Reversal of cardiac dysfunction by selective ET-A receptor antagonism

1. The effectiveness of a selective endothelin receptor-A (ET-A) antagonist, A-127722 (approximately 10 mg kg-1 day-1 as 200 mg kg-1 powdered food), to reverse existing cardiac remodelling and prevent further remodelling was tested in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. 2. Uninephrectomised rats (UNX) administered DOCA (25mg every 4th day sc) and 1% NaCl in drinking water for 28 days developed hypertension (systolic BP: UNX 128 6, DOCA-salt 182 5* mmHg; *P<0.05 vs UNX), left ventricular hypertrophy (UNX 1.99 0.06, DOCA-salt 3.30 0.08* mg/kg body wt), decreased left ventricular internal diameter (UNX 6.69 0.18, DOCA-salt 5.51 0.37* mm), an increased left ventricular monocyte/macrophage infiltration together with an increased interstitial collagen from 2.7 0.3 to 11.7 1.3%, increased passive diastolic stiffness (UNX 21.1 0.5, DOCA-salt 30.1 1.3*), prolongation of the action potential duration at 20% and 90% of repolarization (APD20 - UNX 6.8 1.1, DOCA-salt 10.1 1.5* msec; APD90 - UNX 34.4 3.5, DOCA-salt 64.3 10.4* msec) and vascular dysfunction (2.6 fold decrease in maximal contractile response to noradrenaline, 3.5 fold decrease in maximal relaxation response to acetylcholine). 3. Administration of A-127722 for 14 days starting 14 days after surgery attenuated the increases in systolic blood pressure (150 6** mmHg, **P<0.05 vs DOCA-salt), left ventricular wet weight (2.65 0.06** mg/kg body wt) and internal diameter (6.39 0.31** mm), prevented left ventricular monocyte/macrophage accumulation, attenuated the increased left ventricular interstitial collagen (7.6 1.3%**), reversed the increased passive diastolic stiffness (22.1 1.2**), attenuated the action potential duration prolongation (APD20 - 7.6 1.4**, APD90 - 41.5 6.9** msec) and normalized changes in vascular function. 4. ET-A receptor antagonism both reverses and prevents the cardiac and vascular remodelling in DOCA-salt hypertension and improves cardiovascular function

The Supreme Court and the Transformation of Juvenile Sentencing

In the past decade, the Supreme Court has transformed the constitutional landscape of juvenile crime regulation. In three strongly worded opinions, the Court held that imposing harsh criminal sentences on juvenile offenders violates the Eighth Amendment prohibition against cruel and unusual punishment. In combination, these cases create a special status for juveniles under Eighth Amendment doctrine as a category of offenders whose culpability is mitigated by their youth and immaturity, even for the most serious offenses. The Court also emphasized that juveniles are more likely to reform than adult offenders, and that most should be given a meaningful opportunity to demonstrate that they have done so. In short, because of young offenders’ developmental immaturity, harsh sentences that may be suitable for adult criminals are seldom appropriate for juveniles. These opinions announce a powerful constitutional principle – that “children are different” for purposes of criminal punishment. In articulating this principle, the Supreme Court has also provided general guidance to courts sentencing juveniles and to lawmakers charged with implementing the rulings. At the same time, the Court did not directly address the specifics of implementation and it left many questions unanswered about the implications of the opinions for juvenile sentencing regulation. In the years since Roper, Graham, and Miller, courts and legislatures have struggled to interpret the opinions and to create procedures and policies that are compatible with constitutional principles and doctrine. This report addresses the key issues facing courts and legislatures under this new constitutional regime, and provides guidance based on the Supreme Court’s Eighth Amendment analysis and on the principles the Court has articulated. Part I begins with the constitutional sentencing framework, grounded in the opinions and embodying the key elements of the Court’s analysis. It then explains the underlying developmental knowledge that supports the constitutional framework and the “children are different” principle. Part II Part II examines how courts and legislatures have responded to the Eighth Amendment opinions, through reforms of state laws regulating juvenile life without parole (JLWOP). While some state lawmakers appear to ignore or subvert the Supreme Court’s holdings, others have responded in ways that clearly embody the principles underlying Miller and Graham. In Montgomery v. Louisiana, the Court held that Miller applies retroactively because it established a substantive rule of constitutional law. Part III translates Miller’s directive that specific factors be considered in making individualized sentencing decisions. The report\u27s aim is to guide courts and clinicians in structuring sentencing hearings that incorporate sound developmental research and other evidence supporting or negating mitigation, without going beyond the limits of science. Part IV explores the broader implications of the Supreme Court’s developmental framework for juvenile sentencing and parole, implications that have already sparked law reforms beyond the relatively narrow holdings of Graham and Miller. Finally, the paper ends on a cautionary note, pointing to evidence that constitutionally sound, developmentally-based policies may be vulnerable to political and other pressures. Aside from mandates in the holdings themselves, reforms can be dismantled or discounted if conditions change. Measures to sustain the current trend in law reform are discussed

