OBJECTIVE: To investigate the inhibitory effect of Zhenwu Decoction on ventricular hypertrophy in rats with uremic cardiomyopathy and explore the mechanism. METHODS: Cardiocytes isolated from suckling rats were divided into control group and indoxyl sulfate (IS) group, and the protein synthesis was assayed with [H]- leucine incorporation and cellular protein expressions were detected using Western blotting. Fifty SD rats were randomly divided into sham operation group, model group, and low- and high-dose Zhenwu Decoction treatment groups, and except for those in the sham operation group, all the rats underwent 5/6 nephrectomy. Four weeks after the operation, the rats in low- and high-dose treatment groups were given Zhenwu Decoction gavage at the dose of 4.5 g/kg and 13.5 g/kg, respectively; the rats in the sham-operated and model groups were given an equal volume of distilled water. After 4 weeks of treatment, serum levels of IS were determined, and cardiac and ventricular mass indexes were measured in the rats; cardiac ultrasound was performed and Western blotting was used to measure the expressions of BNP, p-ERK1/2, p-p38 and p-JNK in the myocardium. RESULTS: Rat cardiomyocytes treated with IS showed significantly enhanced protein synthesis and increased expression levels of BNP, p-erk1/2, and p-p38 as compared with the control cells ( < 0.01), but the expression of p-jnk was comparable between the two groups. In the animal experiment, the rats in the model group showed significantly increased serum creatinine (SCr) and urea nitrogen (BUN) levels, 24-h urine protein (24 hUpro), plasma IS level, left ventricular mass index (LVMI) and whole heart mass index (HMI) compared with those in the sham group ( < 0.01); Both LVESD and LVEDD were significantly reduced and LVAWS, LVAWD, LVPWS and LVPWD were significantly increased in the model rat, which also presented with obvious cardiomyocyte hypertrophy and increased myocardial expressions of BNP, p-ERK1/2, p-p38 and p-jnk ( < 0.01). Compared with the rats in the model group, the rats treated with low-dose and high-dose Zhenwu Decoction had significantly lowered levels of SCr, BUN, 24 hUpro and IS ( < 0.05) and decreased LVMI and HMI; LVESD, LVEDD, LVPWS, LVAWS, and LVAWD were improved more obviously in the high-dose group, and the myocardial expressions of BNP, p-ERK1/2, p-p38 and p-JNK was significantly downregulated after the treatment. CONCLUSIONS Zhenwu Decoctin can reduce plasma IS levels and inhibit ventricular hypertrophy to delay ventricular remodeling in rats with uremic cardiomyopathy.
Animals ; Blood Urea Nitrogen ; Cardiomegaly ; prevention & control ; Cardiomyopathies ; complications ; Creatinine ; blood ; Drugs, Chinese Herbal ; pharmacology ; Heart Ventricles ; Indican ; blood ; pharmacology ; Myocytes, Cardiac ; drug effects ; metabolism ; Nephrectomy ; Random Allocation ; Rats ; Rats, Sprague-Dawley

