异丙基肾上腺素充血性心力衰竭大鼠模型心肌细胞凋亡的改变

目的建立异丙基肾上腺素诱导SD大鼠充血性心力衰竭模型,观察大鼠心肌细胞凋亡的变化。方法实验选用雄性SD大鼠60只,随机分为对照组10只、心衰组50只;用ISO（170mg/kg）对雄性SD大鼠皮下注射2次,6周后应用超声心动图检测,以左心室射血分数（LVEF）≤45%确定造模成功,18周使用左心导管进行血流动力学检查,取心脏观察左心室重量指数等病理形态学特征。并利用琼脂糖凝胶电泳法检测DNA断片化,和免疫印迹分析法检测Bcl-2,Bax,caspase-9和caspase-3的表达。结果与对照组相比,模型组HR、LVEDP、LVWI显著升高（P〈0.01）,LVSP明显降低（P〈0.01）和左心室压力上升/下降最大数率（±dp/dtmax）明显降低（P〈0.01）,左心室重量指数明显增加（P〈0.01）,心肌DNA断片比例升高,Bax、caspase-9和caspase-3表达升高,而Bcl-2表达下降。结论异丙基肾上腺素可诱导大鼠心衰模型,该作用可能与心肌细胞凋亡增加有关。     

Kalopanaxsaponin B Ameliorates TNBS-Induced Colitis in Mice

The stem-bark of Kalopanax pictus (KP, family Araliaceae), of which main constituent is kalopanaxsaponin B, has been used for asthma, rhinitis, and arthritis in Chinese traditional medicine. To clarify anticolitic effect of KP, we examined anti-inflammatory effect of KP extract and kalopanaxsaponin B in lipopolysaccharide (LPS)-stimulated peritoneal macrophage and 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitic mice. Of KP extracts, KP BuOH-soluble fraction most potently inhibited LPS-induced IL-1β, IL-6 and TNF-α expression, as well as NF-κB activation. However, KP BuOH fraction increased IL-10, an anti-inflammatory cytokine. KP BuOH fraction also inhibited colon shortening and myeloperoxidase activity in TNBS-induced colitic mice. KP BuOH fraction also potently inhibited the expression of the pro-inflammatory cytokines, IL-1β, IL-6 and TNF-α as well as the activation of NF-κB. Kalopanaxsaponin B, a main constituent of KP, inhibited TNBS-induced colonic inflammation, including colon shortening, and TNBS-increased myeloperoxidase activity pro-inflammatory cytokine expression and NF-κB activation in mice. Based on these findings, KP, particularly its main constituent, kalopanaxsaponin B, may ameliorate colitis by inhibiting NF-κB pathway.     

A Methanol Extract of Adansonia digitata L. Leaves Inhibits Pro-Inflammatory iNOS Possibly via the Inhibition of NF-κB Activation

This study examined the total polyphenol content of eight wild edible plants from Ethiopia and their effect on NO production in Raw264.7 cells. Owing to its relatively high polyphenol concentration and inhibition of NO production, the methanol extract of Adansonia digitata L. leaf (MEAD) was subjected to detailed evaluation of its antioxidant and anti-inflammatory effects. Antioxidant effects were assessed by measuring free-radical-scavenging activity using 1,1-diphenyl-2-picrylhydrazyl (DPPH) and oxygen-radical-absorbance capacity (ORAC) assays, while anti-inflammatory effects were assessed by measuring inducible nitric oxide synthase (iNOS) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. In the ORAC assay, MEAD was 10.2 times more potent than vitamin C at eliminating peroxyl radicals. In DPPH assay, MEAD also showed a strong ROS scavenging effect. MEAD significantly inhibited iNOS activity (IC₅₀=28.6 μg/ml) of LPS-stimulated Raw264.7 cells. We also investigated the relationship between iNOS expression and nuclear factor kappa B (NF-κB) activation. MEAD inhibited IκBα degradation and NF-κB translocation from the cytosol to the nucleus in LPS-induced RAW264.7 cells without significant cytotoxic effects, as confirmed by MTT assay. These results suggest that MEAD inhibits anti-inflammatory iNOS expression, which might be related to the elimination of peroxyl radicals and thus the inhibition of IκBα-mediated NF-κB signal transduction.     

