阿托伐他汀对自发性高血压大鼠心肌组织PPARs表达的影响

目的： 探讨阿托伐他汀对自发性高血压大鼠心肌组织PPARs（peroxisome proliferator-activated receptors, PPARs）表达的影响及其对心肌肥厚的逆转作用与可能机制。方法: 自发性高血压大鼠分为阿托伐他汀灌胃治疗组（SHR-A，30 mg·kg-1·d-1）及模型组（SHR），治疗8周，同周龄Wistar-Kyoto 鼠为正常血压对照组。治疗前及治疗后2、4、8周测量大鼠尾动脉血压。治疗后测血浆血脂水平，以心脏组织病理分析判断心肌肥厚，Western blotting 检测心肌组织PPARα、PPARγ的表达水平。结果: 经过8周治疗， SHR-A组及SHR组血压及血脂水平无明显差异（P＞0.05）。SHR-A组左室重量指数低于SHR组（P＜0.01）。在SHR-A组，PPARα及PPARγ表达高于SHR组（P＜0.01）。结论: 阿托伐他汀显著改善自发性高血压大鼠心肌组织PPARs表达，有效逆转左室肥厚，可能与其降压及降脂作用无关。     

Functional and stereologic estimations of myocardial capillary exchange capacity in treated and untreated spontaneously hypertensive rats.

Myocardial capillary exchange capacity was investigated by stereologic and functional techniques in parallel during pressure-overload cardiac hypertrophy and after long-term antihypertensive therapy with the vasodilator felodipine. In 26-week-old female spontaneously hypertensive rats (SHR) blood pressure increased by 25% and left ventricular weight (LVW/BW) increased by 18% compared to Wistar-Kyoto rats (WKY). Myocardial capillary surface and volume densities normalized for organ weight were similar in both ventricles for both strains. Moreover, capillary surface density was higher sub-epicardially (EPI) than in the subendocardium (ENDO) in the left ventricle of SHR. Thirteen weeks of felodipine-therapy (SHR-Felo) normalized blood pressure without affecting LVW/BW although a transition from concentric to eccentric hypertrophy is known to occur. Myocardial capillary surface and volume densities and the left ventricular ENDO-EPI-gradient in surface density were similar to untreated SHR. However, felodipine-treatment increased right ventricular weight and capillary volume density. Functional capillary exchange was estimated in terms of permeability surface area products (PS) for Cr-EDTA and vitamin B12 and normalized for organ weight. PSCr-EDTA, PSB12 and the ratio PSCr-EDTA/PSB12 (an index of capillary permeability) were similar in SHR and WKY. Furthermore, the relation between functional and stereological indices of exchange capacity was investigated in a multiple linear regression analysis. However, no significant correlation between PS and neither capillary surface nor volume density was found. In conclusion, myocardial capillary exchange capacity was well adapted to the pressure overload cardiac hypertrophy present in female SHR. Despite induction of right ventricular hypertrophy, felodipine-treatment did not affect capillary exchange capacity. Furthermore, when functional and stereologic estimates were performed in parallel, the importance of dynamic factors for myocardial capillary exchange capacity (e.g. heterogeneity) was illustrated.     

氯沙坦逆转高血压大鼠心肌重塑的实验研究

目的探讨氯沙坦对自发性高血压大鼠(SHR)心肌重塑的影响。方法16周龄雄性SHR20只,随机分为氯沙坦治疗组和SHR对照组。同龄雄性WKY鼠10只作为正常对照组。给予氯沙坦每天30mg/kg溶于饮水灌胃治疗17周。测定动脉收缩压、左心室壁的厚度、左心室重量与体重之比(LVW/BW)。透射电镜评估左心室肥厚(LVH)的程度。用真彩色图像分析系统计算左心室胶原容积分数。结果氯沙坦治疗组血压、LVW/BW、左室壁厚度与SHR对照组相比明显降低,但与WKY相比有所升高。透射电镜下氯沙坦治疗组心肌的超微结构与WKY相似,SHR的结构有异常改变。与SHR对照组相比,氯沙坦治疗组左心室胶原容积分数下降。结论氯沙坦能有效地降低SHR的血压、逆转高血压左室重塑。     

