Norepinephrine-induced cardiac hypertrophy of the cat heart

Norepinephrine administration causes progressive hypertrophy of the mammalian heart as measured by myocardial mass. The purpose of this study was to determine the growth response of the myocardial tissue components as well as the myocardial cell itself to norepinephrine. Young, adult cats were given low doses of norepinephrine in dextrose or dextrose alone twice daily for 15 days. On day 16, there were no changes in the animals body weight, right ventricular systolic pressure, right ventricular end-diastolic pressure, heart rate, cardiac index, or blood pressure. However, the right ventricle/body weight, the left ventricle/body weight and the total heart weight/body weight were increased significantly in the norepinephrine treated animals. The increase was on the order of 40%. The cardiac muscle cell was also significantly increased in size and both the right and left ventricular cardiac muscle cells exhibited a dramatic increase in size as measured by cross sectional area. Upon stereological examination it was found that the amount of hypertrophy as seen in the cardiac muscle cells was paralleled by the hypertrophy seen in the other tissue components of the myocardium. The volume density of the muscle cells, the interstitial components, as well as the blood vessel compartment were identical in the control and in the norepinephrine-treated groups. In conclusion, this study demonstrates that the response of the myocardium to norepinephrine is similar to that seen in response to a volume overload rather than that seen in response to pressure overload.     

Reversibility of the structural effects of pressure overload hypertrophy of cat right ventricular myocardium

The purpose of the present quantitative structural study was to determine whether the histological alterations seen in pressure overloaded myocardium return to normal, as in vitro contractile function does, upon removal of the pressure overload stimulus. Three experimental groups of four cats each were studied: a group with pulmonary artery banding to create a pressure overload, a group that had been subjected to an equivalent duration of pressure overload and then had that pressure overload removed, and a group of sham-operated controls. Seven to 10 weeks after each operative procedure, the right ventricular pressure was elevated only in the pulmonary artery-banded group. The right ventricle/body weight ratio was significantly increased in the pressure overloaded group only. The body weight at sacrifice, the left ventricle/body weight ratio, and the right ventricular end-diastolic pressure did not differ significantly in the three groups. The striking histological changes in the right ventricular myocardium hypertrophing in response to a pressure overload were the decrease in the volume density of cardiocytes and the increase in connective tissue in papillary muscles. These were reversed when the pressure overload was removed. This study demonstrates that when a pressure overload is removed, myocardial structure returns to normal as the function returns to normal. Given the critical importance of the proportion of cardiocytes and connective tissue components to both systolic and diastolic cardiac function, these data support the hypothesis that the abnormal proportions of these structures provide a potential morphological basis for at least some of the functional abnormalities observed in pressure overload hypertrophy of the cat right ventricle.     

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.     

Chronic right ventricular pressure overload results in a hyperplastic rather than a hypertrophic myocardial response

Myocardial hyperplasia is generally considered to occur only during fetal development. However, recent evidence suggests that this type of response may also be triggered by cardiac overload after birth. In congenital heart disease, loading conditions are frequently abnormal, thereby affecting ventricular function. We hypothesized that chronic right ventricular pressure overload imposed on neonatal hearts initiates a hyperplastic response in the right ventricular myocardium. To test this, young lambs (aged 2-3 weeks) underwent adjustable pulmonary artery banding to obtain peak right ventricular pressures equal to left ventricular pressures for 8 weeks. Transmural cardiac tissue samples from the right and left ventricles of five banded and five age-matched control animals were studied. We found that chronic right ventricular pressure overload resulted in a twofold increase in right-to-left ventricle wall thickness ratio. Morphometric right ventricular myocardial tissue analysis revealed no changes in tissue composition between the two groups; nor were right ventricular myocyte dimensions, relative number of binucleated myocytes, or myocardial DNA concentration significantly different from control values. In chronic pressure overloaded right ventricular myocardium, significantly (P < 0.01) more myocyte nuclei were positive for the proliferation marker proliferating cellular nuclear antigen than in control right ventricular myocardium. Chronic right ventricular pressure overload applied in neonatal sheep hearts results in a significant increase in right ventricular free wall thickness which is primarily the result of a hyperplastic myocardial response.     