Cancer Cell Growth Inhibitory Effect of Bee Venom via Increase of Death Receptor 3 Expression and Inactivation of NF-kappa B in NSCLC Cells

Our previous findings have demonstrated that bee venom (BV) has anti-cancer activity in several cancer cells. However, the effects of BV on lung cancer cell growth have not been reported. Cell viability was determined with trypan blue uptake, soft agar formation as well as DAPI and TUNEL assay. Cell death related protein expression was determined with Western blotting. An EMSA was used for nuclear factor kappaB (NF-κB) activity assay. BV (1–5 μg/mL) inhibited growth of lung cancer cells by induction of apoptosis in a dose dependent manner in lung cancer cell lines A549 and NCI-H460. Consistent with apoptotic cell death, expression of DR3 and DR6 was significantly increased. However, deletion of DRs by small interfering RNA significantly reversed BV induced cell growth inhibitory effects. Expression of pro-apoptotic proteins (caspase-3 and Bax) was concomitantly increased, but the NF-κB activity and expression of Bcl-2 were inhibited. A combination treatment of tumor necrosis factor (TNF)-like weak inducer of apoptosis, TNF-related apoptosis-inducing ligand, docetaxel and cisplatin, with BV synergistically inhibited both A549 and NCI-H460 lung cancer cell growth with further down regulation of NF-κB activity. These results show that BV induces apoptotic cell death in lung cancer cells through the enhancement of DR3 expression and inhibition of NF-κB pathway.     

Tetramethylphenylenediamine protects the isolated heart against ischaemia-induced apoptosis and reperfusion-induced necrosis

BACKGROUND AND PURPOSE

Cytochrome c when released from mitochondria into cytosol triggers assembly of the apoptosome resulting in caspase activation. Recent evidence suggests that reduced cytochrome c is unable to activate the caspase cascade. In this study, we investigated whether a chemical reductant of cytochrome c, N,N,N′,N′-tetramethylphenylene-1,4-diamine (TMPD), which we have previously shown to block cytochrome c-induced caspase activation, could prevent ischaemia-induced apoptosis in the rat perfused heart.

EXPERIMENTAL APPROACH

The Langendorff-perfused rat hearts were pretreated with TMPD and subjected to stop-flow ischaemia or ischaemia/reperfusion. The activation of caspases (measured as DEVD-p-nitroanilide-cleaving activity), nuclear apoptosis of cardiomyocytes (measured by dUTP nick end labelling assay), mitochondrial and cytosolic levels of cytochrome c (measured spectrophotometrically and by elisa), and reperfusion-induced necrosis (measured as the activity of creatine kinase released into perfusate) were assessed.

KEY RESULTS

We found that perfusion of the hearts with TMPD strongly inhibited ischaemia- or ischaemia/reperfusion-induced activation of caspases and partially prevented nuclear apoptosis in cardiomyocytes. TMPD did not prevent ischaemia- or ischaemia/reperfusion-induced release of cytochrome c from mitochondria into cytosol. TMPD also inhibited ischaemia/reperfusion-induced necrosis.

CONCLUSIONS AND IMPLICATIONS

These results suggest that TMPD or related molecules might be used to protect the heart against damage induced by ischaemia/reperfusion. The mechanism of this protective effect of TMPD probably involves electron reduction of cytochrome c (without decreasing its release) which then inhibits the activation of caspases.     

Icariin attenuates cardiac remodelling through down-regulating myocardial apoptosis and matrix metalloproteinase activity in rats with congestive heart failure

Objectives In this study, the anti‐heart failure effect of icariin, a natural flavonol glycoside, and the underlying mechanisms were investigated. Methods Heart failure was induced by isoproterenol in male Sprague–Dawley rats. Matrix metalloproteinase activity was determined by gelatin zymography assay. The mRNA expression was determined by real‐time PCR. The protein expression was determined by Western bolt. Mitochondria structure was examined by transmission electron microscopy. Key findings Isoproterenol administration resulted in a severe heart failure, as shown by the increased levels of left ventricular weight index, heart rate, left ventricular end diastolic pressure, maximal rate of left ventricular pressure decline (dp/dt_min), decreased levels of left ventricular systolic pressure and maximal rate of left ventricular pressure rise (dp/dt_max). Against these, icariin dose‐dependently reversed the changes of these cardiac morphometric and haemodynamic parameters. In addition, icariin significantly inhibited serum levels of tumour necrosis factor‐α, noradrenaline, angiotensin II and brain natriuretic peptide in rats with congestive hear failure and improved the histological changes, including cardiocyte hypertrophy, cardiocyte degeneration, inflammatory infiltration and cardiac desmoplasia. Furthermore, the expression and activity of matrix metalloproteinase (MMP)‐2 and MMP‐9, which regulate collagen production, were also blocked by icariin. Moreover, myocardial apoptosis was remarkably attenuated by icariin through regulating Bcl‐2/Bax axle. Conclusions Icariin ameliorates left ventricular dysfunction and cardiac remodelling through down‐regulating matrix metalloproteinase‐2 and 9 activity and myocardial apoptosis in rats with congestive heart failure.     

