Rat Model Of Congestive Heart Failure Research Articles

Qiliqiangxin improves cardiac function and attenuates cardiac remodelling in doxorubicin-induced heart failure rats

Context Therapeutic doxorubicin administration is restricted as this anticancer drug may be cardiotoxic. The traditional Chinese medicine qiliqiangxin has been approved for clinical treatment of chronic heart failure. Objective To explore the protective effects and molecular mechanisms of qiliqiangxin on doxorubicin-induced congestive heart failure (CHF) in rats. Materials and methods A CHF rat model was established via intraperitoneal DOX injections (2.5 mg/kg/week) for 6 weeks. The rats were randomly assigned to control, CHF, CHF + QL (1.0 g/kg/d), or captopril (3.8 mg/kg/d) treatment groups (n = 10) for 4 weeks. MicroRNA sequencing elucidated the molecular mechanisms of qiliqiangxin on doxorubicin-induced CHF in rats. Results Unlike in the CHF group, QL significantly reduced Bax:Bcl-2 (2.05 ± 0.23 vs. 0.94 ± 0.09, p < 0.05) and the levels of collagen I (0.19 ± 0.02 vs. 0.15 ± 0.01, p < 0.05), collagen III (0.19 ± 0.02 vs. 0.14 ± 0.02, p < 0.05), TGF-β1 (5.28 ± 0.89 vs. 2.47 ± 0.51, p < 0.05), Smad3 (1.23 ± 0.12 vs. 0.78 ± 0.09, p < 0.05), MMP-2 (0.89 ± 0.01 vs. 0.53 ± 0.05, p < 0.05), and TIMP-2 (0.24 ± 0.03 vs. 0.44 ± 0.03, p < 0.05). QL also upregulated TGF-β3 (0.65 ± 0.06 vs. 0.96 ± 0.10, p < 0.05) and Smad7 (0.09 ± 0.01 vs. 0.19 ± 0.023, p < 0.05). Moreover, Smad3 was a target of miR-345-3p. Discussion and Conclusions The beneficial effects of QL on DOX-induced CHF in rats are mediated by reduction in myocardial fibrosis, promotion of TGF-β3/Smad7, and inhibition of TGF-β1/Smad3. QL may also modulate specific miRNAs. These results provide evidence that QL might be an effective treatment for DOX-induced CHF.

Atrial fibrillation promotion in a rat model of heart failure induced by left ventricle radiofrequency ablation

BackgroundAtrial fibrillation (AF) frequently coexists with congestive heart failure (CHF). The increased susceptibility to AF in CHF has been attributed to a variety of structural and electrophysiological changes in the atria, particularly dilation and interstitial fibrosis. We evaluated atrial remodeling and AF vulnerability in a rat model of CHF induced by left ventricle (LV) radiofrequency (RF) ablation. MethodsWistar rats were divided into 3 groups: RF-induced CHF (Ab, n = 36), CHF animals treated with spironolactone (AbSpi, n = 20) and sham controls (Sham, n = 29). After 12 weeks, animals underwent echocardiographic and electrophysiological evaluation and were sacrificed for histological (atrial fibrosis) and Western blotting (TGF-β1, collagen I/III, connexin 43 and CaV1.2) analysis. ResultsMild LV dysfunction and marked atrial enlargement were noted in both ablated groups. AF inducibility (episodes ≥2 s) increased in the Ab group compared to sham animals (31/36, 86%; vs. 15/29, 52%; p = 0.005), but did not differ from the AbSpi group (16/20, 80%; p = NS). Sustained AF (>30 s) was also more frequent in the Ab group compared to shams (56% vs. 28%; p = 0.04). Spironolactone reduced atrial fibrosis (p < 0.01) as well as TGF-β1 (p < 0.01) and collagen I/III (p < 0.01) expression but did not affect connexin 43 and CaV1.2 expression. ConclusionsRats with RF-induced CHF exhibit pronounced atrial structural remodeling and enhanced AF vulnerability. This model may be useful for studying AF substrate in CHF.