Methodische Untersuchungen zur polarographischen Messung der Atmung und des „kritischen Sauerstoffdrucks” bei Mitochondrien und isolierten Zellen mit der membranbedeckten Platinelektrode

Summary In growing rats adapted to a simulated altitude of 3500 m for about 4 weeks and in their controls the evolution of cardiac ventricular weight was followed. The increase of total ventricular weight found in the adapted animals can be attributed exclusively to the increase of right ventricular weight. In other adapted and control animals cardiac capillary densities, muscle fiber diameter and external capillary radius were estimated and fiber—capillary ratio and diffusion distance were calculated. There was an increase of capillary density together with a decrease of muscle fiber density, fiber-capillary ratio and diffusion distance in the right but not in the left ventricle of the adapted rats. The muscle fiber diameters, however, were larger in both heart ventricles of the rats exposed to a simulated high altitude, especially in the right ventricle. This indicates that true hypertrophy of the muscle fibers is mainly responsible for the increase of right ventricular weight. In the left ventricle, however, a hypertrophy of the muscle fibers together with a decrease of stroma components is demonstrated. The physiological importance of the shorter diffusion distance in the right ventricle of the high altitude adapted rats is discussed and it is suggested that the shorter diffusion distance may help to keep the tissue O₂ partial pressure above the critical value, mainly also in extreme situations with high myocardial O₂ consumption.     

Ventricular hypertrophy In sleep apnoea

SUMMARY  Ventricular hypertrophy is associated with an increased risk of cardiovascular death and cardiac events. In response to a haemodynamic load, ventricular hypertrophy may either be eccentric (dilation in response to volume overload) or concentric (increase in wall thickness in response to pressure overload). Ventricular hypertrophy increases with age, weight, blood pressure, and the presence of cardiovascular disease. It is greater in men than in women when adjusting for other variables. Echocardiography is the best method for accurate quantification of left ventricular mass and for detecting right ventricular hypertrophy. In obstructive sleep apnoea there are reports of both eccentric and concentric hypertrophy of the left ventricle. However, many of these reports have failed to control for patient weight or age. More recent reports indicate that much of the hypertrophy of the left ventricle reported in obstructive sleep apnoea can be related to patients' age, blood pressure, or size. However, right ventricular hypertrophy appears to be distinctly associated with the presence and severity of obstructive sleep apnoea. Right ventricular hypertrophy secondary to obstructive sleep apnoea may be the substrate for the eventual development of cor pulmonale and right heart failure. Its pathophysiological significance and potential use as a marker of severe OSA requires further investigation. Further investigation into left ventricular hypertrophy and sleep apnoea must control for the potentially confounding variables listed above and will require population-based and/or carefully matched case control studies.     

短链酰基辅酶A脱氢酶在大鼠生理性和病理性心肌肥大中的作用

 目的：研究短链酰基辅酶A脱氢酶(short-chain acyl-CoA dehydrogenase, SCAD)在大鼠生理性和病理性心肌肥大中的变化,探讨其与心肌肥大之间的关系。方法：以自发性高血压大鼠作为病理性心肌肥大模型,游泳运动训练性大鼠作为生理性心肌肥大模型。检测大鼠的血压、左室重量指数、血清和心肌游离脂肪酸含量、SCAD mRNA、蛋白表达及其酶活性的变化,采用超声心动图观察心脏的结构及功能。结果：与对照组比较,运动组大鼠出现了明显的离心性肥大,心肌收缩功能增强;而高血压组大鼠呈现出明显的向心性肥大,心肌收缩功能减退。与对照组比较,运动组和高血压组大鼠的左室重量指数均明显增高,但两组间比较无显著差异,二者发生了相同程度的心肌肥大。与对照组比较,运动组大鼠左心室SCAD mRNA和蛋白表达均明显上调,酶活性增高,血清和心肌游离脂肪酸含量明显减少;而自发性高血压大鼠左心室SCAD mRNA和蛋白表达均明显下调,酶活性下降,血清和心肌游离脂肪酸含量明显增多。结论：SCAD在生理性和病理性心肌肥大中呈现出不一致的变化趋势,可能作为区别2种不同心肌肥大的分子标志物以及病理性心肌肥大的潜在治疗靶点。     