Functional and stereologic estimations of myocardial capillary exchange capacity in treated and untreated spontaneously hypertensive rats

Myocardial capillary exchange capacity was investigated by stereologic and functional techniques in parallel during pressure-overload cardiac hypertrophy and after long-term antihypertensive therapy with the vasodilator felodipine. In 26-week-old female spontaneously hypertensive rats (SHR) blood pressure increased by 25 % and left ventricular weight (LVW/BW) increased by 18% compared to Wistar-Kyoto rats (WKY). Myocardial capillary surface and volume densities normalized for organ weight were similar in both ventricles for both strains. Moreover, capillary surface density was higher sub-epicardially (EPI) than in the subendocardium (ENDO) in the left ventricle of SHR. Thirteen weeks of felodipine-therapy (SHR-Felo) normalized blood pressure without affecting LVW/BW although a transition from concentric to eccentric hypertrophy is known to occur. Myocardial capillary surface and volume densities and the left ventricular ENDO-EPI-gradient in surface density were similar to untreated SHR. However, felodipine-treatment increased right ventricular weight and capillary volume density. Functional capillary exchange was estimated in terms of permeability surface area products (PS) for Cr-EDTA and vitamin B₁₂ and normalized for organ weight. PS_cr-EDTA, PS_B12 and the ratio PS_cr-EDTA/PS_B12 (an index of capillary permeability) were similar in SHR and WKY. Furthermore, the relation between functional and stereological indices of exchange capacity was investigated in a multiple linear regression analysis. However, no significant correlation between PS and neither capillary surface nor volume density was found. In conclusion, myocardial capillary exchange capacity was well adapted to the pressure overload cardiac hypertrophy present in female SHR. Despite induction of right ventricular hypertrophy, felodipine-treatment did not affect capillary exchange capacity. Furthermore, when functional and stereologic estimates were performed in parallel, the importance of dynamic factors for myocardial capillary exchange capacity (e.g. heterogeneity) was illustrated.     

苯那普利对高血压大鼠细胞外信号调节激酶和B型钠尿肽的影响

目的：研究苯那普利对自发性高血压大鼠（SHR）细胞外信号调节激酶（ERK）和B型钠尿肽（BNP）的影响。方法：选择Wistar Kyoto（WKY）大鼠作对照，将21只14周龄雄性SHR随机分成3组：未治疗组、肼苯哒嗪组和苯那普利组，每组7只。药物溶于载体（0.5%羧甲基纤维素钠）以灌胃法给予，肼苯哒嗪10 mg·kg-1·d-1，苯那普利10 mg·kg-1·d-1，SHR未治疗组及WKY组灌喂载体，共10周。以左心室重量与体重的比值反映心肌肥厚的程度；用袖带式尾动脉测压法测量大鼠尾动脉血压；分别用Western blotting方法和RT-PCR法半定量测定大鼠心肌中磷酸化ERK（p-ERK）的蛋白表达以及BNP mRNA的含量；酶联免疫吸附法检测大鼠血浆BNP水平。结果：（1） 治疗后SHR苯那普利组和SHR肼苯哒嗪组血压相似，均显著低于SHR未治疗组（P<0.01）。（2） SHR苯那普利组心肌肥厚指数显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.01) ，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组心肌肥厚指数无显著差异(P>0.05)。（3）SHR苯那普利组大鼠心肌p-ERK表达显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05) ，与WKY组无显著差异(P>0.05)。SHR肼苯哒嗪组和SHR未治疗组大鼠心肌p-ERK表达无明显差异(P>0.05)。（4） SHR苯那普利组大鼠心肌BNP mRNA和血浆BNP水平显著低于SHR肼苯哒嗪组和SHR未治疗组(P<0.05)，与WKY组无显著差异(P>0.05)；SHR肼苯哒嗪组和SHR未治疗组大鼠心肌BNP mRNA和血浆BNP水平无明显差异(P>0.05)。结论：苯那普利能通过抑制ERK活性逆转心肌肥厚，伴随BNP水平下降；而降压效果相似的肼苯哒嗪不能抑制心肌肥厚，对p-ERK和BNP水平没有影响，提示BNP水平可以反映逆转心肌肥厚药物疗效。     

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.     