High-Intensity Training Improves Global and Segmental Strains in Severe Congestive Heart Failure

BackgroundHigh-intensity training (HIT) is superior to moderate aerobic training (MAT) for improving quality of life in congestive heart failure (CHF) patients. Speckle-tracking echocardiography (STE) has recently been suggested for estimation of left ventricle global and regional function. We evaluated the utility of STE for characterizing differences in cardiac function following MAT or HIT in a CHF rat model. Methods and ResultsAfter baseline physiologic assessment, CHF was induced by means of coronary artery ligation in Sprague-Dawley rats. Repeated measurements confirmed the presence of CHF (ejection fraction 52 ± 10%, global circumferential strain (GCS) 10.5 ± 4, and maximal oxygen uptake (V˙O2max) 71 ± 11 mL⋅min−1⋅kg−1; P < .001 vs baseline for all). Subsequently, rats were divided into training protocols: sedentary (SED), MAT, or HIT. After the training period, rats underwent the same measurements and were killed. Training intensity improved V˙O2max (73 ± 13 mL⋅min−1⋅kg−1 in MAT [P < .01 vs baseline] and 82 ± 6 mL⋅min−1⋅kg−1 in HIT [P < .05 vs baseline or SED] and ejection fraction (50 ± 21% in MAT [P < .001 vs baseline] and 66 ± 7% in HIT [P > .05 vs baseline]). In addition, strains of specific segments adjacent to the infarct zone regained basal values (P > .05 vs baseline), whereas global cardiac functional parameters as assessed with the use of 2-dimensional echocardiography did not improve. ConclusionsHigh-intensity exercise training improved function in myocardial segments remote from the scar, which resulted in compensatory cardiac remodeling. This effect is prominent, yet it could be detected only with the use of STE.

Testosterone suppresses ventricular remodeling and improves left ventricular function in rats following myocardial infarction.

Men with congestive heart failure (CHF) have relatively low testosterone levels. Several studies demonstrated that testosterone treatment increases cardiac output and reduces peripheral vascular resistance. However, the effects of testosterone on heart function, cardiomyocyte apoptosis and ventricular remodeling have not been fully elucidated. This study was conducted to investigate the effects of testosterone on heart function, cardiomyocyte apoptosis and ventricular remodeling in male rats post-myocardial infarction. A total of 86 male rats were randomly assigned to undergo ligation of the coronary artery (n=70) or pseudosurgery (n=16). After 6 weeks, a left ventricular ejection fraction (LVEF) of ≤45% was defined as a successful model of CHF. The model rats were randomly assigned to 3 groups, namely low-dose testosterone (TU), high-dose TU and placebo (PL) groups. After treatment for 12 weeks, the expression of several mRNA transcripts in myocardial tissue was measured by quantitative polymerase chain reaction. Immunofluorescence was used to measure myocardial caspase-3 expression. Compared to the PL group, LVEF was significantly improved in the TU treatment groups. Moreover, the mRNA expression of atrial natriuretic peptide, brain natriuretic peptide, matrix metalloproteinase-2 and sarcoendoplasmic reticulum Ca2+-ATPase 2a was significantly reduced, while the mRNA expression of glycogen synthase kinase 3β and tissue inhibitor of metalloproteinase-2 was markedly increased in the TU groups. TU treatment also significantly reduced caspase-3 expression. Therefore, different doses of TU suppressed ventricular remodeling and improved left ventricular function, reduced apoptosis and prevented mortality in a CHF rat model.

The Effects of High Thoracic Epidural Anesthesia on Sympathetic Activity and Apoptosis in Experimentally Induced Congestive Heart Failure

To evaluate the effect of high thoracic epidural analgesia (HTEA) in congestive heart failure (CHF). Rat model of CHF. Harbin Medical University, Harbin, Heilongjiang, China. One hundred thirty-five rats. HTEA involved 5 times daily injections of 0.1% lidocaine at the T3-T4 level. The authors examined myocardial norepinephrine (NE), angiotensin II (Ang II), endothelin-1 (ET1), and tumor necrosis factor-α (TNF-α) concentrations 2, 4, and 6 weeks after the start of HTEA. They also examined histologic changes in heart tissue and myocardial expression of apoptosis-inducing factor (AIF) and poly (ADP-ribose) polymerase (PARP). Sham rats were used as a control. In the time course, myocardial NE, Ang II, ET1, and TNF-α concentrations were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Similarly, PARP and AIF protein expression levels were significantly higher in the CHF group compared with the HTEA and sham groups (p< 0.05). Microscopy revealed pronounced damage to myocardial cell structures in the CHF group; this damage clearly was reduced in the HTEA group. In addition, cardiac function evaluation indicated treatment with HTEA resulted in similar heart function as animals that did not have surgically induced CHF. The findings suggest that HTEA induces changes in sympathetic nervous system, renin-angiotensin system, endothelial, and inflammatory process activity involved in CHF.

