Left Ventricular Pressure Fall Research Articles

Analysis of Relaxation Phase in the Rat Heart

The rate and depth of myocardial relaxation determine left ventricular (LV) filling in early diastole. To analyze the relaxation phase, the method of logarithm of LV pressure fall in rats was used. A gradual acceleration of relaxation was found during the transition from the isovolumic phase to the auxovolumic phase, immediately before the opening of the atrioventricular valves. The relaxation rate constant in this phase has been inversely correlated with the values of the minimum LV diastolic pressure and LV endsystolic volume. The results suggest that the gradual acceleration of relaxation is due to the straightening of the spring-like structure of connectin (titin), which is compressed during contraction.

Role of activating the nuclear factor kappa B signaling pathway in the development of septic cardiomyopathy in rats with sepsis.

Despite advances in the treatment of sepsis over time, this condition remains both a serious threat and a cause of death among critical patients. This study aimed to explore the role of the nuclear factor kappa B (NF-κB) signaling pathway in the development of septic cardiomyopathy in rats with sepsis. A total of 32 Sprague Dawley rats were randomized into a sham operation group and three groups with sepsis, which were tested at one of the following time-points: 3, 6, or 12 h. Each group included eight rats. Sepsis models were created via cecal ligation and puncture procedures. All the study rats had the following cardiac parameters and serum levels measured at either 3, 6, or 12 h after the operation (according to their assigned group): heart rate, left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure rise (+dP/dtmax) and fall (-dP/dtmax), tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), and cardiac troponin I (cTnI). The myocardium of the left ventricle was collected and subjected to hematoxylin and eosin staining to observe the changes in pathological morphology. The expression of toll-like receptor 4 (TLR4) and NF-κB in the myocardium were detected by western blot analysis. Compared with the sham operation group, the rats in the sepsis subgroups exhibited significantly lower values for all the cardiac parameters measured, including the heart rate (sham operation group = 386.63 ± 18.62 beats per minute [bpm], sepsis 3-h group = 368.38 ± 12.55 bpm, sepsis 6-h group = 341.75 ± 17.05 bpm, sepsis 12-h group = 302.13 ± 21.15 bpm), LVSP (sham operation group = 125.50 ± 11.45 mmHg, sepsis 3-h group = 110.88 ± 7.51 mmHg, sepsis 6-h group = 100.00 ± 15.06 mmHg, sepsis 12-h group = 91.38 ± 14.73 mmHg), +dp/dtmax (sham operation group = 7137.50 ± 276.44 mm Hg/sec, sepsis 3-h group = 5745.00 ± 346.16 mm Hg/sec, sepsis 6-h group = 4360.00 ± 312.04 mm Hg/sec, sepsis 12-h group = 2871.25 ± 443.99 mm Hg/sec), and -dp/dtmax (sham operation group = 6363.75 ± 123.86 mm Hg/sec, sepsis 3-h group = 6018.75 ± 173.49 mm Hg/sec, sepsis 6-h group = 5350.00 ± 337.89 mm Hg/sec, sepsis 12-h group = 4085.00 ± 326.76 mm Hg/sec). They also displayed significantly higher levels of serum cytokines, including TNF-α (sham operation group = 14.72 ± 2.90 pg/mL, sepsis 3-h group = 34.90 ± 4.79 pg/mL, sepsis 6-h group = 24.91 ± 2.57 pg/mL, sepsis 12-h group 22.06 ± 3.11 pg/mL), IL-1β (sham operation group = 42.25 ± 16.91, 3-h group = 112.25 ± 13.77, sepsis 6-h group = 207.90 ± 22.64, sepsis 12-h group = 157.18 ± 23.06), IL-6 (sham operation group = 39.89 ± 5.74, sepsis 3-h group = 78.27 ± 9.31, sepsis 6-h group = 123.75 ± 13.11, sepsis 12-h group = 93.21 ± 8.96), and cTnI (sham operation group = 0.07 ± 0.03 ng/mL, sepsis 3-h group = 0.18 ± 0.06 ng/mL, sepsis 6-h group = 0.67 ± 0.19 ng/mL, sepsis = 12-h group 1.28 ± 0.10 ng/mL). The rats in the sepsis groups exhibited pathological changes in the myocardium, which deteriorated gradually over time. The animals in all the sepsis groups exhibited significantly higher levels of TLR4 and NF-κB protein expression compared with the sham group. The TLR4 protein expressions were 0.376 in the sham operation group, 0.534 in the sepsis 3-h group, 0.551 in the sepsis 6-h group, and 0.719 in the sepsis 12-h group. The NF-κB protein expressions were 0.299 in the sham operation group, 0.488 in the sepsis 3-h group, 0.516 in the sepsis 6-h group, and 0.636 in the sepsis 12-h group. Sepsis can lead to myocardial injury and cardiac dysfunction. This may be related to the activation of the NF-κB intracellular signal transduction pathway and the release of inflammatory factors as a result of lipopolysaccharides acting on TLR4 during the onset of sepsis.

