The isolated working heart model in infarcted rat hearts

Congestive heart failure (CHF) is one of the most common causes of death in western countries. The aim of this study was to establish and validate the working heart model in rat hearts with CHF. In the rat model the animals show parameters and symptoms that can be extrapolated to the clinical situation of patients with end-stage heart failure. The focus of attention was the evaluation of cardiodynamics (e.g.contractility) in the isolated 'working heart' model. The geometric properties of the left ventricle were measured by planimetry (stereology). Formulae available in the past for determining certain parameters in the working heart model (e.g.external heart work) have to be fitted to the circumstances of the infarcted rat hearts with its different organ properties.CHF was induced in Wistar Kyoto (WKY/NHsd) and spontaneously hypertensive rats (SHR/NHsd) by creating a permanent (8 week) occlusion of the left coronary artery, 2 mm distal to the origin from the aorta, by a modified technique (Itter et al. 2004). This resulted in a large infarction of the free left ventricular wall.We were able to establish and adapt a new and predictive working heart model in spontaneously hypertensive rat hearts with myocardial infarction (MI) 8-12 weeks after coronary artery ligation. At this stage the WKY rat did not show any symptoms of CHF. The SHR rat represented characteristic parameters and symptoms that could be extrapolated to the clinical situation of patients with end-stage heart failure (NYHA III-IV). Upon inspection, severe clinical symptoms of CHF such as dyspnoea, subcutaneous oedema, palebluish limbs and impaired motion were prominent. On necropsy the SHR showed lung oedema, hydrothorax, large dilated left and right ventricular chambers and hypertrophy of the septum. In the working heart model the infarcted animals showed reduced heart power, diminished contractility and enhanced heart work, much more so in the SHR/NHsd than in the Wistar Kyoto rat (WKY/NHsd).The aim for the future is to find a causal therapy of heart failure treatment. At present, only palliative therapy is possible for patients with heart failure. For this reason the working heart model in CHF rat hearts should provide a valuable method for early testing of new therapeutic approaches for patients with CHF.     

Gene expression of adrenomedullin in failing myocardium: comparison to atrial natriuretic peptide.

The expression of adrenomedullin (AM) and atrial natriuretic factor (ANF) were investigated in the myocardium of a rat model of chronic ischemic heart failure (CHF) compared with sham-operated controls. In addition, human myocardium of patients with end-stage heart failure due to idiopathic dilated cardiomyopathy compared with myocardium of normal subjects (NF) was studied. In CHF, similar AM levels but increased ANF expression were observed in left ventricular myocardium, as assessed by semiquantitative PCR. Functional experiments with freshly excised papillary muscles showed no influence of AM on myocardial contractility. In NF human myocardium, the expression of AM mRNA was threefold higher in atrial compared with ventricular tissue. In analogy, ANF mRNA was increased by approximately 15-fold in atrial tissue. In dilated cardiomyopathy, the expression of AM was significantly increased in right and left ventricles compared with NF. In parallel, ventricular ANF expression was enhanced.     

Heart failure progression is accelerated following myocardial infarction in type 2 diabetic rats

Clinical studies have shown a greater incidence of myocardial infarction in diabetic patients, and following an infarction, diabetes is associated with an increased risk for the development of left ventricular (LV) dysfunction and heart failure. The goal of this study was to determine if the progression of heart failure following myocardial infarction in type 2 diabetic (T2D) rats is accelerated compared with nondiabetic rats. Male nondiabetic Wistar-Kyoto (WKY) and T2D Goto-Kakizaki (GK) rats underwent coronary artery ligation or sham surgery to induce heart failure. Postligation (8 and 20 wk), two-dimensional echocardiography and LV pressure measurements were made. Heart failure progression, as assessed by enhanced LV remodeling and contractile dysfunction, was accelerated 8 wk postligation in the T2D animals. LV remodeling was evident from increased end-diastolic and end-systolic diameters and areas in the GK compared with the WKY infarcted group. Furthermore, enhanced LV contractile dysfunction was evident from a greater deterioration in fractional shortening and enhanced myocardial performance index (an index of global LV dysfunction) in the GK infarcted group. This accelerated progression was accompanied by greater increases in atrial natriuretic factor and skeletal alpha-actin (gene markers of heart failure and hypertrophy) mRNA levels in GK infarcted hearts. Despite similar decreases in metabolic gene expression (i.e., peroxisome proliferator-activated receptor-alpha-regulated genes associated with fatty acid oxidation) between infarcted WKY and GK rat hearts, myocardial triglyceride levels were elevated in the GK hearts only. These results, demonstrating enhanced remodeling and LV dysfunction 8 wk postligation provide evidence of an accelerated progression of heart failure in T2D rats.     

