CHF Rats Research Articles

A hypothesis: Glucagon-like peptide-1 may play a protective role in diabetic cardiomyopathy

Article history: Received 7 June 2015 Accepted 26 June 2015 Available online 30 June 2015 stress effect [9]. Liraglutide can inhibit PKC-α and NF-Kappa B signaling pathways of endothelial cells, and reduces the NADPH oxidase activity to reduce inflammation factors on endothelial cell injury [9]. In addition, GLP-1 also plays an important role in cardiovascular disease [10]. It can inhibit myocardial remodeling of CHF rats, improve left ventricular ejection fraction and end-diastolic pressure, and reduce the mortality in rats after myocardial infarction [11]. Recent studies also

Modulatory effect of diphenyl diselenide in Carioca High- and Low-conditioned Freezing rats

Diphenyl diselenide ([PhSe]2)is an organoselenium compound that has interesting pharmacological properties, including antioxidant, glutathione peroxidase-mimetic, and neuroprotective effects. The objective of the present study was to investigate the possible modulatory effect of (PhSe)2 in 17th-generation Carioca high-and low-conditioned freezing (CHF and CLF) rats, an animal model of generalized anxiety disorders. (PhSe)2 was administered at three doses (10, 50, and 100mg/kg) in CHF and CLF rats, and their anxiety-like profiles (conditioned freezing patterns) were measured before and 30min after treatment. A significant difference was found in freezing scores between CHF and CLF animals before treatment (t70=12.50, p<0.001). Treatment with (PhSe)2 at 10 and 50mg/kg decreased freezing in CHF rats but significantly increased freezing at 100mg/kg. (PhSe)2 increased freezing in CLF animals at 50 and 100mg/kg (p<0.01). These results indicate that (PhSe)2 exerts both anxiolytic- and anxiogenic-like effects in bi-directional rat lines. Distinct genetic profiles of the CHF and CLF lines may influence biochemical functions and lead to differential responses to aversive situations and various drugs like (PhSe)2.

Calibration of baroreflex equilibrium diagram based on exogenous pressor agents in chronic heart failure rats.

A baroreflex equilibrium diagram describes the relation between input pressure and sympathetic nerve activity (SNA) and that between SNA and arterial pressure (AP). To calibrate the SNA axis (abscissa) of the baroreflex equilibrium diagram, the AP response to intravenous bolus injections of phenylephrine (0.2–50 μg/kg) or norepinephrine (NE, 0.02–5 μg/kg) was examined in normal control rats (NC, n = 9) and rats with chronic heart failure (CHF, n = 6). The maximum slope of the dose–effect curve was significantly smaller in the CHF group than in the NC group (57.3 ± 5.2 vs 80.9 ± 6.3 mmHg/decade for phenylephrine, 60.2 ± 7.8 vs 80.4 ± 5.9 mmHg/decade for NE; P < 0.01). The CHF/NC ratio of the maximum slope was used to calibrate SNA. While the calibrated baroreflex equilibrium diagram showed increased maximum SNA and operating-point SNA in CHF rats compared with NC rats, the magnitude of increase was smaller than that expected from the excess plasma NE concentration in CHF rats. Plasma NE concentration in the CHF group could be disproportionally high relative to SNA.

Anxious phenotypes plus environmental stressors are related to brain DNA damage and changes in NMDA receptor subunits and glutamate uptake

This study aimed at investigating the effects of chronic mild stress on DNA damage, NMDA receptor subunits and glutamate transport levels in the brains of rats with an anxious phenotype, which were selected to represent both the high-freezing (CHF) and low-freezing (CLF) lines. The anxious phenotype induced DNA damage in the hippocampus, amygdala and nucleus accumbens (NAc). CHF rats subjected to chronic stress presented a more pronounced DNA damage in the hippocampus and NAc. NMDAR1 were increased in the prefrontal cortex (PC), hippocampus and amygdala of CHF, and decreased in the hippocampus, amygdala and NAc of CHF stressed. NMDAR2A were decreased in the amygdala of the CHF and stressed; and increased in CHF stressed. NMDRA2A in the NAc was increased after stress, and decreased in the CLF. NMDAR2B were increased in the hippocampus of CLF and CHF. In the amygdala, there was a decrease in the NMDAR2B for stress in the CLF and CHF. NMDAR2B in the NAc were decreased for stress and increased in the CHF; in the PC NMDAR2B increased in the CHF. EAAT1 increased in the PC of CLF+stress. In the hippocampus, EAAT1 decreased in all groups. In the amygdala, EAAT1 decreased in the CLF+stress and CHF. EAAT2 were decreased in the PC for stress, and increased in CHF+control. In the hippocampus, the EAAT2 were increased for the CLF and decreased in the CLF+stress. In the amygdala, there was a decrease in the EATT2 in the CLF+stress and CHF. These findings suggest that an anxious phenotype plus stress may induce a more pronounced DNA damage, and promote more alterations in the glutamatergic system. These findings may help to explain, at least in part, the common point of the mechanisms involved with the pathophysiology of depression and anxiety.