Impaired pulmonary blood flow distribution in congestive heart failure assessed using synchrotron radiation microangiography

Synchrotron radiation microangiography is a powerful tool for assessing adverse changes in pulmonary vessel density associated with primary pulmonary hypertension (PH). Congestive heart failure (CHF) leads to a `secondary' onset of PH, yet it is unknown whether secondary PH is also associated with reduced vessel density. This study utilized synchrotron radiation to assess both pulmonary vessel density and endothelial function in a Dahl rat model of CHF with secondary PH. High salt-fed Dahl salt-sensitive (Dahl-S) and salt-resistant (Dahl-R) rats were anesthetized and microangiography was performed to assess the pulmonary vessel density and vascular responses to (i) sodium nitroprusside (5.0 µg kg(-1) min(-1)), (ii) acetylcholine (3.0 µg kg(-1) min(-1)) and (iii) ET-1A receptor blockade, BQ-123 (1 mg kg(-1)). Dahl-S rats developed CHF and secondary PH as evident by endothelial dysfunction, impaired vasodilatory responses to acetylcholine, enhanced vasodilatory responses to BQ-123 and extensive pulmonary vascular remodeling. Consequently, the pulmonary vessel density was adversely reduced. Interestingly, the etiology of secondary PH manifests with structural and functional changes that are comparable with that previously reported for primary PH. One important discrepancy, however, is that ET-1 modulation of pulmonary vessels is most striking in vessels with a diameter range of 100-200 µm in secondary PH, in contrast to a range of 200-300 µm in primary PH. Such discrepancies should be considered in future studies investigating primary and secondary forms of PH.

Doxorubicin dose for congestive heart failure modeling and the use of general ultrasound equipment for evaluation in rats. Longitudinal in vivo study

For the evaluation of the congestive heart failure (CHF) in rat models, the use of special equipment for echocardiography for dynamic evaluation is suggested. The optimal doxorubicin dose for CHF induction has still not been established. The aims of our study was to find a reliable doxorubicin CHF rat model using a general ultrasound (US) equipment for in vivo ultrasound examination of the systemic circulation, to establish the optimal doxorubicin dose, and to assess the feasibility of US guided administration of the drug. Sixty Wistar rats, weighing 180-200 g were assigned to 3 groups (n=20 in each): group A - 4 time intraperitoneal doxorubicin "Sigma"administration, cumulative dose 2.49 mg/animal or 12.45 mg/kg; group B and 5 time doxorubicin administration, cumulative dose 3.03 mg/animal or 15.15 mg/kg; and group C- controls (injected same volume of saline). Dynamic US using linear 12 MHz transducer was used to establish the CHF modifications. Two rats with CHF were injected under US guidance in the pleural cavity with 0.06 ml cardiotropic drug levosimendan and two rats in the pericardial cavity. We established the optimal cumulative doxorubicin dose for CHF induction at 12.45 mg/kg. At a higher dose, more than 40% of animals died. A lower dose did not induce significant clinical and US CHF criteria. Congestion (followed by weight gain) led to lower animal mortality. Preliminary results indicate a similar positive cardioprotective effect of drug injection into pericardial and pleural cavities under US guidance, demonstrating that this technique is useful for drug administration. US is an effective modality for in vivo monitoring of the rat organs for the study of cardiovascular function or for drug administration under US guidance. Suggested model (optimal dose of doxorubicin for simulation of CHF of 2.5 mg/animal, a cumulative dose of 12.45 mg/kg in 4 injections every 3 days) can be used for research purposes.