Myocardial hypertropy in rabbits with renovascular hypertension under pharmacological blockade of angiotensin II synthesis and its interaction with specific receptors

The dynamics of blood pressure, the weight of the heart and its subdivisions, and morphology of myocardium were studied in the rabbits with experimental renovascular hypertension. Treatment with inhibitors of angiotensin II synthesis (lotensin) or its interaction with specific receptors (valsartan) decreased blood pressure and the weight of the left ventricle, but did not affect the interrelations between structural elements in the heart, which remained the same as in hypertension-induced myocardial hypertrophy. In addition, these drugs impaired some parameters of cardiac activity attesting to myocardial overload, increase in collagen content in the myocardium, and decrease in the ratio of the numbers of capillaries and mitochondria to the weight of myofibrils. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 127, No. 5, pp. 506–509, May, 1999     

Weights of the body and cardiac ventricles in pulmonary emphysema

Summary We analysed statistically the association of emphysema, determined on inflation fixed specimens, with the weights of the body and heart, and of the cardiac ventricles, weighed separately, in 170 male and 86 female adult autopsies. The cases were grouped according to the cause of death into cardiovascular, cancer and other deaths. In men the body weight was inversely proportional to the severity of emphysema, but no association existed between the body weight and the cause of death. In male cardiovascular deaths the total heart weight, total ventricular weight and the weight of the left ventricle with the septum were also inversely proportional to the severity of emphysema while this was not true in the other deaths. In male cardiovascular deaths a decrease, and in the other deaths an increase, of the weight of the free wall of the right ventricle was associated with an increasing severity of emphysema. In all male deaths, however, the left to right ratio decreased with an increasing severity of emphysema. Thus, pulmonary emphysema is associated both with a general atrophy, including the myocardium, and a mainly relative right ventricular hypertrophy. An absolute right ventricular hypertrophy, however, seems to accompany emphysema only in the absence of other major cardiovascular diseases.     

致心律失常性右室心肌病心力衰竭期的病理特点分析

目的 通过分析致心律失常性右室心肌病(ARVC)心力衰竭期的病理改变,以进一步了解其临床分期与病理表型的关系.方法 从2004-2007 年在阜外心血管病医院接受心脏移植的心力衰竭病例中,收集病理诊断为ARVC的受体心脏8例,测量心脏重量,评价左右心室心腔扩张、心肌细胞肥大、脂肪浸润、纤维化、附壁血栓和伴发心肌炎等指标,注意左心室受累情况,并进行病理分型.结果 8例中的7例为经典型(即右心室改变为主),1例为左优势型(左心室改变为主),未见双室型病例.组织学均为纤维脂肪型,未见单纯脂肪型病例.经典型病例的右心室中、重度扩张,少数有室壁瘤形成,其中6例伴左心室受累,受累左心室轻、中度扩张,心肌广泛间质纤维化,部分病例伴替代性疤痕,而脂肪浸润量小,多局限于心外膜下.左心室心肌细胞肥大普遍.而左优势型的左心室重度扩张,弥漫间质纤维化和局部透壁性脂肪浸润.8例中3例左心室明显肥厚,3例查见双室附壁血栓,1例伴局灶性心肌炎.结论 ARVC心力衰竭期的左心室受累多见而严重,左心室间质纤维化突出,心肌细胞肥大明显,但脂肪替代少见和局限.左、右心室多扩张,可见附壁血栓,应注意与扩张型心肌病等鉴别.     

