Central Bromocriptine‐Induced Tachycardia is Reversed to Bradycardia in Conscious,Deoxycorticosterone Acetate‐Salt Hypertensive Rats

Abstract: A central dopaminergic origin has been demonstrated for the bromocriptine‐induced tachycardia in conscious, normotensive rats. The present study investigated the effect of bromocriptine on heart rate and the principal site of action of this agonist in conscious, deoxycorticosterone acetate‐salt hypertensive rats, in which altered central dopaminergic activity has been previously reported. Intravenous administration of bromocriptine (150 μg/kg) increased heart rate (49±5 beats/min.) in uninephrectomized control rats, while it induced a significant bradycardia (50±6 beats/min.) in deoxycorticosterone acetate‐salt hypertensive rats. In the latter animals, intravenous (500 μg/kg) or intrathecal (40 μg/rat at T₉–T₁₀) pretreatment with domperidone, a selective dopamine D₂ receptor antagonist that does not cross the blood‐brain barrier, reduced partially, but significantly, the bradycardiac responses to bromocriptine (reduction of about 44% and 48% of the maximal effect, respectively). In contrast, the bromocriptine‐induced bradycardia was fully abolished by intravenous pretreatment with metoclopramide (300 μg/kg), a dopamine D₂ receptor antagonist that crosses the blood‐brain barrier, or by combined pretreatment with intravenous and intrathecal domperidone. These results indicate that, in deoxycorticosterone acetate‐salt hypertensive rats, bromocriptine decreases rather than increases heart rate, an effect that is mediated partly through a peripheral D₂ dopaminergic mechanism and partly through stimulation of spinal dopamine D₂ receptors. They further support the concept that, in normotensive, conscious rats, the central tachycardia of bromocriptine appears to predominate and to mask the bradycardia of this agonist at both peripheral and spinal dopamine D₂ receptors.     

Rosuvastatin Attenuates Heart Failure and Cardiac Remodelling in the Ageing Spontaneously Hypertensive Rat

Abstract: 3‐hydroxy‐3‐methylglutaryl(HMG)‐Coenzyme(Co)A reductase inhibitors such as rosuvastatin may improve clinical status in patients with hypertension and heart failure. The ageing spontaneously hypertensive rat (SHR) closely mimics the chronic heart failure disease process observed in humans. This study examined the structural and functional changes in the cardiovascular system of 15‐month‐old SHR and normotensive Wistar‐Kyoto (WKY) rats treated with rosuvastatin (20 mg/kg/day perorally) for 24 weeks. Cardiovascular structure and function were monitored serially by echocardiography. At 21 months, ex vivo Langendorff, electrophysiological or histological studies were performed. Chronic rosuvastatin treatment attenuated elevations of left ventricular wet weight (mg/g body weight: 21‐month WKY, 2.30 ± 0.04; 15‐month SHR, 3.03 ± 0.08; 21‐month SHR, 4.09 ± 0.10; 21‐month SHR + rosuvastatin, 3.50 ± 0.13), myocardial extracellular matrix content (% left ventricular area: 21‐month WKY, 7.6 ± 0.5; 15‐month SHR, 13.2 ± 0.8; 21‐month SHR 19.6 ± 1.0; 21‐month SHR with rosuvastatin 14.6 ± 1.2) and diastolic stiffness (κ: 21‐month WKY, 24.9 ± 0.6; 15‐month SHR, 26.4 ± 0.4; 21‐month SHR, 33.1 ± 0.8; 21‐month SHR + rosuvastatin, 27.5 ± 0.6) as well as attenuating the deterioration of systolic and diastolic function (fractional shortening %: 21‐month WKY, 66 ± 2; 15‐month SHR, 51 ± 3; 21‐month SHR, 38 ± 3; 21‐month SHR + rosuvastatin, 52 ± 4). There was no effect on the increased systolic blood pressure, plasma low‐density lipoprotein concentrations or the prolonged action potential duration. Thus, chronic rosuvastatin treatment may attenuate myocardial dysfunction in heart failure by preventing fibrosis.     