高血压大鼠血管外周脂肪组织对血管调节功能的改变及他汀类药物治疗的影响

目的：观察自发性高血压大鼠 (SHR) 血管外周脂肪组织释放血管舒张因子功能的改变及他汀类药物干预的影响。方法:SHR 10周龄后，分别给予阿托伐他汀钙50 mg/kg·d,血脂康 2 400 mg/kg·d干预16周。观察阿托伐他汀钙干预组（SHR-A）、血脂康干预组（SHR-X）、对照SHR组和WKY组的血压（SBP）变化；于26周龄，把各组大鼠的相邻的两段胸主动脉环分为血管外周脂肪亚组和裸血管亚组，予10-6 mmol/L苯肾上腺素(PHE)刺激,比较两亚组血管收缩力的差异;用液体转移的方法,观察孵育血管外周脂肪组织的培养液对裸血管张力的影响。结果:① WKY组、SHR-A组、SHR-X组SBP实验前后无显著变化，SHR组的SBP实验结束时显著高于实验开始时；② WKY组、SHR-A组、SHR-X组血管外脂肪亚组的收缩力低于裸血管亚组的收缩力,而SHR两血管亚组的收缩力无差别;③ 把WKY组，SHR-A组，SHR-X组孵育的血管外脂肪的培养液转移到裸血管均诱发其快速舒张，而SHR组则无显著血管舒张反应。结论：WKY的血管外周脂肪组织释放一种可转移性血管舒张因子，降低血管对苯肾上腺素的反应性,调节血管功能而SHR的血管外周脂肪组织这种血管调节作用减弱;血管外周脂肪组织这种功能异常可能是高血压血管功能异常的病理基础之一他汀类药物治疗在修复SHR血管外周脂肪组织这种功能异常的同时,还能减缓SHR血压上升。     

Expression and activity of the glutamate transporter EAAT2 in cardiac hypertrophy: implications for ischaemia reperfusion injury

The expression and activity of the glutamate transporter, excitatory amino acid transporter 2 (EAAT2), in cardiac hypertrophy were investigated with respect to glutamate’s potential as a cardioprotective agent. Sarcolemmal vesicles (SV) isolated from hypertrophic hearts of male spontaneously hypertensive rats (SHR) or normotrophic hearts from age-matched male Wistar Kyoto rats (WKY) were used to measure the relative level of EAAT2 expression by Western blotting and the initial rate of 0–0.3 mM l-[¹⁴C]glutamate uptake. The effects of 20-min global normothermic ischaemia ±0.5 mM glutamate on cardiac function were measured in isolated working SHR/WKY hearts. In a separate series of hearts, glutamate, lactate and ATP levels were measured. Both the level of EAAT2 expression and the V _max for sodium-dependent l-[¹⁴C]glutamate uptake were significantly greater in SHR SV compared to WKY SV. The reperfusion cardiac output (CO) of SHR hearts was significantly worse than that of the WKY hearts (24.3±2.2 ml/min vs 39.8±3.3 ml/min, n=7/9±SE, p<0.01). The addition of 0.5 mM l-glutamate improved the SHR reperfusion CO to 45.2±5 ml/min, (n=6±SE, p<0.01) but had no effect on WKYs (46.2±3.8 ml/min, n=6±SE). SHR with 0.5 mM l-glutamate had higher glutamate levels at the start of ischaemia, plus higher glutamate and ATP levels at the end of ischaemia compared to any other group. These results suggest that increased glutamate transporter expression and activity in the SHR hearts helped facilitate glutamate entry into the SHR cardiomyocytes leading to improved myocardial metabolism during ischaemia and better functional recovery on reperfusion.     