Myocardial fibrosis in nonhuman primate with pressure overload hypertrophy.

Characteristics of pressure overload hypertrophy are known to include an accumulation of collagen (or fibrosis) and a biochemical remodeling of fibrillar type I and III collagens. The corresponding structural nature of myocardial fibrosis is less clear. This light morphologic study was undertaken to address this issue in the hypertrophied left ventricle of the nonhuman primate with experimental hypertension. For this purpose, the picrosirius red technique and polarization microscopy were used to examine the myocardium during the evolutionary, early, and late phases of established hypertrophy corresponding to 4, 35, and 88 weeks of experimental hypertension. Evidence of increased thin perimysial fiber formation, together with collagen fiber disruption and edema at 4 weeks of hypertrophy, was found when the chamber volume to left ventricular mass ratio was reduced. After 35 weeks, when this ratio was again normal, a greater number of intermuscular spaces contained both thick and thin perimysial fibers. In addition to this interstitial fibrosis, a reactive fibrosis consisting of a meshwork of thick and thin perimysial fibers was seen extending over muscle fibers. Finally, at 88 weeks, this fibrous meshwork had encircled muscle and there now was evidence of cell necrosis. The accompanying replacement fibrosis consisted of yet another distinctive orthogonal grid of thick and thin collagen fibers. Thus, a continuum of fibrillar collagen remodeling was seen in pressure overload hypertrophy in the nonhuman primate myocardium. Structurally distinct patterns of myocardial fibrosis were recognized based on the alignment of perimysial fibers with muscle that may explain the cellular remodeling and altered mechanical behavior of the concentrically hypertrophied myocardium.     

Early morphological alterations of pressure-overloaded cat right ventricular myocardium

Pressure overload of the right ventricle results in an increase in ventricular mass. It also results in abnormal in vitro contractile function in advance of the onset of congestive heart failure as determined in papillary muscles removed from these ventricles. To correlate these functional abnormalities with any early underlying morphological changes, a band was placed around the proximal pulmonary artery of cats. This band restricted the lumen to 20% of normal and was left in place for 2 weeks. At that time, hemodynamic variables were measured to insure that right ventricular pressure overload had been produced. The hearts were then perfusion fixed, and papillary muscles from the right ventricle were prepared for light and transmission electron microscopy. Quantitative morphological data were obtained for the volume density both of several tissue components and of several organelles. It was found that there are significant increases in myocyte cross-sectional area and diameter in hypertrophied tissue with a concurrent increase in the volume density of interstitial tissue. There are no alterations in the volume density of organelles in the hypertrophied myocytes. We suggest that the substantial increase in the proportion of connective tissue and the decrease in the surface area to volume ratio that accompany pressure overload cardiac hypertrophy may be early underlying structural changes that relate directly to the abnormal contractile function found in this type of hypertrophy.     

Right ventricular hypertrophy in monocrotaline pyrrole treated rats

Single, tail-vein injections of 2–4 mg/kg body weight of monocrotaline pyrrole produced an endothelial lesion in the cells lining the capillaries and arterioles of the rat lung. Within 4 weeks, numerous pulmonary vessels became partially or completely occluded by fibrin and platelet thrombi, by enlargement of the endothelium, and by hypertrophy of smooth muscle cells in the tunica media. Impairment of the pulmonary blood flow led to tissue hypoxia which was reflected by an increase in hemoglobin, hematocrit, and erythrocyte count values. In addition, there was a fourfold increase in peak systolic blood pressure within the lumen of the right ventricle. This hypertension was progressive and caused an increase in the workload of the right heart. Right ventricular hypertrophy developed gradually over 2–3 weeks so that by 4 weeks the right side of the heart weighed almost 3 times that of the controls. It is suggested that monocrotaline pyrrole injected animals provide a readily reproducible model for experimental cardiac hypertrophy which mimics the gradual onset of cardiac disease observed clinically in man.     