806 IMPAIRED PULMONARY BLOOD FLOW DISTRIBUTION IN CONGESTIVE HEART FAILURE – REACTIVE DYSFUNCTION OF THE ENDOTHELIUM

Background: Congestive heart failure (CHF) commonly leads to the secondary onset of pulmonary hypertension (PH). In primary forms of PH, endothelial dysfunction instigates adverse changes of the pulmonary vasculature, ultimately impairing pulmonary blood flow distribution. In this study, we utilized synchrotron radiation microangiography to determine the extent of endothelial dysfunction, and whether it adversely impacts on pulmonary blood flow distribution, in a Dahl rat model of CHF with secondary PH. Methods: High salt-fed Dahl salt-sensitive (Dahl-S) and salt-resistant rats (Dahl-R) were anesthetized and microangiography was performed to assess pulmonary blood flow distribution and dynamic changes in vessel internal diameter (ID) in response to i) acetylcholine (3.0 μg/kg/min), ii) sodium nitroprusside (5.0 μg/kg/min), and iii) the ET-1A receptor antagonist, BQ-123 (1 mg/kg). Results: A high salt diet induced CHF and secondary PH in Dahl-S rats. The development of PH was attributable to ‘reactive’ pulmonary endothelial dysfunction, evident by impaired vasodilatory responses to acetylcholine, an enhanced vasodilatory response to BQ-123, an elevated expression of endothelial ET-1 and eNOS protein, and extensive pulmonary vascular remodeling. Consequently, pulmonary blood flow distribution was significantly impaired. Conclusions: The development of PH secondary to CHF is associated with impaired pulmonary blood flow distribution and endothelial dysfunction, which appears comparable to that previously reported for primary PH. However, ET-1 modulation of pulmonary vessels in primary PH differs regionally compared to secondary PH. Accordingly, such discrepancies should be considered in future studies investigating underlying pathomechanisms of primary and secondary forms of PH.

Lung endothelial dysfunction in heart failure: Role of impaired Ca2+ signaling and cytoskeletal reorganization

Congestive heart failure (CHF) causes lung endothelial (EC) dysfunction, which in turn aggravates lung vascular remodeling and right ventricular failure. Here, we elucidated the mechanisms underlying lung EC dysfunction in a rat model of CHF induced by supracoronary aortic banding. Lung EC dysfunction was evident in CHF as impaired EC‐dependent vasodilation and NO synthesis in response to mechanical stress, acetylcholine or histamine, although expression of endothelial NO synthase was unmitigated. Reconstitution of cytosolic Ca2+ ([Ca2+]i) signaling by Ca2+ ionophore restored NO production. Impaired lung EC [Ca2+]i homeostasis and signaling in CHF in response to mechanical stress, histamine, acetylcholine or thapsigargin was confirmed by real‐time fluorescence imaging, yet was not attributable to downregulation of EC Ca2+ influx channels. Rather, we identified a massive remodeling of the endothelial cytoskeleton by increased β‐actin expression and F‐actin formation, which contributed critically to endothelial dysfunction in CHF, since cytoskeletal disruption by cytochalasin reconstituted endothelial [Ca2+]i signaling and NO production. Our findings show that lung EC dysfunction in CHF results from impaired EC [Ca2+]i signaling, and identify the endothelial cytoskeleton as critical regulator of EC [Ca2+]i homeostasis.Sponsored by EU IP Pulmotension and Kaiserin‐Friedrich Foundation Berlin.

Symbolic analysis detects alterations of cardiac autonomic modulation in congestive heart failure rats

Congestive heart failure (CHF) is associated with neurohumoral activation. Only very few studies have examined the progression of autonomic dysfunction in CHF in humans and scanty data are available in animal models of CHF. This study was performed to assess the changes in cardiac autonomic modulation during the progression of CHF in a rat model, using an innovative analysis of heart rate variability. Progression of cardiovascular autonomic dysfunction was assessed in a rat model of CHF induced by coronary artery ligation. Spectral and symbolic analyses were performed on heart period (approximated with pulse interval, PI) and systolic arterial pressure (SAP) signals, acquired ~2 and ~4 weeks after the surgical procedure. As CHF developed, symbolic analysis revealed a decrease of rhythmical physiological sympathetic modulation, as indicated by the reduction of the percentage of stable patterns. In addition, symbolic analysis revealed that runs of short–long–short and/or long–short–long PI values and high–low–high and/or low–high–low SAP values were more and more frequent as CHF progressed. On the contrary, spectral analysis of PI and SAP series was not able to detect any impairment of autonomic regulation. Indeed, low frequency and high frequency powers derived from both PI and SAP series were not significantly changed. These data indicate that the autonomic cardiovascular modulation is altered during the progression of CHF and that symbolic analysis seems to be more suitable than spectral analysis to describe alterations of heart period dynamics and of cardiovascular regulation in this animal model of CHF.

