High‐fat diet and chronic stress reduce central pressor and tachycardic effects of apelin in Sprague–Dawley rats

Central application of apelin elevates blood pressure and influences neuroendocrine responses to stress and food consumption. However, it is not known whether the central cardiovascular effects of apelin depend also on caloric intake or chronic stress. The purpose of the present study was to determine the effects of intracerebroventricular administration of apelin on blood pressure (mean arterial blood pressure) and heart rate in conscious Sprague–Dawley rats consuming either a normal‐fat diet (NFD) or high‐fat diet (HFD) for 12 weeks. During the last 4 weeks of the food regime, the rats were exposed (NFDS and HFDS groups) or not exposed (NFDNS and HFDNS groups) to chronic stress. Each group was divided into two subgroups receiving intracerebroventricular infusions of either vehicle or apelin. Apelin elicited significant increase of mean arterial blood pressure and heart rate in the NFDNS rats. This effect was abolished in the HFDNS, HFDS and NFDS groups. HFD resulted in a significant elevation of blood concentrations of total cholesterol, triglycerides glucose and insulin. Chronic stress reduced plasma concentration of total and high‐density lipoprotein cholesterol, and increased plasma corticosterone concentration and APJ receptor mRNA expression in the hypothalamus, whereas a combination of a HFD with chronic stress resulted in the elevation of plasma triglycerides, total cholesterol and low‐density lipoprotein cholesterol, and in increased plasma corticosterone concentration, apelin concentration and APJ receptor mRNA expression in the hypothalamus. It is concluded that a HFD and chronic stress result in significant suppression of the central pressor action of apelin, and cause significant though not unidirectional changes of metabolic and endocrine parameters.     

Central interaction between the apelinergic and vasopressinergic systems in the regulation of the haemodynamic parameters in rats maintained on a high-fat diet

A high-fat diet can affect the central activity of the apelinergic and vasopressinergic systems, which can have a significant impact on cardiovascular regulation. The aim of the study was to investigate the role of the central interaction between apelin and vasopressin in the regulation of the cardiovascular system in Sprague Dawley rats maintained on a normal-fat diet (NFD) or on a high-fat diet (HFD). The animals were instrumented with a cannula implanted into the left cerebral ventricle for intracerebroventricular (ICV) infusions of saline (0.9% NaCl), apelin-13 (APLN-13), V1a receptor antagonist (V1aRANT) APJ receptor antagonist (F13A), vasopressin (AVP); and with a catheter placed within the femoral artery for mean arterial blood pressure and heart rate monitoring. Blood, the hypothalamus and the medulla oblongata were collected for biochemical analysis. The hypertensive effect of APLN-13 was blocked by a prior ICV infusion of V1aRANT, only in the NFD rats. However, the hypertensive effect of AVP was blocked by the prior ICV infusion of F13A in both the NFD and HFD rats. A HFD caused an increase in the protein level of APJ and V1a receptors, both in the hypothalamus and the medulla oblongata. This study confirms the presence of an interaction between both peptides in the central regulation of the cardiovascular system in rats on a NFD or a HFD.     

Metformin prevents vascular prostanoid release alterations induced by a high‐fat diet in rats

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Synergistic effects of prenatal nicotine exposure and post‐weaning high‐fat diet on hypercholesterolaemia in rat offspring of different sexes

Hypercholesterolaemia is considered a disease with intrauterine origin. Recently, we reported that prenatal nicotine exposure (PNE) induced an abnormal level of total cholesterol in rat offspring before and after birth. However, there were little data about sex differences in serum cholesterol level in PNE offspring. In addition, many previous studies reported that blood cholesterol is associated with daily diet. This study was designed to analyse the interaction among PNE, high‐fat diet (HFD) and sex on cholesterol metabolism in the rat. Pregnant Wistar rats were administered 2 mg/kg nicotine subcutaneously from gestational day (GD) 11 until parturition. After weaning, pups were fed with normal diet or HFD till 24 weeks, and then, serum cholesterol phenotypes and hepatic cholesterol metabolism‐related genes were tested. Results showed that PNE manifested a distinct programming effect on cholesterol phenotype and cholesterol metabolism‐related genes. HFD aggregated PNE‐induced hypercholesterolaemia in adult offspring and exacerbated liver cholesterol metabolism dysfunction in PNE offspring. There was no sex difference in serum cholesterol level, but there were interactions among PNE, HFD and sex on cholesterol metabolic genes in adult offspring, which indicates that cholesterol metabolism in female offspring is more likely to be affected by PNE and HFD. In conclusion, HFD exacerbated PNE‐induced hypercholesterolaemia, and sex differences existed in liver cholesterol metabolic genes in PNE‐ or HFD‐treated offspring.     