Correlation of alpha-skeletal actin expression, ventricular fibrosis and heart function with the degree of pressure overload cardiac hypertrophy in rats

We have analysed alterations of alpha-skeletal actin expression and volume fraction of fibrosis in the ventricular myocardium and their functional counterpart in terms of arrhythmogenesis and haemodynamic variables, in rats with different degrees of compensated cardiac hypertrophy induced by infra-renal abdominal aortic coarctation. The following coarctation calibres were used: 1.3 (AC1.3 group), 0.7 (AC0.7) and 0.4 mm (AC0.4); age-matched rats were used as controls (C group). One month after surgery, spontaneous and sympathetic-induced ventricular arrhythmias were telemetrically recorded from conscious freely moving animals, and invasive haemodynamic measurements were performed in anaesthetized animals. After killing, subgroups of AC and C rats were used to evaluate in the left ventricle the expression and spatial distribution of alpha-skeletal actin and the amount of perivascular and interstitial fibrosis. As compared with C, all AC groups exhibited higher values of systolic pressure, ventricular weight and ventricular wall thickness. AC0.7 and AC0.4 rats also showed a larger amount of fibrosis and upregulation of alpha-skeletal actin expression associated with a higher vulnerability to ventricular arrhythmias (AC0.7 and AC0.4) and enhanced myocardial contractility (AC0.4). Our results illustrate the progressive changes in the extracellular matrix features accompanying early ventricular remodelling in response to different degrees of pressure overload that may be involved in the development of cardiac electrical instability. We also demonstrate for the first time a linear correlation between an increase in alpha-skeletal actin expression and the degree of compensated cardiac hypertrophy, possibly acting as an early compensatory mechanism to maintain normal mechanical performance.     

Myocardial force development and structural changes associated with monocrotaline induced cardiac hypertrophy and heart failure

In this study alterations are characterized which occur, in myocardial force development morphological appearance and protein composition, during the development of cardiac hypertrophy and heart failure in monocrotaline (MCT) treated rats. The transition from cardiac hypertrophy to heart failure was studied by comparing the results from control (CON) and two MCT groups (40 and 44 mg/kg body weight). The three experimental groups consisted of at least five animals each. Parameters studied were: body weight (measured daily), lung/body weight ratio, right ventricular wall volume and thickness, and force development in thin right ventricular trabeculae at 27°C, using different extracellular calcium concentrations and pacing frequencies. MCT injection resulted in marked right ventricular hypertrophy and heart failure as evidenced by an up to 2-fold increase in lung/body weight ratio and a 1.7-fold increase in wall volume. The MCT groups showed a negative force–frequency relation and maximum force was up to 2-fold less than in the CON group. Protein analysis by means of one- and two-dimensional gel electrophoresis revealed a marked (7-fold) up-regulation of the slow myosin heavy chain isoform as well as a 4.5-fold increase in the content of the cytoskeletal protein desmin, whereas the mitochondrial protein ATP-synthase content was reduced. Hence MCT-induced cardiac hypertrophy and heart failure result in altered cellular calcium handling, depression of maximum force output, an increase in the economy of myocardial contraction and changes in cytoskeletal structure and energy supply.     

Activities of Some Caspase Cascade Enzymes and Myocardial Contractility in Experimental Left Ventricular Focal Ischemia

Focal left ventricular ischemia was modeled in male Chinchilla rabbits. Activities of caspase-3 and caspase-8 in the left and right ventricular myocardium and myocardial contractility were studied after 1, 3, and 5 days. Caspase-3 activity increased significantly in the left ventricular peri-infarction zone and right ventricular myocardium, while caspase-8 activity did not differ from the control. Left ventricular contractility decreased significantly and the hemodynamic load of the right ventricle sharply increased. These results attest to induction of the internal (mitochondrial) pathway of apoptosis in myocardial cells most likely caused by left ventricular hypoxia and right ventricular overload.     

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.     