Triptolide improves myocardial fibrosis in rats through inhibition of nuclear factor kappa B and NLR family pyrin domain containing 3 inflammasome pathway

Myocardial fibrosis (MF) is the result of persistent and repeated aggravation of myocardial ischemia and hypoxia, leading to the gradual development of heart failure of chronic ischemic heart disease. Triptolide (TPL) is identified to be involved in the treatment for MF. This study aims to explore the mechanism of TPL in the treatment of MF. The MF rat model was established, subcutaneously injected with isoproterenol and treated by subcutaneous injection of TPL. The cardiac function of each group was evaluated, including LVEF, LVFS, LVES, and LVED. The expressions of ANP, BNP, inflammatory related factors (IL-1β, IL-18, TNF-α, MCP-1, VCAM-1), NLRP3 inflammasome factors (NLRP3, ASC) and fibrosis related factors (TGF-β1, COL1, and COL3) in rats were dete cted. H&E staining and Masson staining were used to observe myocardial cell inflammation and fibrosis of rats. Western blot was used to detect the p-P65 and t-P65 levels in nucleoprotein of rat myocardial tissues. LVED and LVES of MF group were significantly upregulated, LVEF and LVFS were significantly downregulated, while TPL treatment reversed these trends; TPL treatment downregulated the tissue injury and improved the pathological damage of MF rats. TPL treatment downregulated the levels of inflammatory factors and fibrosis factors, and inhibited the activation of NLRP3 inflammasome. Activation of NLRP3 inflammasome or NF-κB pathway reversed the effect of TPL on MF. Collectively, TPL inhibited the activation of NLRP3 inflammasome by inhibiting NF-κB pathway, and improved MF in MF rats.     

Inhibitory effects of rosiglitazone on paraquat-induced acute lung injury in rats

Aim:

To investigate the effects of the PPAR-γ agonist rosiglitazone on acute lung injury induced by the herbicide paraquat (PQ) and the underlying mechanisms of action.

Methods:

Male Sprague-Dawley rats were injected with PQ (20 mg/kg, ip). Rosiglitazone (3 or 10 mg/kg, ip) was administered 1 h before PQ exposure. Peripheral blood was collected at 4, 8, 24 and 72 h after PQ exposure for measuring the levels of MDA, TNF-α and IL-1β, and the SOD activity. Lung tissues were collected at 72 h after PQ exposure to determine the wet-to-dry (W/D) ratios and lung injury scores, as well as the protein levels of NF-κBp65, PPAR-γ, Nrf2, IκBα and pIκBα.

Results:

At 72 h after PQ exposure, the untreated rats showed a 100% cumulative mortality, whereas no death was observed in rosiglitazone-pretreated rats. Moreover, rosiglitazone pretreatment dose-dependently attenuated PQ-induced lung edema and lung histopathological changes. The pretreatment significantly reduced the levels of TNF-α, IL-1β and MDA, increased SOD activity in the peripheral blood of PQ-treated rats. The pretreatment also efficiently activated PPAR-γ, induced Nrf2 expression and inhibited NF-κB activation in the lung tissues of PQ-treated rats. Furthermore, the pretreatment dose-dependently inhibited IκB-α degradation and phosphorylation, thus inhibiting NF-κB activation.

Conclusion:

Pretreatment with rosiglitazone protects rats against PQ-induced acute lung injury by activating PPAR-γ, inducing Nrf2 expression and inhibiting NF-κB activation.     

Activation of muscarinic receptors elicits inotropic responses in ventricular muscle from rats with heart failure through myosin light chain phosphorylation

Background and purpose:

Muscarinic stimulation increases myofilament Ca²⁺ sensitivity with no apparent inotropic response in normal rat myocardium. Increased myofilament Ca²⁺ sensitivity is a molecular mechanism promoting increased contractility in failing cardiac tissue. Thus, muscarinic receptor activation could elicit inotropic responses in ventricular myocardium from rats with heart failure, through increasing phosphorylation of myosin light chain (MLC).