Novel Omega-3 Fatty Acid Epoxygenase Metabolite Reduces Kidney Fibrosis.

Cytochrome P450 (CYP) monooxygenases epoxidize the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid into novel epoxydocosapentaenoic acids (EDPs) that have multiple biological actions. The present study determined the ability of the most abundant EDP regioisomer, 19,20-EDP to reduce kidney injury in an experimental unilateral ureteral obstruction (UUO) renal fibrosis mouse model. Mice with UUO developed kidney tubular injury and interstitial fibrosis. UUO mice had elevated kidney hydroxyproline content and five-times greater collagen positive fibrotic area than sham control mice. 19,20-EDP treatment to UUO mice for 10 days reduced renal fibrosis with a 40%-50% reduction in collagen positive area and hydroxyproline content. There was a six-fold increase in kidney α-smooth muscle actin (α-SMA) positive area in UUO mice compared to sham control mice, and 19,20-EDP treatment to UUO mice decreased α-SMA immunopositive area by 60%. UUO mice demonstrated renal epithelial-to-mesenchymal transition (EMT) with reduced expression of the epithelial marker E-cadherin and elevated expression of multiple mesenchymal markers (FSP-1, α-SMA, and desmin). Interestingly, 19,20-EDP treatment reduced renal EMT in UUO by decreasing mesenchymal and increasing epithelial marker expression. Overall, we demonstrate that a novel omega-3 fatty acid metabolite 19,20-EDP, prevents UUO-induced renal fibrosis in mice by reducing renal EMT

Resistance of Leishmania (Leishmania) amazonensis and Leishmania (Viannia) braziliensis to nitric oxide correlates with disease severity in Tegumentary Leishmaniasis

BACKGROUND: Nitric oxide (NO(•)) plays a pivotal role as a leishmanicidal agent in mouse macrophages. NO(• )resistant Escherichia coli and Mycobacterium tuberculosis have been associated with a severe outcome of these diseases. METHODS: In this study we evaluated the in vitro toxicity of nitric oxide for the promastigote stages of Leishmania (Viannia) braziliensis and Leishmania (Leishmania) amazonensis parasites, and the infectivity of the amastigote stage for human macrophages. Parasites were isolated from patients with cutaneous, mucosal or disseminated leishmaniasis, and NO(• )resistance was correlated with clinical presentation. RESULTS: Seventeen isolates of L. (L.) amazonensis or L. (V.) braziliensis promastigotes were killed by up to 8 mM of more of NaNO(2 )(pH 5.0) and therefore were defined as nitric oxide-susceptible. In contrast, eleven isolates that survived exposure to 16 mM NaNO(2 )were defined as nitric oxide-resistant. Patients infected with nitric oxide-resistant Leishmania had significantly larger lesions than patients infected with nitric oxide-susceptible isolates. Furthermore, nitric oxide-resistant L. (L.) amazonensis and L. (V.) braziliensis multiplied significantly better in human macrophages than nitric oxide-susceptible isolates. CONCLUSION: These data suggest that nitric oxide-resistance of Leishmania isolates confers a survival benefit for the parasites inside the macrophage, and possibly exacerbates the clinical course of human leishmaniasis

Rosuvastatin attenuates hypertension-induced cardiovascular remodeling without affecting blood pressure in DOCA-salt hypertensive rats

