cardiac surgery under cardiopulmonary bypass (CPB).. A prospective randomized study was conducted with 150 patients who underwent scheduled coronary artery bypass grafting to compare a group of patients receiving 0.02 microg x kg(-1) x min(-1) of hANP from the initiation of CPB with a group not receiving hANP. Hemodynamics, levels of atrial and brain natriuretic peptides (BNP), angiotensin-II and aldosterone, renin activity, and left ventricular (LV) function were examined. The hANP group showed significantly lower renin activity and lower levels of angiotensin-II and aldosterone during the early postoperative period, compared with the non-hANP group. The incidence of postoperative ventricular arrhythmia and the postoperative peak level of creatine kinase-MB were significantly lower in the hANP group. BNP at 1 month after surgery and measures of LV function were also significantly lower in the hANP group.. Low-dose continuous infusion of hANP during cardiac surgery not only had a compensatory effect for the imperfections of CPB during the early postoperative period but also an inhibitory effect on postoperative LV remodeling and a reduction in ischemia/reperfusion injury. hANP should be part of the postoperative care for cardiac surgery.

Topics: Aged; Aldosterone; Arrhythmias, Cardiac; Atrial Natriuretic Factor; Blood Pressure; Cardiopulmonary Bypass; Coronary Artery Disease; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Natriuretic Peptide, Brain; Postoperative Period; Renin; Reperfusion Injury; Ventricular Function, Left; Ventricular Remodeling

Ischemic stroke followed by cerebral artery occlusion is a main cause of chronic disability worldwide. Recombinant human brain natriuretic peptide (rhBNP) has been reported to alleviate sepsis-induced cognitive dysfunction and brain I/R injury. However, the function and molecular mechanisms of rhBNP in ischemic brain injury have not been clarified. For establishment of an animal model of ischemic brain injury, C57BL/6 mice were treated with middle cerebral artery occlusion (MCAO) surgery for 1 h and reperfusion for 24 h. After subcutaneous injection of rhBNP into model mice, neurologic deficits were assessed by evaluating behavior of mice according to Longa scoring system, and TTC staining was utilized to determine the brain infarct size of mice. The levels of oxidative stress markers, superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA), were detected in hippocampal tissues of mice by corresponding kits. Cell apoptosis in hippocampus tissues was examined by TUNEL staining. Protein levels of antioxidant enzymes (HO-1 and NQO1) in cerebral cortex, apoptotic markers (Bax, Bcl-2, and cleaved caspase), and PI3K/AKT pathway-associated factors in hippocampus were tested by western blot analysis. The results revealed that injection of rhBNP decreased neurologic deficit scores, the percent of brain water content, and infarct volume. Additionally, rhBNP downregulated MDA level, upregulated the levels of SOD, CAT, and GSH in hippocampus of mice, and increased protein levels of HO-1 and NQO1 in the cortex. Cell apoptosis in hippocampus tissues of model mice was inhibited by rhBNP which was shown as the reduced TUNEL-positive cells, the decreased Bax, cleaved caspase-3, and cleaved caspase-9 protein levels, and the enhanced Bcl-2 protein level. In addition, rhBNP treatment activated the PI3K/AKT signaling pathway and upregulated the protein levels of HO-1 and NRF2. Overall, rhBNP activates the PI3K/AKT/HO-1/NRF2 pathway to attenuate ischemic brain injury in mice after MCAO by suppression of cell apoptosis and oxidative stress.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Brain Injuries; Brain Ischemia; Humans; Infarction, Middle Cerebral Artery; Mice; Mice, Inbred C57BL; Natriuretic Peptide, Brain; NF-E2-Related Factor 2; Oxidative Stress; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reperfusion Injury; Superoxide Dismutase

The present study aimed to investigate the role of vascular endothelial growth factor (VEGF) in the neuroprotective effect of Crocus sativus (saffron) against cerebral ischemia/reperfusion injury (I/R) in rats. Four groups of a total forty I/R rats with 60-min occlusion followed by 48 h reperfusion or sham surgery were used. The sham and left-brain I/R control groups where treated with normal saline. The rats of the other two groups received saffron extract (100 or 200 mg/kg, ip, respectively) for 3 successive weeks prior to left-brain I/R. Other four doses of saffron extract were received by the rats of the last 2 groups 60 min prior to operation, during the surgery, and on days 1 and 2 following reperfusion. I/R group showed marked neurobehavioral, neurochemical and histopathological alterations. The results revealed a significant reduction in neurological deficit scores in the saffron-treated rats at both doses. Saffron significantly attenuated lipid peroxidation, decreased NO and brain natriuretic peptide (BNP) contents in I/R-brain tissue. On the other hand, saffron reversed the depletion of GSH in the injured brain. Moreover, saffron treatment evidently reduced apoptosis as revealed by a decrease in caspase-3 and Bax protein expression with a marked decrease in the apoptotic neuronal cells compared to I/R group. In addition, saffron administration effectively upregulated the expression of VEGF in I/R-brain tissue. In conclusion, saffron treatment offers significant neuroprotection against I/R damage possibly through diminishing oxidative stress and apoptosis and enhancement of VEGF.