Matrine improved the function of heart failure in rats via inhibiting apoptosis and blocking β3‑adrenoreceptor/endothelial nitric oxide synthase pathway.

Matrine, an alkaloid isolated from the traditional Chinese medicine Sophora flavescens AIT has exhibited a number of therapeutic effects on cardiovascular and liver diseases. The purpose of the present study was to investigate whether matrine has a protective effect on heart failure in rats. Coronary artery ligation was used to induce a heart failure (CHF) model in rats. Four weeks following the procedure, the rats were treated with different doses of matrine for one month. Histopathological examination demonstrated that matrine treatment alleviated myocardial hypertrophy and cardiac fibrosis in failing hearts. Furthermore, matrine administration also inhibited the increase of plasma aspartate amino transferase, creatine phosphokinase and lactate dehydrogenase levels in CHF rats. The rats with heart failure exhibited a significant reduction in ejection fraction and fractional shortening, as well as an increase in the left ventricular end systolic dimension, and matrine attenuated this decline in heart function. Further investigation demonstrated that matrine treatment also inhibited the upregulation of Bax and increase in the Bcl‑2 expression in the failing hearts. Furthermore, the upregulation of β3-adrenoreceptor (AR) and endothelial nitric oxide synthase proteins following heart failure were also attenuated by matrine. In conclusion, matrine had a preventive role in heart failure in rats at least in part by inhibiting myocardial apoptosis and the β3-AR pathway.

Cardiac and renal distribution of ACE and ACE-2 in rats with heart failure

Congestive heart failure is often associated with impaired kidney function. Over-activation of the renin–angiotensin–aldosterone system (RAAS) contributes to avid salt and water retention in heart failure. While the expression of angiotensin converting enzyme (ACE), a key enzyme in the synthesis of angiotensin II (Ang II), is well established, the expression of angiotensin converting enzyme-2 (ACE-2), an enzyme responsible for angiotensin 1–7 generation, is largely unknown. This issue is of a special interest since angiotensin 1–7 counteracts many of the proliferative and hypertensive effects of angiotensin II. Therefore, the present study was designed to investigate the expression of both enzymes in the kidney and heart of rats with heart failure. Heart failure (CHF) was induced in male Sprague Dawley rats (n=9) by the creation of a surgical aorto-caval fistula. Sham-operated rats served as controls (n=8). Two weeks after surgery, the animals were sacrificed and their hearts and kidneys were harvested for assessment of cardiac remodeling and ACE and ACE-2 immunoreactivity by immunohistochemical staining. ACE immunostaining was significantly increased in the kidneys (4.34±0.39% vs. 2.96±0.40%, P<0.05) and hearts (4.57±0.54% vs. 2.19±0.37%, P<0.01) of CHF rats as compared with their sham controls. In a similar manner, ACE-2 immunoreactivity was also elevated in the kidneys (4.65±1.17% vs. 1.75±0.29%, P<0.05) and hearts (5.48±1.11% vs. 1.13±0.26%, P<0.01) of CHF rats as compared with their healthy controls. This study showed that both ACE and ACE-2 are overexpressed in the cardiac and renal tissues of animals with heart failure as compared with their sham controls. The increased expression of the beneficial ACE-2 in heart failure may serve as a compensatory response to the over-activity of the deleterious isoform, namely, angiotensin converting enzyme 1(ACE-1).