PURPOSE: The mechanisms underlying repolarization abnormalities during pregnancy are not fully understood. Although maternal serotonin (5-hydroxytryptamine, 5-HT) production is an important determinant for normal fetal development in mice, its role in mothers remains unclear. We evaluated the role of serotonin in ventricular repolarization in mice hearts via 5Htr3 receptor (Htr3a) and investigated the mechanism of QT-prolongation during pregnancy. MATERIALS AND METHODS: We measured current amplitudes and the expression levels of voltage-gated K⁺ (Kv) channels in freshly-isolated left ventricular myocytes from wild-type non-pregnant (WT-NP), late-pregnant (WT-LP), and non-pregnant Htr3a homozygous knockout mice (Htr3a(−/−)-NP). RESULTS: During pregnancy, serotonin and tryptophan hydroxylase 1, a rate-limiting enzyme for the synthesis of serotonin, were markedly increased in hearts and serum. Serotonin increased Kv current densities concomitant with the shortening of the QT interval in WT-NP mice, but not in WT-LP and Htr3a(−/−)-NP mice. Ondansetron, an Htr3 antagonist, decreased Kv currents in WT-LP mice, but not in WT-NP mice. Kv4.3 directly interacted with Htr3a, and this binding was facilitated by serotonin. Serotonin increased the trafficking of Kv4.3 channels to the cellular membrane in WT-NP. CONCLUSION: Serotonin increases repolarizing currents by augmenting Kv currents. Elevated serotonin levels during pregnancy counterbalance pregnancy-related QT prolongation by facilitating Htr3-mediated Kv currents.
*Action Potentials/drug effects ; Animals ; Cell Membrane/drug effects/metabolism ; Disease Models, Animal ; Electrocardiography ; Female ; HSC70 Heat-Shock Proteins/metabolism ; HSP90 Heat-Shock Proteins/metabolism ; Heart Ventricles/drug effects/*metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Myocytes, Cardiac/drug effects/metabolism ; Potassium Channels/metabolism ; Pregnancy ; Rabbits ; Rats, Sprague-Dawley ; Receptors, Serotonin, 5-HT3/metabolism ; Serotonin/*metabolism ; Serotonin 5-HT3 Receptor Agonists/pharmacology

OBJECTIVETo analyze the effects of salvianolate on myocardial infarction in a murine in vivo model of ischemia and reperfusion (I/R) injury.

METHODSMyocardial I/R injury model was constructed in mice by 30 min of coronary occlusion followed by 24 h of reperfusion and pretreated with salvianolate 30 min before I/R (SAL group). The SAL group was compared with SHAM (no I/R and no salvianolate), I/R (no salvianolate), and ischemia preconditioning (IPC) groups. Furthermore, an ERK1/2 inhibitor PD98059 (1 mg/kg), and a phosphatidylinositol-3-kinase (PI3-K) inhibitor, LY294002 (7.5 mg/kg), were administered intraperitoneal injection (i.p) for 30 min prior to salvianolate, followed by I/R surgery in LY and PD groups. By using a double staining method, the ratio of the infarct size (IS) to left ventricle (LV) and of risk region (RR) to LV were compared among the groups. Correlations between IS and RR were analyzed. Western-blot was used to detect the extracellular signal-regulated kinase 1/2 (ERK1/2) and protein kinase B (AKT) phosphorylation changes.

RESULTSThere were no significant differences between RR to LV ratio among the SHAM, I/R, IPC and SAL groups (P>0.05). The SAL and IPC groups had IS of 26.1%±1.4% and 22.3%±2.9% of RR, respectively, both of which were significantly smaller than the I/R group (38.5%±2.9% of RR, P<0.05, P<0.01, respectively). Moreover, the phosphorylation of ERK1/2 was increased in SAL group (P<0.05), while AKT had no significant change. LY294002 further reduced IS, whereas the protective role of salvianolate could be attenuated by PD98059, which increased the IS. Additionally, the IS was not linearly related to the RR (r=0.23, 0.45, 0.62, 0.17, and 0.52 in the SHAM, I/R, SAL, LY and PD groups, respectively).

CONCLUSIONSalvianolate could reduce myocardial I/R injury in mice in vivo, which involves an ERK1/2 pathway, but not a PI3-K signaling pathway.

Animals ; Blotting, Western ; Cardiotonic Agents ; pharmacology ; therapeutic use ; Flavonoids ; pharmacology ; Heart Ventricles ; drug effects ; pathology ; MAP Kinase Signaling System ; drug effects ; Male ; Mice, Inbred C57BL ; Mitogen-Activated Protein Kinase 1 ; metabolism ; Mitogen-Activated Protein Kinase 3 ; metabolism ; Myocardial Reperfusion Injury ; drug therapy ; enzymology ; pathology ; Organ Size ; drug effects ; Phosphorylation ; drug effects ; Plant Extracts ; chemistry ; pharmacology ; therapeutic use ; Protein Kinase Inhibitors ; pharmacology ; Staining and Labeling

OBJECTIVETo compare the effect of Shen-Fu Injection (SFI) and epinephrine on the expression of sarcoplasmic reticulum Ca(2+) ATPase 2a (SERCA2a) in a pig model with post-resuscitation myocardial dysfunction.

