Functional Effects of Endogenous Bradykinin in Congestive Heart Failure

AbstractObjectives. The purpose of this study was to determine the level and functional effects of endogenous bradykinin in congestive heart failure (CHF).Background. There is experimental evidence that bradykinin is increased in several cardiac disease states. However, it is unknown whether plasma levels of bradykinin are elevated in CHF. Further, the cardiac and vascular responses to bradykinin in CHF are unclear.Methods. The circulating levels of bradykinin and the effects of endogenous bradykinin were assessed in eight instrumented, conscious dogs both before and after pacing-induced CHF.Results. Before CHF, the plasma bradykinin level was 53.1 ± 12.4 pg/ml. Blocking endogenous bradykinin with HOE-140 (0.3 mg/kg), a specific bradykinin B2-receptor antagonist, produced no significant alterations in heart rate, left ventricular (LV) end-systolic pressure (Pes), total systemic resistance (TSR), the time constant of LV relaxation (tau) or the maximal rate of LV filling (dV/dtmax). However, coronary blood flow was significantly reduced (p < 0.05). LV contractile performance measured by the slopes of pressure–volume relations was unaffected. After induction of CHF, the plasma bradykinin level increased to 234.2 ± 19.4 pg/ml (p < 0.05). Blocking endogenous bradykinin with HOE-140 reduced coronary blood flow and produced significant increases in Pesand TSR, prolonged tau, decreased dV/dtmaxand elevated minimal LV pressure and mean left atrial pressure. Furthermore, the slopes of pressure–volume relations (p < 0.05) were decreased, indicating depressed contractility with HOE-140 after CHF.Conclusions. Before CHF, endogenous bradykinin results in coronary dilation but has no effect on systemic arterial vasodilation or cardiac performance. After CHF, endogenous bradykinin is significantly increased and, acting through B2-receptors, produces coronary and arterial vasodilation and improves LV relaxation and contractile performance. Thus, endogenous bradykinin may play an important role in preserving cardiovascular function in CHF

Effects of Thiophene Units on Substituted Benzothiadiazole and Benzodithiophene Copolymers for Photovoltaic Applications

Two conjugated copolymers, P1 and P2, comprising of benzodithiophene and 5, 6-dioctyloxy-benzothiadiazole (DOBT) derivatives with/without thiophene unit, were synthesized via Stille cross-coupling polymerization reaction. These copolymers are promising for the applications in BHJ solar cells due to their good solubilities， proper thermal stability and moderate hole mobility as well as low bandgap. The photovoltaic properties of the copolymers were investigated based on the blend of the different polymer/PC71BM weight ratio under AM1.5G illumination, 100 mW/cm2. The device with ITO/PEDOT:PSS/P2: PC71BM (1:2, w/w)/Ca/Al gave relatively better photovoltaic performance, with a power conversion efficiency of 1.55%

De novo malignant solitary fibrous tumor of the kidney

The kidney is a relatively infrequent site for solitary fibrous tumor (SFT). Among the previously reported cases, only two cases of malignant renal SFT developing via dedifferentiation from a pre-existing benign SFT have been reported. Here we reported a case of de novo malignant renal SFT clinically diagnosed as renal cell carcinoma in a 50-year-old woman. The tumor was circumscribed but unencapsulated and showed obvious hemorrhagic necrosis. Microscopically, the tumor was composed of patternless sheets of alternating hypercellular and hypocellular areas of spindle cells displaying mild to moderate nuclear atypia, frequent mitoses up to 8 per 10 high power fields, and a 20% Ki-67 proliferative index. Immunohistochemical studies revealed reactivity for CD34, CD99 and vimentin, with no staining for all other markers, confirming the diagnosis of SFT. No areas of dedifferentiation were seen after extensive sampling. Based on the pathologic and immunohistochemical features, a diagnosis of de novo malignant renal SFT was warranted. Our report expands the spectrum of malignant progression in renal SFTs. Even though this patient has been disease-free for 30 months, long-term follow-up is still mandatory

Isolated tracheal injury after whiplash

AbstractWhiplash, a sudden acceleration–deceleration movement that can cause diverse symptoms such as neck pain, cervicogenic headache, restricted neck movement, tingling of the arms (central cord syndrome), and dizziness. However, laryngotracheal injuries after whiplash are extremely rare. We report the case of a 25-year-old Taiwanese female who presented to the emergency department with severe posterior midline neck pain after a rear-end motorcycle collision. Her C-spine X-ray showed no definite fracture; furthermore, her neck noncontrast-enhanced CT scan revealed paratracheal free air. She was discharged uneventfully after a 12-h observation period. Laryngotracheal injuries after whiplash, a hyperextension–hyperflexion movement, are potentially life-threatening and could lead to airway obstruction. Such injuries should not be overlooked. To the best of our knowledge, this is the first case report of isolated laryngotracheal injury after whiplash

Effects of atrial natriuretic peptide on left ventricular performance in conscious dogs before and after pacinginduced heart failure.