Acetyl‐l‐Carnitine Ameliorates Caerulein‐induced Acute Pancreatitis in Rats

Abstract: In the present study, we have addressed the possible protective role of acetyl‐l ‐carnitine in caerulein‐induced acute pancreatitis in male Swiss albino rats. Acute pancreatitis paradigm was developed by challenging animals with a supramaximal dose of caerulein (20 µg/kg, SC) four times at hourly intervals. Caerulein induced acute pancreatitis that was well‐characterized morphologically and biochemically. Severe oedema with marked increased relative pancreatic weight, marked atrophy of acini with increased interacinar spaces, vacuolization, and extensive leucocytic infiltration were diagnostic fingerprints of the pancreatitis phenotype. A biochemical test battery that confirmed the model comprised increased plasma amylase and lipase activities, calcium levels as well as increased pancreatic enzymatic myeloperoxidase and glutathione‐S‐transferase activities, beside increased pancreatic contents of nitric oxide and malondialdehyde and reduced pancreatic glutathione level. Prior administration of acetyl‐l ‐carnitine (200 mg/kg, IP) for seven consecutive days ahead of caerulein challenge alleviated all the histological and biochemical manifestations of acute pancreatitis. These results suggest a possible protective role of the carnitine ester in such a murine acute pancreatitis model probably via regulation of the oxidant/antioxidant balance, beside modulation of the myeloperoxidase and nitric oxide systems, which are involved in the inflammatory cascade that most often associate the disease.     

The Effects of l‐Carnitine Against Cyclophosphamide‐Induced Injuries in Mouse Testis

In order to explore the possibility of l ‐carnitine (LC) as a protector of male fertility in chemotherapy, we observed the damage of cyclophosphamide (CTX) to Sertoli cells and the protective effect of LC on the testis Sertoli cells from such damage in this study. Healthy adult male mice were divided into three groups: chemotherapy group were injected intraperitoneally with the CTX; protective agent group were injected both LC and CTX; control group mice were injected only with isochoric physiological saline; all once a day for 5 days. After 5 days, the mice were, respectively, killed at 24 hr after the last injection. The testis and epididymis were removed. Epididymis was for sperm analysis immediately, and immunohistochemistry, RT‐PCR and Western blot for the assessments of occludin, glial cell‐derived neurotrophic factor (GDNF) and TGF‐β3 mRNA and protein expression. The sperm analysis of epididymis showed that CTX can significantly decrease sperm count and motility; and administration of LC resulted in significant recovery of the sperm count and sperm motility. Compared with control group, the expressions of occludin and GDNF decreased and the expression of TGF‐β3 increased significantly (p < 0.05) in the CTX group. In the LC + CTX group, the expressions of occludin and GDNF were higher than those of the CTX group and similar to those of the control group; the TGF‐β3 expression was lower (p < 0.05) than that of the CTX group and similar to that of the control group. The results of this study showed that CTX could damage the spermatogenesis and reduce the expression of occludin and GDNF, and increase the expression of TGF‐β3 in testis of mouse, which indicates CTX's damage or efficacy to testis Sertoli cells. LC could protect the Sertoli cells of testis from these damages caused by CTX, and promote or protect the spermatogenesis. In conclusion, this study provides meaningful information about the possible damage to male fertility by chemotherapeutics and potential of LC in the protection of male fertility during chemotherapy.     

Pharmacological Evaluation of a β‐Hydroxyphosphonate Analogue of l‐Carnitine in Obese Zucker fa/fa Rats

In this study, we evaluated the effect of an analogue of l ‐carnitine on parameters involved with Metabolic Syndrome in obese Zucker rats. Twenty‐four rats were treated for 5 weeks with l ‐carnitine (300 mg/kg) and its analogue at two concentrations (100 and 250 mg/kg) to assess their impact on glucose, triglycerides and cholesterol in liver and blood samples, as well as the amount of liver glycogen. Liver slices were also analysed. The analogue reduced the levels of glucose, triglycerides and cholesterol in liver and the level of triglycerides in serum. At 100 mg/kg, the analogue proved more effective than l ‐carnitine in improving the biochemical alterations present in liver. The amount of liver glycogen content was higher in obese animals treated with both l ‐carnitine and the analogue. No changes on insulin and leptin were observed in animals treated. l ‐carnitine and its analogue reduced the microvesicular fatty infiltration in liver. This study demonstrated that the analogue tested is more potent and efficient than l ‐carnitine and improves the pharmacological profile of l ‐carnitine.     