Altered Na+/Ca2+-exchanger activity due to downregulation of Na+/K+-ATPase 2-isoform in heart failure

The Na+/K+-ATPase (NKA) alpha2-isoform is preferentially located in the t-tubules of cardiomyocytes and is functionally coupled to the Na+/Ca(+-exchanger (NCX) and Ca2+ regulation through intracellular Na+ concentration ([Na+]i). We hypothesized that downregulation of the NKA alpha2-isoform during congestive heart failure (CHF) disturbs the link between Na+ and Ca2+, and thus the control of cardiomyocyte contraction. NKA isoform and t-tubule distributions were studied using immunocytochemistry, confocal and electron microscopy in a post-infarction rat model of CHF. Sham-operated rats served as controls. NKA and NCX currents (I NKA and I NCX) were measured and alpha2-isoform current (I NKA,alpha2) was separated from total I NKA using 0.3 microM ouabain. Detubulation of cardiomyocytes was performed to assess the presence of alpha2-isoforms in the t-tubules. In CHF, the t-tubule network had a disorganized appearance in both isolated cardiomyocytes and fixed tissue. This was associated with altered expression patterns of NKA alpha1- and alpha2-isoforms. I NKA,alpha2 density was reduced by 78% in CHF, in agreement with decreased protein expression (74%). When I NKA,alpha2 was blocked in Sham cardiomyocytes, contractile parameters converged with those observed in CHF. In Sham, abrupt activation of I NKA led to a decrease in I NCX, presumably due to local depletion of [Na+]i in the vicinity of NCX. This decrease was smaller when the alpha2-isoform was downregulated (CHF) or inhibited (ouabain), indicating that the alpha2-isoform is necessary to modulate local [Na+]i close to NCX. Downregulation of the alpha2-isoform causes attenuated control of NCX activity in CHF, reducing its capability to extrude Ca2+ from cardiomyocytes.

Inhalation of the Phosphodiesterase-3 Inhibitor Milrinone Attenuates Pulmonary Hypertension in a Rat Model of Congestive Heart Failure

Most patients with congestive heart failure (CHF) develop pulmonary venous hypertension, but right ventricular afterload is frequently further elevated by increased pulmonary vascular resistance. To investigate whether inhalation of a vasodilatory phosphodiesterase-3 inhibitor may reverse this potentially detrimental process, the authors studied the effects of inhaled or intravenous milrinone on pulmonary and systemic hemodynamics in a rat model of CHF. In male Sprague-Dawley rats, CHF was induced by supracoronary aortic banding, whereas sham-operated rats served as controls. Milrinone was administered as an intravenous infusion (0.2-1 microg.kg body weight.min) or by inhalation (0.2-5 mg/ml), and effects on pulmonary and systemic hemodynamics and lung water content were measured. In CHF rats, intravenous infusion of milrinone reduced both pulmonary and systemic arterial blood pressure. In contrast, inhalation of milrinone predominantly dilated pulmonary blood vessels, resulting in a reduced pulmonary-to-systemic vascular resistance ratio. Repeated milrinone inhalations in 20-min intervals caused a stable reduction of pulmonary artery pressure. No hemodynamic effects were detected when 0.9% NaCl was administered instead of milrinone or when milrinone was inhaled in sham-operated rats. No indications of potentially adverse effects of milrinone inhalation in CHF, such as left ventricular volume overload, were detected. Moreover, lung edema was significantly reduced by repeated milrinone inhalation. If these results can be confirmed in humans, inhalation of nebulized milrinone may present a novel, effective, safe, and pulmonary selective strategy for the treatment of pulmonary venous hypertension in CHF.

Urotensin-II blockade with SB-611812 attenuates cardiac dysfunction in a rat model of coronary artery ligation