Simultaneous measurement of atrial natriuretic polypeptide (ANP) messenger RNA and ANP in rat heart--evidence for a preferentially increased synthesis and secretion of ANP in left atrium of spontaneously hypertensive rats (SHR)

Tissue levels of atrial natriuretic polypeptide (ANP) messenger RNA (ANPmRNA) and ANP in the rat heart were measured simultaneously. In Wistar rats, ANPmRNA of the same size (approximately 0.95 kbp) was detected in all four chambers of the rat heart. The ANPmRNA level was the highest in the right atrium, and the left atrial level was slightly lower than the right atrial level. Ventricular levels were more than two orders of magnitude lower than atrial levels. Tissue ANP concentrations of four chambers were roughly parallel to ANPmRNA levels. In spontaneously hypertensive rats (SHR) with the elevated plasma ANP level, the ANPmRNA level in the left atrium was substantially increased. The left/right ratio of atrial ANPmRNA level in SHR (150%) was higher than that in control Wistar Kyoto rats (WKY) (90%). In contrast, the left/right ratio of atrial ANP concentration was decreased in SHR (44%) compared with that in WKY (84%). The ratio of ANP to ANPmRNA levels in the left atrium of SHR was about three times smaller than that in the right atrium of SHR, and those in bilateral atria of WKY. These results indicate that the biosynthesis and secretion of ANP from the left atrium is preferentially increased in SHR. Thus, simultaneous determination of ANPmRNA and ANP levels is a refined strategy of investigation for the biosynthesis, storage and secretion of ANP.     

Alteration of collagenous protein profile in congestive heart failure secondary to myocardial infarction

The rat model of myocardial infarction is characterized by progressive cardiac hypertrophy and failure. Rats with infarcts greater than 30% of the left ventricle exhibited early and moderate, stages of heart failure 4 and 8 weeks after the occlusion of the left coronary artery, respectively. As heart failure is usually associated with remodeling of the extracellular matrix, a histological and biochemical study of cardiac collagenous proteins was carried out using failing hearts. Total collagen content in the right ventricle increased at 2, 4, and 8 weeks following occlusion of the left coronary artery whereas such a change in viable left ventricle was seen after 4 and 8 weeks. Total cardiac hydroxyproline concentration was increased in both right and left ventricular samples from the infarcted animals when compared to those of control; this increase was due to elevation of pepsin-insoluble collagen fraction. The myocardial noncollagenous/collagenous protein ratio was decreased in experimental right and left ventricular samples when compared to control samples. These findings suggest that an increase in cross-linking of cardiac collagen as well as disparate synthesis of collagenous and noncollagenous proteins occurs in this model of congestive heart, failure.     