The pleiotropic effects of statins represent potential mechanisms for the treatment of end-organ damage in hypertension. This study has investigated the effects of rosuvastatin in a model of cardiovascular remodelling, the DOCA-salt hypertensive rat. Male Wistar rats weighing 300-330g were uninephrectomized (UNX) or uninephrectomized and treated with DOCA (25 mg subcutaneously every fourth day) and 1% NaCl in the drinking water. Compared with UNX controls, DOCA-salt rats developed hypertension, cardiovascular hypertrophy, inflammation with perivascular and interstitial cardiac fibrosis, endothelial dysfunction and prolongation of ventricular action potential duration at 28 days. Rosuvastatin treated rats received 20mg/kg/day of the drug in 10% Tween 20 by oral gavage for 32 days commencing 4 days before uninephrectomy. UNX and DOCA-salt controls received vehicle only. Rosuvastatin therapy attenuated the development of cardiovascular hypertrophy, inflammation, fibrosis and ventricular action potential prolongation, but did not modify hypertension or vascular dysfunction. We conclude that the pleiotropic effects of rosuvastatin include attenuation of aspects of cardiovascular remodelling in the DOCA-salt model of hypertension in rats without altering systolic blood pressure

Mast Cells: Key Contributors to Cardiac Fibrosis

Historically, increased numbers of mast cells have been associated with fibrosis in numerous cardiac pathologies, implicating mast cells in the development of cardiac fibrosis. Subsequently, several approaches have been utilised to demonstrate a causal role for mast cells in animal models of cardiac fibrosis including mast cell stabilising compounds, rodents deficient in mast cells, and inhibition of the actions of mast cell-specific proteases such as chymase and tryptase. Whilst most evidence supports a pro-fibrotic role for mast cells, there is evidence that in some settings these cells can oppose fibrosis. A major gap in our current understanding of cardiac mast cell function is identification of the stimuli that activate these cells causing them to promote a pro-fibrotic environment. This review will present the evidence linking mast cells to cardiac fibrosis, as well as discuss the major questions that remain in understanding how mast cells contribute to cardiac fibrosis

Increased calcium influx mediates increased cardiac stiffness in hyperthyroid rats

Cardiac remodeling (hypertrophy and fibrosis) and an increased left ventricular diastolic stiffness characterize models of hypertension such as the SHR and DOCA-salt hypertensive rats. By contrast, hyperthyroidism induces hypertrophy and hypertension, yet collagen expression and deposition is unchanged or decreased, whereas diastolic stiffness is increased. We determined the possible role of increased calcium influx in the development of increased diastolic stiffness in hyperthyroidism by administering verapamil (15 mg/[kg x d] orally) to rats given triiodothyronine (T3) (0.5 mg/[kg x d] subcutaneously for 14 d). Administration of T3 significantly increased body temperature (control: 36.7 +/- 0.2 degrees C; T3: 39.6 +/- 0.2 degrees C), left ventricular wet weight (control: 2.09 +/- 0.02 mg/kg; T3 3.07 +/- 0.07 mg/kg), systolic blood pressure (control: 128 +/- 5 mmHg; T3: 156 +/- 4 mmHg), and left ventricular diastolic stiffness (control: 20.6 +/- 2.0; T3: 28.8 +/- 1.4). Collagen content of the left ventricle was unchanged. Contractile response to noradrenaline in thoracic aortic rings was reduced. Relaxation in response to acetylcholine (ACh) was also reduced in T3-treated rats, whereas sodium nitroprusside response was unchanged. Verapamil treatment of hyperthyroid rats completely prevented the increased diastolic stiffness and systolic blood pressure while attenuating the increased body temperature and left ventricular weight; collagen content remained unchanged. ACh response in thoracic aortic rings was restored by verapamil. Thus, in hyperthyroid rats, an increased calcium influx is a potential mediator of the increased diastolic stiffness independent of changes in collagen

The role of neuropeptides in adverse myocardial remodeling and heart failure

In addition to traditional neurotransmitters of the sympathetic and parasympathetic nervous systems, the heart also contains numerous neuropeptides. These neuropeptides not only modulate the effects of neurotransmitters, but also have independent effects on cardiac function. While in most cases the physiological actions of these neuropeptides are well defined, their contributions to cardiac pathology are less appreciated. Some neuropeptides are cardioprotective, some promote adverse cardiac remodeling and heart failure, and in the case of others their functions are unclear. Some have both cardioprotective and adverse effects depending on the specific cardiac pathology and progression of that pathology. In this review, we briefly describe the actions of several neuropeptides on normal cardiac physiology, before describing in more detail their role in adverse cardiac remodeling and heart failure. It is our goal to bring more focus toward understanding the contribution of neuropeptides to the pathogenesis of heart failure, and to consider them as potential therapeutic targets