Abstract P2077: FoxO3 Transcription Factor Regulates Myocyte Contractility And Calcium Homeostasis In Diabetic Cardiomyopathy

Diabetes is a risk factor for heart failure with preserved ejection fractions (HFpEF). Calcium (Ca 2+ ) mishandling and diastolic abnormalities are the characteristics of diabetic cardiomyopathy (DCM), but the molecular mechanisms of these are elusive. FoxO transcription factors (FoxOs) are suppressed by insulin and this study evaluated the role of FoxO3 in myocardial contractility and Ca 2+ handling in the heart of a mouse model of type 1 diabetes. We show that cardiomyocyte-restricted deletion of FoxO3 (H-FoxO3 KO) prevented reduction in the peak rate of left ventricular (LV) pressure (dP/dt max) and prevented the increase in the minimum rate of fall in LV pressure (dP/dt min) that was evident after 4-7 weeks of Streptozotocin (STZ) diabetes. Time for pressure decay of LV while relaxation (Tau) was partially increased in STZ hearts and tended to decrease in STZ H-FoxO3 KO. Echocardiography showed LVEF was unchanged in control and H-FoxO3 KO animals treated with/without STZ. Ca 2+ imaging in perfused hearts found that Ca 2+ transient amplitude was decreased and decay kinetics prolonged (indicates decreased SERCA activity) in STZ hearts, but these changes were prevented in STZ H-FoxO3 KO. Phosphorylation of SERCA at Thr484 by SPEG (Striated muscle preferentially expressed protein kinase) controls Ca 2+ re-uptake and cardiac contractility. We show that STZ diabetes decreases SPEG protein and pSERCA2a Thr484 , but levels of each were normalized or increased in STZ H-FoxO3 KO. Mechanistically, overexpression of FoxO3 in neonatal cardiomyocytes increases high-molecular weight SPEG adducts when proteasome degradation was inhibited with MG-132, suggesting that ubiquitin-mediated degradation of SPEG is a mechanism by which FoxO3 controls Ca 2+ handling via SERCA phosphorylation. SERCA function requires ATP, thus, we evaluated mitochondrial energetics in these animals. Respiratory capacity in saponin-permeabilized cardiac fibers was unchanged in hearts from controls and H-FoxO3 KO treated with/without STZ. ATP generation was decreased in STZ hearts but was not normalized in STZ-H FoxO3 KO. These data indicate FoxO3 regulates myocyte contractility via SPEG degradation to control intracellular Ca 2+ via pSERCA2a Thr484 in the heart in a type 1 diabetes model.

Kukoamine A activates Akt/GSK-3β signaling pathway to inhibit oxidative stress and relieve myocardial ischemia-reperfusion injury.

ABSTRACTPurpose:Myocardial ischemia/reperfusion (MI/R) injury refers to a pathological condition of treatment of myocardial infarction. Oxidative stress and inflammation are believed to be important mechanisms mediating MI/R injury. Kukoamine A (KuA), a sperm, is the main bioactive component extracted from the bark of goji berries. In this study, we wanted to investigate the possible effects of KuA on MI/R injury.Methods:In this experiment, all rats were divided into sham operation group, MI/R group, KuA 10 mg + MI/R group, KuA 20 mg + MI/R group. After 120 min of ischemia/reperfusion treatment, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximal rates of rising and fall of left ventricular pressure (±dp/dtmax), and ischemic area were detected. Serum samples of rats in each group were collected. The enzyme activities of catalase (CAT), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD), levels of malondialdehyde (MDA), CK muscle/brain (CK-MB), tumor necrosis factor (TNF), interleukin-1β (IL-1β), and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay (ELISA). The apoptosis of myocardium in each group was detected according to the instructions of the terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expressions of mammalian target of glycogen synthase kinase-3β (GSH-3β) and protein kinase B (Akt) mRNA level in myocardial tissues were detected via reverse transcription-polymerase chain reaction (RT-PCR).Results:MI/R rats showed a significant increase in oxidative stress and inflammation. In addition, we showed that KuA significantly improved the myocardial function such as LVSP, left ventricular ejection fraction, +dp/dt, and -dp/dt. Here, it attenuated dose-dependent histological damage in ischemia-reperfused myocardium, which is associated with the enzyme activities of SOD, GSH-PX, and levels of MDA, IL-6, TNF-α, L-1β.Conclusions:KuA inhibited gene expression of Akt/GSK-3β, inflammation, oxidative stress and improved MR/I injury. Taken together, our results allowed us to better understand the pharmacological activity of KuA against MR/I injury.

Trastuzumab-Induced Negative Chronotropic and Lusitropic Effects in Cynomolgus Monkeys.

