Pressure-overloaded Rats Research Articles

Activation of pyruvate dehydrogenase (PDH) does not prevent the onset of heart failure in pressure overloaded rats

Shifting substrate oxidation in heart muscle from fatty acids to glucose (substrate-switch) may prevent the onset of heart failure and improve contractile function. First drugs are used clinically. We tested whether application of two agents (etomoxir and 10J) capable of inducing a substrate-switch is able to prevent the onset of heart failure in pressure-overloaded rats.

Estrogen Withdrawal Prolonged Vascular Inflammation and Aggravated Diastolic Function in Pressure-overloaded Female Rats

Estrogen Withdrawal Prolonged Vascular Inflammation and Aggravated Diastolic Function in Pressure-overloaded Female Rats

Tedisamil attenuates foetal transformation of myosin in the hypertrophied rat myocardium.

1 Reduction in repolarizing potassium currents has controversial effects on hypertrophic responses in cardiomyocytes of transgenic models and cultured cardiomyocytes. It remains thus unknown whether a blockade of potassium channels with tedisamil (N,N'dicyclopropylmethylene-9,9-tetramethylene-3,7-diazabicyclo(3.3.1)nonane dihydrochloride) has any effects on cardiac growth during postnatal development or pressure overload. 2 To test the hypothesis that a treatment with tedisamil affects cardiac growth or protein phenotype, sham-operated rats and rats with ascending aorta constriction were treated with tedisamil (36 mg kg day(-1)) for 7 weeks. Left ventricular mass and geometry, relative expression of myosin isoforms, hydroxyproline concentration and isovolumic ventricular function were assessed. 3 Rats with aortic constriction exhibited a marked increase in left ventricular weight and the diastolic pressure-volume relationship was shifted to smaller volumes. The hydroxyproline concentration remained unaltered. The proportion of alpha-myosin heavy chains was, however, reduced (P<0.05). Hypertrophied left ventricles manifested an enhanced overall performance but depressed myocardial contractility. 4 Administration of tedisamil was associated with decreased heart rate (P<0.05). In contrast, cardiac growth in sham-operated rats and concentric left ventricular hypertrophy of pressure-overloaded animals was not significantly altered. Hypertrophied hearts from rats treated with tedisamil expressed more alpha-myosin heavy chains (65+/-4 versus 57+/-4%; P<0.05). Also, maximal rate of wall stress rise and decline was higher (P<0.05) in tedisamil-treated pressure-overloaded rats. 5 In the rat model of pressure-overloaded hypertrophy, tedisamil had no effect on cardiac growth but partially corrected myocardial dysfunction. Postulated mechanism of this effect is the phenotype modification of myosin filaments in hypertrophied myocardium.

Transforming Growth Factor-β Function Blocking Already Effective as Therapeutic Strategy

To the Editor: Kuwahara et al1 report a very interesting study in which transforming growth factor (TGF)-β is demonstrated to have a pivotal role in myocardial fibrosis and diastolic dysfunction. They elegantly show that repeated administration of an anti-TGF-β neutralizing antibody inhibits fibroblast activation, collagen induction, and myocardial fibrosis, and also reverses diastolic dysfunction in pressure-overloaded rats. They conclude that TGF-β blockade may be a “potential” therapeutic strategy. Investigations involving ocular wound healing models have shown a similar pattern of TGF-β activity to that described by Kuwahara et al1 in their cardiac model, with peak TGF-β expression occurring predominantly in fibroblasts at …

Transforming growth factor-beta function blocking prevents myocardial fibrosis and diastolic dysfunction in pressure-overloaded rats.

Excessive myocardial fibrosis impairs cardiac function in hypertensive hearts. Roles of transforming growth factor (TGF)-beta in myocardial remodeling and cardiac dysfunction were examined in pressure-overloaded rats. Pressure overload was induced by a suprarenal aortic constriction in Wistar rats. Fibroblast activation (proliferation and phenotype transition to myofibroblasts) was observed after day 3 and peaked at days 3 to 7. Thereafter, myocyte hypertrophy and myocardial fibrosis developed by day 28. At day 28, echocardiography showed normal left ventricular fractional shortening, but the decreased ratio of early to late filling velocity of the transmitral Doppler velocity and hemodynamic measurement revealed left ventricular end-diastolic pressure elevation, indicating normal systolic but abnormal diastolic function. Myocardial TGF-beta mRNA expression was induced after day 3, peaked at day 7, and remained modestly increased at day 28. An anti-TGF-beta neutralizing antibody, which was administered intraperitoneally daily from 1 day before operation, inhibited fibroblast activation and subsequently prevented collagen mRNA induction and myocardial fibrosis, but not myocyte hypertrophy. Neutralizing antibody reversed diastolic dysfunction without affecting blood pressure and systolic function. TGF-beta plays a causal role in myocardial fibrosis and diastolic dysfunction through fibroblast activation in pressure-overloaded hearts. Our findings may provide an insight into a new therapeutic strategy to prevent myocardial fibrosis and diastolic dysfunction in pressure-overloaded hearts.