METHODSVentricular fibrillation (VF) was electrically induced in Wu-zhi-shan miniature pigs. After 8 min of untreated VF and 2 min of cardiopulmonary resuscitation (CPR), all animals were randomly administered a bolus injection of saline placebo (SA group, n=10), SFI (0.8 mg/kg, SFI group, n=10) or epinephrine (20 μg/kg, EPI group, n=10). After 4 min of CPR, a 100-J shock was delivered. If the defibrillation attempt failed to attain restoration of spontaneous circulation (ROSC), manual chest compressions were rapidly resumed for a further 2 min followed by a second defibrillation attempt. Hemodynamic variables were recorded, and plasma concentrations of catecholamines were measured. Adenylate cyclase (AC), cyclic adenosine monophosphate (cAMP) and the expressions of β1-adrenoceptor (AR) and SERCA 2a were determined.

RESULTSCardiac output, left ventricular dp/dtmax and negative dp/dtmax were significantly higher in the SFI group than in the SA and EPI groups at 4 and 6 h after ROSC. The expression of β1-AR and SERCA2a at 24 h after ROSC were significantly higher in the SFI group than in the SA and EPI groups (P<0.05 or P<0.01).

CONCLUSIONSThe administration of epinephrine during CPR decreased the expression of SERCA2a and aggravated postresuscitation myocardial function (P<0.01). SFI attenuated post-resuscitation myocardial dysfunction, and the mechanism might be related to the up-regulation of SERCA2a expression.

Adenylyl Cyclases ; metabolism ; Animals ; Blotting, Western ; Cardiac Output ; drug effects ; Cardiopulmonary Resuscitation ; Cyclic AMP ; metabolism ; Dopamine ; metabolism ; Drugs, Chinese Herbal ; pharmacology ; Enzyme-Linked Immunosorbent Assay ; Epinephrine ; blood ; Heart Ventricles ; drug effects ; metabolism ; physiopathology ; Hemodynamics ; drug effects ; Injections ; Male ; Myocardium ; enzymology ; pathology ; Norepinephrine ; blood ; Receptors, Adrenergic, beta-1 ; metabolism ; Sarcoplasmic Reticulum Calcium-Transporting ATPases ; metabolism ; Swine ; Swine, Miniature ; Up-Regulation ; drug effects

OBJECTIVETo investigate the effect of panax notoginseng saponins (PNS) injection on pulmonary artery pressure and the expression of p38MAPK in lung tissue of rats subjected to chronic hypoxia.

METHODSThirty adult male Sprague Dawley rats were randomly divided into three groups (ten in each group): rats in control group were exposed to normoxic condition and the rats in hypoxia group and PNS group were subjected to 4-week hypoxia, and PNS injection (50 mg · kg(-1) · d(-1)) was administrated intraperitoneally at 30 min in the PNS group daily before the rats were kept in the hypoxic chamber, while rats in the other two groups received equal dose of normal saline instead. After chronic hypoxia, mean pulmonary artery pressure (mPAP) and mean carotid artery pressure (mCAP) were measured. The heart and lung tissues were harvested, and right ventricle (RV) and left ventricle plus ventricular septum (LV+S) were weighed to calculate the ratio of RV/(LV+S). The expression of p38MAPK mRNA was determined by reverse transcription-polymerase chain reaction, the quantity of phosphorylated p38MAPK (p-p38MAPK) in rat lung tissues and pulmonary arterioles was determined by Western blot and immunohistochemistry.

RESULTSCompared with the control group, mPAP and the ratio of RV/(LV+S) in the hypoxia group were increased, the expression of p-p38MAPK in pulmonary arterioles and p38MAPK mRNA in the lung were higher (P<0.05). The changes of these parameters in the hypoxia group were significantly attenuated by PNS treatment (P<0.05).