Treatment with trastuzumab, an antihuman epidermal growth factor receptor type 2 humanized monoclonal antibody, has been associated with heart failure in certain patients with cancer; however, the mechanism underlying trastuzumab-induced cardiac dysfunction remains unclear. This study was conducted to clarify the cardiac effects of trastuzumab in cynomolgus monkeys, which are commonly used as cross-reactive species in preclinical safety evaluation. Monkeys were treated with trastuzumab weekly for 1 month (5 doses in total). At first and fifth doses for pressure-volume loop analysis, trastuzumab at 20 mg·kg-1·10 min-1, equivalent to the human therapeutic dose, was administered intravenously to isoflurane-anesthetized animals, followed by 60 mg·kg-1·10 min-1 at a 30-minute interval. The other doses were fixed at 80 mg·kg-1·10 min-1 under unanesthetized conditions. After the first dose, reduced heart rate, decreases in maximal rate of fall of left ventricular pressure, and prolonged time constant for isovolumic relaxation, which are predictors of drug-induced changes in lusitropy, were observed at 20 and 60 mg·kg-1. The changes after the fifth dose were comparable with those after the first dose, indicating trastuzumab did not show exacerbation of cardiac function during the 1-month trial. No significant changes in slope of preload recruitable stroke work, which is a load-independent inotropic parameter, were observed at either dose. In conclusion, trastuzumab-induced little inotropic effect but induced negative chronotropic or lusitropic effects in monkeys, which might be associated with impaired left ventricular diastolic function.

Effect of electroacupuncture preconditioning on myocyte apoptosis in myocardial ischemia-reperfusion injury rats based on FXR/SHP pathway

To observe the effect of electroacupuncture (EA) preconditioning on left-cardiac function, contents of serum TNF-α and IL-6 and expression of myocardial farnesoid X receptor(FXR), small heterodimer partner (SHP), apoptosis inducing factor (AIF) and heat shock proteins 70 (HSP70) genes in myocardial ischemia-reperfusion injury (MIRI) rats, so as to explore its mechanisms underlying improvement of ischemic myocardial injury. Forty male Wistar rats were randomly divided into normal control, sham operation, MIRI model and EA pretreatment groups, with 10 rats in each group. Rats of the sham operation group received exposure of the thorax and heart. The MIRI model was established by occlusion of the anterior descending branch of the left coronary artery (LAD). EA (2 Hz/100 Hz and 1 mA) was applied to bilateral "Neiguan" (PC6), "Zusanli" (ST36) and "Guanyuan" (CV4) for 20 min, once a day for 7 days. The left ventricular end-diastolic pressure (LVEDP), left ventricular systolic pressure (LVSP)and maximal rates of rise and fall of left ventricular pressure (±dp/dtmax) were detected, the contents of serum TNF-α and IL-6 were detected by using enzyme-linked immunosorbent assay (ELISA), and the expression of FXR, SHP, AIF and HSP70 apoptotic genes in the myocardial tissue were measured by fluorescent quantitative RT-PCR. Compared with the normal control group, the LVEDP, contents of serum TNF-α and IL-6, and the expression levels of myocardial FXR, SHP, AIF and HSP70 mRNAs were significantly increased (P<0.05), while LVSP and ±dp/dtmax levels were obviously decreased in the model group (P<0.05). In comparison with the model group, MIRI-induced increases of LVEDP, TNF-α and IL-6 contents, and FXR, SHP and AIF mRNA expression and decreases of ±dp/dtmax and LVSP levels were reversed(P<0.05), except HSP70 mRNA expression with significantly increased (P<0.05) in the EA pretreatment group. EA pretreatment can protect the left ventricular function of the ischemic heart in MIRI rats, which may be related to its effects in reliving peripheral inflammation and regulating the expression levels of apoptosis-related factors FXR, SHP, AIF and HSP70 in the myocardium.

Effects of ranolazine on cardiac function in rats with heart failure.

To investigate the effects of ranolazine on the cardiac function and myocardial apoptosis in rats with heart failure and its possible mechanisms. Thirty Wistar rats were randomly divided into sham operation (negative control; NC), chronic heart failure (CHF), and ranolazine groups. Suprarenal abdominal aortic coarctation was used to induce CHF in rats. Five weeks later, rats in the ranolazine group received ranolazine (50 mg/kg) daily, whereas those in the CHF group received normal saline. After 4 weeks, changes in hemodynamic parameters, cardiac structure and pathology, myocardial apoptosis, and protein expression were assessed. The left ventricular end-diastolic pressure (LVEDP) significantly increased in the CHF group; whereas the maximal rate of left ventricular pressure rise and fall (±dp/dtmax) decreased, compared to those in the NC group. Ranolazine significantly reduced LVEDP and increased ±dp/dtmax (p<0.01), compared to those in the CHF group. Severe impairment of cardiomyocytes was observed in the CHF group with evident inflammation; however, ranolazine reversed these deficits. Rats in the CHF group exhibited an increase in TUNEL-positive cells, which was inhibited by ranolazine, where the apoptotic index significantly decreased in ranolazine-treated rats (p<0.01). Also, ranolazine downregulated caspase-9 expression and upregulated pAKT and Bcl-2 expression in rat cardiomyocytes. Moreover, ranolazine significantly inhibited myocardial apoptosis and caspase-9 expression, promoted AKT phosphorylation, and upregulated pAKT and Bcl-2 expression in vitro, compared to those in the control group (p<0.001). LY294002 inhibited ranolazine-induced suppression of myocardial apoptosis (p<0.001). Ranolazine improved cardiac function and inhibited myocardial apoptosis in rats with CHF, which could be attributed to the regulation of AKT phosphorylation.