ABSTRACT Atrial natriuretic peptide (ANP) has potent vasodilatory and natriuretic actions and may have therapeutic benefit in congestive heart failure (CHF). These benefits may be offset by a negative inotropic effect of ANP seen in isolated preparations. However, ANP&apos;s integrated effect on left ventricular (LV) contraction and relaxation, independent of loading conditions, both under normal conditions and after CHF, is not known. We studied six conscious dogs, instrumented to measure LV and left atrial pressures and to determine LV volume from three dimensions. ANP produced significant (P Ͻ .05) decreases in LV end-systolic pressure (101.2 Ϯ 11.8 versus 91.7 Ϯ 11.2 mm Hg, P Ͻ .05) in normal dogs and in dogs with CHF (93.1 Ϯ 6.4 versus 87.1 Ϯ 4.4 mm Hg, P Ͻ .05). ANP also caused significant reductions of the slope of end-systolic pressure-end-systolic volume relation both before (7.0 Ϯ 1.5 versus 6.3 Ϯ 1.5 mm Hg/ml) and after CHF (4.8 Ϯ 1.3 versus 4.4 Ϯ 1.2 mm Hg/ml, P Ͻ .05). Both before and after CHF, ANP slowed LV relaxation at matched end-systolic pressure. Before CHF, steady-state stroke volume and peak LV filling rate (dV/dt max ) were reduced. However, after CHF, the fall in end-systolic pressure more than offset the load-independent LV depression, as stroke volume, the rate LV relaxation, and dV/dt max were increased and minimum LV pressure reduced. ANP has negative effects on LV contractility and relaxation both before and after CHF. However, after CHF, afterload reduction with ANP overcomes its negative effects, resulting in net improvement of LV ejection and relaxation. Thus, the direct cardiodepressant effects of ANP should not limit its usefulness in CHF. Atrial natriuretic peptide (ANP) is a vasodilatory and natriuretic peptide secreted mainly by atrial myocytes ANP produces vasodilation and natriuresis in both the normal circulation and in CHF Materials and Methods Instrumentation. Six healthy, adult, heartworm-negative mongrel dogs (weight, 25-36 kg) were instrumented under anesthesia after induction with xylazine (2 mg/kg i.m.) and sodium thiopental (

Alpha adrenergic modulation on effects of norepinephrine transporter inhibitor reboxetine in five-choice serial reaction time task

The study examined the effects of a norepinephrine transporter (NET) inhibitor reboxetine (RBX) on an attentional performance test. Adult SD rats trained with five-choice serial reaction time task (5-CSRTT) were administered with RBX (0, 3.0 and 10 mg/kg) in the testing day. Alpha-1 adrenergic receptor antagonist PRA and alpha-2 adrenergic receptor antagonist RX821002 were used to clarify the RBX effect. Results revealed that rat received RBX at 10 mg/kg had an increase in the percentage of the correct response and decreases in the numbers of premature response. Alpha-1 adrenergic receptor antagonist Prazosin (PRA) at 0.1 mg/kg reversed the RBX augmented correct responding rate. However, alpha-2 adrenergic receptor antagonist RX821002 at 0.05 and 0.1 mg/kg dose dependently reversed the RBX reduced impulsive responding. Our results suggested that RBX as a norepinephrine transporter inhibitor can be beneficial in both attentional accuracy and response control and alpha-1 and alpha-2 adrenergic receptors might be involved differently

Inhibition of yes-associated protein suppresses brain metastasis of human lung adenocarcinoma in a murine model.