Structural adaptation of the rat left ventricle in response to changes in pressure and volume loads

Female Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were used to explore the structural changes of cardiac dimensions in connection with a sustained hyperkinetic circulation, as induced by pregnancy or thyroxine administration. Cardiac design was assessed by recordings of the diastolic left ventricular pressure-volume relationships in isolated arrested hearts. Left ventricular weight: body weight and end-diastolic volume (EDV) for given end-diastolic pressures (EDP), were both increased about 50% in control SHR, with a marginal reduction of the wall:lumen ratio (w:ri) compared with control WKY. During the hyperkinetic circulatory states of pregnancy and hyperthyroidism, EDV was in WKY increased about 30% and 50%, respectively, with concomitant w:ri reductions. In SHR pregnancy did not significantly alter left ventricular dimensions, whereas EDV was increased by about 20% in hyperthyroid SHR. Thus, the rat left ventricle can, within 3 weeks, markedly alter not only the wall mass but also, and independently, the luminal design in response to different haemodynamic interventions. Early established SHR hypertension is characterized mainly by eccentric left ventricular hypertrophy, despite the elevated arterial pressure. Volume overloads in WKY due to pregnancy or hyperthyroidism can induce marked structural widening of the left ventricle. In SHR these structural luminal changes were only minor, perhaps because considerable eccentric hypertrophy is already present. Such a structural cardiac enlargement may allow delivery of an increased stroke volume for a given myocardial fibre shortening.     

Peroxisomal fatty acid oxidation capacity is more resistant to ischaemic and reperfusion injury than mitochondrial fatty acid oxidation capacity in feline hearts

We investigated ischaemic and postischaemic mitochondrial and peroxisomal fatty acid oxidation capacity, ATP levels and regional function in 40 anaesthetized open chest cats subjected to 10 or 40 min of regional myocardial ischaemia with or without 3 h of reperfusion (n=10 in each situation). Following 10 min of ischaemia, the mitochondrial fatty acid oxidation capacity measured in tissue extracts from ischaemic tissue (nmol min^-1 mg protein^-1) was reduced in both subepi- and subendocardium, but was normalized in reperfused tissue extracts from both wall layers (0.29±0.03 and 0.30±0.04 vs. 0.57±0.05 and 0.59±0.05, P<0.05). Peroxisomal fatty acid oxidation capacity in tissue extracts was unaffected by ischaemia and reperfusion. ATP levels and regional function measured in the LAD region was partly restored transmurally. After 40 min of LAD occlusion, mitochondrial fatty acid oxidation capacity was reduced, with higher activity in subepi- than in subendocardium (0.27±0.05 vs. 0.19±0.04, P<0.05). Reperfusion did not restore mitochondrial fatty acid oxidation capacity. Peroxisomal fatty acid oxidation capacity was increased in the ischaemic subendocardium compared with levels in non-ischaemic subendocardium (0.53±0.02 vs. 0.45±0.03, P<0.05), with normalization at the end of reperfusion. ATP levels were non-uniformly reduced during ischaemia and not repleted during reperfusion. Regional function recovered in circumferential segments but not in longitudinal segments following 40 min of ischaemia. In conclusion fatty acid oxidation enzymes seem to be more resistant to ischaemia in peroxisomes than in mitochondria. Mitochondrial fatty acid oxidation is fully reversible following shortlasting ischaemia, but remains depressed following prolonged ischaemia and reperfusion.     