Left-Ventricular Pressure Relaxation and Diastolic Function of Isolated Working Mammalian Hearts at Hypothermia

Background: Hypothermia is well known to elevate the time constant (whatever model is used) of the isochoric left-ventricular pressure fall. Due to different critera in use, it remained unclear whether prolonged diastole in hypothermia is sufficient for complete relaxation. Detecting and quantifying incomplete relaxation may become a valuable tool to prevent diastolic heart failure in hypothermia.Methods: Left-ventricular pressure decays in isolated guinea pig and rat hearts are analysed by 4-parametric regression at different temperatures, at sinus rhythm and electrical stimulation. Residual contraction (F_RC) is introduced and quantified by extrapolating the model's pressure forecast to end-systole, subtracting the asymptote, and normalising.Resultts: Isochoric pressure decay fits the regression model at all temperatures and heart beat frequencies. Residual contraction is virtually absent at normothermia and remains very small (F_RC&lt;3%) down to 31°C. Lower temperatures or pacing induces higher F_RC. Eventually, the pressure curve becomes considerably elevated and looses its concavity.Conclusions: Despite slower pressure fall, ventricular relaxation remains fairly complete at hypothermia; and depends on considerable autoregulation of the individual heart. It is concluded (not proved) that individual emergence of negative lusitropy may indicate imminent heart failure. Asymptotic pressure rises are interpreted at higher ventricular tonus, independent from velocity of relaxation. Gradual increasing time constants may be attributed to a general slowing of bioreactions as temperature falls. Remarkable curve shape changes may be caused by aftercontractions due to elevated Ca++ sensitivity at hypothermia and high Ca++ load by pacing.

Effects of dexmedetomidine on myocardial ischemia-reperfusion injury through PI3K-Akt-mTOR signaling pathway.

To explore the role of dexmedetomidine (DEX) in myocardial ischemia-reperfusion (I/R) injury model and investigate its specific molecular mechanism. The I/R rat model was established by ligating the anterior descending coronary artery for 30 min and reperfusion for 120 min. In this experiment, all rats were divided into sham operation (SH) group, I/R group, DEX group and I/R + rapamycin (RAP) group. After 120 min of I/R treatment, left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), maximal rates of rise and fall of left ventricular pressure (±dp/dtmax) and ischemic area were detected. Serum samples of rats in each group were collected. The levels of catalase (CAT), glutathione peroxidase (GSH-PX), malondialdehyde (MDA), superoxide dismutase (SOD), creatine kinase (CK), CK-muscle/brain (CK-MB), tumor necrosis factor (TNF) and interleukin-6 (IL-6) were detected using enzyme-linked immunosorbent assay (ELISA). The apoptosis of myocardium in each group was detected according to the instructions of terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. The expressions of mammalian target of rapamycin (mTOR), phosphorylated-mTOR (p-mTOR), protein kinase B (Akt) and p-Akt in myocardial tissues were detected via Western blotting. Moreover, the messenger ribonucleic acid (mRNA) expression level of mTOR in each group was detected using reverse transcription-polymerase chain reaction (RT-PCR). Compared with SH group, LVSP and ±dp/dtmax in I/R group were significantly decreased, whereas LVEDP was remarkably increased in I/R group (p<0.01). After DEX administration, LVSP and ±dp/dtmax were remarkably increased, while LVEDP and infarction area were markedly decreased (p<0.01). After treatment with mTOR inhibitor rapamycin (RAP), LVSP and ±dp/dtmax were evidently decreased, while LVEDP and infarction area were increased when compared with those of DEX group (p<0.01). Compared with SH group, the levels of CK, CK-MB, TNF-α and IL-6 in I/R group were significantly increased. However, the levels of these molecules were significantly decreased after DEX treatment in I/R rats. After the combination of DEX and RAP, the expression levels of these indexes were significantly increased. No significant differences were found between DEX + RAP group and model group, and between I/R + RAP group and model group. MDA level in I/R group was significantly higher than that of SH group, while the levels of SOD, CAT and GSH-PX were notably lower (p<0.01). Compared with I/R group, the level of MDA in DEX group was significantly reduced, but the levels of SOD, CAT and GSH-PX were markedly increased (p<0.05, p<0.01). Meanwhile, compared with DEX group, MDA level in I/R group was significantly increased. However, the levels of SOD, CAT and GSH-PX were remarkably decreased after the application of combined DEX and mTOR inhibitor (p<0.01). After the addition of RAP, no significant changes were found in each index compared with I/R group. DEX could alleviate myocardial cell apoptosis caused by I/R treatment (p<0.01). The levels of p-mTOR and p-Akt in I/R group were significantly increased when compared with those of SH group. However, the levels of these indexes in DEX group were evidently higher than those of I/R group after DEX administration based on myocardial I/R model (p<0.01). After combination of DEX and RAP, the latter canceled the effect of the former on enhancing the expression of p-mTOR and the phosphorylation level of mTOR. Furthermore, there was no significant change in mTOR and its mRNA expression in each group. DEX can play a protective role in myocardial I/R rats, improve the cardiac function of I/R rats, eliminate oxygen free radicals, relieve oxidative stress injury, inhibit inflammatory responses and reduce the release of CK and other substances. The myocardial protection effects of DEX are mainly achieved through the phosphatidylin-ositol-3-kinase (PI3K)-Akt-mTOR pathway.