Anti‐contractile effects of perivascular adipose tissue in thoracic aorta from rats fed a high‐fat diet: role of aerobic exercise training

The aim of the present study was to evaluate the effects of aerobic exercise training on perivascular adipose tissue (PVAT) function in thoracic aorta from rats fed a high‐fat diet. Aortic vascular reactivity was performed in sedentary (SD), trained (TR), sedentary high‐fat diet (SD‐HF), and trained high‐fat diet (TR‐HF) male Wistar rats in the absence (PVAT?) or in the presence (PVAT+) of thoracic PVAT. We also measured circulatory concentrations of leptin and tumour necrosis factor alpha (TNF‐α), as well as the protein expressions of TNF‐α receptor 1 (TNFR1) and inducible nitric oxide synthase (iNOS) on PVAT. In the SD‐HF group, the body weight, epididymal fat pad, thoracic PVAT, circulatory triglycerides, insulin, leptin and TNF‐α were increased when compared with the SD group, whereas exercise training reduced these values in TR‐HF group. The relaxing response curves to acetylcholine and sodium nitroprusside were not modified by either intervention (high‐fat diet or exercise training) or the presence of PVAT. The presence of PVAT had an anti‐contractile effect in response to serotonin in all groups. In SD‐HF group, the increased magnitude of anti‐contractile effects was in parallel with an up‐regulation of iNOS protein expression in PVAT without alteration in TNFR1. Exercise training was effective in normalizing the vascular reactivity in rings PVAT+ and in reducing the iNOS protein expression. Exercise training prevented the PVAT–induced alteration in thoracic aorta from rats fed a high‐fat diet.     

Endothelin ETB receptors contribute to sex differences in blood pressure elevation in angiotensin II hypertensive rats on a high‐salt diet

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Alleviative effect of ciliary neurotrophic factor analogue on high fat‐induced hepatic steatosis is partially independent of the central regulation

Ciliary neurotrophic factor (CNTF) analogues were reported to ameliorate fatty liver in db/db or high‐fat diet‐fed mice. It is generally thought that CNTF exerts its actions centrally. The aim of this study was to investigate whether peripheral effects of CNTF analogues are involved in the therapeutic effect on high fat‐induced hepatic steatosis. The rat model of fatty liver was induced by a high‐fat diet (HFD) for 12 weeks. In the next 2 weeks, rats were fed the HFD along with subcutaneous injection of vehicle or mutant recombinant human CNTF (rhmCNTF 0.05‐0.2 mg/kg per day). Steatotic HepG2 cells were induced by 50% fetal bovine serum (FBS) for 48 hours, and then treated with rhmCNTF for 24 hours. The results showed that after rhmCNTF treatment, hepatic triglyceride (TG) accumulation was attenuated both in vivo and in vitro. RhmCNTF increased protein expression of CPT‐1 and PPARα, and decreased SREBP‐1c, FAS and SCD‐1 in steatotic HepG2 cells. But the production of nitric oxide and 8‐isoPGF_2α in steatotic HepG2 cells was not affected by rhmCNTF. These results suggest that rhmCNTF has a peripheral effect that alleviates fat‐induced hepatic steatosis.     

