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

Effect of different intensities of physical activity on cardiometabolic markers and vascular and cardiac function in adult rats fed with a high-fat high-carbohydrate diet

Background: Physical activity (PA) and diet are 2 lifestyle factors that affect cardiometabolic risk. However, data on how a high-fat high-carbohydrate (HFHC) diet influences the effect of different intensities of PA on cardiometabolic health and cardiovascular function in a controlled setting are yet to be fully established. This study investigated the effect of sedentary behavior, light-intensity training (LIT), and high-intensity interval training (HIIT) on cardiometabolic markers and vascular and cardiac function in HFHC-fed adult rats. Methods: Twelve-week-old Wistar rats were randomly allocated to 4 groups (12 rats/group): control (CTL), sedentary (SED), LIT, and HIIT. Biometric indices, glucose and lipid control, inflammatory and oxidative stress markers, vascular reactivity, and cardiac electrophysiology of the experimental groups were examined after 12 weeks of HFHC-diet feeding and PA interventions. Results: The SED group had slower cardiac conduction (p = 0.0426) and greater thoracic aortic contractile responses (p < 0.05) compared with the CTL group. The LIT group showed improved cardiac conduction compared with the SED group (p = 0.0003), and the HIIT group showed decreased mesenteric artery contractile responses compared with all other groups and improved endothelium-dependent mesenteric artery relaxation compared with the LIT group (both p < 0.05). The LIT and HIIT groups had lower visceral (p = 0.0057 for LIT, p = 0.0120 for HIIT) and epididymal fat (p < 0.0001 for LIT, p = 0.0002 for HIIT) compared with the CTL group. Conclusion: LIT induced positive adaptations on fat accumulation and cardiac conduction, and HIIT induced a positive effect on fat accumulation, mesenteric artery contraction, and endothelium-dependent relaxation. No other differences were observed between groups. These findings suggest that few positive health effects can be achieved through LIT and HIIT when consuming a chronic and sustained HFHC diet

Discovery of the Zintl-phosphide BaCd2_{2}P2_{2} as a long carrier lifetime and stable solar absorber

Thin-film photovoltaics offers a path to significantly decarbonize our energy production. Unfortunately, current materials commercialized or under development as thin-film solar cell absorbers are far from optimal as they show either low power conversion efficiency or issues with earth-abundance and stability. Entirely new and disruptive materials platforms are rarely discovered as the search for new solar absorbers is traditionally slow and serendipitous. Here, we use first principles high-throughput screening to accelerate this process. We identify new solar absorbers among known inorganic compounds using considerations on band gap, carrier transport, optical absorption but also on intrinsic defects which can strongly limit the carrier lifetime and ultimately the solar cell efficiency. Screening about 40,000 materials, we discover the Zintl-phosphide BaCd$_{2}$P$_{2}$ as a potential high-efficiency solar absorber. Follow-up experimental work confirms the predicted promises of BaCd$_{2}$P$_{2}$ highlighting an optimal band gap for visible absorption, bright photoluminescence, and long carrier lifetime of up to 30 ns even for unoptimized powder samples. Importantly, BaCd$_{2}$P$_{2}$ does not contain any critical elements and is highly stable in air and water. Our work opens an avenue for a new family of stable, earth-abundant, high-performance Zintl-based solar absorbers. It also demonstrates how recent advances in first principles computation can accelerate the search of photovoltaic materials by combining high-throughput screening with experiment

Levothyroxine in Women with Thyroid Peroxidase Antibodies before Conception

BackgroundThyroid peroxidase antibodies are associated with an increased risk of miscarriage and preterm birth, even when thyroid function is normal. Small trials indicate that the use of levothyroxine could reduce the incidence of such adverse outcomes.MethodsWe conducted a double-blind, placebo-controlled trial to investigate whether levothyroxine treatment would increase live-birth rates among euthyroid women who had thyroid peroxidase antibodies and a history of miscarriage or infertility. A total of 19,585 women from 49 hospitals in the United Kingdom underwent testing for thyroid peroxidase antibodies and thyroid function. We randomly assigned 952 women to receive either 50 μg once daily of levothyroxine (476 women) or placebo (476 women) before conception through the end of pregnancy. The primary outcome was live birth after at least 34 weeks of gestation.ResultsThe follow-up rate for the primary outcome was 98.7% (940 of 952 women). A total of 266 of 470 women in the levothyroxine group (56.6%) and 274 of 470 women in the placebo group (58.3%) became pregnant. The live-birth rate was 37.4% (176 of 470 women) in the levothyroxine group and 37.9% (178 of 470 women) in the placebo group (relative risk, 0.97; 95% confidence interval [CI], 0.83 to 1.14, P=0.74; absolute difference, −0.4 percentage points; 95% CI, −6.6 to 5.8). There were no significant between-group differences in other pregnancy outcomes, including pregnancy loss or preterm birth, or in neonatal outcomes. Serious adverse events occurred in 5.9% of women in the levothyroxine group and 3.8% in the placebo group (P=0.14).ConclusionsThe use of levothyroxine in euthyroid women with thyroid peroxidase antibodies did not result in a higher rate of live births than placebo. (Funded by the United Kingdom National Institute for Health Research; TABLET Current Controlled Trials number, ISRCTN15948785.