Rate of left ventricular pressure change by Doppler echocardiography in dogs with chronic mitral valve disease at different stages of congestive heart failure.

Although the major pathological feature of chronic mitral valve disease is mitral regurgitation, myocardial dysfunction has been suggested to be present in dogs with chronic mitral valve disease. However, accurate assessment of myocardial function remains challenging. Doppler-derived rate of left ventricular pressure change is a simple, less load-dependent method for evaluating myocardial function. We aimed to evaluate Doppler-derived rate of left ventricular pressure change for assessing myocardial function in different stages of dogs with chronic mitral valve disease. This analytical cross-sectional study recruited 55 client-owned dogs with chronic mitral valve disease prospectively. Based on physical examination, indirectly measured blood pressure, routine hematologic and biochemistry examinations, thoracic radiography, electrocardiography, and echocardiography, dogs were diagnosed as mitral valve disease and excluded for systemic diseases and other cardiac diseases. They were classified according to the International Small Animal Cardiac Health Council scales. Doppler-derived rates of left ventricular pressure rise and fall (dP/dt and -dP/dt) were analyzed by two investigators using continuous-wave Doppler imaging. Doppler-derived dP/dt was higher in dogs of class IIIa than in those of the other classes, whereas values of -dP/dt decreased significantly with the severity of congestive heart failure. The peak velocity of the early diastolic wave and -dP/dt were identified as independent predictors of congestive heart failure. Our findings suggested that Doppler-derived dP/dt and -dP/dt, used in combination with conventional echocardiographic variables, could allow a better understanding of myocardial dysfunction and a possibility for prediction of the risk of heart failure in dogs with chronic mitral valve disease.

Icariin influences cardiac remodeling following myocardial infarction by regulating the CD147/MMP-9 pathway.

ObjectiveWe investigated the protective effect of icariin on myocardial infarction-induced cardiac remodeling.MethodsA cardiac remodeling model was constructed by ligating rats’ coronary artery. Different icariin and CD147 concentrations were administered in the model group, and echocardiography was used to detect systolic function, screening out ideal experimental concentrations. The ventricular systolic function, myocardial apoptosis rate, and expression of collagen type I (Col I), Col III, CD147, matrix metalloproteinase 9 (MMP-9), and tissue inhibitor of metalloproteinase 1 (TIMP-1) were detected by hematoxylin–eosin staining, TUNEL assay, and western blot. MMP-9 activity was evaluated by gelatin zymography.ResultsThe expression of Col I, Col III, CD147, and MMP-9 was higher, the expression of TIMP-1 was lower, and the maximal rates of left ventricular pressure rise and fall (+dp/dtmax and −dp/dtmax, respectively) were lower in model than control rats. The expression of CD147, MMP-9, Col I, and Col III was lower, the expression of TIMP-1 was higher, and the +dp/dtmax and −dp/dtmax were higher in the icariin than model group. The apoptosis rate was lower in the icariin and icariin + CD147 groups than control group.ConclusionIcariin attenuated myocardial apoptosis following myocardial infarction by apoptosis rate reduction and CD147/MMP-9 pathway inhibition.

Protective role and mechanism of snakegourd peel against myocardial infarction in rats