Oral administration of alcalase potato protein hydrolysate‐APPH attenuates high fat diet‐induced cardiac complications via TGF‐β/GSN axis in aging rats

Consumption of high fat diet (HFD) is associated with increased cardiovascular risk factors among elderly people. Aging and obesity induced‐cardiac remodeling includes hypertrophy and fibrosis. Gelsolin (GSN) induces cardiac hypertrophy and TGF‐β, a key cytokine, which induces fibrosis. The relationship between TGF‐β and GSN in aging induced cardiac remodeling is still unknown. We evaluated the expressions of TGF‐β and GSN in HFD fed 22 months old aging SD rats, followed by the administration of either probucol or alcalase potato protein hydrolysate (APPH). Western blotting and Masson trichrome staining showed that APPH (45 and 75 mg/kg/day) and probucol (500 mg/kg/day) treatments significantly reduced the aging and HFD‐induced hypertrophy and fibrosis. Echocardiograph showed that the performance of the hearts was improved in APPH, and probucol treated HFD aging rats. Serum from all rats was collected and H9c2 cells were cultured with collected serums separately. The GSN dependent hypertrophy was inhibited with an exogenous TGF‐β in H9c2 cells cultured in HFD+ APPH treated serum. Thus, we propose that along with its role in cardiac fibrosis, TGF‐β also acts as an upstream activator of GSN dependent hypertrophy. Hence, TGF‐β in serum could be a promising therapeutic target for cardiac remodeling in aging and/or obese subjects.     

The role of NO in the posterior hypothalamus in amygdala‐generated pressor responses in conscious rats

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Comparison of cardioprotective efficacy resulting from a combination of atorvastatin and ischaemic post‐conditioning in diabetic and non‐diabetic rats

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The role of galectin‐3 in heart failure and cardiovascular disease

Galectin‐3, a β‐galactoside‐binding lectin, is a new important player in the progression of heart failure (HF) and is also linked to poor outcome in patients with cardiovascular disease. Genetic or pharmacological inhibition of galectin‐3 slows down the progression of myocardial inflammation, reduces collagen production, attenuates cardiac remodelling, and ameliorates cardiac function. In this review, we summarize recent progress in research on galectin‐3 as a regulatory molecule involved in cardiovascular fibrosis in HF and its potential role in the diagnosis, risk assessment and treatment of cardiovascular diseases.     

Effect of exercise training on renal function and renal aquaporin‐2 expression in rats with chronic heart failure

1. Chronic heart failure (CHF) is often accompanied by renal dysfunction. Exercise training may relieve the symptomatic burden and improve the overall prognosis of CHF. In the present study, the effects of exercise training on renal function and renal aquaporin (AQP)‐2 expression in CHF rats were examined to determine whether exercise training could relieve renal dysfunction in CHF rats. 2. Male Sprague–Dawley rats were divided into three groups: sham, sedentary CHF (Sed‐CHF) and exercise training CHF (Ex‐CHF) groups. Cardiorenal function was assessed in each group by haemodynamic measurement and ultraviolet spectrophotometry. Pathological changes in cardiac and renal tissues were evaluated histologically and the collagen volume fraction (CVF) was calculated. The expressions of AQP‐2 and β‐tubulin were determined by western blotting and immunohistochemistry. 3. The Sed‐CHF rats were found to have increased left ventricular end‐diastolic pressure (LVEDP) and CVF in the heart compared with sham rats. Exercise training decreased LVEDP and CVF values in Ex‐CHF rats. The Sed‐CHF rats were found to have increased serum levels of creatinine (sCr), blood urea nitrogen (BUN) and arginine vasopressin (AVP), as well as increased CVF in the kidney, compared with sham rats. Exercise training decreased levels of sCr, BUN, AVP and CVF in Ex‐CHF rats. Moreover, exercise training decreased AQP‐2 and β‐tubulin protein expression in the kidney of CHF rats. 4. The results suggest that exercise training can significantly improve the renal dysfunction in CHF rats and that the underlying mechanism may be related to water reabsorption and preventing changes to the cytoskeleton.     