A quantitative analysis of muscle cell changes in compensatory hypertrophy and work-induced hypertrophy

The cytological characteristics of two modes of muscle hypertrophy were studied in the extensor digitorum longus muscle of the rat. Compensatory hypertrophy (CH) was produced by tenotomy of the tibialis anterior muscle and work-induced hypertrophy (WIH) was produced by forced swimming of the animal. While both methods produced an increase in muscle weight and cell size, these two parameters did not correlate. Morphometric analyses of the hypertrophied muscle cells demonstrated that in CH-muscle there was an increase in mitochondrial volume density, a decrease in myofibrillar volume density and no change in sarcotubular or nuclear volume density. WIH-muscle demonstrated an increase in sarcotubular volume density but no change in mitochondrial, myofibrillar or nuclear volume density. It is concluded that in CH-muscle, the cell volume increase is attributable to mitochondrial volume increase and that there is no increase in the contractile myofibrillar component of the cell. WIH-muscle, on the other hand, has a cell volume increase which is attributable to a proportional increase in these organelles.     

阿托伐他汀影响自发性高血压大鼠血压的机制探讨

目的：探讨阿托伐他汀控制自发性高血压大鼠（SHR）高血压的机制，研究阿托伐他汀对SHR血浆内皮素-1（ET-1）和主动脉一氧化氮合酶（NOS）的影响，以及对SHR的主动脉平滑肌细胞（ASMC）凋亡和P27蛋白表达的影响。 方法： 选用8周龄SHR 12只，随机分为阿托伐他汀治疗组（ATV组, n=6）和SHR组（n=6），并以同周龄WKY（n=6）作为对照。ATV组给以阿托伐他汀（50 mg·kg-1·d-1）灌胃。10周后观察3组大鼠血压、血清总胆固醇（TC）、总甘油三酯（TG）含量变化，血浆ET-1和主动脉NOS活性的改变，以及TUNEL法检测ASMC凋亡率，测定动脉ASMC P27蛋白表达。 结果： 阿托伐他汀给药10周后，ATV组动脉收缩压显著低于SHR组［（134.17±3.60）mmHg vs （173.33±3.78）mmHg, P<0.01］；ATV组血清TC和TG浓度均显著低于SHR组（P<0.01, P<0.01）。同时，阿托伐他汀显著降低SHR血浆ET-1水平［（130.04±40.07）ng/L vs （196.74±59.69）ng/L，P<0.05］和增加SHR主动脉NOS活性［(0.189±0.040）kU/g protein vs （0.124±0.057）kU/g protein，P<0.01］；ATV组ASMC凋亡率显著高于SHR组（16.94%±3.08% vs 9.01%±2.36%, P<0.01）；ATV组ASMC P27蛋白表达阳性率显著高于WKY大鼠（33.02%±5.01% vs 24.25%±4.41%, P<0.05），而SHR组该指标明显低于WKY大鼠（16.08%±7.09% vs 24.25%±4.41%, P<0.05）。 结论： 阿托伐他汀控制SHR血压增高，其机制可能与降低SHR的血浆ET-1水平和增高主动脉NOS活性，以及增高ASMC凋亡率和P27蛋白表达阳性率有关。     

依那普利对自发性高血压大鼠心肌ACE和ACE2表达的影响

 目的 观察自发性高血压大鼠(spontaneously hypertensive rats, SHR)心肌的血管紧张素转换酶(angiotensin-converting enzyme, ACE)和ACE2的表达,以及依那普利干预的影响。方法 将15只SHR随机分为2组：SHR对照组(n=7)和依那普利组(n=8),分别给以安慰剂、依那普利15mg.kg-1.d-1灌胃干预4周。干预结束后处死大鼠,分离左心室,行RT-PCR、western blot蛋白质免疫印迹检测。同步取10只WKY大鼠作为正常血压对照组。结果SHR心肌的ACE的mRNA和蛋白质的表达都显著高于)WKY组(1.68±0.34 vs 0.33±0.12, P＜0.05;1.21±0.14 vs 0.71±0.11, P＜0.05),而ACE2 的mRNA和蛋白质表达皆明显低于WKY组(0.50±0.15 vs 1.16±0.24, P＜0.05; 0.71±0.24 vs 1.22±0.14, P＜0.05)。依那普利明显降低ACE的mRNA和蛋白质表达(0.44±0.19 vs 1.68±0.34, P＜0.01; 0.87±0.13 vs 1.21±0.14, P＜0.05),提升ACE2的mRNA表达(1.77±0.49 vs 0.50±0.15, P＜0.05),对ACE2的蛋白表达无明显影响(0.42±0.22 vs 0.71±0.24, P＞0.05)。结论 SHR心肌ACE明显升高,ACE2显著降低,有利于血压上调。依那普利能降低ACE,提升ACE2,可能是血管紧张素转换酶抑制剂(angiotensin-converting enzyme inhibitors, ACEI)的降压机制之一。     