Yes-associated protein (YAP) is a main mediator of the Hippo pathway and promotes cancer development and progression in human lung cancer. We sought to determine whether inhibition of YAP suppresses metastasis of human lung adenocarcinoma in a murine model. We found that metastatic NSCLC cell lines H2030-BrM3(K-rasG12C mutation) and PC9-BrM3 (EGFRΔexon19 mutation) had a significantly decreased p-YAP(S127)/YAP ratio compared to parental H2030 (K-rasG12C mutation) and PC9 (EGFRΔexon19 mutation) cells (P&nbsp;&lt;&nbsp;.05). H2030-BrM3 cells had significantly increased YAP mRNA and expression of Hippo downstream genes CTGF and CYR61 compared to parental H2030 cells (P&nbsp;&lt;&nbsp;.05). Inhibition of YAP by short hairpin RNA (shRNA) and small interfering RNA (siRNA) significantly decreased mRNA expression in downstream genes CTGF and CYR61 in H2030-BrM3 cells (P&nbsp;&lt;&nbsp;.05). In addition, inhibiting YAP by YAP shRNA significantly decreased migration and invasion abilities of H2030-BrM3 cells (P&nbsp;&lt;&nbsp;.05). We are first to show that mice inoculated with YAP shRNA-transfected H2030-BrM3 cells had significantly decreased metastatic tumour burden and survived longer than control mice (P&nbsp;&lt;&nbsp;.05). Collectively, our results suggest that YAP plays an important role in promoting lung adenocarcinoma brain metastasis and that direct inhibition of YAP by shRNA suppresses H2030-BrM3 cell brain metastasis in a murine model

β-Lapachone induces heart morphogenetic and functional defects by promoting the death of erythrocytes and the endocardium in zebrafish embryos

<p>Abstract</p> <p>Background</p> <p>β-Lapachone has antitumor and wound healing-promoting activities. To address the potential influences of various chemicals on heart development of zebrafish embryos, we previously treated zebrafish embryos with chemicals from a Sigma LOPAC1280™ library and found several chemicals including β-lapachone that affected heart morphogenesis. In this study, we further evaluated the effects of β-lapachone on zebrafish embryonic heart development.</p> <p>Methods</p> <p>Embryos were treated with β-lapachone or dimethyl sulfoxide (DMSO) at 24 or 48 hours post fertilization (hpf) for 4 h at 28°C. Heart looping and valve development was analyzed by whole-mount <it>in situ </it>hybridization and histological analysis. For fractional shortening and wall shear stress analyses, AB and Tg (<it>gata1</it>:<it>DsRed</it>) embryos were recorded for their heart pumping and blood cell circulations via time-lapse fluorescence microscopy. Dextran rhodamine dye injection into the tail reticular cells was used to analyze circulation. Reactive oxygen species (ROS) was analyzed by incubating embryos in 5-(and 6-)-chloromethyl-2',7'-dichloro-dihydrofluorescein diacetate (CM-H₂DCFDA) and recorded using fluorescence microscopy. <it>o</it>-Dianisidine (ODA) staining and whole mount <it>in situ </it>hybridization were used to analyze erythrocytes. TUNEL assay was used to examine DNA fragmentation.</p> <p>Results</p> <p>We observed a linear arrangement of the ventricle and atrium, bradycardia arrhythmia, reduced fractional shortening, circulation with a few or no erythrocytes, and pericardial edema in β-lapachone-treated 52-hpf embryos. Abnormal expression patterns of <it>cmlc2</it>, <it>nppa</it>, <it>BMP4</it>, <it>versican</it>, and <it>nfatc1</it>, and histological analyses showed defects in heart-looping and valve development of β-lapachone-treated embryos. ROS production was observed in erythrocytes and DNA fragmentation was detected in both erythrocytes and endocardium of β-lapachone-treated embryos. Reduction in wall shear stress was uncovered in β-lapachone-treated embryos. Co-treatment with the NQO1 inhibitor, dicoumarol, or the calcium chelator, BAPTA-AM, rescued the erythrocyte-deficiency in circulation and heart-looping defect phenotypes in β-lapachone-treated embryos. These results suggest that the induction of apoptosis of endocardium and erythrocytes by β-lapachone is mediated through an NQO1- and calcium-dependent pathway.</p> <p>Conclusions</p> <p>The novel finding of this study is that β-lapachone affects heart morphogenesis and function through the induction of apoptosis of endocardium and erythrocytes. In addition, this study further demonstrates the importance of endocardium and hemodynamic forces on heart morphogenesis and contractile performance.</p