L-Arginine attenuates cardiovascular impairment in DOCA-salt hypertensive rats

Nitric oxide (NO) is essential for normal function of the cardiovascular system. This study has determined whether chronic administration of L-arginine, the biological precursor of NO, attenuates the development of structural and functional changes in hearts and blood vessels of deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Uninephrectomized rats treated with DOCA (25 mg every 4th day sc) and 1% NaCl in the drinking water for 4 wk were treated with L-arginine (5% in food, 3.4 plus/minus 0.3 g per kg body wt-1 per day-1). Changes in cardiovascular structure and function were determined by echocardiography, microelectrode studies, histology, and studies in isolated hearts and thoracic aortic rings. DOCA-salt hypertensive rats developed hypertension, left ventricular hypertrophy with increased left ventricular wall thickness and decreased ventricular internal diameter, increased inflammatory cell infiltration, increased ventricular interstitial and perivascular collagen deposition, increased passive diastolic stiffness, prolonged action potential duration, increased oxidative stress, and inability to increase purine efflux in response to an increased workload. L-Arginine markedly attenuated or prevented these changes and also normalized the reduced efficacy of norepinephrine and acetylcholine in isolated thoracic aortic rings of DOCA-salt hypertensive rats. This study suggests that a functional NO deficit in blood vessels and heart due to decreased NO synthase activity or increased release of reactive oxygen species such as superoxide may be a key change initiating many aspects of the cardiovascular impairment observed in DOCA-salt hypertensive rats. These changes can be prevented or attenuated by administration of L-arginine

Chronic [beta]-adrenoceptor antagonist treatment controls cardiovascular remodeling in heart failure in the aging spontaneously hypertensive rat

Selective β1-adrenoceptor antagonists are part of standard therapy to prolong survival in human heart failure. This study has measured structural, functional, and electrical changes in the cardiovascular system of aging male spontaneously hypertensive rats (SHRs) to determine whether β1-adrenoceptor antagonist treatment can prevent or reverse the development of cardiovascular remodeling and heart failure in these rats. Fifteen-month-old male Wistar-Kyoto (WKY) rats or SHRs were treated with increasing metoprolol doses (30 mg·kg·d for 4 weeks, then 50 mg·kg·d for 4 weeks, then 80 mg·kg·d for 16 weeks po). Cardiovascular structure and function were determined using organ wet weight, in vivo echocardiography, histological analysis of inflammation and collagen, isolated heart and thoracic aortic ring preparations, and single cell microelectrode measurements. From 15 months, untreated SHRs developed left ventricular dilation, hypertrophy, inflammatory cell infiltration and fibrosis, and action potential prolongation together with progressive systolic, diastolic, and endothelial dysfunction and increased cardiac stiffness. Treatment with metoprolol decreased systolic blood pressure at 21 months only but improved survival, decreased ventricular weight, prevented chamber dilation, reduced inflammation, decreased fibrosis, attenuated action potential prolongation, improved systolic and diastolic function, decreased stiffness and improved endothelium-independent vascular responses. Chronic metoprolol treatment markedly attenuated both cardiac and vascular remodeling in the aging SHRs, thus attenuating the onset of heart failure and improving survival, independent of blood pressure reduction

Targets for pharmacological modulation of cardiac fibrosis

'The heart consists of the myocytes to produce force, the extracellular matrix to provide structural support and the blood vessels to supply nutrients and remove waste products. Studies on the mechanisms of cardiovascular disease, especially heart failure, have traditionally emphasised either deficiencies in myocyte function as the major cause of heart failure or inadequate perfusion as the major cause of ischaemic disease, for example atherosclerosis leading to coronary heart disease and myocardial infarction. The interest in the role of the third component, the extracellular matrix, in cardiovascular disease is much more recent and has emphasised the role of the collagens. The studies of Karl Weber and his colleagues [1-4] have played a key role in the realisation that excessive interstitial and perivascular collagen deposition, termed reactive fibrosis in contrast to reparative fibrosis (scar formation), is a critical component of cardiac remodelling in cardiovascular disease. Thus, Weber [4] argues that it is not the quantity but rather the quality of the myocardium that accounts for ventricular dysfunction in hypertension, the major risk factor for heart failure. This argues strongly that the extracellular matrix is a dynamic, rather than a static, component of the heart. This review will mention the biochemical processes leading to the synthesis and removal of collagens in the heart as the basis for understanding the targets for pharmacological intervention. The major emphasis of this review will be the drugs that may alter these biochemical processes involved in fibrosis. The ultimate aim of therapy with these drugs is to prevent or reverse deficits in cardiac function by controlling or reversing fibrosis to improve the quality of the myocardium.'--p. 275

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

L-arginine improves cardiovascular function in DOCA-salt hypertensive rats

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