Expression of urotensin II (UII) is significantly elevated in the hearts of patients with congestive heart failure (CHF). Recent reports have also shown increased plasma levels of UII in patients with CHF, and these levels correlated with the severity of disease. We therefore hypothesized that blockade of UII signaling would improve cardiac function in a rat model of CHF. CHF was induced in rats by ligating the left coronary artery. Animals were randomized to either treatment with a specific UT receptor antagonist, SB-611812 (30 mg/kg/day, UID by gavage), or vehicle, starting either 30 min prior to coronary ligation (early treatment) or 10 days after ligation (delayed treatment). Treatment drug or vehicle was administered daily thereafter for 8 weeks. We measured cardiac function and evaluated the levels of mRNA expression for mediators of CHF. In addition, we evaluated UII and UT protein levels using immunohistochemistry and Western blotting. Cardiomyocyte hypertrophy was evaluated by measuring cardiomyocyte cross-sectional area. Animals with CHF showed increased UII and UT expression as evidenced by immunohistochemistry and Western blotting. Treatment with the SB-611812 significantly reduced overall mortality, left ventricular end-diastolic pressure by 72%, lung edema by 71%, right ventricular systolic pressure by 92%, central venous pressure by 59%, cardiomyocyte hypertrophy by 54%, and ventricular dilatation by 79% (P < 0.05). Therefore, blockade of the UT receptor reduced mortality and improved cardiac function in this model of myocardial infarction and CHF, suggesting an important role for UII in the pathogenesis of this condition.

Nicorandil but not ISDN Upregulates Endothelial Nitric Oxide Synthase Expression, Preventing Left Ventricular Remodeling and Degradation of Cardiac Function in Dahl Salt-sensitive Hypertensive Rats With Congestive Heart Failure

Cardiac endothelial nitric oxide synthase (ecNOS) was suppressed and inducible NOS (iNOS) enhanced at the decompensated heart failure stage in 18-week-old Dahl salt-sensitive (DS) hypertensive rats to which a high-salt diet had been administered from the age of 6 weeks. Nicorandil (NIC) enhanced ecNOS by activating Adenosine triphosphate-sensitive potassium channels (K-ATP channels) in the normal rat left ventricle. In this study, left ventricular hypertrophy, remodeling, function, cardiac ecNOS, and iNOS were compared between NIC and isosorbide dinitrate (ISDN) treatments in DS hypertensive rats with congestive heart failure. We examined DS hypertensive rats of 18 weeks of age to which 8% NaCl had been administered from the age of 6 weeks, and to which subdepressor doses of NIC (6 mg/kg/d), ISDN (6 mg/kg/d), and vehicle (CON) were administered from the age of 11 weeks. Contractility (Ees), stiffness (Eed), left ventricular end-diastolic volume, and left ventricular end-systolic volume were measured by conductance catheter and micromanometer on the basis of the pressure-volume relationship, and mRNA and protein levels of ecNOS and iNOS in the left ventricle were measured by reverse transcription-polymerase chain reaction and Western blot analysis at 18 weeks. LV mass index and LV dimensions were smaller in the NIC and ISDN groups than in the CON group (P < 0.01), and the first parameter was lower in the NIC than in the ISDN group (P < 0.01). Ees was also better maintained in the NIC and ISDN groups than in the CON group (NIC: 3349 +/- 649; ISDN: 2950 +/- 577, P < 0.05 vs. NIC; CON: 1424 +/- 375 mL/mmHg, P < 0.01 vs. treatments). Eed was exacerbated only in the ISDN group. NIC enhanced whereas ISDN suppressed ecNOS mRNA and protein levels (NIC 2.0-fold and 1.8-fold, ISDN 0.70-fold and 0.8-fold vs. CON; P < 0.01, respectively). However, no intragroup differences in iNOS mRNA or protein levels were observed for the 3 groups. More significant improvements in cardiac function and LV hypertrophy regression were observed in an NIC group than in an ISDN group of DS hypertensive rats. Activation of the K-ATP channel seems to induce this beneficial effect, which may be mediated in part by enhanced ecNOS expression in the heart in DS hypertensive congestive heart failure rat model.

Normalization of renal aquaporin-2 water channel expression by fosinopril, valsartan, and combination therapy in congestive heart failure: a new mechanism of action