Antihypertensive and anti‐inflammatory actions of combined azilsartan and chlorthalidone in Dahl salt‐sensitive rats on a high‐fat,high‐salt diet

Metabolic syndrome (MetS) and chronic kidney disease are global health issues. Metabolic syndrome induces hypertension and commonly results in renal damage. The optimal therapy for hypertension in MetS is unknown. Thiazide diuretics are first‐line therapy; however, these drugs may have untoward effects. In the present study we investigated the effects of azilsartan (AZL), chlorthalidone (CLTD) and their combination on blood pressure and renal injury in a rodent model with features of MetS. Dahl salt‐sensitive rats were fed high‐fat (36% fat), high‐salt (4% NaCl) diet. Groups were then treated with vehicle, AZL (3 mg/kg per day), CLTD (5 mg/kg per day) or AZL + CLTD. Mean arterial pressure was recorded continuously by telemetry. After 26 days, rats were killed humanely and their kidneys were harvested for histology. Both AZL and CLTD attenuated the rise in blood pressure compared with vehicle and the combination further reduced blood pressure compared with CLTD alone. All treatments reduced proteinuria and albuminuria. Nephrinuria was prevented only in groups treated with AZL. Nephrinuria was 57% lower and proteinuria was 47% lower with combination therapy compared with AZL alone. All treatments reduced the number of inflammatory cells in the kidney. In conclusion, in our model, AZL and CLTD lower blood pressure and exhibit renal protective effects. Treatment with AZL offers additional protection, as evidenced by lower nephrinuria and plasma monocyte chemoattractant protein‐1 levels. Combination therapy afforded the greatest protective effects and may be the best choice for hypertensive therapy in MetS.     

The effect of continuous positive airway pressure on heart rate variability during the night in patients with chronic heart failure and central sleep apnoea

Continuous positive airway pressure (CPAP) improves autonomic activity in patients with chronic heart failure (CHF) and central sleep apnoea (CSA), but its effect on heart rate variability (HRV) during therapy has not been reported. We hypothesized that CPAP may decrease HRV, despite its beneficial effects on sympathetic overactivation, due to the expected stabilization of breathing. Sixty‐seven CHF patients underwent polysomnography (PSG). Ten of them presented with CSA (age 66.1±8.5 years, apnoea‐hypopnea index [AHI]=57.6±23.3, central AHI [cAHI]=41.6±24.6 [mean±SD]) and were subjected to a second PSG with manual CPAP titration. Beat‐to‐beat heart intervals for a 6‐hour period of sleep were extracted from each recording and HRV was analysed. CPAP significantly reduced AHI (AHI=23.1±18.3 P=.004). Standard deviation of normal‐normal interbeat interval (SDNN) (61.5±29.0 vs 49.5±19.3 ms, P=.021), root mean square of successive differences (RMSSD) (21.8±9.2 vs 16.4±7.1 ms, P=.042), total power (lnTP=7.8±1.1 vs 7.4±0.8 ms², P=.037), low frequency power (lnLF=5.5±1.5 vs 5.0±1.4 ms², P=.003) and high frequency power (lnHF=4.6±1.0 vs 4.0±1.0 ms², P=.024) were decreased. There was a strong correlation between the decrease in AHI and the decrease in lnHF (Spearman's ρ=.782). CPAP leads to a decrease in spectral and time domain parameters of HRV during therapy in CHF patients with CSA. These changes are best explained by the effect which CPAP‐influenced breathing pattern and lowered AHI exert on HRV.     

注射用益气复脉（冻干）对心力衰竭感染性休克大鼠的药效研究

目的 探讨注射用益气复脉（冻干）（YQFM）对心力衰竭感染性休克大鼠的药效作用。方法 通过结扎冠状动脉左前降支以及尾静脉推注脂多糖（LPS，25 mg·kg^-1）的方法建立心力衰竭感染性休克大鼠模型，随机将造模后大鼠分为模型组，肾上腺素（10 μg·kg^-1）组，YQFM低、高剂量（232.2、464.3 mg·kg^-1）组，联合给药（肾上腺素10 μg·kg^-1＋YQFM 464.3 mg·kg^-1）组，假手术组进行同样操作但不结扎不推注LPS。造模后即给药，尾iv给药1次，模型组和假手术组大鼠给予等体积的0.9%氯化钠注射液。使用八通道无创血压仪检测造模前、造模后及给药后大鼠收缩压变化；ELISA法检测各组大鼠血清中脑钠肽（BNP）、氨基端前心钠肽（NT-proANP）、肌酸激酶同工酶（CK-MB）、乳酸脱氢酶（LDH）、丙氨酸氨基转移酶（ALT）、天冬氨酸氨基转移酶（AST）和超氧化物歧化酶（SOD）水平。结果 各组大鼠的基础收缩压无显著性差异，与假手术组比较，造模各组大鼠收缩压显著降低（P＜0.001）；与模型组比较，各给药组大鼠收缩压显著回升（P＜0.05、0.001）。与假手术组相比，模型组血清NT-proANP、BNP、CK-MB、LDH、ALT、AST水平显著升高（P＜0.001），SOD水平显著降低（P＜0.001）；与模型组相比，肾上腺素组，YQFM 232.2、464.3 mg·kg^-1组和联合给药组的NT-proANP、BNP、CK-MB、LDH、ALT、AST水平均显著下降（P＜0.05、0.01、0.001），肾上腺素组、YQFM 464.3 mg·kg^-1组和联合给药组SOD水平显著升高（P＜0.05、0.01、0.001）。结论 YQFM可以显著回升心力衰竭感染性休克大鼠的收缩压水平，改善血清中相关生化指标水平，并且与肾上腺素联合应用效果最好。     