Hypoinnervation is an early event in experimental myocardial remodelling induced by pressure overload

Structural and functional remodelling of cardiomyocytes, capillaries and cardiac innervation occurs in left ventricular hypertrophy (LVH) and heart failure (HF) in response to pressure‐induced overload. However, the onset, time course and the extent of these morphological alterations remain controversial. In the present study, we tested the hypothesis that the progression from hypertrophy to HF is accompanied by changes in the innervation (hyper‐ or hypoinnervation). Left ventricles of wild‐type murine hearts subjected to pressure overload‐induced hypertrophy by transverse aortic constriction (TAC) were investigated by morphometric and design‐based stereological methods at 1 and 4 weeks after TAC and compared with sham‐operated mice. Mice developed compensated LVH at 1 week and typical signs of HF, such as left ventricular dilation, reduced ejection fraction and increased relative lung weight at 4 weeks post‐TAC. At the (sub‐)cellular level, cardiomyocyte myofibrillar and mitochondrial volume increased progressively in response to mechanical overload. The total length of capillaries was not significantly increased after TAC, indicating a misrelationship between the cardiomyocyte and the capillary compartment. The myocardial innervation decreased already during the development of LVH and did not significantly decrease further during the progression to HF. In conclusion, our study suggests that early loss of myocardial innervation density and increased heterogeneity occur during pressure overload‐induced hypertrophy, and that these changes appear to be independent of cardiomyocyte and capillary remodelling.     

心肌脂肪酸氧化酶的基因调控机制及PPARα的作用

心肌是耗能最多的组织之一。在胚胎时期哺乳动物心肌处于相对缺氧的环境 ,以葡萄糖及丙酮酸作为主要的能源物质 ,出生后迅速转为依赖脂肪酸氧化。这一代谢模式的转化虽然以增加耗氧量为代价 ,但可为心肌提供大量的ＡＴＰ。正常心肌能量的70 %来源于脂肪酸的氧化 ,在饥饿、运动时脂肪酸的动员更多。因此 ,线粒体脂肪酸的 β氧化对维持心肌能量代谢及泵功能具有重要意义。脂肪酸的β氧化具有精密的调控机制[1] ,其中涉及各种相关的酶。过氧化物酶体增殖物激活受体α(ＰＰＡＲα)对心肌脂肪酸氧化酶的基因表达具有重要的调节功能 ,能促进心肌细…     

Neostigmine and pilocarpine attenuated tumour necrosis factor alpha expression and cardiac hypertrophy in the heart with pressure overload.

The inflammatory cytokine tumour necrosis factor alpha (TNF alpha) is known to be a major factor contributing to cardiac remodelling and dysfunction. Parasympathetic nervous system cholinergic function can inhibit TNF alpha expression during systemic infection. In the present study, we tested the effects of a cholinesterase inhibitor, neostigmine, and a muscarinic cholinergic agonist, pilocarpine, on cardiac hypertrophy and TNF alpha levels during pressure overload. Rats with transverse aortic constriction exhibited elevated TNF alpha protein levels in the heart, increased heart weight to body weight ratios (an index of cardiac hypertrophy) and decreased left ventricular diastolic function. Two weeks of infusion with neostigmine (6 microg kg(-1) day(-1)) or pilocarpine (0.3 mg kg(-1) day(-1)) significantly reduced cardiac hypertrophy, reduced TNF alpha levels and elevated interleukin-10 levels in heart tissues, and improved ventricular function in rats with transverse aortic constriction. Neither of these treatments significantly changed ventricular pressure load. Furthermore, in primary cultured neonatal cardiac cells, treatment with pilocarpine attenuated adrenergic agonist phenylephrine-induced increased TNF alpha expression and [3H]leucine (a marker of protein synthesis) incorporation in the cells. Collectively, both cholinergic agents decreased TNF alpha levels and attenuated cardiac hypertrophy. Since both agents potentially enhanced cholinergic function, the anti-inflammatory action may be involved in the cardioprotective effect of the treatments with these agents.