CONCLUSIONPNS injection was shown to prevent hypoxic pulmonary hypertension at least partly by regulating p38MAPK pathway.

Animals ; Arterioles ; drug effects ; metabolism ; Blood Pressure ; drug effects ; Blotting, Western ; Carotid Arteries ; drug effects ; physiopathology ; Disease Models, Animal ; Heart Ventricles ; drug effects ; physiopathology ; Hemodynamics ; drug effects ; Hypertension, Pulmonary ; complications ; enzymology ; physiopathology ; Hypoxia ; complications ; enzymology ; physiopathology ; Injections ; Lung ; drug effects ; enzymology ; pathology ; physiopathology ; MAP Kinase Signaling System ; drug effects ; Male ; Panax notoginseng ; chemistry ; Pulmonary Artery ; drug effects ; physiopathology ; RNA, Messenger ; genetics ; metabolism ; Rats, Sprague-Dawley ; Saponins ; administration & dosage ; pharmacology ; p38 Mitogen-Activated Protein Kinases ; genetics ; metabolism

The aim of the present study is to investigate the protective effect of chrysin (5,7-dihydroxyflavone) on right ventricular remodeling in a rat model of monocrotaline-induced pulmonary arterial hypertension (PAH). PAH rats were induced by a single injection of monocrotaline (60 mg x kg(-1), sc) and were administered with chrysin (50 or 100 mg x kg(-1) x d(-1)) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. Right ventricle (RV) to left ventricle (LV) + septum (S) and RV to tibial length were calculated. Right ventricular morphological change was observed by HE staining. Masson's trichrome stain was used to demonstrate collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. The expressions of collagen I, collagen III, NADPH oxidase 4 (NOX4) and nuclear factor-kappa B (NF-κB) were analyzed by immunohistochemisty, qPCR and (or) Western blot. The results showed that chrysin treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV+S and RV/Tibial length) of PAH rats induced by monocrotaline. Furthermore, monocrotaline-induced right ventricular collagen accumulation and collagen I and collagen III expression were both significantly suppressed by chrysin. The expressions of NOX4, NF-κB and MDA contents were obviously decreased, while the T-AOC was significantly increased in right ventricule from PAH rats with chrysin treatment. These results suggest that chrysin ameliorates right ventricular remodeling of PAH induced by monocrotaline in rats through its down-regulating of NOX4 expression and antioxidant activity, and inhibiting NF-κB expression and collagen accumulation.
Animals ; Blotting, Western ; Collagen ; metabolism ; Disease Models, Animal ; Flavonoids ; pharmacology ; Heart Ventricles ; drug effects ; metabolism ; Hypertension, Pulmonary ; chemically induced ; metabolism ; Monocrotaline ; toxicity ; NADPH Oxidase 4 ; NADPH Oxidases ; metabolism ; NF-kappa B ; metabolism ; Rats ; Ventricular Remodeling ; drug effects

The present study was designed to determine the effects of Guanfu base A (GFA) on the late sodium current (INa.L), transient sodium current (INa.T), HERG current (IHERG), and Kv1.5 current (IKv1.5). The values of INa.L, INa.T, IHERG and IKv1.5 were recorded using the whole-cell patch clamp technique. Compared with other channels, GFA showed selective blocking activity in late sodium channel. It inhibited INa.L in a concentration-dependent manner with an IC50 of (1.57 ± 0.14) μmol · L(-1), which was significantly lower than its IC50 values of (21.17 ± 4.51) μmol · L(-1) for the INa.T. The inhibitory effect of GFA on INa,L was not affected by 200 μmol · L(-1) H2O2. It inhibited IHERG with an IC50 of (273 ± 34) μmol · L(-1) and has slight blocking effect on IKv1.5, decreasing IKv1.5 by only 20.6% at 200 μmol · L(-1). In summary, GFA inhibited INa.L selectively and remained similar inhibition in presence of reactive oxygen species. These findings may suggest a novel molecular mechanism for the potential clinical application of GFA in the treatment of cardiovascular disorders.
Analysis of Variance ; Animals ; Anti-Arrhythmia Agents ; pharmacology ; Dose-Response Relationship, Drug ; Female ; Guinea Pigs ; HEK293 Cells ; Heart Ventricles ; drug effects ; Heterocyclic Compounds, 4 or More Rings ; pharmacology ; Humans ; Inhibitory Concentration 50 ; Male ; Membrane Potentials ; drug effects ; Myocytes, Cardiac ; metabolism ; Patch-Clamp Techniques ; Sodium Channel Blockers ; pharmacology ; Sodium Channels ; drug effects

