Effects of angiotensin-converting enzyme inhibition and bradykinin peptides in rats with myocardial infarction

Background and objective: Angiotensin-converting enzyme (ACE) inhibitors have been reported to decrease myocardial remodeling and faciliate cardiac function improvement in the setting myocardial infarction by affecting bradykinin. The purpose of this study was to evaluate the combination effects of perindopril and bradykinin (BK) in rats with myocardial infarction. Methods: Wistar Rats underwent to left anterior descending (LAD) coronary artery ligation were allocated into MI group (n = 6); Perindopril group (n = 7); Perindopril + BK group (n = 7). An additional sham operation group (Sham group, n = 6) were also established. After 4 weeks, the left ventricle function, myocardial tissue morphology, myocardial collagen volume faction, infracted ventricular wall thickness, myocardial infarction area and neovascular formation were evaluated. Results: Combination treatment with perindopril and BK were showed significant improvement on LVEDV, LVEF and LVFS than MI group. Moreover, a significant improvement on LVEF was found in Perindopril + BK group than Perindopril group but not on LVEDV and LVFS between these two groups. Furthermore, neo-vessel density was significantly increased in Perindopril + BK group than other groups while no significant improvement on vessel density was found after the treatment of perindopril. In addition, myocardial infarction thickness improvement was found in Perindopril and group than MI group while combination treatment with perindopril and BK can significant improve the myocardial infarction thickness than perindopril only. Conclusions: Combination treatment with ACE inhibitor perindopril and BK can significantly improve the ventricle function in the rat model of myocardial infarction. Our data suggest BK can serve as adjuvant treatment in myocardial infarction treatment.     

Effect of angiotensin-converting enzyme inhibition on skeletal muscle oxidative function and exercise capacity in streptozotocin-induced diabetic rats

Since exercise capacity is related to the mitochondrial respiration rate in skeletal muscle and both parameters are potentially modulated by the onset of diabetes and by inhibition of the angiotensin-converting enzyme (ACE), we investigated whether skeletal muscle oxidative functions and exercise capacities are impaired in chronic streptozotocin-induced diabetic (STZ) rats and whether ACE inhibition could reverse such abnormalities. The ACE inhibitor perindopril (2 mg kg(-1) day(-1)) was given for a period of 5 weeks to 7-month-old STZ rats (DIA-PE, n = 8) whose haemodynamic function, skeletal muscle mitochondrial function and exercise capacity were compared with those of untreated diabetic (DIA, n = 8) and control rats (CONT, n = 8). Increased arterial blood pressure (157 +/- 12 versus 130 +/- 6 mmHg, P < 0.05) and reduced exercise capacity (29 +/- 2 versus 91 +/- 2 min, respectively, P < 0.01) were observed in DIA compared with CONT. The oxidative capacity of the gastrocnemius muscle was significantly reduced in DIA compared with CONT rats (5.4 +/- 0.5 versus 10.6 +/- 0.7 micromol O(2) min(-1)(g dry weight)(-1), respectively, P < 0.001). Moreover, the coupling between oxidation and phosphorylation was significantly impaired in DIA (-52%, P < 0.001). Angiotensin-converting enzyme inhibition (ACEi) normalized blood pressure without improving mitochondrial function (4.3 +/- 0.8 micromol O(2) min(-1) (g dry weight)(-1) in DIA-PE rats) but reduced exercise capacity to even lower levels (10 +/- 1 min, P < 0.01). Exercise capacity correlated positively with blood pressure in DIA-PE (r = 0.79, P < 0.05). In experimental type 1 diabetic rats, both skeletal muscle mitochondrial respiration and exercise capacity are impaired. The ACEi failed to restore the muscular function and worsened exercise capacity. Further studies will be useful to determine whether an inadequate muscular blood flow secondary to the reduction in mean systemic blood pressure can explain these results.     