EPA-1266 – Anxiety behavior extinction is influenced by early environment in a genetic background-dependent way

Introduction Several factors influence the emotional behavior, including environment, genetic and the interaction between them. Objective The aim of this work is to investigate the interaction between environmental and genetic influences in the divergent behavior of Carioca High and Low Freezing (CHF and CLF) rats - a genetic model to study fear and anxiety. The Carioca rat lines were produced from selective breeding method, from animals with the highest and lowest levels of freezing behavior in the contextual fear conditioning, a model to study anxiety-like behavior. Methods To investigate the gene-environment interplay, we employed the cross-fostering procedure, which CHF rat pups were raised by CLF dams, and vice-versa, since pos natal day (PND) 1 until weaning at PND21. The litters were culled in 8 pups, and we fostered only 2–3 male pups per litter. We also maintained CHF and CLF control, no-fostered litters. On PND60, male animals of the four groups (CHF (n=7), CHF-CLF (CHF pups raised by CLF dams) (n=6), CLF (n=4) and CLF-CHF (n=3)) were exposed to the contextual fear conditioning. Results The freezing behavior on the day after foot shocks was analyzed. A two-way ANOVA showed that, although CHF rats had a higher time in freezing in this task comparing to the CLF (p CLF-CHF = CLF. On PND120, the same male rats were exposed to a 12-minutes-session, two-session extinction paradigm, in the same context. In these sessions, no foot shock was used. Comparing the freezing time in the context session on the conditioning paradigm to the freezing time on the first extinction session, we observed a significant decrease in this behavior for the CHF-CLF group, but not in the CHF group (p Conclusions This data suggest an existence of an early environment influence in the anxiety behavior extinction, but it was dependent of the genetic background.

Behavioral evaluation of male and female carioca high- and low-freezing rats

Recent years have seen growing interest in the development of genetic animal models to investigate the bidirectional relationship between trait anxiety and defensive reactions. The present study further analyzed behavioral correlates of two novel breeding lines of rats, Carioca high-and low-conditioned freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. Male and female rats from the 10th generation were used to assess anxiety-like reactions in the elevated plus maze (EPM), depressive-like behavior in the forced swim test (FST), and aversive memory in the contextual fear conditioning paradigm. In the EPM, female rats showed lower anxiety-like behavior than males, whereas CHF rats were more anxious than CLF rats. The same pattern of results was found in the contextual fear conditioning paradigm. No differences were found between lines or sexes in the FST. Such differences in emotionality responses in the 10th generation of selected rats further indicate a possible use of this model to study correlations between trait anxiety and defensive reactions. The face validity of the model and its use to experimentally simulate generalized anxiety disorder in humans are also discussed.

Anesthetized Exercise Model Mimics the Characteristics of Respiratory Pattern in CHF Rat

Anesthetized Exercise Model Mimics the Characteristics of Respiratory Pattern in CHF Rat

Inhibition of hydrogen sulfide restores normal breathing stability and improves autonomic control during experimental heart failure

Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione γ-lyase dl-propargylglycine (PAG), we tested the effects of H2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40-60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF.

Association between oxidative stress and contextual fear conditioning in Carioca high- and low-conditioned freezing rats

We recently reported two novel breeding lines of rats known as Carioca high-and low-conditioned freezing (CHF and CLF), based on defensive freezing responses to contextual cues previously associated with electric footshock. The anxiety-like profile of these animals from the 7th generation was tested in the elevated plus maze. The results indicated that CHF animals presented a significantly more “anxious” phenotype compared with CLF animals. Animals from the 12th generation were used to evaluate the oxidative stress status of the cortex, hippocampus, and cerebellum. Reactive oxidative species (ROS) were evaluated using 2,7-dichlorofluorescin diacetate (DCFH-DA; a sensor of reactive oxygen species [ROS]), and the levels of malondialdehyde (MDA), an early marker of lipid peroxidation, were assessed. The results indicated that free radical concentrations and MDA levels were significantly higher in all three brain structures in CHF rats compared with CLF rats. Our data also showed that the hippocampus had the highest reactive species and MDA concentrations compared with the cortex and cerebellum in CHF rats. Animals from the 16th generation were used to evaluate the antioxidant enzyme activity of catalase (CAT) and glutathione peroxidase (GPx) within these three brain structures. The results indicated that CAT activity was lower in the cortex and hippocampus in CHF rats compared with CLF rats. No significant difference was observed in the cerebellum. The enzymatic activity of GPx was significantly decreased in all three structures in CHF rats compared with CLF rats. The hippocampus exhibited the highest GPx activity compared with the other two brain structures. These findings suggest the involvement of a redox system in these two bidirectional lines, and the hippocampus might be one of the prime brain structures involved in this state of oxidative stress imbalance.