蛋白激酶C对自发性高血压大鼠肥大心肌细胞无负荷收缩功能的调节

在慢性压力超负荷引起心肌肥大过程中,蛋白激酶C(protein kinase C,PKC)的激活起关键性作用,激活的PKC也能调节心肌收缩性能.本文旨在研究自发性高血压大(spontaneously hypertensive rat,SHR)心肌肥大的不同阶段PKC调节心肌收缩性能的特征.采用胶原酶法分离4月龄与10月龄Wistar-Kyoto(WKY)、SHR大鼠的心肌细胞,观测单个心肌细胞无负荷缩短幅值以及在PKC激动剂与抑制剂作用下心肌收缩性能的变化.结果表明:刺激频率从1 Hz增至3 Hz,WKY大鼠心肌细胞无负荷缩短幅值逐渐增加,呈正阶梯效应;4月龄SHR大鼠心肌细胞的缩短幅值较WKY大鼠增强,但在各刺激频率下其缩短幅值基本保持不变;10月龄SHR大鼠心肌细胞的缩短幅值在1 Hz刺激条件下与WKY大鼠无差别,随刺激频率增加,缩短幅值降低,呈负阶梯效应.在PKC激动剂PMA灌流条件下,50、100与200 nmol/L的PMA分别降低WKY大鼠心肌细胞缩短幅值至(69.8±1.9)%、(58.2 2.2)%与(22.7±2.5)%(均P<0.01),呈浓度依赖关系;PMA对4月龄SHR大鼠心肌细胞缩短幅值的降低更明显,分别降至(6.1±0.7)%、(2.4±0.2)%与(12.5±2.6)%(均P<0.01);PMA降低10月龄SHR大鼠心肌细胞缩短幅值至(65.7±1.6)%、(53.9±4.0)%与(16.3±2.0)%(均P<0.01),小于对4月龄SHR大鼠心肌细胞缩短幅值的作用.PKC抑制剂staurosporine增加WKY大鼠心肌细胞缩短幅值,在200 nmol/L的staurosporine灌流条件下,WKY大鼠、4月龄SHR大鼠、10月龄SHR大鼠心肌细胞缩短幅值分别增JJH(63.63±4.53)%、(80.82±4.61)%、(80.97±4.59)%(均P<0.05).结果提示,在SHR大鼠心肌肥大初期,具有负性肌力作用的PKC异构体可能被激活,并参与对心肌收缩性能的调节;而心肌肥大稳定阶段,这些PKC活性可能恢复至正常水平.     

Rapid transient analysis of myosin cross-bridge kinetics in hypertrophied hearts

Essential hypertension, with pressure overload leading to left ventricular hypertrophy, often results in coronary artery disease and congestive heart failure. The spontaneously hypertensive rat (SHR) is an attractive model for studying the effects of long-term antihypertensive therapy on the contractile properties of the myocardium. In this study we investigated differences in mechanical and biochemical characteristics of papillary muscles from SHR and normal (Wistar-Kyoto [WKY]) rats as a function of age and treatment. We found that the rate of delayed force redevelopment after rapid stretch was less in SHR than in WKY in every age group studied, even at 2 wk of age, before hypertension was evident in the SHR. In the treated SHR, blood pressure was lower, hypertrophy was reduced and the rate of delayed force redevelopment was increased compared with the untreated SHR. Finally, the pattern of myosin isoenzymes was different in treated than in untreated SHR, being shifted to more of the fast V1 and less of the slow V3 isomyosin. We conclude that long-term antihypertensive therapy not only prevents the development of left ventricular hypertrophy, but may do so by preventing the shift in myosin isoenzyme pattern normally found in hearts subjected to a long-term pressure overload.     

Noradrenergic content and turnover rate in kidney and heart shows gender and strain differences.

The objective of this study was to compare strain and gender differences in kidney and heart norepinephrine (NE) content and turnover rate in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR, SHR/a, and SHR/y). Our laboratory has shown that the Y chromosome has a significant effect on blood pressure in the SHR model of hypertension through the use of two new rat stains, SHR/a and SHR/y, to study the Y chromosome. SHR/a have a SHR autosomal genetic background with a WKY Y chromosome, whereas the SHR/y rats have a WKY autosomal genetic background with a SHR Y chromosome. Tissues were homogenized after alpha-methyl-DL-p-tyrosine injection and analyzed for NE. The male kidney NE content was significantly lower in the WKY compared with the SHR, SHR/y, and SHR/a. Kidney and heart NE content was significantly higher in females compared with males in all strains except the SHR/y. The WKY and SHR/y females had significantly lower kidney NE turnover rates, and the SHR and SHR/a females had significantly higher kidney NE turnover rates than strain-matched males. This study suggests both a strain and gender difference in sympathetic nervous system activity through noradrenergic neurotransmission.     