Topics: Animals; Behavior, Animal; Brain; Brain Ischemia; Crocus; Lipid Peroxidation; Male; Natriuretic Peptide, Brain; Neuroprotective Agents; Nitric Oxide; Plant Extracts; Rats; Rats, Wistar; Reperfusion Injury; Tandem Mass Spectrometry; Vascular Endothelial Growth Factor A

The current study is focusing on the role of brain natriuretic peptide (BNP), a substrate of dipeptidyl peptidase-4 (DPP-4) enzyme, and its signaling survival pathway in the cardioprotective mechanism of sitagliptin, a DPP-4 inhibitor.. Pretreatment with sitagliptin provided significant protection against I/R injury as manifested by decreasing, percentage of infarct size, suppressing the elevated ST segment, reducing the increased cardiac enzymes, as well as DPP-4 activity and elevating both heart rate (HR) and left ventricular developed pressure (LVDP). However, the addition of either blocker to sitagliptin regimen reversed partly its cardioprotective effects. Although I/R increased BNP content, it unexpectedly decreased that of cGMP; nevertheless, sitagliptin elevated both parameters, an effect that was not affected by the use of the two blockers. On the molecular level, sitagliptin decreased caspase-3 activity and downregulated the mRNA levels of BNP, Bax, and Cyp D, while upregulated that of Bcl2. The use of either KT-5823 or 5-HD with sitagliptin hindered its effect on the molecular markers tested.. The results of the present study suggest that the cardioprotective effect of sitagliptin is mediated partly, but not solely, through the BNP/cGMP/PKG survival signaling pathway.

Topics: Animals; bcl-2-Associated X Protein; Carbazoles; Cardiotonic Agents; Caspase 3; Cyclic GMP; Cyclophilins; Decanoic Acids; Dipeptidyl Peptidase 4; Hemodynamics; Hydroxy Acids; Male; Natriuretic Peptide, Brain; Peptidyl-Prolyl Isomerase F; Proto-Oncogene Proteins c-bcl-2; Rats; Reperfusion Injury; Signal Transduction; Sitagliptin Phosphate

In animal models of acute myocardial infarction (AMI), B-type natriuretic peptide (BNP) administered before and during coronary occlusion limits infarct size. However, the relation between plasma BNP levels and ischemia/reperfusion injury remains unclear.. 302 patients with ST-segment elevation AMI (STEMI) received emergency percutaneous coronary intervention within six hours from the onset. The patients were divided into two groups according to the plasma BNP level before angiography: group L (n=151), BNP ≤ 32.2 pg/ml; group H (n=151), BNP >32.2 pg/ml. The Selvester QRS-scoring system was used to estimate infarct size.. The rate of ischemia/reperfusion injury immediately after reperfusion, defined as reperfusion ventricular arrhythmias (26% vs. 11%, p=0.001) and ST-segment re-elevation (44% vs. 22%, p=0.008), was higher in group L than in group H. Group L had a greater increase in the QRS score during percutaneous coronary intervention (3.55 ± 0.17 vs. 2.09 ± 0.17, p<0.001) and a higher QRS score 1 h after percutaneous coronary intervention (5.77 ± 0.28 vs. 4.51 ± 0.28, p=0.002). On multivariate analysis, plasma BNP levels in the lower 50th percentile were an independent predictor of reperfusion injury (odds ratio, 2.620; p<0.001). The odds ratios of reperfusion injury according to decreasing quartiles of BNP level, as compared with the highest quartile, were 1.536, 3.692 and 4.964, respectively (p trend=0.002).. Plasma BNP level before percutaneous coronary intervention may be a predictor of ischemia/reperfusion injury and the resultant extent of myocardial damage. Our findings suggest that high plasma BNP levels might have a clinically important protective effect on ischemic myocardium in patients with STEMI who receive percutaneous coronary intervention.