Interaction between “mental stress” and baroreceptor reflexes concerning effects on heart rate,mean arterial pressure and renal sympathetic activity in conscious spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) were compared concerning the interactions between cortico-hypothalamic alerting responses and baroreflex influences on neurogenic cardiovascular control. For this purpose mean arterial pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) were continuously recorded during night time in conscious, otherwise undisturbed rats. Baroreceptor sensitivity was assessed as percentage HR and RSNA reductions per mmHg MAP elevation when a standardized phenylephrine infusion was performed. A state of acute “mental stress” could be induced by a likewise standardized sudden blowing of air. These two opposing influences on neurogenic cardiovascular control were also experimentally superimposed in various ways and the effects on MAP, HR and RSNA followed. During “rest” RSNA was higher in SHR than in WKY and it also increased more during “mental stress”. The baroreflex sensitivity was clearly reduced in SHR and WKY concerning HR reduction (0.44±0.06 vs. 0.78±0.08%/mmHg; p<0.01) but not so concerning RSNA, which was similar in SHR and WKY (2.6±0.2 vs. 2.9±0.4%/mmHg). If expressed (HR + 1±3%; p<0.025 vs. SHR and RSNA + 11%±10, p<0.01 vs. SHR). These results) (0.10±0.02 vs. 0.06±0.01 μV/mmHg; p<0.12). Also single fibre recordings in anaesthetized rats showed the same principle difference between SHR and WKY. Addition of “mental stress” during phenylephrine baroreflex activation clearly increased both HR (24±7%) and RSNA (114±21 %) in SHR, while almost no change then occurred in WKY (HR + 1±3%; p<0.025 vs. SHR and RSNA + 11%±10, p<0.01 vs. SHR). These results suggest that a modestly accentuated cortico-hypothalamic activity ordinarily prevails in SHR, explaining the suppressed baroreflex control of heart rate and the augmented sympathetic activity to e.g. renal and splanchnic areas. Further, environmental alerting stimuli induce in SHR more powerful defence reactions which, unlike the situation in WKY, readily overcome baroreflex inhibitory influences on sympathetic activity.     

Angiotensin converting enzyme inhibition prevents polyploidization of cardiomyocytes in spontaneously hypertensive rats with left ventricular hypertrophy

Polyploidization of cardiomyocyte nuclei is a physiological phenomenon that increases in pathological conditions such as myocardial hypertrophy. The purpose of this study was to evaluate the potential benefit of the angiotensin converting enzyme (ACE) inhibitor quinapril in reversing the polyploidization of cardiomyocyte nuclei in spontaneously hypertensive rats (SHR) with established left ventricular hypertrophy (LVH). Sixteen week-old male SHR were treated with oral quinapril (average dose 10 mg/kg per day) for 20 weeks. Sixteen- and 36-week-old untreated SHR and 16- and 36-week-old normotensive Wistar-Kyoto (WKY) rats were used as controls. Nuclear polyploidization was determined by DNA flow cytometry of frozen tissues from the left ventricle, at least 20 000 nuclei being measured in each sample. The rates of tetraploidy in the 16- and 36-week-old SHR groups were 2·8 per cent (range 2·16-3 per cent) and 5·4 per cent (range 4·9–5·9 per cent), respectively. Treated SHR had a similar rate of DNA tetraploidy to the 16- and 36-week-old WKY rat groups: 1·8 per cent (range 1·5–2·3 per cent), 1·55 per cent (range 1·5–1·6 per cent), and 1·5 per cent (range 1·4–1·6 per cent), respectively. The differences in the percentage of tetraploid cardiomyocytes between the SHR untreated groups and the SHR treated group were statistically significant (P<0·05). Regression of LVH and normalization of blood pressure were observed in treated rats. These results indicate that DNA tetraploidy in the myocardium of SHR increases with hypertrophy and decreases on quinapril treatment. It is suggested that ACE inhibition modifies nuclear processes involved in myocyte growth in arterial hypertension.     