Echocardiographic detection of congestive heart failure in postinfarction rats

In studies of congestive heart failure (CHF) treatment, it is essential to select animals with a similar degree of cardiac dysfunction. However, this is difficult to establish without hemodynamic evaluation in rat postinfarction-induced CHF. This study aimed to diagnose CHF in long-term follow-up postinfarction rats using only echocardiographic criteria through a J-tree cluster analysis and Fisher's linear discriminant function. Two sets of sham and infarcted rats were studied. The first was used to perform cluster analysis and the second to prospectively validate the results. Six months after inducing myocardial infarction (MI), rats were subjected to transthoracic echocardiography. Infarct size was measured by histological analysis. Six echocardiographic variables were used in the cluster analysis: left ventricular (LV) systolic dimension, LV diastolic dimension-to-body weight ratio, left atrial diameter-to-body weight ratio, LV posterior wall shortening velocity, E wave, and isovolumetric relaxation time. Cluster analysis joined the rats into one sham and two MI groups. One MI cluster had more severe anatomical and echocardiographic changes and was called MI with heart failure (MI/HF+, n = 24, infarct size: 42.7 ± 5.8%). The other had less severe changes and was called MI without heart failure (MI/HF-, n = 11, infarct size: 32.3 ± 9.9%; P < 0.001 vs. MI/HF+). Three rats with small infarct size (21.6 ± 2.2%) presenting mild cardiac alterations were misallocated in the sham group. Fisher's linear discriminant function was built using these groups and used to prospectively classify additional groups of sham-operated (n = 20) and infarcted rats (n = 57) using the same echocardiographic parameters. The discriminant function therefore detected CHF with 100% specificity and 80% sensitivity considering allocation in MI/HF+ and sham group, and 100% specificity and 58.8% sensitivity considering MI/HF+ and MI/HF- groups, taking into account pathological criteria of CHF diagnosis. Echocardiographic analysis can be used to accurately predict congestive heart failure in postinfarction rats.     

Effect of chronic colchicine administration on the myocardium of the aging spontaneously hypertensive rat

Colchicine has been demonstrated to suppress the release of fibroblast growth factors, retard collagen formation and augment collagenase activity. Trials with colchicine in patients with hepatic fibrosis have suggested clinical benefit. The development of impaired myocardial function in the spontaneously hypertensive rat (SHR) is associated with a marked increase in myocardial fibrosis. The present study was carried out to test the hypothesis that chronic colchicine administration to the SHR would prevent the development of fibrosis and impaired myocardial performance.Colchicine (1 mg/l drinking water) was administered to male SHR and WKY rats from at age 13 months until 24 months or until evidence of heart failure was observed. Age-matched untreated SHR and colchicine treated and untreated WKY served as controls. At study, active and passive properties of isolated left ventricular muscle preparations were determined. Myocardial fibrosis was assessed by measuring hydroxyproline and histologic determination of interstitial cross-sectional area. Increases in LV hydroxyproline and interstitial area were found in untreated SHR relative to WKY; passive myocardial stiffness was increased and active muscle properties were depressed. In comparing colchicine treated vs untreated SHR, no differences in hydroxyproline, interstitial area or intrinsic myocardial function were found. In the WKY, colchicine increased myocardial interstitium and passive stiffness without changing hydroxyproline. Active myocardial function was not depressed.Thus, chronic colchicine administration neither attenuated the development of interstitial fibrosis nor prevented impaired myocardial function in the SHR. Colchicine treatment was associated with increased interstitium in WKY with increased passive myocardial stiffness. (Mol Cell Biochem 166: 45-54, 1997)     

Differential expression of TRPC channels in the left ventricle of spontaneously hypertensive rats

This study was designed to identify the differential expression of the canonical transient receptor potential (TRPC) channels in the left ventricle of spontaneously hypertensive rats (SHR). Echocardiography studies were performed to compare the left ventricular function in SHR vs. Wistar-Kyoto rats (WKY), and the mRNA level of the TRPC channels was determined by quantitative real-time RT-PCR (qRT-PCR). Western blots were performed to examine whether the mRNA expression corresponded with the protein expression. Compared with the WKY, the mRNA expression of TRPC4 and TRPC5 was significantly increased in the 10-week-old SHR (P = 0.032 for TRPC4 and P = 0.043 for TRPC5), so did the TRPC4/5 protein content. The midwall fractional shortening (mFS) of SHR was lower than WKY (P = 0.016). Furthermore, increased expression of TRPC4/5 was correlated with both increased blood pressure and decreased mFS. These findings suggest that TRPC4 and 5 seem to be the main subtypes expressed in the heart of the SHR at the beginning period of hypertension. Theses channels may participate in the development of left ventricular systolic dysfunction.     