Attenuated fatigue in slow twitch skeletal muscle during isotonic exercise in rats with chronic heart failure.

During isometric contractions, slow twitch soleus muscles (SOL) from rats with chronic heart failure (chf) are more fatigable than those of sham animals. However, a muscle normally shortens during activity and fatigue development is highly task dependent. Therefore, we examined the development of skeletal muscle fatigue during shortening (isotonic) contractions in chf and sham-operated rats. Six weeks following coronary artery ligation, infarcted animals were classified as failing (chf) if left ventricle end diastolic pressure was >15mmHg. During isoflurane anaesthesia, SOL with intact blood supply was stimulated (1s on 1s off) at 30Hz for 15 min and allowed to shorten isotonically against a constant afterload. Muscle temperature was maintained at 37°C. In resting muscle, maximum isometric force (Fmax) and the concentrations of ATP and CrP were not different in the two groups. During stimulation, Fmax and the concentrations declined in parallel sham and chf. Fatigue, which was evident as reduced shortening during stimulation, was also not different in the two groups. The isometric force decline was fitted to a bi-exponential decay equation. Both time constants increased transiently and returned to initial values after approximately 200 s of the fatigue protocol. This resulted in a transient rise in baseline tension between stimulations, although this effect which was less prominent in chf than sham. Myosin light chain 2s phosphorylation declined in both groups after 100 s of isotonic contractions, and remained at this level throughout 15 min of stimulation. In spite of higher energy demand during isotonic than isometric contractions, both shortening capacity and rate of isometric force decline were as well or better preserved in fatigued SOL from chf rats than in sham. This observation is in striking contrast to previous reports which have employed isometric contractions to induce fatigue.

Lowered activation of voltage‐gated sodium channels contributes to blunted baroreflex sensitivity in heart failure rats

Voltage‐gated sodium (Nav) channels are responsible for initiation and propagation of action potential in the neurons. Here we measured the role of Nav channels on aortic baroreceptor neuron excitability and baroreflex sensitivity in sham and CHF rats. CHF was induced by left coronary artery ligation. Immunofluorescent data indicated that Nav1.7 was expressed in A‐type (myelinated) and C‐type (unmylinated) nodose neurons but Nav1.8 and Nav1.9 were expressed only in C‐type nodose neurons. Real‐time RT‐PCR and western blot data showed that CHF reduced mRNA and protein expression levels of Nav channels in nodose neurons. In addition, using the whole cell patch‐clamp technique, we found that Nav current density and cell excitability of the aortic baroreceptor neurons were lower in CHF rats than that in sham rats. Aortic baroreflex sensitivity was blunted in anesthetized CHF rats, compared with that in sham rats. Furthermore, Nav channel activator (rATX II, 100 nM) significantly enhanced Nav current density and cell excitability of aortic baroreceptor neurons and improved aortic baroreflex sensitivity in CHF rats. These results suggest that reduced Nav channel activation is involved in the attenuation of baroreceptor neuron excitability, which subsequently contributes to the impairment of baroreflex in CHF state.

Nitric Oxide (NO) Bioavailability Underlies Muscle Microvascular O2 Delivery/Utilization Imbalance in Chronic Heart Failure (CHF) Rats