l‐Arginine Attenuates Cardiac Dysfunction,But Further Down‐Regulates α‐Myosin Heavy Chain Expression in Isoproterenol‐Induced Cardiomyopathy

In view of previously reported increased capacity for nitric oxide production, we suggested that l ‐arginine (ARG), the nitric oxide synthase (NOS) substrate, supplementation would improve cardiac function in isoproterenol (ISO)‐induced heart failure. Male Wistar rats were treated with ISO for 8 days (5 mg/kg/day, i.p.) or vehicle. ARG was given to control (ARG) and ISO‐treated (ISO+ARG) rats in water (0.4 g/kg/day). ISO administration was associated with 40% mortality, ventricular hypertrophy, decreased heart rate, left ventricular dysfunction, fibrosis and ECG signs of ischaemia. RT‐PCR showed increased mRNA levels of cardiac hypertrophy marker atrial natriuretic peptide, but not BNP, decreased expression of myosin heavy chain isoform MYH6 and unaltered expression of pathological MYH7. ISO increased the protein levels of endothelial nitric oxide synthase, but at the same time it markedly up‐regulated mRNA and protein levels of gp91phox, a catalytical subunit of superoxide‐producing NADPH oxidase. Fibrosis was markedly increased by ISO. ARG treatment moderately ameliorated left ventricular dysfunction, but was without effect on cardiac hypertrophy and fibrosis. Combination of ISO and ARG led to a decrease in cav‐1 expression, a further increase in MYH7 expression and a down‐regulation of MYH6 that inversely correlated with gp91phox mRNA levels. Although ARG, at least partially, improved ISO‐impaired basal left ventricular systolic function, it failed to reduce cardiac hypertrophy, fibrosis, oxidative stress and mortality. The protection of contractile performance might be related to increased capacity for nitric oxide production and the up‐regulation of MYH7 which may compensate for the marked down‐regulation of the major MYH6 isoform.     

Docosahexaenoic acid and l‐Carnitine prevent ATP loss in SH‐SY5Y neuroblastoma cells after exposure to silver nanoparticles

Silver nanoparticles (AgNPs) are among the most commonly used nanomaterials, but thus far, little is known about ways to mitigate against potential toxic effects of exposure. In this study, we examined the potential effects of AgNPs on mitochondrial function and cellular ATP levels, and whether these could be prevented by treatment with docosahexaenoic acid (DHA) and l ‐carnitine (LC). Acute exposure of AgNPs for 1 h to SH‐SY5Y cells resulted in decreased mitochondrial membrane potential, and decreased ATP and ADP levels, indicating mitochondrial damage and reduced production of ATP. Incubation of cells with DHA partially reduced, while treatment with LC and DHA completely abolished the AgNP induced decreases in ATP and ADP levels. This could be due to a LC‐facilitated entry of DHA to mitochondria, for repair of damaged phospholipids. It is postulated that DHA and LC may be useful for treatment of accidental environmental exposure to AgNPs. © 2014 Wiley Periodicals, Inc. Environ Toxicol 31: 224–232, 2016.     

乐卡地平对原发性高血压大鼠动脉粥样硬化血管内皮功能的影响

目的观察乐卡地平对原发性高血压大鼠动脉粥样硬化血管内皮的保护作用,探讨乐卡地平抗动脉粥样硬化的机制。方法采用大剂量维生素D3联合高脂饲料饲养的方法建立原发性高血压大鼠动脉粥样硬化模型。将20只8周龄雄性原发性高血压大鼠分为原发性高血压大鼠动脉粥样硬化模型组(模型组)和乐卡地平治疗组(治疗组),10只8周龄WKY大鼠设为空白对照组(对照组)。于实验结束时,取血检测一氧化氮(NO)水平和一氧化氮合酶(NOS)活性,并取胸主动脉下段做HE和Vonkossa染色,进行病理形态学观察。结果模型组大鼠的血清NO水平及诱导型NOS(iNOS)、内皮型NOS(eNOS)活性与对照组间差异均有统计学意义(P<0.01);治疗组大鼠的血清iNOS、eNOS活性与模型组间差异有统计学意义(P<0.05)。结论乐卡地平可升高eNOS活性,降低iNOS活性,促进内皮源性NO释放,改善内皮依赖性舒张功能,这可能是发挥其抗动脉粥样硬化作用的机制之一。     