Indapamide-induced prevention of myocardial fibrosis in spontaneous hypertension rats is not nitric oxide-related

We studied the effect of thiazide-like diuretic--indapamide on fibrosis development in the left ventricle of young spontaneously hypertensive rats (SHR) and assessed the involvement of nitric oxide in this process. Six-week-old male SHR were treated with indapamide (1 mg/kg/day) for six weeks. Age-matched SHR were used as hypertensive and Wistar-Kyoto rats (WKY) as normotensive control. Systolic blood pressure was measured by tail-cuff plethysmography. Nitric oxide synthase (NOS) activity, protein expressions of endothelial (eNOS) and inducible NOS (iNOS), myocardial fibrosis and collagen type I and III were determined in the left ventricle. Indapamide treatment partially prevented SBP increase in SHR (SHR+Indapamide: 157+/-4, SHR: 171+/-3, WKY: 119+/-3 mmHg). Indapamide prevented myocardial fibrosis development in SHR, but without affecting collagen type I to type III ratio. Indapamide did not affect NOS activity as well as eNOS and iNOS protein expressions in the left ventricles evaluated by both Western blot and immunohistochemically. In conclusion, our results indicate that indapamide-induced prevention of myocardial fibrosis is not mediated by nitric oxide-related mechanism.     

Kallikrein gene delivery attenuates cardiac remodeling and promotes neovascularization in spontaneously hypertensive rats

Hypertension that results in left ventricular (LV) hypertrophy and/or fibrosis can lead to cardiac dysfunction. Spontaneously hypertensive rats (SHR) develop high blood pressure and LV hypertrophy at an early age and are a popular model of human essential hypertension. To investigate the role of the tissue kallikrein-kinin system in cardiac remodeling, an adenovirus containing the human tissue kallikrein gene was injected intravenously into adult SHR and normotensive Wistar-Kyoto (WKY) rats. The blood pressure of WKY rats remained unchanged throughout the experiment. Alternatively, kallikrein gene transfer reduced blood pressure in SHR for the first 2 wk, but had no effect from 3 to 5 wk. Five weeks after kallikrein gene delivery, SHR showed significant reductions in LV-to-heart weight ratio, LV long axis, and cardiomyocyte size; however, these parameters were unaffected in WKY rats. Interestingly, cardiac collagen density was decreased in both SHR and WKY rats receiving the kallikrein gene. Kallikrein gene transfer also increased cardiac capillary density in SHR, but not in WKY rats. The morphological changes after kallikrein gene transfer were associated with decreases in JNK activation as well as transforming growth factor (TGF)-beta 1 and plasminogen activator inhibitor-1 levels in the heart. In addition, kallikrein gene delivery elevated LV nitric oxide and cGMP levels in both rat strains. These results indicate that kallikrein-kinin attenuates cardiac hypertrophy and fibrosis and enhances capillary growth in SHR through the suppression of JNK, TGF-beta 1, and plasminogen activator inhibitor-1 via the nitric oxide-cGMP pathway.     

Altered expression of G-protein mRNA in spontaneously hypertensive rats.

We have recently demonstrated that the decreased ability of hormones, forskolin and GTP to stimulate adenylate cyclase in heart and aorta from spontaneously hypertensive rats (SHR), as compared to their age-matched Wistar-Kyoto control rats (WKY), was associated with enhanced levels of Gi- and not with Gs-regulatory proteins. In the present studies we have investigated the expression of Gi-regulatory proteins at the mRNA level by Northern blotting. Total RNA of heart ventricle and aorta from WKY and SHR was probed with radiolabeled cDNA inserts encoding Gi alpha-2 and Gi alpha-3. The Gi alpha-2 and Gi alpha-3 probes detected a message of 2-3 and 3-5 kb, respectively, in both WKY and SHR, however, the message was significantly enhanced in SHR, as compared by WKY. On the other hand the cDNA probe encoding Gs alpha detected a message of 1.8 kb in heart and aorta from both WKY and SHR, however, no difference in the levels of Gs alpha mRNA was detected in SHR and WKY tissues. These results indicate that the mRNA levels of Gi alpha-2 and Gi alpha-3 and not of Gs are overexpressed in heart and aorta from SHR, which may be responsible for the increased levels of Gi as shown earlier by immunoblotting techniques. It may be suggested that the enhanced vascular tone and impaired cardiac contractility in hypertension may partly be the consequences of increased levels of Gi in heart and aorta.     