Protective effects of melatonin and glucagon‐like peptide‐1 receptor agonist (liraglutide) on gastric ischaemia–reperfusion injury in high‐fat/sucrose‐fed rats

Ischaemia–reperfusion (I–R) injury is a serious pathology that is often encountered with thrombotic events, during surgery when blood vessels are cross‐clamped, and in organs for transplantation. Increased oxidative stress is the main pathology in I–R injury, as assessed in studies on the heart, kidney, and brain with little data available on gastric I–R (GI–R). Liraglutide is a GLP‐1 receptor agonist that has insulinotropic and weight reducing actions, and melatonin that has been much studied as a chronotropic hormone; have also studied as being anti‐oxidative stress agents. Herein, we aimed to explore the effects of liraglutide and melatonin on GI–R injury with high‐fat/sucrose diet. Rats were divided into six groups; two diet‐control, two melatonin‐ and two liraglutide‐pretreated groups. All rats were subjected to 30 minutes of gastric ischaemia followed by 1 hour of reperfusion. Gastric tissues were assessed for the percentage of DNA fragmentation, myeloperoxidase activity, total oxidant status, total antioxidant capacity, oxidative stress index, BMI and histopathological examination. We showed that high‐fat feeding for four weeks prior to GI–R significantly increased BMI, oxidative stress indices and decreased total antioxidant capacity, with a neutral effect on apoptosis compared to controls. Pretreatment with either melatonin (10 mg/kg per day orally) or liraglutide (25 μg/kg per day ip) reverses these effects. Furthermore, both drugs reduced weight only in HFS‐fed rats. Both liraglutide and melatonin have nearly similar protective effects on gastric I–R injury through decreasing the oxidative stress and apoptosis.     

胰岛素治疗对高脂喂养的糖尿病大鼠胰腺内胰岛素含量及胰岛素基因表达变化的影响

目的观察胰岛素治疗对长期高脂喂养的糖尿病(DM)大鼠胰腺内胰岛素含量和胰岛素基因表达的影响。方法Wistar大鼠随机分为正常饮食对照组(NC,n=10),糖尿病正常饮食组(DN,n=10),糖尿病高脂饮食组(DH,n=10)及糖尿病高脂饮食胰岛素治疗组(DHI,n=10)。测定空腹血浆游离脂肪酸(FFA)、甘油三酯(TG)和空腹葡萄糖(FBG)及口服葡萄糖负荷后2h血糖。留取胰腺标本分别测定胰腺内TG、FFA、胰岛素含量以及胰岛素基因表达水平。结果与NC组相比,DN组血浆及胰腺内TG和FFA含量明显增多(P<0·05~P<0·01),而胰岛素基因表达水平和胰岛素含量则明显降低(P<0·01、P<0·01);在两个糖尿病组之间,上述指标亦存在着差异,DH组血浆及胰腺内TG和FFA含量比DN组进一步增多(分别为P<0·01、P<0·01、P<0·01、P<0·05),且胰岛素基因表达水平和胰岛素含量进一步下降(P<0·05、P<0·01)。胰岛素治疗后,与DH组相比,血循环中的TG和FFA水平虽然没有改善(P>0·05),但胰腺内TG和FFA含量明显下降(P<0·01、P<0·01),同时胰岛素基因表达水平和胰岛素含量亦升高(P<0·01、P<0·01)。结论长期高脂喂养可损伤胰岛素的产生;胰岛素治疗对高脂饮食所致的上述影响有一定的改善作用。     