Non-invasive temperature imaging of muscles with magnetic resonance imaging using spin-echo sequences

The application of spin-echo magnetic resonance imaging sequences on non-invasive temperature imaging for temperature mapping of human limbs is investigated. In an in vitro expriment performed on a meat sample, the equilibrium magnetisation P and the spin-lattice relaxation time T₁ are calculated from the values for the repetition time TR and the signal intensities obtained by a spin-echo sequence at different tissue temperatures tures as measured by a fibre-optic probe. T₁ is linearly correlated to the tissue temperature, and P is linearly correlated to the reciprocal value of the absolute temperature. Both effects, taken together, lead to a non-linear dependency of the signal intensity on temperature. Therefore a TR leading to maximum temperature dependency of the signal intensity is calculated and used in the futher experiments. In the in vivo experiments, the lower legs of two volunteers are cooled from outside. Images are acquired with a spin-echo sequence (1.5T, TR=1200 ms, TE=10 ms). A rise in signal intensity in the muscle with falling skin temperature is observed, particularly in more peripheral muscle layers. This study shows that spin-echo sequences can be used to monitor temperature changes and temperature differences in living muscle tissue.     

Respiratory effects in human functional magnetic resonance imaging due to bulk susceptibility changes.

Functional magnetic resonance imaging relies on detecting small changes in the signal in the presence of noise from various sources. It has been shown that periodic variations in the signal at the respiratory frequency occur in the brain and various techniques have been proposed to remove them. However, the precise mechanism by which respiration affects the fMRI signal has not yet been proven. Here, we explore the nature of respiratory signal variations and the artefacts they produce in brain images. Our results demonstrate conclusively that bulk susceptibility variations in the lungs during respiration cause variations in the static magnetic field within the brain tissue. These variations in field strength and homogeneity lead to a shift of the image and a shading of image intensity in the phase encoding direction. These artefacts, if left uncorrected, may lead to the production of spurious activations and/or decreased statistical significance of true activations in fMRI. In addition, these results suggest that respiration effects may not necessarily be well characterized as simple additive noise and that an alternative model based on the physical origins of susceptibility variations may be more appropriate.     

Cardiopreventive effect of ethanolic extract of Date Palm Pollen against isoproterenol induced myocardial infarction in rats through the inhibition of the angiotensin-converting enzyme

The present study aimed to examine the putative preventive effect of the ethanolic extract Date Palm Pollen (DPP, Phoenix dactylifera L., family Arecaceae) on isoproterenol-induced myocardial infarction (MI) in rats. Twenty four rats were randomly divided into four groups including control. They were treated with DPP extract (400 mg/kg) and clopidogrel (0.2 mg/kg) for 7 days followed by myocardial injury induction using subcutaneous isoproterenol (100 mg/kg) with an interval of 24 h for two days (6th and 7th day). Administration of isoproterenol exhibited indicative changes in the ECG pattern evidenced by significant elevation of ST-segment and cardiac injury markers viz.; troponin-T, creatine phosphokinase (CPK), alanine aminotransferase (ALT) and lactate dehydrogenase (LDH) by 315%, 71%, 64% and 170%, respectively as compared to control. Additionally, the angiotensin-converting enzyme (ACE) activity in plasma was increased by 33% associated to histological myocardial necrosis. However, pre-co-treatment with DPP extract improved the cardiac biomarkers injury, normalized cardiac function indices and prevented the ventricular remodeling process through inhibition of ACE activity by 34% and the inhibition of the generation of radical oxygen species. Extensive characterization of this DPP extract using LC-HRMS revealed numerous flavonoids and phenols compounds which could be endowed with cardiopreventive actions. Overall, these results proved that DPP extract has preventive effects on cardiac remodeling process.     

Effects of oestrogen treatment and angiotensin-converting enzyme inhibition on the microvasculature of ovariectomized spontaneously hypertensive rats

We investigated the role of oestrogen in the function and structure of the microcirculation of female spontaneously hypertensive rats (SHRs), and evaluated the effect of 17beta-oestradiol on their cardiovascular response to pharmacological agents that block the formation of angiotensin II. Ten-week-old SHRs were randomly assigned to the following groups: intact, ovariectomized, and ovariectomized treated with 17beta-oestradiol (1.5 mg delivered over 60 days) and/or captopril (5 mg kg(-1) day(-1) for 8 weeks). Systolic blood pressure was determined from the time of ovariectomy up to 18 weeks of age, at which time endothelial function and microvascular density in skeletal muscle were evaluated. Both 17beta-oestradiol and captopril prevented development of hypertension in ovariectomized rats. Furthermore, coadministration of both drugs had a greater antihypertensive effect than either one alone. Acetylcholine-induced vasodilatation was impaired in ovariectomized SHRs, and the response was improved by treatment with 17beta-oestradiol and/or captopril. In addition, 17beta-oestradiol replacement in ovariectomized rats enhanced the effect of captopril on acetylcholine-induced vasodilatation. Ovariectomized rats also showed lower microvascular density than intact rats, an effect that was prevented by 17beta-oestradiol replacement or captopril treatment and, to a significantly larger extent, by coadministration of both. We concluded that both 17beta-oestradiol and captopril attenuated the development of hypertension and improved the impairment in microvascular density of ovariectomized SHRs. Moreover, when simultaneously administered, oestradiol and captopril had an additive effect on blood pressure and the microvasculature.     