Topics: Aged; Aged, 80 and over; Biomarkers; Female; Humans; Male; Middle Aged; Myocardial Infarction; Myocardial Reperfusion; Natriuretic Peptide, Brain; Percutaneous Coronary Intervention; Predictive Value of Tests; Reperfusion Injury

Accumulation and release of atrial and brain natriuretic peptides (ANP and BNP) in right atrial cardiac muscle cells has been investigated in rats after 60 minutes and 60 days after the reperfusion start. The total ischemia was simulated by the method of V. G. Korpachev. Immunocytochemical localization of peptides in cardiomyocytes was performed in ultrathin sections using polyclonal antibodies. The intensity of accumulation/excretion of ANP and BNP were analyzed by the method of counting the number of granules (A- and B-types) with immunoreactive labels in 38 x 38 mkm2 visual fields in transmission electron microscope Morgagni 268D (FEI). The results were assessed using Mann-Whitney U-test (p < 0.05). After 60 minutes and 60 days post-reperfusion period, we detected an increase in the synthesis and release of ANP and BNP. The reaction of BNP was more pronounced than ANP. This is due to the fact that ANP is the main hormone of the natriuretic peptide system involved in the regulation of blood pressure in normal conditions, while BNP is the principal regulator of pressure in cardiovascular pathology.

Topics: Animals; Atrial Natriuretic Factor; Humans; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Rats; Reperfusion; Reperfusion Injury

We investigated whether the pathways linked to Toll-like receptors 2 and 4 (TLRs) are involved in renal ischemia-reperfusion (I/R)-induced cardiac hypertrophy. Wild type (WT) C57BL/6J, TLR2-/- and TLR4-/- mice were subjected to left kidney ischemia for 60 min followed by reperfusion for 5, 8, 12 and 15 days. Proton density magnetic resonance showed alterations in the injured kidney from WT mice, together with signs of parenchymal edema and higher levels of vimentin mRNA, accompanied by: (i) small, but significant, increase in serum urea after 24 h, (ii) 100% increase in serum creatinine at 24 h. A serum peak of inflammatory cytokines occurred after 5 days of reperfusion. Heart weight/body weight and heart weight/tibia length ratios increased after 12 and 15 days of reperfusion, respectively. Cardiac hypertrophy markers, B-type natriuretic peptide (BNP) and α-actin, left ventricle mass, cardiac wall thickness and myocyte width increased after 15 days of reperfusion, together with longer QTc and action potential duration. Cardiac TLRs, MyD88, HSP60 and HSP70 mRNA levels also increased. After 15 days of reperfusion, absence of TLRs prevented cardiac hypertrophy, as reflected by similar values of left ventricular cardiac mass and heart weight/body weight ratio compared to the transgenic Sham. Renal tissular injury also ameliorated in both knockout mice, as revealed by the comparison of their vimentin mRNA levels with those found in the WT on the same day after I/R. The I/R TLR2-/- group had TNF-α, IFN-γ and IL-1β levels similar to the non-I/R group, whereas the TLR4-/- group conserved the p-NF-κB/NF- κB ratio contrasting with that found in TLR2-/-. We conclude: (i) TLRs are involved in renal I/R-induced cardiac hypertrophy; (ii) absence of TLRs prevents I/R-induced cardiac hypertrophy, despite renal lesions seeming to evolve towards those of chronic disease; (iii) TLR2 and TLR4 selectively regulate the systemic inflammatory profile and NF- κB activation.

Topics: Actins; Animals; Cardiomegaly; Chaperonin 60; Cytokines; Heart; HSP70 Heat-Shock Proteins; Ischemia; Kidney; Kidney Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Myeloid Differentiation Factor 88; Myocardium; Natriuretic Peptide, Brain; Reperfusion Injury; Toll-Like Receptor 2; Toll-Like Receptor 4; Vimentin