Clonidine fails to reduce pressor responsiveness of conscious spontaneously hypertensive rats to vasopressin

Pressor responses and heart rate responses to intravenous injections (3.5-50.0 pmol/kg) of arginine vasopressin (AVP) were recorded in saline- and clonidine-treated spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. Clonidine (20 micrograms/kg, i.v.) caused a marked fall of arterial pressure in SHR but not in WKY rats so that, 20 min after the injection of the alpha 2-adrenoceptor agonist, arterial pressure was similar in the two strains of rats. The curve expressing the relationship between the dose of AVP and the increase of arterial pressure for saline-treated SHR was positioned to the left of that for saline-treated WKY rats. This enhanced pressor responsiveness of SHR to AVP may have been related to impaired reflex activity since heart rate fell much less in SHR than in WKY rats for a given elevation in pressure. Pressure responses to AVP were augmented by clonidine in both SHR and WKY rats so that, similar to saline-treated rats, pressor responsiveness to the peptide was still greater in SHR. Heart rate responses to AVP were not altered significantly by clonidine. The results indicate that clonidine fails to enhance reflex activity and reduce pressor responsiveness of SHR to AVP. The increased pressor responsiveness of both SHR and WKY rats to AVP following clonidine was an unexpected finding and may be related to a peripheral interaction between alpha-adrenergic agonists and AVP.     

A new inbred Wistar-Kyoto rat substrain exhibiting apparent salt sensitivity and borderline hypertension

The normotensive Wistar-Kyoto (WKY) rat strain is a traditional control for the spontaneously hypertensive rat (SHR). We found trait differences between two inbred normotensive WKY strains, derived originally from different vendors, and compared these two strains from La Jolla-Taconic Farms (WKY/lj-tf) and La Jolla-Charles River (WKY/lj-cr) with the inbred SHR/lj-cr for cardiovascular, diurnal, and activity traits under normal and high (8%) NaCl diets. Marked genetic diversity was found between the two vendor-derived WKY. By using an extended study design and radiotelemetry, we compared WKY/lj-cr, WKY/lj-tf, and SHR/lj-cr with the following results: systolic pressure (120 +/- 1, 133 +/- 1, 168 +/- 3 mmHg, respectively); diurnal variation in heart rate (DeltaHR: 46 +/- 3, 71 +/- 4, 57 +/- 2 beats/min, respectively); and salt sensitivity of arterial pressure (Deltasystolic: 10 +/- 1, 21 +/- 1, 20 +/- 1 mmHg, respectively). The WKY/lj-tf genotype apparently results in compromised control of arterial pressure and heart rate, especially during high NaCl intake, and greater susceptibility to high pressure (i.e., high NaCl-induced secondary changes). WKY/lj-tf thus constitutes a new inbred borderline hypertensive WKY substrain offering unique opportunities for genomic studies into the development of genetic hypertension.     

Potentiation of pressor response to angiotensin II at the preoptic area in spontaneously hypertensive rat

Cardiovascular responses to angiotensin II(AII) at the preoptic area (POA) were compared between normotensive Wistar Kyoto rat (WKY) and spontaneously hypertensive rat(SHR) by measuring blood pressure and heart rate under unrestrained, conscious state via a catheter implanted chronically into the abdominal aorta and by injection of drugs into POA through a chronic guide cannula. AII injected into POA at doses of 0.3 ng and 1 ng produced a dose-dependent pressor response, accompanied with a slight decrease of heart rate, in both WKY and SHR. However, in SHR, the pressor response to AII was more than 2 times greater than that in WKY and was quick in onset and lasted about 30 min. When AII in combination with [Sar1, Ile8]-angiotensin II (0.5 microgram), an AII receptor antagonist, were simultaneously administered to POA, the pressor response to AII was strongly inhibited in both WKY and SHR. The results suggest that the pressor response to AII due to its receptor stimulation at POA is markedly potentiated in SHR.     