Diastolic properties of the hypertrophied left ventricle in spontaneously hypertensive rats

The influence of myocardial hypertrophy on left ventricular volume compliance was studied in vitro in isolated hearts of 4 and 19 month old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). In both SHR groups diastolic volume compliance was similar to that in the controls, despite the presence of left ventricular hypertrophy. This seems to be mainly due to an altered geometric situation, since with increased wall thickness to internal radius ratio (w/ri), which was at hand, the less are outer myocardial layers stretched at a given increase in ventricular volume. This may imply that these layers will only little interfere with luminal distension (and thereby with diastolic volume compliance) in SHR. It was also observed that the progressive increase of ventricular hypertrophy from 4 to 19 months of age did not further increase w/ri in SHR, indicating an increase in overall ventricular size with age. Left ventricular end diastolic pressure (LVEDP) was also measured in conscious 5 week and 4 month old SHR compared with matched controls. LVEDP increased with the development of hypertension and was significantly elevated in 4 month old SHR. This will increase also the average diastolic pre-stretch of the SHR left ventricle and mobilize the "Starling mechanism" to maintain a normal stroke volume against the increased afterload for the heart in established hypertension. This seems particularly important since the hypertrophic w/ri increase (about 20%) is smaller than the great elevation of mean arterial pressure (40-50%) in SHR.     

Myocardial concentration of cardiac troponin T as an early discriminator of mechanisms of cardiac hypertrophy

Measurement of myocardial concentration of the myofibrillar protein, cardiac troponin T (cTnT), was used as a biochemical correlate of myocardial myofibrillar volume fraction to confirm and extend results of histomorphometric studies of changes in myofibrillar density during hypertrophy. Rat models were used to study concentric cardiac hypertrophy due to pressure overload (spontaneous hypertension), eccentric cardiac hypertrophy due to volume overload (administration of minoxidil for 4 weeks), and mixed cardiac hypertrophy due to growth factor stimulation (administration of triiodothyronine for 4 weeks). Mean myocardial cTnT concentration was 583±60 g/g wet weight tissue in 40 control rats aged 10–20 weeks. We confirmed that pressure overload increased myofibrillar density by up to 30%, whereas volume overload decreased myofibrillar density, in our study, by up to 15%. Growth factor-induced hypertrophy was confirmed to occur by a mixture of processes; while myofibrillar density had increased by 31% at 1 week, it had normalised by 4 weeks. Minoxidil-induced hypertrophy was also confirmed to occur by a mixture of the processes, with myofibrillar density first decreased by 15% at 1 week before normalising by 4 weeks. Progressive, pathological hypertrophy, as modelled with spontaneous hypertension, was confirmed to be associated with abnormal myocardial myofibrillar density. We conclude that myocardial cTnT concentration may be used as a simple and precise biomarker of myofibrillar volume density, which, assessed over time, discriminates early physiological mechanisms involving myocyte thickening from those involving myocyte elongation and may discriminate between physiological and pathological hypertrophy.     

Temporal characteristics of cardiomyocyte hypertrophy in the spontaneously hypertensive rat.