Sheng-Mai-San (SMS), a well-known Chinese medicinal plant formula, is widely used for the treatment of cardiac diseases characterized by deficiency of Qi and Yin syndrome. A mouse chronic intermittent hypoxia (CIH) model was established to mimic the primary clinical features of deficiency of Qi and Yin syndrome. Mice experienced CIH for 28 days (nadir 7% to peak 8% oxygen, 20 min per day), resulting in left ventricle (LV) dysfunction and structure abnormalities. After administration of SMS (0.55, 1.1, and 5.5 g·kg(-1)·d(-1)) for four weeks, improved cardiac function was observed, as indicated by the increase in the ejection fraction from the LV on echocardiography. SMS also preserved the structural integrity of the LV against eccentric hypotrophy, tissue vacuolization, and mitochondrial injury as measured by histology, electron microscopy, and ultrasound assessments. Mechanistically, the antioxidant effects of SMS were demonstrated; SMS was able to suppress mitochondrial apoptosis as indicated by the reduction of several pro-apoptotic factors (Bax, cytochrome c, and cleaved caspase-3) and up-regulation of the anti-apoptosis factor Bcl-2. In conclusion, these results demonstrate that SMS treatment can protect the structure and function of the LV and that the protective effects of this formula are associated with the regulation of the mitochondrial apoptosis pathway.
Animals ; Antioxidants ; pharmacology ; therapeutic use ; Apoptosis ; Cardiomyopathies ; drug therapy ; etiology ; Caspase 3 ; metabolism ; Cytochromes c ; metabolism ; Disease Models, Animal ; Drug Combinations ; Drugs, Chinese Herbal ; pharmacology ; therapeutic use ; Heart Ventricles ; drug effects ; pathology ; physiopathology ; Hypoxia ; Male ; Mice, Inbred ICR ; Mitochondria ; drug effects ; metabolism ; Myocardium ; pathology ; Oxygen ; metabolism ; Phytotherapy ; Qi ; Up-Regulation ; Ventricular Dysfunction, Left ; drug therapy ; etiology ; bcl-2-Associated X Protein ; metabolism

OBJECTIVETo investigate the effect of tanshinone II(A) on the expression of different components in the renin-angiotensin system of left ventricles of renal hypertensive rats.

METHODThe renal hypertension model was established in rats by the two-kidney-one-clip (2K1C) method. In the experiment, all of the rats were randomly divided into four groups (n = 15 per group) before the operation: the sham-operated (Sham) group, the hypertensive model (Model) group, the low-dose tanshinone II(A) group and the high-dose tanshinone II(A) group. At 5 week after the renal artery narrowing, the third and fourth groups were administered with 35 mg kg(-1) x d(-1) and 70 mg x kg(-1) x d(-1) of tanshinone II(A), respectively. The blood pressure in rats was determined by the standard tail-cuff method in each week after the operation. After the drug treatment for 8 weeks, all the rats were put to death, and their left ventricles were separated to determine the ratio of left ventricle weight to body weight (LVW/BW), the myocardial collagen content, and the expressions of different components in myocardial RAS, including angiotensin converting enzyme (ACE), angiotensin converting enzyme 2 (ACE2), angiotensin 1-type receptor (AT1R), Mas receptor mRNA expression and angiotensin II (Ang II) and angiotensin (1-7) [Ang (1-7)] content.