NO bioavailability has been implicated in the muscle microvascular dysfunction of CHF at rest and during contractions.PURPOSETo test the hypothesis that differences in the O2 delivery/utilization balance, which sets the microvascular O2 partial pressure (PO2mv), between control (C) and severe CHF rats following the onset of contractions are due substantially to NO reduction.METHODSPO2mv was measured via phosphorescence quenching in the spinotrapezius muscle of 6 C and 4 CHF rats (male Sprague‐Dawley, 7‐10 wk post‐myocardial infarction, LVEDP 35+2 mmHg). Separate electrically‐induced contraction bouts (1 Hz) were performed with superfusion of SNP (300 μmol), Krebs‐Henseleit buffer (KH), and L‐NAME (1.5 mmol). The area under the PO2mv profile (PO2AREA) was calculated from 0‐60 s of each bout (expressed below as mmHg·s/min).RESULTSFor KH, C had a greater (P &lt; 0.05) PO2AREA (1042 ± 62) than CHF (721 ± 141). SNP increased PO2AREA (C: 1371 ± 59, CHF: 1263 ± 97, P &gt; 0.05) whereas L‐NAME reduced PO2AREA (C: 613 ± 74, CHF: 416 ± 70, P &gt; 0.05) to equivalent values in C and CHF rats.CONCLUSIONSThis demonstrates, for the first time, that the impaired muscle microvascular O2 delivery/utilization balance in CHF is eliminated by increasing (SNP) or removing (L‐NAME) NO bioavailability suggesting that the dysfunctional CHF PO2mv profile results principally from endogenous NO alterations.AHA, Heartland Affiliate 0750090Z

Training Effects On Skeletal Muscle Calcium Handling In Chronic Heart Failure (CHF) Patients And Controls

CHF patients typically complain about increased skeletal muscle fatigability. This is not due to reduced skeletal muscle blood flow and seems to persist even after cardiac transplantation. We have previously reported that in contrast to normal muscle, reduced intracellular calcium release was not related to fatigue development in CHF rats (Lunde et al. Circ Res 98:1514, 2006). Therefore we hypothesize that training might affect intracellular calcium cycling differently in muscles from patients with CHF as compared with healthy controls (HS).

Cytokine blockade attenuates sympathoexcitation in heart failure: Cross‐talk between nNOS, AT‐1R and cytokines in the hypothalamic paraventricular nucleus

To investigate evidence for the interplay between cytokines, angiotensin II and nNOS in the paraventricular nucleus (PVN), for regulating sympathetic outflow in a rat model of CHF. Heart failure was induced in Sprague-Dawley rats by coronary artery ligation. One group of rats was treated with pentoxifylline (PTX, 30 mg/kg IP), a cytokine blocker, or vehicle, for 5 weeks. Another group of rats was pre-treated with PTX before coronary ligation to study prior cytokine blocking effect on survival. Both groups were combined in the analysis. Echocardiography demonstrated an increase in LV end-diastolic pressure and Tei index after 5 weeks in CHF rats. ELISA revealed a significant increase in plasma TNF-alpha and IL-1beta in CHF rats. Inducible NOS (iNOS) and angiotensin receptor-type 1 (AT-1R) mRNA expressions were increased, while neuronal NOS (nNOS) was decreased in the PVN of CHF rats; these changes were reversed by PTX. PTX treatment also decreased plasma norepinephrine and epinephrine levels and improved baroreflex control of renal sympathoexcitation in CHF rats. Immunohistochemistry revealed elevated 3-nitrotyrosine formation in the heart and the PVN of CHF rats, but not in PTX treated rats. PTX decreased both peripheral and central cytokine expression, alleviated nitric oxide dysregulation, and inhibited the formation of peroxynitrite in the PVN resulting in decreased sympathoexcitation in CHF rats.

Inhalation of diluted diesel engine emission impacts heart rate variability and arrhythmia occurrence in a rat model of chronic ischemic heart failure

Both increase in cardiac arrhythmia incidence and decrease in heart rate variability (HRV) have been described following human and experimental animal exposures to air pollutants. However, the potential causal relationship between these two factors remains unclear. Incidence of ventricular arrhythmia and HRV were evaluated during and after a 3 h period of Diesel engine exhaust exposure in ten healthy and ten chronic ischemic heart failure (CHF, 3 months after coronary ligation) Wistar rats using implantable ECG telemetry. Air pollutants were delivered to specifically designed whole body individual exposure chambers at particulate matter concentrations similar to those measured inside cabins of cars inserted in congested urban traffic. Recordings were obtained from unrestrained and unsedated vigil rats. Immediate decrease in RMSSD was observed in both healthy (6.64 +/- 2.62 vs. 4.89 +/- 1.67 ms, P < 0.05) and CHF rats (8.01 +/- 0.89 vs. 6.6 +/- 1.37 ms, P < 0.05) following exposure. An immediate 200-500% increase in ventricular premature beats was observed in CHF rats only. Whereas HRV progressively returned to baseline values within 2.5 h after exposure start, the proarrhythmic effect persisted as late as 5 h after exposure termination in CHF rats. Persistence of ventricular proarrhythmic effects after HRV normalization suggests that HRV reduction is not the mechanism of cardiac arrhythmias in this model. Our methodological approach, closely reflecting the real clinical situations, appeared to be a unique tool to provide further insight into the pathophysiological mechanisms of traffic related airborne pollution health impact.