Simvastatin inhibits cardiac hypertrophy and angiotensin-converting enzyme activity in rats with aortic stenosis.

1. In the present study, we tested the hypothesis that long-term administration of the hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor simvastatin may regress hypertrophy and the possible effect of simvastatin on angiotensin-converting enzyme (ACE) activity in rats with pressure-overload cardiac hypertrophy. 2. Pressure-overload left ventricular hypertrophy (LVH) of rats was induced by part coarctation of the abdominal aorta; a sham-operated group served as the control. Six weeks after operation, animals were divided into three groups and an 8 week treatment period was insitgated as follows: (i) the simvastatin treatment group received simvastatin at 3.6 mg/kg per day, p.o.; (ii) the ACE inhibitor group received captopril at 50 mg/kg per day, p.o.; and (iii) the LVH control group received no drug treatment. 3. At the end of the treatment period, left ventricular systolic pressure (LVSP) and left ventricular end-diastolic pressure (LVEDP) were monitored in vivo. Diastolic pressure-volume relationships were evaluated in a Langendorff preparation with a balloon-in-left ventricle (LV) heart. Myocyte cell width was measured. Angiotensin-converting enzyme activity and angiotensin (Ang)II and hydroxyproline contents of the LV were determined. 4. At the end of the experiments, LVH was established in the LVH control group by increases in LV weight, LV weight/body-weight ratio, LV weight/right ventricle weight ratio, LV myocyte cell width, LVSP and LVEDP by 40, 26, 19, 61, 56 and 59%, respectively (all P < 0.01), compared with the sham-operated group. In the simvastatin-treated and ACE inhibitor groups all these parameters were significantly reduced compared with sham-operated controls. In the LVH control group, ACE activity and AngII and hydroxyproline contents of LV tissue increased by 180, 123 and 70, respectively (all P < 0.01), compared with the sham-operated group. Compared with the LVH group, in the simvastatin-treated and ACE inhibitor groups ACE activity was reduced by 36 (P < 0.05) and 48% (P < 0.01), respectively, AngII content was reduced by 11 (P < 0.05) and 43% (P < 0.01), respectively, and hydroxyproline content was reduced by 23 (P < 0.01) and 10% (P < 0.05), respectively. 5. For the first time, the results of the present study demonstrate that simvastatin significantly reduces LVH, cardiac tissue ACE activity and improves LV performance in pressure-overloaded rats. Because, compared with captopril, simvastatin is more potent in its reduction of LVH and less potent in its inhibition of ACE activity, the mechanism of its antihypertrophic action, in addition to ACE inhibition, may involve inhibition of the mevalonic acid pathway, the main target of action of statins. Thus, HMG-CoA reductase inhibitors may be beneficial for the clinical treatment of cardiac hypertrophy.

Involvement of gp130-mediated signaling in pressure overload-induced activation of the JAK/STAT pathway in rodent heart.

Previously, we showed that the JAK/STAT pathway was activated in pressure-overloaded rat heart, and that angiotensin II was partially involved in this activation. The present study was designed to investigate whether gp130-mediated signaling is involved in this activation, and if so, which interleukin (IL)-6 family cytokine is involved. Pressure overload was produced by ligation of the abdominal aorta of Wistar rats or ICR mice. IP-Western blot was performed to detect tyrosine phosphorylation of STATs, gp130, and the association of gp130 with JAK kinases. The serum concentration of IL-6 was measured by enzyme-linked immunosorbent assay. Expression of IL-6, IL-11, leukemia inhibitory factor (LIF), ciliary neurotrophic factor (CNTF), oncostatin M (OSM), and cardiotrophin-1 (CT-1) mRNA was quantitated. After pressure overload, rapid phosphorylation of STAT1 and STAT3 was observed at 5 min, STAT1 was rephosphorylated at 60 min, and intense phosphorylation of STAT3 was observed at 60 min. Both the phosphorylation of gp130 and the association of gp130 with JAK1 and JAK2 were increased after pressure overload. IL-6 was significantly increased by two-fold in the pressure-overloaded rats. Only CT-1 mRNA expression could be detected by Northern blot, and it increased after pressure overload. Reverse transcription-polymerase chain reaction revealed that IL-6 mRNA expression was increased 9.5-fold. IL-11, LIF, CNTF, and OSM expression were unaffected by pressure overload. These results suggested that gp130-mediated signaling was involved in the pressure overload-induced activation of the JAK/STAT pathway, and that IL-6 and CT-1 might be involved in this activation.