BackgroundInjection of snakegourd peel (SP), an herb used in traditional Chinese medicine, is used to treat coronary artery disease and stable angina in China. However, its therapeutic role and mechanism of action for the treatment of myocardial infarction (MI) is not fully understood. PurposeThe present study was designed to investigate the effect of SP on MI-induced cardiac injury and elucidate its underlying molecular mechanisms. MethodsTo create an in vivo model of MI, we ligated the left coronary artery of Wistar rats. For our in vitro model of MI, we treated primary neonatal rat ventricular myocytes with hypoxia. Myocardial infarct size was measured by triphenyltetrazolium chloride (TTC) staining. Intracellular calcium concentration (Ca2+) was measured by confocal microscopy, and cardiomyocyte apoptosis was assessed by TUNEL assay. Western blot was applied to determine protein levels. ResultsThree days post-MI, SP significantly improved MI-induced impairment of cardiac function, as indicated by increased left ventricular systolic pressure (LVSP), maximum rate of left ventricular pressure rise and fall (± dp/dt max), and decreased left ventricular end-diastolic pressure (LVEDP). In addition, SP treatment markedly reduced the infarct size and serum lactate dehydrogenase (LDH) activity; inhibited cardiomyocyte apoptosis and Caspase-3 activation both in vivo and in vitro; and decreased intracellular calcium overload, Cav1.2, phosphorylated JNK (p-JNK), and p38 MAPK (p-p38 MAPK) levels in ischemic myocardium. ConclusionSP alleviated cardiac ischemic injury and inhibited cardiomyocyte apoptosis by attenuating intracellular calcium overload, suppressing Caspase-3 activation, and downregulating protein expression of p-JNK and p-p38MAPK. These results suggest that SP may serve as a potential novel therapeutic drug for MI.

The vasodilatory effect of allopurinol mediates its antihypertensive effect: Effects on calcium movement and cardiac hemodynamics

Despite the reported reduction in blood pressure in hypertensive patients treated with allopurinol, the mechanism of the allopurinol hypotensive effect is still unclear. In the current study, the hypotensive effect of allopurinol has been fully investigated in hypertensive rats. Hypertension was induced in rats by angiotensin II (120 ng/min/kg) infusion for two weeks. Rats were then subjected to real-time recording of blood pressure, left ventricular pressure and volume and surface ECG. After 10 min of basal recording, allopurinol was slowly injected into the femoral vein with a dose of 10 μmole/kg. Then, invasive blood pressure, cardiac hemodynamics and ECG were continuously recorded for an additional 20 min. In addition, the vasodilation effect of allopurinol was studied using the isolated artery technique. Allopurinol injection reduced systolic, diastolic and pulse blood pressure. Allopurinol suppressed both cardiac systolic and diastolic hemodynamics as is apparent from the reduction in the rate of rise and the rate of fall in left ventricular pressure. Allopurinol reduced the general cardiac output quickly. Allopurinol addition to the organ bath (10–1000 μM) produced significant vasodilation of PE pre-constricted aortae that was not affected by endothelium denudation, L-NAME or indomethacin. However, allopurinol ameliorated the calcium induced contraction of aorta pre-constricted with KCl in calcium-free media. Erk or ROCK inhibition did not attenuated allopurinol produced vasodilation. In conclusion, allopurinol has an antihypertensive effect that is mediated, probably, by reducing cardiac output and decreasing vascular resistance. The vasodilator effect of allopurinol is most likely mediated by calcium blocking activities.

(-)-Epigallocatechin-3-gallate, the major green tea catechin, regulates the desensitization of β1 adrenoceptor via GRK2 in experimental heart failure.

We investigated the effect of (-)-epigallocatechin-3-gallate (EGCG) on cardiac function and its mechanism, which focused on the desensitization of β1-AR and GRK2 in heart failure (HF) rats. HF was induced by abdominal aortic coarctation. Four weeks after HF induction, the rats were given EGCG (25, 50, 100mg/kg/day). Cardiac function was assessed by measuring haemodynamic parameters. Histological changes were analyzed by HE and Masson's trichrome staining. The expression of β1-AR was detected by immunohistochemistry and immunofluorescence. The membrane expression of β1-AR and GRK2 was detected by western blot. The expression levels of β1-AR mRNA and GRK2 mRNA were evaluated by Q-PCR. Compared to the control group, the left ventricular end diastolic pressure, mean blood pressure, heart weight/body weight, and posterior wall thickness in the HF group were significantly increased, whereas the left ventricular systolic pressure, maximum rate of left ventricular pressure rise (+dP/dt max) and maximum rate of left ventricular pressure fall (-dP/dt max) were clearly decreased. EGCG could improve cardiac function by regulating these parameters. Inflammatory cell infiltration, irregularly arranged cardiomyocytes, swelling of cardiomyocytes and myocardial fibrosis were observed in HF rats' myocardial morphology, and EGCG obviously improved the morphological signs. The expression of β1-AR was significantly decreased in the left ventricle tissue of HF rats by immunohistochemistry and immunofluorescence. The membrane expression of β1-AR decreased, whereas GRK2 increased in vivo and in vitro by western blot. EGCG could down-regulate the membrane expression of GRK2 and up-regulate the expression of β1-AR. There were no significant differences in the total expression of β1-AR mRNA and GRK2 mRNA. EGCG has therapeutic effects on the heart function of HF rats. The mechanism might be related to the inhibition of the transfer membrane of GRK2 and to the reduction of the desensitization of β1-AR.