乐卡地平对原发性高血压大鼠动脉粥样硬化血管内皮功能的影响

目的 观察乐卡地平对原发性高血压大鼠动脉粥样硬化血管内皮的保护作用,探讨乐卡地平抗动脉粥样硬化的机制.方法 采用大剂量维生素D3联合高脂饲料饲养的方法建立原发性高血压大鼠动脉粥样硬化模型.将20只8周龄雄性原发性高血压大鼠分为原发性高血压大鼠动脉粥样硬化模型组(模型组)和乐卡地平治疗组(治疗组),10只8周龄WKY大鼠设为空白对照组(对照组).于实验结束时,取血检测一氧化氮(NO)水平和一氧化氮合酶(NOS)活性,并取胸主动脉下段做HE和Von kossa染色,进行病理形态学观察.结果 模型组大鼠的血清NO水平及诱导型NOS(iNOS)、内皮型NOS(eNOS)活性与对照组间差异均有统计学意义(P＜0.01);治疗组大鼠的血清iNOS、eNOS活性与模型组间差异有统计学意义(P＜0.05).结论 乐卡地平可升高eNOS活性,降低iNOS活性,促进内皮源性NO释放,改善内皮依赖性舒张功能,这可能是发挥其抗动脉粥样硬化作用的机制之一.     

Endothelium-dependent Vascular Responses in 1,3-Dipropyl-8-sulphophenylxanthine (DPSPX) Hypertensive Rats

The study was undertaken to test the endothelium-mediated vascular responses in rats rendered hypertensive by chronic administration of 1,3-dipropyl-8-sulphophenylxanthine (DPSPX). The relaxant effect of carbachol (an endothelium-dependent relaxing drug) and of sodium nitroprusside (an endothelium-independent relaxing drug) as well as the potentiation of the contractile effect of noradrenaline by N^G-nitro-l-arginine methyl ester (l-NAME) were compared in aortic rings from normotensive and DPSPX-hypertensive rats. Carbachol and sodium nitroprusside caused concentration-dependent relaxations in aortic rings precontracted by 1 μM noradrenaline. The relaxant effect of carbachol was significantly reduced in tissues of DPSPX-hypertensive rats: the maximal relaxant effect being 86 ± 3% and 64 ± 4% (of the pre-existing tone) in normal and hypertensive rats, respectively, while there were no significant differences in the relaxant effect of sodium nitroprusside. l-NAME (100 μM) significantly reduced the EC50 values of noradrenaline (3.71 ± 0.28 times, n = 8 and 2.96 ± 0.27 times, n = 7, in normal and hypertensive rats, respectively) and significantly enhanced the maximal contractile effect of noradrenaline (46 ± 8%, n = 8 and 35 ± 6%, n = 7, in normal and hypertensive rats respectively): the factors of reduction of EC50 values and the percentages of enhancement of the maximal contractile effect in the aorta of normal and hypertensive rats were not significantly different. The results obtained provide evidence of functional impairment of the endothelium in DPSPX-hypertensive rats.     

Fluoxetine Attenuates Chronic Methamphetamine‐induced Pulmonary Arterial Remodelling: Possible Involvement of Serotonin Transporter and Serotonin 1B Receptor

Epidemiological data have shown that methamphetamine (MA) abuse significantly increases the risk of developing pulmonary arterial hypertension (PAH). To investigate whether MA could induce PAH and its possible mechanism, rats were exposed daily to MA for 5 weeks in the absence or presence of fluoxetine. The results showed that the pulmonary arterial pressure was not significantly increased, but the pulmonary arterial remodelling was markedly developed in the MA exposure group. The protein expressions of the serotonin transporter (5‐HTT) and 5‐HT_1B receptor were increased in the lungs and in the pulmonary arteries of MA‐treated rats. Fluoxetine attenuated the pulmonary arterial remodelling and down‐regulated the protein expression of 5‐HTT and 5‐HT_1B receptor in pulmonary arteries of MA‐treated rats. These findings suggest that fluoxetine has a novel potential suppressive effect on the chronic MA‐induced pulmonary vascular remodelling and also suggest that 5‐HTT and 5‐HT_1B receptor may be involved as part of its mechanism.     