BACKGROUND: The spontaneously hypertensive rat (SHR) is frequently used as model of cardiovascular disease, with considerable disparity in reported parameters of hypertrophy. The aim of this study was to assess the temporal changes occurring during the development and progression of cardiomyocyte hypertrophy in SHR, subsequent to pressure overload, compared to changes associated with normal aging using the normotensive Wistar-Kyoto (WKY) rat. METHODS: Ventricular cardiomyocytes were isolated from rats at 8, 12, 16, 20 and 24 weeks, and parameters of hypertrophy (cell dimensions, protein mass, de novo protein synthesis, and gene expression) and function (contraction and hypertrophic responsiveness in vitro) were assessed. RESULTS: Hypertension was evident at > or =7 weeks in SHRs. Heart:body mass ratio, cardiomyocyte protein mass and width were elevated (P<.05) in SHRs at 16-20 weeks compared to WKYs. In SHRs compared to WKYs at 16 weeks, there was a transient increase (P<.05) in protein synthesis, enhanced hypertrophic responsiveness to phorbol-12-myristate-13-acetate, and induced hypertrophic responsiveness to isoprenaline. Skeletal-alpha-actin mRNA was detected in SHR but not WKY cells at all ages. ANP mRNA was lower in SHR than in WKY cells at 8-20, but progressively increased (P<.05) from 12 to 24 weeks within SHRs. Contractile function increased (P<.05) at 20 weeks in SHR compared to WKY rats. CONCLUSION: Structural and functional changes occurring at the cellular level in the myocardium of SHR follow a distinct pattern, such that pressure overload was initially accompanied by expressional changes (8-12 weeks), followed by active hypertrophic growth and enhanced function (16-20 weeks), which subsequently decelerated as stable compensation was attained.     

Control of myocardial tissue components and cardiocyte organelles in pressure-overload hypertrophy of the cat right ventricle

Previous studies have demonstrated that there is a disproportionate increase in connective tissue in right ventricular myocardium subjected to pressure-overload hypertrophy associated with depressed cardiac contractility. While the myocardium is primarily responsive to load, the aim of the present study was to determine whether catecholamines also modulate the response of myocardial tissue components and cardiocyte organelles in pressure-overload-induced cardiac hypertrophy. Four experimental groups of cats were examined: (1) a sham-operated control group, (2) a group which had their pulmonary arteries banded in order to induce a pressure overload, (3) a group which had been subjected to the same pressure overload, but in addition had β-adrenoceptor blockade produced prior to and during the pressure overloading, and (4) a group which had been subjected to the same pressure overload, but in addition had α-adrenoceptor blockade produced prior to and maintained during the pressure overloading. As in our previous study, there was a significant and equivalent degree of right ventricular hypertrophy in all experimental groups with pressure overload when assessed either as the ratio of right ventricular weight to body weight or as cardiocyte cross-sectional area. At the light microscopic level, the disproportionate increase in the volume density of myocardial connective tissue seen in banded animals was completely prevented by either α- or β-adrenoceptor blockade. At the electron microscopic level, there was a reduction in the mitochondrial and myofibrillar volume fractions following β-adrenoceptor blockade. The results of this study provide evidence for a modulatory role of catecholamines in the control of myocardial connective-tissue proliferation in pressure-overload-induced cardiac hypertrophy. There is also evidence to support the role of the adrenergic nervous system in regulating cardiocyte subcellular organelles, independent of the regulation of cardiocyte size.     

螺内酯和缬沙坦对高血压大鼠心肌细胞外信号调节激酶的影响

目的:观察血管紧张素Ⅱ受体拮抗剂缬沙坦和醛固酮受体拮抗剂螺内酯对SHR心肌中活化的ERK的影响。方法:将18只雄性SHR随机分为三组,每组6只。其中两组分别用缬沙坦30mg/kg/天、螺内酯20mg/kg/天溶于饮水灌胃,连续治疗13周;对照组给正常饮水,并与Wist-ar-kyoto大鼠(WKY)比较。用Western-blot方法检测大鼠心肌磷酸化ERK的表达。结果:SHR对照组心肌磷酸化ERK/actin值高于其余三组(P<0.01),螺内酯和缬沙坦组高于WKY组(P<0.01),两用药组之间无差异。结论:血管紧张素Ⅱ受体拮抗剂缬沙坦和醛固酮受体拮抗剂均能通过抑制ERK途径而抑制左室肥厚和心肌纤维化。