Economic and outcomes assessment of magnetic resonance imaging in the evaluation of headache

We sought to evaluate the economic impact and diagnostic utility of magnetic resonance imaging (MRI) in the management of patients with headache and nonfocal physical examinations. Computerized medical records were retrospectively reviewed of 1,233 patients presenting for MRI of headache at our institution over a 3-year period (1992-1995). Patients with focal findings at physical examination, prior brain surgery, head trauma, or immunocompromise were excluded. A model was developed to assess the cost associated with the MR test results, and actual average institutional costs of performing an examination applied. Correlative statistical analysis of referring specialties and positive tests was also performed. Three hundred twenty-eight patients who met the above criteria were retained in the sample. One hundred sixty-three patients (50%) had negative MR test results. Of the 50% of patients with positive studies, only 5 (1.5%) had clinically significant MR results. The average cost of an MR examination was 517 dollars (1998 dollars). The cost per clinically significant managed case detected was 34,535 dollars. No statistically significant difference was found among referring specialties and clinically significant MR results. Our results indicate that MRI of nonfocal headache yields a low percentage of positive clinically significant results and has limited cost-effectiveness. Referring specialty had no significant bearing on these outcomes, regardless of specialist experience.     

Renal cortical accumulation of hyaluronan in adult rats exposed neonatally to angiotensin-converting enzyme inhibition.

Neonatal inhibition of the renin-angiotensin system [angiotensin-converting enzyme (ACE) inhibition] in the rat results in long-term abnormal renal morphology and function, including interstitial inflammation and fibrosis. Hyaluronan (hyaluronic acid, HA) has pathological implications in inflammatory diseases and renal ischaemia-reperfusion injury. The present study aimed at determining if renal cortical HA in the adult rat is correlated to the abnormal morphology and function in rats treated neonatally with the ACE inhibitor enalapril. In adult control rats (23 weeks old), the cortical HA content was very low [about 5 microg g(-1) dry weight (d.w.)] and about 1% of the papillary HA content. In rats treated neonatally with enalapril (days 3-13), the cortical HA level was 15 times that in control rats already at 21 days after birth, and it persisted at this level during adulthood (at 23 weeks). At 13 weeks the enalapril-treated animals showed markedly reduced ability (-53%) to concentrate urine during 24-h thirst provocation. At 21 days as well as at 23 weeks the enalapril-treated kidneys displayed morphological changes, such as papillary atrophy, dilation of the tubules and cellular infiltration of the cortical tissue. Histochemical staining confirmed the HA quantification assay and revealed a patchy staining for HA located in the same regions as the infiltrating cells. In conclusion, neonatal treatment with the ACE inhibitor enalapril results in renal morphological and functional abnormalities during adulthood. Cortical HA levels are already seriously elevated at day 21 and coexist with infiltrating cells. Besides the known effects of angiotensin II in development, the accumulation of HA in these kidneys may be involved in the genesis of at least the cortical abnormalities in enalapril-treated animals because of the proinflammatory effects and water-binding properties of HA.     

Chronic activation of endogenous angiotensin-converting enzyme 2 protects diabetic rats from cardiovascular autonomic dysfunction