Brain natriuretic peptide (BNP) has a protective effect on acute injury of the heart, brain, and lung. However, its role in acute kidney injury (AKI) remains unclear. The aim of this study was to investigate the effect of lyophilized recombinant human BNP (lrh-BNP) on AKI and the underlying molecular mechanisms. An experimental model for AKI was established using an ischemia/reperfusion (I/R) procedure. Healthy adult BALB/c mice were randomized to the sham, I/R, and lrh-BNP-treated post-I/R (BNP + I/R) groups. Post-operatively, the BNP + I/R group was subcutaneously injected with lrh-BNP (0.03 μg·kg(-1)·min(-1)), whereas the other groups received saline at the same dose. Serum creatinine (Scr) and blood urea nitrogen levels were examined; tissue staining was performed to evaluate the degree of I/R injury (IRI). Ki67 positive staining of renal tubular epithelial cells was observed using immunofluorescence confocal laser scanning to assess the effect of BNP on cell proliferation after IRI. Inflammatory factor expression levels were detected to evaluate the effect of BNP on renal inflammation. Compared with the sham group, the I/R group showed increased Scr levels, severe tubular injury of the renal outer medulla, increased Kim-1 mRNA expression, an increased number of infiltrative macrophages in the renal interstitium, and increased TNF-α, IL- 1β, IL-6, MCP-1, and HIF-1α mRNA expression. BNP delivery significantly reduced all pathological changes in the I/R group. The protective role of BNP in murine renal IRI may be associated with its inhibition of renal interstitial inflammation and hypoxia and its promotion of renal tubule repair.

Topics: Acute Kidney Injury; Animals; Disease Models, Animal; Epithelium; Humans; Hypoxia; Inflammation; Kidney Function Tests; Kidney Tubules; Male; Mice; Natriuretic Peptide, Brain; Protective Agents; Recombinant Proteins; Reperfusion Injury

Brain natriuretic peptide (BNP) reduces the extent of myocardial infarction. We aimed to determine whether BNP may reduce skeletal muscle mitochondrial dysfunctions and oxidative stress through mitochondrial K(ATP) (mK(ATP)) channel opening after ischemia-reperfusion (IR). Wistar rats were assigned to four groups: sham, 3-h leg ischemia followed by 2-h reperfusion (IR), pretreatment with BNP, and pretreatment with 5-hydroxydecanoic acid, an mK(ATP) channel blocker, before BNP. Mitochondrial respiratory chain complex activities of gastrocnemius muscles were determined using glutamate-malate (V(max)), succinate (V(succ)), and N,N,N',N'-tetramethyl-p-phenylenediamine dihydrochloride ascorbate (V(TMPD/asc)). Apoptosis (Bax-to-Bcl2 mRNA ratio and caspase-3 activity) and oxidative stress (dihydroethidium staining) were also assessed. Compared with the sham group, IR significantly decreased V(max), reflecting complex I, II, and IV activities (-36%, 3.7 ± 0.3 vs. 5.8 ± 0.2 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01), and V(TMPD/asc), reflecting complex IV activity (-37%, 8.6 ± 0.8 vs. 13.7 ± 0.9 μmol O(2)·min(-1)·g dry wt(-1), P < 0.01). IR increased Bax-to-Bcl2 ratio (+57%, 1.1 ± 0.1 vs. 0.7 ± 0.1, P < 0.05) and oxidative stress (+45%, 9,067 ± 935 vs. 6,249 ± 723 pixels, P > 0.05). BNP pretreatment reduced the above alterations, increasing V(max) (+38%, P < 0.05) and reducing Bax-to-Bcl2 ratio (-55%, P < 0.01) and oxidative stress (-58%, P < 0.01). BNP protection against deleterious IR effects on skeletal muscles was abolished by 5-hydroxydecanoic acid. Caspase-3 activities did not change significantly. Conversely, BNP injected during ischemia failed to protect against muscle injury. In addition to maintaining the activity of mitochondrial respiratory chain complexes and possibly decreasing apoptosis, pretreatment with BNP protects skeletal muscle against IR-induced lesions, most likely by decreasing excessive production of radical oxygen species and opening mK(ATP) channels.

Topics: Animals; Apoptosis; Caspase 3; Decanoic Acids; Electron Transport; Hydroxy Acids; KATP Channels; Male; Mitochondria, Muscle; Models, Animal; Muscle, Skeletal; Natriuretic Peptide, Brain; Oxidative Stress; Potassium Channel Blockers; Rats; Rats, Wistar; Reactive Oxygen Species; Reperfusion Injury

Brain natriuretic peptide (BNP) and monocyte chemotactic protein-1 (MCP-1) are biomarkers of heart failure (HF). The aim of the present study was to determine the role of oxidized low-density lipoprotein (Ox-LDL) in the induction of these biomarkers and the signaling pathways involved in vitro. Incubation of HL-1 cardiomyocytes and human myocytes with Ox-LDL induced the expression of BNP and MCP-1 genes, while native LDL had no effect. When peroxides associated with Ox-LDL were reduced to hydroxides, the ability to induce BNP and MCP-1 gene expression was abolished. Furthermore, exposure of HL-1 cells to ischemic conditions alone had no effect on BNP gene expression, while ischemia followed by reperfusion resulted in increased expression of BNP gene. Inhibitors of ERK and JNK inhibited the induction of BNP. Signaling array results suggested that the induction of both MAPK and NF-κB pathways is involved in the induction of BNP by Ox-LDL. These results suggest that Ox-LDL or peroxidized lipids formed in oxidatively stressed myocytes during ischemia-reperfusion injury may play a role in the induction of BNP and MCP-1.