The propionyl- l-carnitine hypothesis: An alternative approach to treating heart failure

Propionyl- l-carnitine (PLC) is a naturally occurring compound that has been considered for the treatment of congestive heart failure (CHF). The rationale for its use in this pathology is related to its effects on cardiac and skeletal muscle. Chronic treatment with PLC improves the contraction of isolated and aerobic perfused rabbit hearts. The compound improves energy metabolism and myocardial contractility in different experimental models of heart failure, such as pressure-overloaded rats, infarct model of heart failure, and rabbit with streptozotocin-induced diabetes. In general, the effect of PLC is apparent in situations of high energy demand such as those induced by increased workload. It therefore seems likely that PLC is able to correct some metabolic steps of the process that leads to heart failure. In addition, PLC may be helpful in heart failure because of its specific action on peripheral skeletal muscle. Administration of PLC in patients with CHF improves skeletal muscle metabolism by increasing pyruvate flux into the Krebs cycle and by decreasing lactate production. These effects occur in the absence of major hemodynamic and neuroendocrinologic changes and may underlie the ability of PLC to increase exercise performance in patients with heart failure. In a randomized study of 50 patients with mild CHF, PLC increased the maximal exercise time, reduced lactate production, and improved left ventricular ejection fraction. There have been two large-scale trials on the effects of PLC on both cardiac and peripheral muscle function in CHF. One is ongoing; the other one, which just ended, failed to show an improvement in exercise capacity in the population studied. A benefit was evident only in a subgroup of patients with preserved ejection fraction and impaired baseline exercise duration.

Effects of enalapril in rats with pressure overload cardiac hypertrophy

1. 1. The effects of the ACE inhibitor enalapril were studied in rats with cardiac hypertrophy induced by abdominal aortic constriction. This experimental model has shown that pump failure can be evidenced only during increased workload. 2. 2. Under basal conditions, enalapril at 1–3 mg/kg induced a significant reduction in blood pressure. During the acute volume loading or the increase in afterload due to a total aortic occlusion, only rats treated with 3 mg/kg enalapril, but not 1 mg/kg, received a hemodynamic benefit that was paralleled by a significant reduction in cardiac hypertrophy. 3. 3. The present study demonstrates that reduction in blood pressure on its own was not sufficient to improve cardiac function. A decrease in blood pressure accompanied with hypertrophy regression were necessary to normalize hemodynamic parameters in pressure-overloaded rats.

Early changes in the functions of cardiac sarcoplasmic reticulum in volume-overloaded cardiac hypertrophy in rats.

By sequestering activator calcium, the sarcoplasmic reticulum (SR) plays the central role in the excitation-contraction (E-C) cycle of cardiac muscle. Hence, functional changes in the SR in diseased myocardium might critically determine its mechanical characteristics. Previously, we demonstrated that both Ca2+ release and uptake were increased in SR isolated from hearts showing compensatory left ventricular (LV) hypertrophy taken from pressure-overloaded rats. However, it has not been elucidated whether such alterations also occur in the volume-overloaded myocardium. Rats in which volume-overloaded hypertrophy had been induced by aortocaval shunt 12 weeks prior to the investigation were compared to sham-operated controls in terms of SR Ca2+ uptake and release, and density of Ca2+ releasing channels (ryanodine receptors, RyR). Isometric tension and intracellular Ca2+ transients were also measured using the bioluminescent Ca2+ indicator, aequorin, in isolated LV papillary muscles. The extent of hypertrophy was verified by measuring the ratio of biventricular weight to body weight. In vivo, the aortocaval shunt rats showed normal LV contractility and slightly depressed LV relaxation, indicating a compensatory (adaptive) stage of LV function. In contrast, Ca2+ release, uptake, and maximal number of [3H]-ryanodine binding sites were all significantly lower in aortocaval shunt rats than in controls. Both the Ca2+ transients and isometric relaxation of the isolated myocardium were significantly prolonged in aortocaval shunt rats, though their amplitudes were similar in the two groups. Thus, the volume-overloaded cardiac hypertrophy, even at its hemodynamically compensatory (adaptive) stage, (i) was accompanied by abnormal Ca2+ handling, as indicated by prolonged intracellular Ca2+ transients and isometric tension traces, (ii) seems to involve subcellular mechanisms related to decreases in SR Ca2+ release and uptake functions, as well as to a decrease in the number of RyR. Therefore, changes in the intracellular processes underlying cardiac E-C coupling, including SR function, precede the development of this type of heart disease.