In this study, we evaluated whether the activation of endogenous angiotensin-converting enzyme 2 (ACE2) would improve the cardiovascular autonomic dysfunction of diabetic rats. Ten days after induction of type 1 diabetes (streptozotocin, 50 mg kg(-1) i.v.), the rats were treated orally with 1-[(2-dimethylamino)ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one (XNT), a newly discovered ACE2 activator (1 mg kg(-1) day(-1)), or saline (equivalent volume) for 30 days. Autonomic cardiovascular parameters were evaluated in conscious animals, and an isolated heart preparation was used to analyse cardiac function. Diabetes induced a significant decrease in the baroreflex bradycardia sensitivity, as well as in the chemoreflex chronotropic response and parasympathetic tone. The XNT treatment improved these parameters by ≈ 76% [0.82 ± 0.09 versus 1.44 ± 0.17 Ratio between changes in pulse interval and changes in mean arterial pressure (ΔPI/ΔmmHg)], ～85% (-57 ± 9 versus -105 ± 10 beats min(-1)) and ≈ 205% (22 ± 2 versus 66 ± 12 beats min(-1)), respectively. Also, XNT administration enhanced the bradycardia induced by the chemoreflex activation by v 74% in non-diabetic animals (-98 ± 16 versus -170 ± 9 Δbeats min(-1)). No significant changes were observed in the mean arterial pressure, baroreflex tachycardia sensitivity, chemoreflex pressor response and sympathetic tone among any of the groups. Furthermore, chronic XNT treatment ameliorated the cardiac function of diabetic animals. However, the coronary vasoconstriction observed in diabetic rats was unchanged by ACE2 activation. These findings indicate that XNT protects against the autonomic and cardiac dysfunction induced by diabetes. Thus, our results provide evidence for the viability and effectiveness of oral administration of an ACE2 activator for the treatment of the cardiovascular autonomic dysfunction caused by diabetes.     

In vivo monitoring of age-related changes in rat brain using quantitative diffusion magnetic resonance imaging and magnetic resonance relaxometry

Ghrelin is a novel peptide that stimulates the release of growth hormone from the pituitary and is involved in hypothalamic feeding regulation. A pre-embedding immunostaining technique was used to study the ultrastructure and synaptic relationships of ghrelin-containing neurons in the rat arcuate nucleus (ARC). Ghrelin-like immunoreactive (ghrelin-LI) neurons were found in the ARC, and were especially abundant in its ventral part. At the electron microscopic level, ghrelin-LI neurons received afferent synapses from many unknown axon terminals. Ghrelin-LI products in the immunoreactive cell bodies, processes, and axon terminals were detected mainly in dense granular vesicles about 110 nm in diameter. Ghrelin-LI presynaptic axon terminals often made synapses with unknown immunonegative neurons. These results suggest that ghrelin acts to regulate food intake through synaptic connections in hypothalamic neuronal networks.     

心肌梗死模型家猪存活心肌的磁共振延迟成像评价

背景：心脏磁共振延迟成像被认为是极有前景的无创性判断心肌存活状态的影像检查手段。目前常用的对比剂Gd-DTPA存在过高或过低评价存活心肌和不可逆性梗死心肌,而坏死亲和性对比剂ECIII-600可以准确地反映坏死心肌的面积。 目的：对比冠脉内注射坏死亲和性对比剂在猪再灌注急性心肌梗死存活心肌诊断中的应用价值。 方法：三四个月龄普通家猪12头,建立急性再灌注心肌梗死动物模型,分别冠脉内注射0.1 mmol/kg Gd-DTPA或         0.005 mmol/kg ECIII-600。胸导R波触发心电门控,T1加权FAST序列,短轴面延迟强化扫描成像。扫描结束后沿短轴面将心脏切成6 mm断面行氯化三苯基四氮唑染色和光镜检查。比较相应层面的MRI延迟强化区和氯化三苯基四氮唑染色所示梗死区的关系。 结果与结论：注射Gd-DTPA的延迟成像10 min时强化区面积与氯化三苯基四氮唑染色相比过高估计梗死心肌面积约21%,30 min时强化区面积与氯化三苯基四氮唑染色结果一致,之后则过低估计坏死心肌的面积;注射ECIII-600的延迟磁共振成像在坏死区显示强烈而持续的对比增强,强化区面积与氯化三苯基四氮唑染色所示心肌梗死面积一致。说明ECIII-600增强磁共振延迟成像可以准确反映急性心肌梗死面积。Gd-DTPA评价心肌梗死面积不稳定,观察时间窗短,心脏磁共振成像应在对比剂注射后1 h以内完成。     

Functional assessment of tissue-engineered meniscal cartilage by magnetic resonance imaging and spectroscopy

A perfusion bioreactor system was used to grow bioartificial meniscal cartilage tissue in vitro. Magnetic resonance imaging and magnetic resonance spectroscopy methods were used to characterize the flow and perfusion profiles and the growth, distribution, and bioenergetics of the fibrochondrocytes in the resulting constructs. These measurements were correlated with each other and with subsequent histologic analysis. The study has demonstrated that these noninvasive magnetic resonance methods will be useful for designing bioreactor operation strategies and cell scaffolds that lead to the production of tissue-engineered meniscal cartilage constructs with properties resembling those of the native tissue.     