An experimental study of the protective effect of simvastatin on sepsis-induced myocardial depression in rats

Many patients with sepsis died of heart failure caused by sepsis-induced myocardial depression. Patients with cardiovascular diseases treated by statins have a lower incidence and mortality of sepsis, although the mechanisms remain elusive. To investigate the protective effect of simvastatin on sepsis-induced myocardial depression and to explore possible mechanisms of action. Thirty six adult male Wistar rats were pretreated with simvastatin (0.2μg/g, q12h) for one week before cecal ligation and puncture (CLP). It was found that in simvastatin-treated rats, cardiac function indices, including left ventricular systolic pressure (LVESP) and maximal rate of rise and fall of left ventricular pressure (±dp/dtmax) and mean arterial pressure(MAP) markedly improved. Myocardial cells examined with hematoxylin and eosin (HE) were only partially swollen and degenerated and with fewer inflammatory cells infiltrating. Expressions of TLR4 and NF-κB p65 protein were significantly lower in simvastatin-treated rats than that in sepsis rats at the same time point. Levels of TNF-α, IL-1β, IL-6, MCP-1 and NO in myocardial tissues, together with levels of CTnI in serum were significantly declined in simvastatin-treated rats. Simvastatin has a protective effect on myocardial depression caused by sepsis. The effect may be mediated by the inhibition of TLR4-NF-κB signaling pathway, which leads to reduced levels of downstream inflammatory factors such as TNF-α, IL-1β, IL-6, MCP-1 and NO.

Donor Preconditioning After the Onset of Brain Death With Dopamine Derivate n-Octanoyl Dopamine Improves Early Posttransplant Graft Function in the Rat.

Heart transplantation is the therapy of choice for end-stage heart failure. However, hemodynamic instability, which has been demonstrated in brain-dead donors (BDD), could also affect the posttransplant graft function. We tested the hypothesis that treatment of the BDD with the dopamine derivate n-octanoyl-dopamine (NOD) improves donor cardiac and graft function after transplantation. Donor rats were given a continuous intravenous infusion of either NOD (0.882 mg/kg/h, BDD+NOD, n = 6) or a physiological saline vehicle (BDD, n = 9) for 5 h after the induction of brain death by inflation of a subdural balloon catheter. Controls were sham-operated (n = 9). In BDD, decreased left-ventricular contractility (ejection fraction; maximum rate of rise of left-ventricular pressure; preload recruitable stroke work), relaxation (maximum rate of fall of left-ventricular pressure; Tau), and increased end-diastolic stiffness were significantly improved after the NOD treatment. Following the transplantation, the NOD-treatment of BDD improved impaired systolic function and ventricular relaxation. Additionally, after transplantation increased interleukin-6, tumor necrosis factor TNF-α, NF-kappaB-p65, and nuclear factor (NF)-kappaB-p105 gene expression, and increased caspase-3, TNF-α and NF-kappaB protein expression could be significantly downregulated by the NOD treatment compared to BDD. BDD postconditioning with NOD through downregulation of the pro-apoptotic factor caspase-3, pro-inflammatory cytokines, and NF-kappaB may protect the heart against the myocardial injuries associated with brain death and ischemia/reperfusion.

The inflammatory state provokes sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats

Although cardiotoxicity has been recognized as an adverse effect of cyclosporine A (CSA), no information exists regarding sex specificity of CSA cardiotoxicity. We tested the hypothesis that left ventricular (LV) and electrocardiographic (ECG) effects of CSA and related inflammatory/histopathological derangements are sex related. CSA reduced the LV slope of end-systolic pressure volume relationship and increased isovolumic relaxation constant. These effects were more pronounced in male compared to female rats, suggesting LV systolic and diastolic dysfunction. ECG recordings showed elevated ST segments and increased QTc and T peak trend intervals in CSA-treated male rats, markers of LV ischemia and arrhythmogenesis. In female rats, CSA delayed AV conduction, as reflected by prolonged PR interval. Other sex-related effects for CSA included (i) increased blood cholesterol, and reduced rates of rise and fall in LV pressure and nuclear factor kappa B and angiotensin receptors type 1 expressions in male rats, and (ii) increased LV adiponectin in females. Histopatholgically, CSA caused vascular congestion, blood extravasation, and pyknotic or even absent nuclei in both sexes. In conclusion, rats exhibit sex-independent susceptibility to negative LV and histopathological influences of CSA. These effects become more intensified in male rats, perhaps on account of aggravated ischemic and inflammatory milieus.