RESULTCompared with the sham group, the hypertensive model group exhibited a markable increase in the content of Ang II and Ang (1-7) and the mRNA expressions of ACE, ACE2, AT1R and Mas (P < 0.01). However, the treatment with tanshinone II(A) showed the does dependence, inhibited left ventricle hypertrophy, decreased myocardial Ang II content and the mRNA expression of ACE and AT, R in renal hypertensive rats (P < 0. 01) , further increased the myocardial Ang (1-7) content and the mRNA expression of ACE2 and Mas (P < 0.01) , but without any change in the blood pressure of hypertensive rats.

CONCLUSIONThe treatment with tanshinone II(A) could inhibit left ventricle hypertrophy of renal hypertensive rats. Its mechanism may be partially related to the expression of different components in the renin-angiotensin system for regulating myocardial tissues.

Angiotensin I ; genetics ; metabolism ; Angiotensin II ; genetics ; metabolism ; Animals ; Blood Pressure ; drug effects ; Diterpenes, Abietane ; administration & dosage ; Heart Ventricles ; drug effects ; metabolism ; Humans ; Hypertension ; drug therapy ; genetics ; metabolism ; physiopathology ; Male ; Peptide Fragments ; genetics ; metabolism ; Peptidyl-Dipeptidase A ; genetics ; metabolism ; Rats ; Rats, Sprague-Dawley ; Renin ; genetics ; metabolism ; Renin-Angiotensin System ; drug effects

OBJECTIVETo investigate the protective effects of rutaecarpine (Rut) on right ventricular remodeling in rats with monocrotaline-induced pulmonary hypertension (PH).

METHODForty-eight SD rats were fed adaptively for 1 week and then were randomly divided into the following 4 groups (n = 12): normal control group, monocrotaline (MCT) treatment group, MCT treatment with Rut (20 mg/kg)group and MCT treatment with Rut (40 mg/kg) group. PH rats were induced by a single injection of monocrotaline (60 mg/kg, sc) and were administered with Rut (20 or 40 mg/kg/d) for 4 weeks. At the end of experiment, the right ventricular systolic pressure (RVSP) and mean pulmonary artery pressure (mPAP) were monitored via the right jugular vein catheterization into the right ventricle. The ratio of right ventricle (RV) to left ventricle (LV) + septum (S) and the ratio of RV to tibial length were calculated. Right ventricular morphological changes were deserved by HE staining. Masson's trichrome staining was used to display collagen deposition. The total antioxidative capacity (T-AOC) and malondialdehyde (MDA) levels in right ventricle were determined according to the manufacturer's instructions. mRNA and protein expression levels of NOX4, collagen I and collagen III were analyzed by immunohistochemisty, real-time PCR and Western blot.

RESULTSThe results showed that Rut treatment for 4 weeks attenuated RVSP, mPAP and right ventricular remodeling index (RV/LV + S and RV/Tibial length) of PH rats induced by monocrotaline. Furthermore, the right ventricular collagen deposition and collagen I and collagen I expression induced by MCT were both significantly suppressed by Rut. The expression levels of NOX4 and MDA were obviously decreased, while the T-AOC was significantly increased in right ventricular from PH rats treated with Rut.

CONCLUSIONThese results suggested that Rut ameliorates the right ventricular remodeling in rats with PH induced by MCT through down-regulating of NOX4 expression and collagen accumulation.

Animals ; Antioxidants ; metabolism ; Heart Ventricles ; metabolism ; Hypertension, Pulmonary ; chemically induced ; drug therapy ; Indole Alkaloids ; pharmacology ; Male ; Malondialdehyde ; metabolism ; Monocrotaline ; adverse effects ; NADPH Oxidase 4 ; NADPH Oxidases ; metabolism ; Quinazolines ; pharmacology ; Rats ; Ventricular Remodeling ; drug effects