Non-invasive characterization of beta-amyloid(1-40) vasoactivity by functional magnetic resonance imaging in mice

Neurovascular regulation, which is critical to the efficient functioning of the brain, is impaired in Alzheimer's disease and in transgenic mice overexpressing Abeta. Although senile plaques and neurofibrillary tangles represent neuropathological hallmarks of Alzheimer's disease, deposition of Abeta in cerebral blood vessels also likely plays a significant role in this debilitating and fatal disease. Further, soluble Abeta, which shows greater correlation with disease progression and severity than deposited plaques or tangles, displays strong vasoactive properties. The aim of this study was to develop a non-invasive model of cerebral vasoactivity that would ultimately be translatable to Alzheimer's disease as a marker for disease-modifying efficacy of novel small molecule and biologics drugs. Relative changes in cerebral blood volume following relevant doses of soluble Abeta(1-40) (0.01 or 0.1 mg/mouse), PBS, or the reverse peptide, Abeta(40-1) (0.01 or 0.1 mg/mouse), were monitored non-invasively by contrast-enhanced functional magnetic resonance imaging in anesthetized C57BL/6 mice. Experiments were performed on a 7T horizontal bore scanner using gradient echo echo-planar imaging. As expected, PBS and Abeta(40-1) did not induce any significant change in vascular response. In contrast, Abeta(1-40) significantly decreased CBV in a quantifiable, dose-related and region-specific manner. These data demonstrate for the first time the feasibility of characterizing pathogenic Abeta(1-40)-induced vascular dysfunction in vivo using a non-invasive approach. Further, this technique can be readily applied to preclinical screening in a longitudinal manner for novel drugs or antibodies targeting disease modification.     

Age-related metabolite changes and volume loss in the hippocampus by magnetic resonance spectroscopy and imaging

Magnetic resonance imaging (MRI) studies have produced controversial results concerning the correlation of hippocampal volume loss with increasing age. The goals in this study were: 1) to test whether levels of N-acetyl aspartate (NAA, a neuron marker) change in the hippocampus during normal aging and 2) to determine the relationship between hippocampal NAA and volume changes. Proton magnetic resonance spectroscopic imaging (1H MRSI) and MRI were used to measure hippocampal metabolites and volumes in 24 healthy adults from 36 to 85 years of age. NAA/Cho decreased by 24% (r = 0.53, p = 0.01) and NAA/Cr by 26% (r = 0.61, p < 0.005) over the age range studied, whereas Cho/Cr remained stable, implying diminished NAA levels. Hippocampal volume shrank by 20% (r = 0.64, p < 0.05). In summary, aging effects must be considered in 1H MRSI brain studies. Furthermore, because NAA is considered a marker of neurons, these results provide stronger support for neuron loss in the aging hippocampus than volume measurements by MRI alone.     

calpain-1在辛伐他汀抑制糖尿病大鼠心肌炎症中的作用

目的　探讨钙蛋白酶-1（calpain-1）在辛伐他汀抑制糖尿病大鼠心肌炎症中的作用。 方法　40只SD大鼠随机分为4组：空白对照组（CON组）、链脲佐菌素组（STZ组）、辛伐他汀高剂量（20 mg/kg）治疗组（STZ+SIM20组）及低剂量（10 mg/kg）治疗组（STZ+SIM10组）,给药12周后,采用HE染色观察心肌组织病理学改变;免疫组化检测心肌组织p65的表达;Western Blot 检测心肌组织calpain-1、p65、IκBα的蛋白表达;ELISA检测血清中肿瘤坏死因子-α（TNF-α）、白细胞介素-6（IL-6）的含量。 结果　辛伐他汀治疗组与STZ组相比,心肌细胞排列整齐,炎性细胞浸润减少;胞浆p65、IκBα蛋白表达增加,calpain-1、TNF-α、IL-6、核内p65表达减少。 结论　辛伐他汀对糖尿病大鼠心肌炎症有保护作用,其机制可能与抑制心肌calpain-1 表达有关。