Effect of propionyl-l-carnitine and enalapril on cardiac function of pressure-overloaded rats during increase in load

Chronic administration of propionyl-l-carnitine has been recently shown to correct hypertrophy related abnormalities in muscle mechanics. Accordingly, this study investigated whether the drug would similarly improve cardiac dynamics in rats with pressure overload. Enalapril was used for comparison. Drugs were administered in the drinking water for 3 weeks to Wistar Kyoto rats with a 2 week abdominal aortic constriction. Cardiac function was studied under urethane anaesthesia in basal conditions, during increase in preload, and during increase in afterload. Basal cardiac function was comparable in pressure-over-loaded and sham-operated animals. Neither propionyl-l-carnitine nor enalapril affected the basal performance. Compared to sham-operated animals, untreated pressure-overloaded rats showed an impaired cardiac response (cardiac output, stroke volume) to preload increase induced by saline i.v. infusion. Propionyl-l-carnitine dose dependently improved cardiac function in the range 30–180 mg/kg, without affecting cardiac hypertrophic growth. Enalapril (3 mg/kg) reduced cardiac hypertrophy and improved cardiac function. The two effects were unrelated. The afterload increase by total aortic occlusion evidenced a reduction in the left ventricle pressure generating capacity of hypertrophied hearts. Propionyl-l-carnitine did not modify this parameter, while enalapril afforded a significant improvement. Results show that propionyl-l-carnitine significantly improves in vivo cardiac dynamics under conditions of increased energy demand. The effect is not due to inotropic efficacy, but presumably to increased cardiac efficiency.

In vivo profile of myocardial energy metabolism of pressure-overloaded rat.

Cardiac energy metabolism of pressure-overloaded rat hearts was examined under in vivo and in vitro conditions. Two, 4 and 6 weeks after constriction of the abdominal artery, the hemodynamic and metabolic profiles of hearts in vivo and of perfused hearts were determined. Significant increases in left ventricular weight/body weight (30 to 45% increase relative to the sham group), systolic and diastolic blood pressure (22 to 33% increase) and pressure-rate product (31 to 33% increase) were observed 2, 4 and 6 weeks after the operation, and a slight but significant decrease in heart rate was observed at 2 weeks after the operation. Tissue hydroxyproline content increased (17 to 93%) with time after pressure-overload. These findings are indicators of pressure-overloaded cardiac hypertrophy. The total high-energy phosphates of the in vivo rat myocardium under artificial respiration were lower than those of sham-operated rat myocardium 2 (23%) and 4 weeks (21%), but not 6 weeks after aortic constriction. The maximal oxygen consumption rates of mitochondria, when determined in the skinned cardiac fibers, also decreased 2 (47%) and 4 weeks (36%), but reversed 6 weeks after pressure-overload. However, the myocardial ATP, a utilizing form of high-energy phosphate, of pressure-overloaded rat myocardium remained normal at all times after cardiac hypertrophy. This suggests that alterations in hemodynamic variables of in vivo pressure-overloaded rats may not be attributable to a reduction in the myocardial energy production. In the perfused hearts isolated from pressure-overloaded rats, tissue ATP levels were similar to those of sham-operated rats, although the tissue creatine phosphate tended to be reduced in the pressure-overloaded animals at all stages of cardiac hypertrophy examined. Only a marginal decrease in the tissue high-energy phosphate (13%) was observed 4 weeks after the operation relative to that of sham-operated rats. In contrast, the developed tension of the perfused pressure-overloaded rat hearts was consistently lower (27 to 36%) than that of the sham-operated rat hearts. The results suggest that the high-energy phosphate levels of pressure-overloaded rat myocardium in vitro are unlikely to account for the observed decline in cardiac contractile function. The reduction of myocardial high-energy phosphates of pressure overloaded rats may be due to an adaptative change rather than a causal events.

Changes of the ATPase activity and the subunits of actomyosin of pressure-overloaded rats' cardiac muscle

Changes of the ATPase activity and the subunits of actomyosin of pressure-overloaded rats' cardiac muscle