The central haemodynamic effects of a single intravenous dose of flosequinan in patients with severe heart failure

Summary The acute central haemodynamic and neuroendocrine effects of intravenous flosequinan were studied in a group of 10 patients with severe heart failure.Flosequinan improved cardiac output by a maximum of 1.59 l·min^–1, it reduced pulmonary capillary wedge pressure by 11.9 mm Hg and it also caused a reduction in right atrial pressure by a maximum of 7.2 mm Hg. It tended to cause a fall in plasma adrenaline levels but not in plasma noradrenaline. There was little fall in blood pressure in response to flosequinan and no patient developed an adverse event.Intravenous flosequinan may be a useful candidate drug for controlled clinical studies in patients with severe heart failure.     

注射用益气复脉（冻干）治疗慢性心力衰竭伴低血压的临床研究

目的 观察注射用益气复脉（冻干）治疗慢性心力衰竭伴低血压的疗效。方法 选取郑州市中医院2018年10月-2020年2月心内一科收治的120例慢性心力衰竭并低血压患者,采用随机数字法分为对照组（53例）和观察组（55例）。对照组针对原发病进行一般治疗。观察组在对照组治疗的基础上给予注射用益气复脉（冻干）,2.6~5.2 g加入5%葡萄糖注射液或0.9%氯化钠注射液250~500 mL中静滴,1次/d,连续使用7~14 d。观察两组患者的临床疗效,同时比较两组患者治疗前后的左室射血分数（LVEF）、N端脑钠肽前体（NT-proBNP）、心率、生活质量评分和血压水平。结果 治疗后,观察组患者总有效率为96.4%,显著高于对照组的84.9%,两组比较差异有统计学意义（P<0.05）。治疗后,两组LVEF显著升高,NT-proBNP、心率和生活质量评分均明显降低,同组治疗前后比较差异有统计学意义（P<0.05）;观察组在NTproBNP水平和生活质量评分显著低于于对照组（P<0.05）。治疗后,两组血压均有明显升高,同组治疗前后比较差异有统计学意义（P<0.05）,治疗后,观察组的血压水平显著高于对照组,两组比较差异有统计学意义（P<0.05）。结论 注射用益气复脉（冻干）治疗慢性心力衰竭合并低血压不仅能有效改善患者的心功能,减轻临床症状,而且能进一步提升低血压患者的血压水平。     

Changes in cardiovascular function after venlafaxine but not pregabalin in healthy volunteers: a double‐blind,placebo‐controlled study of orthostatic challenge,blood pressure and heart rate

It is generally thought that venlafaxine raises blood pressure at higher doses; however, some studies have found no effect or a decrease in blood pressure. The aim of this study was to evaluate the cardiovascular (CV) effects of 3 weeks of dosing with venlafaxine, pregabalin and placebo on young healthy adults. Fifty‐four participants, of mean age 23.1 years (sd 4.68), 29 male, were randomised into three parallel groups. Each group received one of the three drugs, dosed incrementally over a 3‐week period to reach daily doses of 150 mg/day venlafaxine and 200 mg/day pregabalin. Blood pressure sphygmomanometer measurements, heart rate measurements, and orthostatic challenges recorded continuously beat‐to‐beat were performed weekly over this period and 5 days after treatment cessation. Results showed resting systolic blood pressure (SBP) and resting and standing diastolic blood pressure (DBP) and heart rate (HR) were significantly raised by venlafaxine compared with the pregabalin and placebo groups. SBP drop on standing was larger, the resulting overshoot was smaller, and recovery was slower on venlafaxine. HR recovery was significantly impaired by venlafaxine. CV changes were observed after only 1 week of dosing at 112.5 mg/day. These effects of venlafaxine are likely to be due to its action of noradrenergic reuptake inhibition. Copyright © 2013 John Wiley & Sons, Ltd.