l‐Carnitine protects against 1,4‐benzoquinone‐induced apoptosis and DNA damage by suppressing oxidative stress and promoting fatty acid oxidation in K562 cells

Widespread occupational and environmental exposure to benzene is unavoidable and poses a public health threat. Studies of potential interventions to prevent or relieve benzene toxicity are, thus, essential. Research has shown l ‐carnitine (LC) has beneficial effects against various pathological processes and diseases. LC possesses antioxidant activities and participates in fatty acid oxidation (FAO). In this study, we investigated whether 1,4‐benzoquinone (1,4‐BQ) affects LC levels and the FAO pathway, as well as analyzed the influence of LC on the cytotoxic effects of 1,4‐BQ. We found that 1,4‐BQ significantly decreased LC levels and downregulated Cpt1a, Cpt2, Crat, Hadha, Acaa2, and Acadvl mRNA expression in K562 cells. Subsequent assays confirmed that 1,4‐BQ decreased cell viability and increased apoptosis and caspase‐3, ‐8, and ‐9 activities. It also induced obvious oxidative stress and DNA damage, including an increase in the levels of reactive oxygen species and malondialdehyde, tail DNA%, and olive tail moment. Additionally, the mitochondrial membrane potential was significantly reduced. Cotreatment with LC (500 μmol/L) relieved these alterations by reducing oxidative stress and increasing the protein expression levels of Cpt1a and Hadha, particularly in the 20 μmol/L 1,4‐BQ group. Thus, our results demonstrate that 1,4‐BQ causes cytotoxicity, reduces LC levels, and downregulates the FAO genes. In contrast, LC exhibits protective effects against 1,4‐BQ‐induced apoptosis and DNA damage by decreasing oxidative stress and promoting the FAO pathway.     

Pharmacokinetics of the Experimental Non‐Nucleosidic DNA Methyl Transferase Inhibitor N‐Phthalyl‐l‐Tryptophan (RG 108) in Rats

DNA methyl transferase (DNMT) inhibitors can re‐establish the expression of tumour suppressor genes in malignant diseases, but might also be useful in other diseases. Inhibitors in clinical use are nucleosidic cytotoxic agents that need to be integrated into the DNA of dividing cells. Here, we assessed the in vivo kinetics of a non‐nucleosidic inhibitor that is potentially free of cytotoxic effects and does not require cell division. The non‐specific DNMT inhibitor N‐phthalyl‐l ‐tryptophan (RG 108) was injected subcutaneously in rats. Blood was drawn 0, 0.5, 1, 2, 4, 6, 8 and 24 hr after injection and RG 108 in plasma was measured by high‐performance liquid chromatography coupled to mass spectrometry. Trough levels and area under the curve (AUC) were significantly higher with multiple‐dose administration and cytochrome inhibition. In this group, time to maximal plasma concentration (t_max, mean ± S.D.) was 37.5 ± 15 min., terminal plasma half‐life was approximately 3.7 h (60% CI: 2.1–15.6 h), maximal plasma concentration (C_max) was 61.3 ± 7.6 μM, and AUC was 200 ± 54 μmol·h/l. RG 108 peak levels were not influenced by cytochrome inhibition or multiple‐dose administration regimens. Maximal tissue levels (C_max in μmol/kg) were 6.9 ± 6.7, 1.6 ± 0.4 and 3.4 ± 1.1 in liver, skeletal and heart muscle, respectively. We conclude that despite its high lipophilicity, RG 108 can be used for in vivo experiments, appears safe and yields plasma and tissue levels in the range of the described 50% inhibitory concentration of around 1 to 5 μM. RG 108 can therefore be a useful tool for in vivo DNMT inhibition.     