Experimental approach:

Contractile force was measured in left ventricular papillary muscles from male Wistar rats, 6 weeks after left coronary artery ligation or sham surgery. Muscles were also frozen, and MLC-2 phosphorylation level was quantified.

Key results:

Carbachol (10 µmol·L⁻¹) evoked a positive inotropic response only in muscles from rats with heart failure approximating 36% of that elicited by 1 µmol·L⁻¹ isoproterenol (20 ± 1.5% and 56 ± 6.1% above basal respectively). Carbachol-evoked inotropic responses did not correlate with infarction size but did correlate with increased left ventricular end diastolic pressure, heart weight/body weight ratio and lung weight, primary indicators of the severity of heart failure. Only muscarinic receptor antagonists selective for M₂ receptors antagonized carbachol-mediated inotropic effects with the expected potency. Carbachol-evoked inotropic responses and increase in phosphorylated MLC-2 were attenuated by MLC kinase (ML-9) and Rho-kinase inhibition (Y-27632), and inotropic responses were abolished by Pertussis toxin pretreatment.

Conclusion and implications:

In failing ventricular muscle, muscarinic receptor activation, most likely via M₂ receptors, provides inotropic support by increasing MLC phosphorylation and consequently, myofilament Ca²⁺ sensitivity. Enhancement of myofilament Ca²⁺ sensitivity, representing a less energy-demanding mechanism of inotropic support may be particularly advantageous in failing hearts.     

氯沙坦对心力衰竭大鼠心肌细胞缝隙连接的作用机制研究

目的观察氯沙坦对心力衰竭(心衰)大鼠心功能的影响并探讨其对心肌细胞缝隙连接的作用机制。方法 SD大鼠60只随机分为假手术组、模型组、氯沙坦高、中、低剂量组,灌胃给药7 d后,采用冠脉结扎复制大鼠心衰模型。测定心功能:左心室压峰值(LVP)、左心室舒张末期压(LVEDP)、左心室内压最大上升速率(+LVdp/dtmax)、左心室内压最大下降速率(-LVdp/dtmax)。采用Western Blot方法测定心肌缝隙连接蛋白43(Cx43)和Cx45的表达。结果氯沙坦能显著改善心衰大鼠心功能,与模型组比较,氯沙坦低、中剂组LVP明显上升(P<0.01),LVEDP明显下降(P<0.05或<0.01),高剂组LVP、+LVdp/dtmax明显上升,LVEDP明显下降(P<0.01);显著提高Cx43表达,降低Cx45表达(P<0.05或<0.01)。结论氯沙坦对心室的间隙连接通道有保护作用,可以提高心室传导速度,从而降低心律失常的发生。     

Tanshinone IIA therapeutically reduces LPS-induced acute lung injury by inhibiting inflammation and apoptosis in mice

Aim:

To study the effects of tanshinone IIA (TIIA) on lipopolysaccharide (LPS)-induced acute lung injury in mice and the underlying mechanisms.

Methods:

Mice were injected with LPS (10 mg/kg, ip), then treated with TIIA (10 mg/kg, ip). Seven hours after LPS injection, the lungs were collected for histological study. Protein, LDH, TNF-α and IL-1β levels in bronchoalveolar lavage fluid (BALF) and myeloperoxidase (MPO) activity in lungs were measured. Cell apoptosis and Bcl-2, caspase-3, NF-κB and HIF-1α expression in lungs were assayed.

Results:

LPS caused marked histological changes in lungs, accompanied by significantly increased lung W/D ratio, protein content and LDH level in BALF, and Evans blue leakage. LPS markedly increased neutrophil infiltration in lungs and inflammatory cytokines in BALF. Furthermore, LPS induced cell apoptosis in lungs, as evidenced by increased TUNEL-positive cells, decreased Bcl-2 content and increased cleaved caspase-3 content. Moreover, LPS significantly increased the expression of NF-κB and HIF-1α in lungs. Treatment of LPS-injected mice with TIIA significantly alleviated these pathological changes in lungs.

Conclusion:

TIIA alleviates LPS-induced acute lung injury in mice by suppressing inflammatory responses and apoptosis, which is mediated via inhibition of the NF-κB and HIF-1α pathways.     