This study investigated the effect of fosinopril (Fos), valsartan (Val), and combination of both drugs (Fos + Val) on the cardiac and renal expression of aquaporin-1 (AQP1) and aquaporin-2 (AQP2) in congestive heart failure (CHF). A rat model of CHF was created by ligating the left anterior descending coronary artery to induce acute myocardial infarction (AMI). Rats were treated by Fos, Val, or Fos + Val for 4 weeks. In renal medulla and cortex, AMI was associated with 2.2- and 1.8-fold increase in AQP2 mRNA expression when compared with Sham-operated rats (medulla: 23.6 ± 2.8 vs. 52.3 ± 8.7%; P < 0.001; cortex: 19.4 ± 3.9 vs. 35.5 ± 7.1%; P < 0.05). All the treatment regimens were able to normalize AQP2 transcription in the renal medulla (Fos, 19.9 ± 4.9%; Val, 22.8 ± 4.9%; Fos + Val, 20.1 ± 5.1%; P = NS vs. Sham) and in the cortex (Fos, 21.2 ± 6.7%; Val, 20.4 ± 6.0%; Fos + Val, 18.9 ± 7.5%; P = NS vs. Sham). Similarly, the AQP2 protein expression increased by 2.1-fold after CHF ( P < 0.05), and was normalized by the treatment regimens (Sham, 0.57 ± 0.19%; CHF, 1.22 ± 0.45%; Fos, 0.39 ± 0.36%; Val, 0.46 ± 0.34%; Fos + Val, 0.36 ± 0.15%; all P < 0.05 vs. CHF). These treatment regimens also prevented the increase in body weight as found in untreated CHF rats (analysis of variance P < 0.05). The renal and cardiac AQP1 gene and protein expressions were unaltered in CHF or by medical therapy. There was no observed cardiac AQP2 expression in all the study groups. Treatment with Fos, Val, or combination therapy was effective in preventing the upregulation of renal AQP2 gene and protein expressions in CHF rats caused by AMI.

Effect of the vasopressin receptor antagonist conivaptan in rats with heart failure following myocardial infarction

Myocardial infarction often induces congestive heart failure accompanied by a significant increase in plasma vasopressin concentration. To delineate the role of vasopressin in the pathogenesis of congestive heart failure, the acute hemodynamic and aquaretic effects of conivaptan (YM087, 4′-(2-methyl-1,4,5,6-tetrahydroimidazo[4,5- d][1]benzoazepine-6-carbonyl)-2-phenylbenzanilide monohydrochloride), a combined vasopressin V 1A and V 2 receptor antagonist, were assessed in rats with heart failure induced by myocardial infarction. Left coronary artery ligation resulted in decreased left ventricular systolic pressure and first derivatives of left ventricular developed pressure, as well as increased left ventricular end-diastolic pressure, lung and right ventricular weight. Single oral administration of conivaptan (0.3 to 3.0 mg/kg) dose-dependently increased urine volume and decreased urine osmolality in heart failure rats. Furthermore, conivaptan (3.0 mg/kg) attenuated the changes in left ventricular end-diastolic pressure, lung and right ventricular weight induced by heart failure while reducing blood pressure. These results show that vasopressin plays a significant role in elevating vascular tone through vasopressin V 1A receptors and plays a major role in retaining free water through vasopressin V 2 receptors in this model of congestive heart failure. Additionally, conivaptan, with its dual vasopressin V 1A and V 2 receptor-inhibiting properties, could exert a beneficial effect on cardiac function in the congestive heart failure rat model.

Myocardial distribution and regulation of GRK and beta-arrestin isoforms in congestive heart failure in rats.

Myocardial G protein-coupled receptor kinase 2 (GRK2) has been shown to be involved in the pathophysiology of congestive heart failure (CHF). However, the cellular distribution of this isoform, as well as the other isoforms of the GRK-arrestin system, has not been studied in myocardial tissue. Thus myocardial expression and cellular distribution of the different GRK and arrestin isoforms were investigated in a rat model of CHF. Rats subjected to ligation of the left coronary artery or sham operation were euthanized 2, 7, or 42 days after the surgical procedure. Myocardial GRK2, GRK5, beta-arrestin-1, and beta-arrestin-2 mRNA levels, but not that of GRK3, were induced in the failing hearts. Consistently, Western blot analysis of tissue extracts from the nonischemic region of the left ventricle revealed 3.0-, 2.6-, and 1.5-fold elevations of GRK2, GRK5, and beta-arrestin-1, respectively, 7 days after induction of myocardial infarction compared with the sham-operated rats (P < 0.05). Immunohistochemical analysis of myocardial tissue sections and Western blot analysis of isolated cells revealed localization of GRK2 and beta-arrestin-1 predominantly in endothelial cells. Conversely, GRK3 was confined to cardiac myocytes. GRK5 immunostaining appeared to be homogeneously distributed in the cellular elements of the myocardium. In conclusion, myocardial mRNA and protein levels of GRK2, GRK5, and beta-arrestin-1 are induced in postinfarction failure in rats. The immunohistochemical analysis suggests that GRK2 and beta-arrestin-1 may act as primary regulators of endothelial function. Conversely, the cellular distribution of GRK3 and GRK5 implicates these isoforms as putative regulators of cardiac myocyte function.