Sexual dimorphism in left ventricular and electrocardiographic effects of chronic cyclosporine in rats

Although cardiotoxicity has been recognized as one of the adverse effects of the immunosuppressant drug cyclosporine A (CSA), limited or no information is available regarding the sex specificity of CSA cardiotoxicity. Here we tested the hypothesis that the left ventricular (LV) and electrocardiographic effects of chronic CSA and related inflammatory and histopathological derangements are sex‐related. Adult male and female rats were treated with CSA (15 mg/kg/day, sc) or its vehicle for three weeks. Afterwards, studies were undertaken to assess: (i) LV and electrocardiographic characteristics, and (ii) alterations in LV inflammatory (nuclear factor kappa B, NFκB; angiotensin receptors type 1, AT1) and histopathological profiles. In both male and female rats, CSA significantly reduced LV slope of end‐systolic pressure volume relationship (ESPVR), and isovolumic relaxation constant (Tau), suggesting LV systolic and diastolic dysfunction. Histopathologically, the treatment of either rat sex with CSA resulted in vascular congestion, blood extravasation, and pyknotic or even absent nuclei. We also report sex‐dependent electrocardiographic effects for CSA. Whereas CSA increased QTc and T peak trend intervals in male rats, markers of LV arrhythmogenesis, evidence of prolonged AV conduction was noted in female rats as reflected by the prolonged P duration and PR interval. Other sex‐related effects for CSA included (i) increased blood cholesterol, rate of rise (dp/dtmax) and fall (dp/dtmin) in LV pressure and LV content of NFκB and AT1 expression in male rats, and (ii) increased LV content of adiponectin and elevated systolic and diastolic blood pressures in female rats. Although the two rat sexes are prone to the negative LV influences of CSA, the male rat seems to be more vulnerable to inflammatory and LV adverse effects of CSA.Support or Funding InformationThis work was funded by the Deanship of Scientific Research (DSR), King Abdulaziz University, Jeddah, under grant No. (166 ‐ 1001 ‐D1435). The authors, therefore, acknowledge with thanks DSR technical and financial support

Cardiorenal protection in experimental hypertension with renal failure: comparison between vasopeptidase inhibition and angiotensin receptor blockade

Objective: The aim of the present study was to compare the preventive impact of treatment with a vasopeptidase inhibitor (VPI) with an angiotensin-receptor blocker (ARB) on left ventricular (LV) function and renal damage in rats with renal failure after 5/6 renal ablation (Nx).Methods: Rats (n = 15–20, each group) underwent either sham-operation (Sham) or 5/6 renal ablation (Nx). Two additional groups of Nx-animals (groups Nx-VPI and Nx-ARB) were treated with the VPI ilepatril (AVE7688, 30 mg kg−1 d−1) or with the ARB olmesartan (10 mg kg−1 d−1). Animals were followed for 4 weeks.Results: Systolic blood pressure (SBP), LV hypertrophy (LVH) and LV end-diastolic pressure (LVEDP) were increased 4 weeks after Nx (p < 0.05). LV pressure rise (+dP/dt/LVPmax), LV pressure fall (−dP/dt/LVPmax), and creatinine clearance decreased, while albuminuria and renal glomerulosclerosis index (GSI) increased with Nx (p < 0.05, respectively). In comparison to Nx, treatment with both VPI and ARB normalized SBP, LVH, LVEDP, +dP/dt/LVPmax, and −dP/dt/LVPmax to Sham control levels. GSI, but not creatinine clearance, was also normalized in response to both treatments. The significant increase in albuminuria observed in Nx (+230-fold versus Sham, p < 0.0001) was partially reduced in Nx-VPI (+47-fold versus Sham, p < 0.0001) and fully abolished in Nx-ARB.Conclusions: Both ilepatril and olmesartan conferred strong cardiorenal protective effects in rats with renal failure. While cardioprotection was clearly comparable with both treatment regimens, the ARB provided a better protection against the increase in albuminuria, although renal function and structural kidney changes were similarly affected by the VIP and ARB.

Involvement of cardiomyocyte apoptosis in myocardial injury of hereditary epileptic rats

Many clinical cases have been reported where epilepsy profoundly influenced the pathophysiological function of the heart; however, the underlying mechanisms were not elucidated. We use the tremor (TRM) rat as an animal model of epilepsy to investigate the potential mechanisms of myocardial injury. Cardiac functions were assessed by arrhythmia score, heart rate, heart:body mass ratio, and hemodynamic parameters including left ventricular systolic pressure (LVSP), left ventricular end-diastolic pressure (LVEDP), and maximum rate of left ventricular pressure rise and fall (+dp/dtmax and -dp/dtmax). Catecholamine level was detected by HPLC. Apoptotic index was estimated by TUNEL assay. The expressions of Bcl-2, Bax, caspase-3, extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal protein kinases (JNK), and p38 were evaluated by Western blot. The results indicated that there existed cardiac dysfunction and cardiomyocyte apoptosis, accompanied by increasing catecholamine levels in TRM rats. Further investigation revealed that apoptosis was mediated by reducing Bcl-2, upregulating Bax, and activating caspase-3. Additional experiments demonstrated that P-ERK1/2 was decreased, whereas P-JNK and P-p38 were up-regulated. Our results suggest that the sympathetic nervous system activation and cardiomyocyte apoptosis are involved in the myocardial injury of TRM rats. The mechanisms of apoptosis might be associated with the activation of the mitochondria-initiated and the mitogen-activated protein kinase pathways.