Topics: Cell Line, Tumor; Chemokine CCL2; Gene Expression Regulation; Heart Failure; Humans; Lipoproteins, LDL; Myocardial Ischemia; Myocytes, Cardiac; Natriuretic Peptide, Brain; Oxidation-Reduction; Oxidative Stress; Reperfusion Injury; Signal Transduction

Chronic thromboembolic pulmonary hypertension leads to pulmonary hypertension and right-sided heart failure. The purpose of this study was to investigate the efficacy of percutaneous transluminal pulmonary angioplasty (PTPA) for the treatment of chronic thromboembolic pulmonary hypertension.. Twenty-nine patients with chronic thromboembolic pulmonary hypertension underwent PTPA. One patient had a wiring perforation as a complication of PTPA and died 2 days after the procedure. In the remaining 28 patients, PTPA did not produce immediate hemodynamic improvement at the time of the procedure. However, after follow-up (6.0 ± 6.9 months), New York Heart Association functional classifications and levels of plasma B-type natriuretic peptide significantly improved (both P<0.01). Hemodynamic parameters also significantly improved (mean pulmonary arterial pressure, 45.3 ± 9.8 versus 31.8 ± 10.0 mm Hg; cardiac output, 3.6 ± 1.2 versus 4.6 ± 1.7 L/min, baseline versus follow-up, respectively; both P<0.01). Twenty-seven of 51 procedures in total (53%), and 19 of 28 first procedures (68%), had reperfusion pulmonary edema as the chief complication. Patients with severe clinical signs and/or severe hemodynamics at baseline had a high risk of reperfusion pulmonary edema.. PTPA improved subjective symptoms and objective variables, including pulmonary hemodynamics. PTPA may be a promising therapeutic strategy for the treatment of chronic thromboembolic pulmonary hypertension.. URL: http://www.umin.ac.jp. Unique identifier: UMIN000001572.

Topics: Aged; Angioplasty, Balloon; Arterial Pressure; Biomarkers; Chronic Disease; Familial Primary Pulmonary Hypertension; Female; Hospital Mortality; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Artery; Pulmonary Edema; Pulmonary Embolism; Recovery of Function; Reperfusion Injury; Risk Factors; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Acute kidney injury (AKI) occurs in 30% of patients undergoing complex cardiovascular surgery, and renal ischemia-reperfusion (I/R) injury is often a contributing factor. A recent meta-analysis observed that perioperative natriuretic peptide administration was associated with a reduction in AKI requiring dialysis in cardiovascular surgery patients. This study was designed to further clarify the potential reno-protective effect of brain natriuretic peptide (BNP) using an established rat model of renal I/R injury.. The study comprised three groups (n = 10 kidneys each): (1) control (no injury); (2) I/R injury (45 min of bilateral renal ischemia followed by 3 h of reperfusion); and (3) BNP (I/R injury plus rat-BNP pretreatment at 0.01 μg/kg/min). Glomerular filtration rate (GFR) and a biomarker of AKI, urinary neutrophil gelatinase-associated lipocalin (uNGAL), were measured at baseline and at 30 minute intervals post-ischemia. Groups were compared using two-way repeated measures analysis of variance (mean ± SD, significance P < 0.05).. Baseline GFR measurements for control, I/R, and BNP groups were 1.07 ± 0.55, 0.88 ± 0.51, and 1.03 ± 0.59 mL/min (P = 0.90), respectively. Post-ischemia, GFR was significantly lower in I/R and BNP compared with controls at 30 min, 1.29 ± 0.97, 0.08 ± 0.04, and 0.06 ± 0.05 mL/min (P < 0.01), and remained lower through 3 h, 1.79 ± 0.44, 0.30 ± 0.17, and 0.32 ± 0.12 mL/min (P < 0.01). Comparing I/R to BNP groups, GFR did not differ significantly at any time point. There was no significant difference in uNGAL levels at 1 h (552 ± 358 versus 516 ± 259 ng/mL, P = 0.87) or 2 h (1073 ± 589 versus 989 ± 218 ng/mL, P = 0.79) between I/R and BNP.. BNP does not reduce the renal injury biomarker, urinary NGAL, or preserve GFR in acute renal ischemia-reperfusion injury.