Matrix Metalloproteinase‐2 Activity is Associated with Divergent Regulation of Calponin‐1 in Conductance and Resistance Arteries in Hypertension‐induced Early Vascular Dysfunction and Remodelling

Matrix metalloproteinase (MMP)‐2 participates in hypertension‐induced maladaptive vascular remodelling by degrading extra‐ and intracellular proteins. The consequent extracellular matrix rearrangement and phenotype switch of vascular smooth muscle cells (VSMCs) lead to increased cellular migration and proliferation. As calponin‐1 degradation by MMP‐2 may lead to VSMC proliferation during hypertension, the hypothesis of this study is that increased MMP‐2 activity contributes to early hypertension‐induced maladaptive remodelling in conductance and resistance arteries via regulation of calponin‐1. The main objective was to analyse whether MMP‐2 exerts similar effects on the structure and function of the resistance and conductance arteries during early hypertension. Two‐kidney, one‐clip (2K‐1C) hypertensive male rats and corresponding controls were treated with doxycycline (30 mg/kg/day) or water until reaching one week of hypertension. Systolic blood pressure was increased in 2K‐1C rats, and doxycycline did not reduce it. Aortas and mesenteric arteries were analysed. MMP‐2 activity and expression were increased in both arteries, and doxycycline reduced it. Significant hypertrophic remodelling and VSMC proliferation were observed in aortas but not in mesenteric arteries of 2K‐1C rats. The contractility of mesenteric arteries to phenylephrine was increased in 2K‐1C rats, and doxycycline prevented this alteration. The potency of phenylephrine to contract aortas of 2K‐1C rats was increased, and doxycycline decreased it. Whereas calponin‐1 expression was increased in 2K‐1C mesenteric arteries, calponin‐1 was reduced in aortas. Doxycycline treatment reverted changes in calponin‐1 expression. MMP‐2 contributes to hypertrophic remodelling in aortas by decreasing calponin‐1 levels, which may result in VSMC proliferation. On the other hand, MMP‐2‐dependent increased calponin‐1 in mesenteric arteries may contribute to vascular hypercontractility in 2K‐1C rats. Divergent regulation of calponin‐1 by MMP‐2 may be an important mechanism that leads to maladaptive vascular effects in hypertension.     

Age-dependent Modifications of the Role of Prostanoids in Cardiac Preparations from Normotensive and Hypertensive Rats

The cardiac response to field stimulation of adrenergic nerve terminals in isolated atrial preparations from adult (6-month-old) normotensive Wistar Kyoto (WKY) and spontaneously hypertensive (SH) rats was enhanced in comparison to that observed in the atrial tissue of young (2-month-old) animals of both strains; the increase in the sympathetic response was significantly higher in preparations from SHR than in those from age-matched WKY rats. The sensitivity of cardiac adrenergic neurotransmission to the prejunctional inhibitory effects exerted by exogenously administered prostaglandin E₂ (0.1 nM-1 μM) and iloprost (0.1-10 μM) did not show any strain-dependent difference in preparations from both young and adult rats. Moreover, acetylsalicylic acid (500 μM) induced a similar degree of potentiation of the response to sympathetic stimulation in atrial tissues of young WKY and SH animals; however, the effect of the cyclo-oxygenase inhibitor was completely missing in preparations from adult rats of both strains. Finally, arachidonic acid (10 μM) inhibited the adrenergic response to a greater extent in preparations from young and adult SH rats than in those from agematched normotensive rats. The results of the study indicate that, at least in cardiac preparations, changes in the modulatory role of endogenous prostaglandins occur as age-dependent processes and, therefore, may not be indicative of possible differences in the role of prostaglandins between hypertensive and normotensive animals. The possible significance of the dissimilar response to arachidonic acid, detected as the only difference between preparations from SH and WKY rats, is discussed.     

天麻芎苓止眩片对自发性高血压大鼠血压及血管重塑的影响

目的探讨天麻芎苓止眩片(Tianma Xiongling Zhixuan tablet,TXZT)对自发性高血压大鼠(spontaneously hypertensive rats,SHR)的降压作用和改善血管重塑作用。方法采用SHR大鼠和正常WKY大鼠进行实验,连续给药4周,比较每周各组大鼠血压值;ELISA法检测血清中eNOS、ET-1、TXA2、AngⅡ的含量变化;HE染色法观察大鼠主动脉的病理变化;免疫组化和Western blotting测定主动脉MMP-2、TIMP-2蛋白表达;RT-PCR测定主动脉MMP-2、TIMP-2 mRNA表达。结果与模型组比较,给药第1~4周,TXZT具有显著的降血压药理作用(P<0.01或P<0.05)。与模型组相比,TXZT能够有效降低SHR大鼠血清ET-1、TXA2、AngⅡ的水平,升高eNOS的水平(P<0.01或P<0.05);且能够明显改善血管病理变化。免疫组化和Western blotting结果显示,与模型组相比,TXZT能显著减弱MMP-2表达、降低MMP-2/TIMP-2比值(P<0.01或P<0.05)。RT-PCR结果显示,经TXZT治疗后大鼠血管MMP-2的mRNA表达下降,TIMP-2的mRNA表达上升,MMP-2/TIMP-2比值降低(P<0.05)。结论 TXZT具有显著的降压和改善血管内皮功能作用,调节MMP-2/TIMP-2蛋白表达是其调节SHR大鼠血管重塑作用机制之一。     