Heart failure affects mitochondrial but not myofibrillar intrinsic properties of skeletal muscle.

Congestive heart failure (CHF) induces abnormalities in skeletal muscle that are thought to in part explain exercise intolerance. The aim of the present study was to determine whether these changes actually result in contractile or metabolic functional alterations and whether they are muscle type specific. With a rat model of CHF (induced by aortic banding), we studied mitochondrial function, mechanical properties, and creatine kinase (CK) compartmentation in situ in permeabilized fibers from soleus (SOL), an oxidative slow-twitch muscle, and white gastrocnemius (GAS), a glycolytic fast-twitch muscle. Animals were studied 7 months after surgery, and CHF was documented on the basis of anatomic data. Alterations in skeletal muscle phenotype were documented with an increased proportion of fast-type fiber and fast myosin heavy chain, decreased capillary-to-fiber ratio, and decreased citrate synthase activity. Despite a slow-to-fast phenotype transition in SOL, no change was observed in contractile capacity or calcium sensitivity. However, muscles from CHF rats exhibited a dramatic decrease in oxidative capacities (oxygen consumption per gram of fiber dry weight) of 35% for SOL and 45% for GAS (P:<0.001). Moreover, the regulation of respiration with ADP and mitochondrial CK and adenylate kinase was impaired in CHF SOL. Mitochondrial CK activity and content (Western blots) were dramatically decreased in both muscles. CHF results in alterations in both mitochondrial function and phosphotransfer systems but unchanged myofibrillar function in skeletal muscles, which suggests a myopathy of metabolic origin in CHF.

Sympathetic inhibition with clonidine prolongs survival in experimental chronic heart failure

Activation of the sympathetic nervous system is associated with increased mortality in congestive heart failure (CHF), and inhibition of the sympathetic nervous system by centrally acting sympatholytic agents has been shown to have beneficial effects on hemodynamics in these patients. However, the effect of sympathetic inhibition on survival in CHF is not clear. In the present study, the effect of sympathetic inhibition with clonidine on survival was examined in a rat model of heart failure. Myocardial infarction and heart failure was induced in rats by ligation of the left coronary artery and sham-operated rats served as the control. Two weeks after surgery, the ligated rats were randomly assigned to the clonidine (100 μg kg −1 d −1, n=30) group or the placebo (vehicle, n=31) group. All rats were followed daily for a 1-year period or until spontaneous death. Compared with placebo therapy, clonidine treatment reduced systolic blood pressure and heart rate throughout the experimental period. The plasma norepinephrine level determined at the end of the experiment was also reduced. Long-term sympathetic inhibition with clonidine treatment improved 1-year survival (50% vs. 22.6%, P<0.05) after surgery in this rat model of CHF.

Long-term effects of nonpeptide vasopressin V2 antagonist OPC-31260 in heart failure in the rat.

The hormone arginine vasopressin (AVP) contributes to water retention and vasoconstriction in congestive heart failure (CHF) through effects at the V2 and V1a receptors, respectively. The effect of long-term V2 receptor (V2R) blockade using OPC-31260 was assessed in a rat model of postinfarction-induced CHF. Rats underwent coronary artery ligation or sham operation and were treated for 6 mo with oral OPC-31260 (10 mg . kg-1 . day-1) or vehicle. CHF was characterized by left ventricular remodeling and impaired systolic function, increased cardiac and lung weight, and elevated plasma atrial natriuretic peptide; plasma AVP and plasma renin activity were not increased. Chronic V2R blockade increased urine volume (P < 0.01) and decreased urine osmolality (P < 0.01) but had no natriuretic effects. V2R blockade did not activate the renin-angiotensin system but increased plasma AVP in CHF (P < 0.01). V2R blockade did not influence cardiac remodeling, cardiac function, or survival. These results suggest that AVP plays a major role in water retention through the renal V2R in a rat model of CHF. V2R blockade using OPC-31260 may represent an alternative to standard diuretic therapy in the management of water retention that characterizes heart failure.