SHR Y chromosome enhances the nocturnal blood pressure in socially interacting rats

Our objective was to test the hypothesis that nocturnal mean arterial pressure (MAP), heart rate (HR), and activity would be increased in 1) colony over individually caged rats and 2) the spontaneously hypertensive rat (SHR) Y chromosome strain (SHR/y colony) compared with Wistar-Kyoto (WKY) rats. MAP, HR, and activity were monitored using radiotelemetry. The nocturnal MAP rise expressed as the percentage change in MAP from light to dark was increased (P < 0.05) in the SHR/y colony. The SHR Y chromosome increased MAP in both the colony and caged groups compared with WKY (P < 0.001). The SHR/y colony animals spent 23% of a 24-h period at a MAP >120 mmHg, whereas the WKY colony animals spent 2% of a 24-h period in this range. The MAP of the SHR/y colony on clonidine was reduced (P < 0.001) to WKY baseline values. Activity but not HR was increased (P < 0.01) in the WKY and SHR/y colonies compared with caged animals. In conclusion, colony housing and the SHR Y chromosome increased MAP compared with individually caged housing.     

Up-regulation of myocardial connexin-43 in spontaneously hypertensive rats fed red palm oil is most likely implicated in its anti-arrhythmic effects

The purpose of this study was to test our hypothesis that red palm oil (RPO) intake may affect abnormalities of myocardial connexin-43 (Cx43) and protein kinase Cε (PKCε) signaling, and consequently the propensity of the spontaneously hypertensive rat heart (SHR) heart to arrhythmias. SHR and Wistar-Kyoto (WKY) rats fed a standard rat chow plus red palm oil (200?μL/day) for 5?weeks were compared with untreated rats. Cytosolic but not particulate PKCε expression as well as Cx43-mRNA, total Cx43 proteins, and its phoshorylated forms were increased, and disordered localization of Cx43 was attenuated in the left ventricle of RPO-fed SHR compared with untreated rats. These alterations were associated with suppression of early post-ischemic-reperfusion-related ventricular tachycardia and electrically inducible ventricular fibrillation. However, the treatment dose of RPO caused down-regulation of myocardial Cx43, but did not alter its cell membrane distribution or overall PKCε expression in WKY rats. It was, however, associated with poor arrhythmia protection, suggesting overdosing. Results indicate that SHR benefit from RPO intake, particularly because of its apparent anti-arrhythmic effects. This protection can be, in part, attributed to the preservation of cell-to-cell communication via up-regulation of myocardial Cx43, but not with PKCε activation.     

Decreased content in left atrium and increased plasma concentration of atrial natriuretic polypeptide in spontaneously hypertensive rats (SHR) and SHR stroke-prone

The atrial contents and concentrations, and the plasma concentrations of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) and SHR stroke-prone (SHRSP) were measured and compared with those of age-matched Wistar Kyoto rats (WKY) using a specific radioimmunoassay (RIA) for alpha-rat ANP (alpha-rANP). The contents of alpha-rANP-LI in the atria of SHR (19.0 +/- 0.9 micrograms, mean +/- SEM) and SHRSP (19.3 +/- 0.6 micrograms) were significantly lower than that of WKY (22.8 +/- 1.4 micrograms) (p less than 0.05). The atrial concentration of alpha-rANP-LI was also significantly lower in SHR (248.2 +/- 11.3 ng/mg, p less than 0.05) and tended to be lower in SHRSP (272.2 +/- 12.4 ng/mg) than that of WKY (300.0 +/- 14.2 ng/mg). Furthermore, the concentrations in the left auricles of SHR and SHRSP were significantly lower than that of WKY (p less than 0.01 and p less than 0.05, respectively). In contrast, no significant difference was observed in the alpha-rANP-LI concentrations in the right auricles of WKY, SHR and SHRSP. Gel filtration studies coupled with RIA showed that gel filtration profiles of the extracts from the right and left auricles of WKY, SHR and SHRSP were essentially identical. The plasma alpha-rANP-LI levels in SHR (260 +/- 34 pg/ml) and SHRSP (319 +/- 19 pg/ml) were significantly higher than that in WKY (170 +/- 17 pg/ml) (p less than 0.05 and p less than 0.01, respectively). These results suggest that the secretion of ANP from the heart is increased in SHR and SHRSP compared with WKY.