Topics: Acute Disease; Acute-Phase Proteins; Animals; Biomarkers; Disease Models, Animal; Glomerular Filtration Rate; Kidney; Lipocalin-2; Lipocalins; Male; Natriuretic Peptide, Brain; Peroxidase; Proto-Oncogene Proteins; Rats; Rats, Sprague-Dawley; Reperfusion Injury

To study the effects of B-type natriuretic peptide (BNP) preconditioning on the apoptosis and expressions of Bcl-2 and Bax in rat cardiomyocytes during myocardial ischemia-reperfusion.. Twenty-one male Sprague-Dawley rats weighing (250 ± 50) g were randomly divided into 3 groups of sham operation (SHAM), ischemia-reperfusion (I/R) and B-type natriuretic peptide (BNP). A rat model of in vivo myocardial ischemia-reperfusion injury was established by ligating the left anterior descending coronary artery for 35 minutes and then reperfusing for 240 minutes. The apoptosis of myocardial cell was determined by terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end-labeling (TUNEL) method. Real-time polymerase chain reaction and Western blot were used to detect the expression changes of Bcl-2 and Bax in rat ischemia myocardium.. The apoptotic indices of SHAM, BNP and I/R groups were 5.4% ± 4.2%, 22.5% ± 9.5% and 45.2% ± 13.0% respectively (P < 0.05). The Bcl-2 protein expression of SHAM, BNP and I/R groups were 0.87 ± 0.09, 0.70 ± 0.07 and 0.38 ± 0.09 respectively (P < 0.05). The Bax protein expression of SHAM, BNP and I/R groups were 0.08 ± 0.04, 0.39 ± 0.09 and 0.71 ± 0.18 respectively (P < 0.01). The Bcl-2/Bax mRNA ratio of SHAN, BNP and I/R groups were 0.763 ± 0.154, 0.099 ± 0.025 and 0.022 ± 0.024 respectively (P < 0.05).. The BNP preconditioning can decrease the myocardial apoptosis induced by ischemia-reperfusion injury. The mechanisms may be associated with an elevated expression of Bcl-2, an increased ratio of Bcl-2/Bax and a lowered expression of Bax.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Ischemic Preconditioning, Myocardial; Male; Myocytes, Cardiac; Natriuretic Peptide, Brain; Proto-Oncogene Proteins c-bcl-2; Rats; Rats, Sprague-Dawley; Reperfusion Injury

The therapy for acute myocardial infarction (AMI) has been improved; yet, AMI remains a major cause of death and heart failure in industrialized countries. B-type natriuretic peptide (BNP), a hormone secreted from the heart, has been shown cardioprotective effects during myocardial ischemia/reperfusion. In the present study, we aimed to examine whether BNP could inhibit myocardial apoptosis during ischemia/reperfusion. Rabbits were randomly divided into three groups (12 animals for each group): sham-operated control and ischemia-reperfusion animals with or without BNP treatment. Occlusion of the left circumflex coronary for 45 min was followed by 3-h reperfusion with infusion of physiological saline (untreated group) or BNP (treated group) starting 5 min before reperfusion and throughout the whole reperfusion. The infarct size, measured by triphenyltetrazolium chloride staining, was reduced by 44% with BNP treatment (P < 0.01). Accordingly, serum levels of creatine kinase and lactate dehydrogenase were markedly reduced in BNP-treated group (P < 0.05) compared with the untreated group. BNP significantly attenuated apoptotic cells (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P < 0.01). The BNP-mediated attenuation of apoptosis was associated with the increased expression of an anti-apoptotic protein Bcl-2 and the reduced expression of a pro-apoptotic protein Bax. Moreover, BNP treatment significantly decreased the magnitude of caspase-3 activation caused by myocardial ischemia-reperfusion. In conclusion, pretreatment with BNP shortly before the onset of reperfusion not only reduces necrosis, but also attenuates myocardial apoptosis. BNP appears to be an ideal pharmacological agent applied as an adjuvant therapy to current myocardial reperfusion strategies.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Blotting, Western; Caspase 3; Creatine Kinase; Heart Ventricles; Hemodynamics; Humans; In Situ Nick-End Labeling; L-Lactate Dehydrogenase; Male; Myocardial Infarction; Myocardium; Myocytes, Cardiac; Natriuretic Peptide, Brain; Organ Size; Rabbits; Reperfusion Injury