辣椒素对自发性高血压大鼠血管平滑肌细胞增殖和迁移的影响

目的 探讨辣椒素对自发性高血压大鼠血管平滑肌细胞（vascular smooth muscle cells,VSMCs）增殖和迁移的影响。方法 体外构建自发性高血压大鼠血管平滑肌细胞系,分别采用20 μmol·L^-1辣椒素（高剂量组）、10 μmol·L^-1辣椒素（中剂量组）、5 μmol·L^-1辣椒素（低剂量组）和1 μmol·L^-1厄贝沙坦（厄贝沙坦组）直接处理细胞或特异性阻断CD36的表达后,再分别用20 μmol·L^-1辣椒素（高剂量组）、10 μmol·L^-1辣椒素（中剂量组）、5 μmol·L^-1辣椒素（低剂量组）和1 μmol·L^-1厄贝沙坦（厄贝沙坦组）处理细胞,采用MTT法检测VSMCs增殖情况,Boyden趋化小室检测VSMCs迁移情况,实时荧光定量PCR（qRT-PCR）和蛋白免疫印迹（Western blotting）检测平滑肌22a蛋白（smooth muscle 22a,SM22a）和调宁蛋白（Calponin）mRNA和蛋白的表达水平。结果 辣椒素和厄贝沙坦分别处理VSMCs后,与对照组相比,高、中、低剂量辣椒素组和厄贝沙坦组细胞增殖率和迁移率均有所降低,SM22a和Calponin的表达上调;与厄贝沙坦组相比,高剂量辣椒素组SM22a和Calponin的表达有所上调,中、低剂量辣椒素组SM22a和Calponin的表达均有所下调。特异性阻断CD36的表达后,与对照组相比,高、中、低剂量辣椒素组和厄贝沙坦组细胞增殖率降低,迁移率进一步降低,SM22a和Calponin表达上调;与厄贝沙坦组相比,高、中、低剂量辣椒素组SM22a的表达均有所上调,高、中、低剂量辣椒素组Calponin的表达有所下调。结论 高、中、低剂量辣椒素能够通过上调SM22a和Calponin的表达,抑制CD36的表达,来促进自发性高血压大鼠VSMCs由未分化表型向分化表型转化,从而抑制VSMCs的增殖及迁移和高血压血管重构的发生,促进其动脉管壁恢复正常的生理功能,有助于降低血压。     

复合离子盐对自发性高血压大鼠胰岛素抵抗相关因素的影响

目的 :本研究通过观察不同剂量复合离子盐对自发性高血压大鼠 (SHR)胰岛素抵抗相关因素的影响 ,探讨复合离子盐能否对原发性高血压起到防治作用。方法 :对61只自发性高血压大鼠分别饲以复合离子盐 (高、低盐实验组 )及普通加碘盐 (高、低盐对照组 ) ,动态观测动物血压变化 ,检测大鼠血糖、血胰岛素水平,计算胰岛素敏感指数。结果 :(1)复合离子盐较普通加碘盐具有明显的预防高血压作用 ,高盐实验组血压明显低于高盐对照组(P<0.01)。 (2)4组血糖水平差别无统计学意义 (P>0.05) ;高盐对照组胰岛素水平高于其他3组 (P<0.05) ,胰岛素敏感指数明显低于其他3组 (P<0.05)。高盐实验组血糖和胰岛素水平与低盐实验组差别无统计学意义 (P>0.05)。结论 :复合离子盐对SHR的高血压有防治作用 ,且不增加胰岛素抵抗