Additive amelioration of left ventricular remodeling and molecular alterations by combined aldosterone and angiotensin receptor blockade after myocardial infarction

The mechanisms underlying the clinical benefits of mineralocorticoid receptor antagonism in patients with left ventricular (LV) dysfunction and heart failure (CHF) after myocardial infarction (MI) are poorly understood. We investigated whether long-term (9 weeks) aldosterone antagonism with eplerenone (100 mg/kg/day) provides additional benefit to angiotensin II type 1 (AT1) receptor inhibition with irbesartan (50 mg/kg/day) on cardiac remodeling after MI in rats. Eplerenone monotherapy, like AT1 receptor blockade, significantly reduced LV end-diastolic pressure (LVEDP), end-systolic volume (LVESV) and end-diastolic volume (LVEDV) compared to placebo. Improvement of LV dilation by aldosterone antagonism was associated with a significant reduction of increased AT1 receptor, angiotensin-converting enzyme (ACE) and endothelin-1 gene expression in the noninfarcted LV myocardium. Combination therapy with irbesartan led to a substantial further leftward shift of the LV pressure-volume curve and decrease in LVEDP, LVESV and LVEDV. Moreover, combination therapy significantly improved LV systolic and diastolic function and reversed LV alterations of alpha- and beta-myosin heavy-chain isoforms, ANF and SERCA2 ATPase expression more effectively than monotherapies. LV collagen type I and type III expression as well as interstitial fibrosis were substantially increased in placebo CHF rats, similarly decreased by eplerenone and irbesartan, and further reduced by eplerenone/irbesartan. However, no additive effects of eplerenone/irbesartan on myocardial AT1 receptor, ACE and endothelin-1 mRNAs were observed. Aldosterone receptor antagonism provides additional benefit to AT1 receptor blockade on LV function and remodeling associated with improvement of molecular alterations responsible for progressive contractile dysfunction post-MI.

Skeletal muscle myofibrillar protein oxidation in heart failure and the protective effect of Carvedilol

Heart failure is characterized by limited exercise tolerance and by a skeletal muscle myopathy with atrophy and shift toward fast fibres. An inflammatory status with elevated pro-inflammatory cytokines and exaggerated free radicals production, can worsen muscle damage. In a well established model of heart failure, the monocrotaline treated rat, we show that CHF is accompanied by oxidation of the skeletal muscle actin, tropomyosin and myosin, which further depresses muscle function and exercise capacity. We have also tested the efficacy of Carvedilol, a non-selective β 1–β 2-blocker, which has been widely used in clinical trials to improve exercise tolerance and reduce mortality in moderate and severe CHF, in preventing contractile protein oxidation in CHF rats. As comparison we used Bisoprolol a β 1 selective agent, without known anti-oxidative properties. Carvedilol at the dose of 2 mg/kg per day was able to prevent the myofibrillar protein oxidation, while Bisoprolol (0.1 mg/kg) did it only partially, as demonstrated by the oxyblot analysis. While Carvedilol improved force production on isolated muscles, Bisoprolol did not. After the COMET trial, the anti-oxidative capacity of Carvedilol has been invoked as one of the mechanism that makes this drug superior to other selective β-blockers in the treatment of CHF. One of the reason of Carvedilol superiority could be the effect on skeletal muscle with reduction of contractile protein peroxidation, amelioration of muscle function and improvement of exercise tolerance. Inhibition of reactive oxygen species (ROS) production, and of pro-inflammatory cytokines may also lead to a decreased muscle wastage, another factor contributing to worsening of exercise tolerance.

Characterizing Blood Pressure, Heart Rate, Physical Activity, Circadian Rhythm and their Response to NOS Inhibitor and Substrate in CHF Rats with Telemetry

Characterizing Blood Pressure, Heart Rate, Physical Activity, Circadian Rhythm and their Response to NOS Inhibitor and Substrate in CHF Rats with Telemetry