Inhibiting glycogen synthase kinase-3 reduces endotoxaemic acute renal failure by down-regulating inflammation and renal cell apoptosis

Background and purpose:

Excessive inflammation and apoptosis are pathological features of endotoxaemic acute renal failure. Activation of glycogen synthase kinase-3 (GSK-3) is involved in inflammation and apoptosis. We investigated the effects of inhibiting GSK-3 on lipopolysaccharide (LPS)-induced acute renal failure, nuclear factor-κB (NF-κB), inflammation and apoptosis.

Experimental approach:

The effects of inhibiting GSK-3 with inhibitors, including lithium chloride (LiCl) and 6-bromo-indirubin-3′-oxime (BIO), on LPS-treated (15 mg·kg⁻¹) C3H/HeN mice (LiCl, 40 mg·kg⁻¹ and BIO, 2 mg·kg⁻¹) and LPS-treated (1 µg·mL⁻¹) renal epithelial cells (LiCl, 20 mM and BIO, 5 µM) were studied. Mouse survival was monitored and renal function was analysed by histological and serological examination. Cytokine and chemokine production, and cell apoptosis were measured by enzyme-linked immunosorbent assay and terminal deoxynucleotidyl transferase-mediated dUTP–biotin nick-end labelling staining, respectively. Activation of NF-κB and GSK-3 was determined by immunostaining and Western blotting, respectively.

Key results:

Mice treated with GSK-3 inhibitors showed decreased mortality, renal tubular dilatation, vacuolization and sloughing, blood urea nitrogen, creatinine and renal cell apoptosis in response to endotoxaemia. Inhibiting GSK-3 reduced LPS-induced tumour necrosis factor-α (TNF-α) and CCL5/RANTES (released upon activation of normal T-cells) in vivo in mice and in vitro in murine kidney cortical collecting duct epithelial M1 cells. Inhibiting GSK-3 did not block TNF-α-induced cytotoxicity in rat kidney proximal tubular epithelial NRK52E or in M1 cells.

Conclusions and implications:

These results suggest that GSK-3 inhibition protects against endotoxaemic acute renal failure mainly by down-regulating pro-inflammatory TNF-α and RANTES.     

促红细胞生成素对慢性心力衰竭大鼠心肌细胞的抗凋亡作用及对AKT 蛋白表达的影响

摘要： 目的 观察促红细胞生成素 （EPO） 对慢性心力衰竭 （CHF） 大鼠心肌细胞的抗凋亡作用及对蛋白激酶 B （AKT） 蛋白表达的影响。方法 30 只成年雄性 SD 大鼠先按随机数字表法分为 2 组, 假手术 （Sham） 组 （n=6） 和模型（Model） 组 （n=24）; 模型组采用腹主动脉缩窄术建立 CHF 模型, 术后 8 周存活 16 只, 再随机分为 EPO 组与对照（Control） 组各 8 只。EPO 组予以 3 000 U/kg EPO 腹腔注射, 3 次/周, 连续 4 周; Sham 组、 Control 组给予等量的生理盐水。分别在术后 4 周、 8 周、 12 周 （即给药 4 周） 行心脏彩超检查大鼠心功能。第 12 周末全部大鼠禁食 24 h 后处死, 观察心肌组织细胞形态、 心肌细胞凋亡及计算凋亡指数 （AI）; 采用 Western blot 法检测心肌 P-AKT/AKT 蛋白表达情况。结果 超声心动图显示 Model 组 4 周时出现心室肥厚, 8 周时出现心力衰竭; EPO 干预 4 周后较 Control 组左室射血分数 （LVEF） 明显升高 （P < 0.05）, 收缩末期室间隔厚度 （IVSs）、 收缩末期左心室后壁厚度 （LVPWs）、 舒张末期室间隔厚度 （IVSd）、 舒张末期左心室后壁厚度 （LVPWd） 明显降低 （P < 0.05）。EPO 组 AI 较 Control 组显著降低（23.87%±1.45% vs 35.58%±2.81%, P < 0.01）; 与 Sham 组 （0.81±0.17） 比较, Control 组 （0.35±0.06） P-AKT/AKT OD 值明显降低, EPO 组 （1.61±0.16） 较 Control 组升高 （P < 0.01）。结论 EPO 可有效改善 CHF 大鼠的心功能, 抑制心肌细胞凋亡, 促进 AKT 的磷酸化。     

卡维地洛对慢性心力衰竭幼鼠心室重构的干预及作用机制

目的:探讨卡维地洛治疗幼鼠慢性心力衰竭(CHF)的疗效及作用机制.方法:采用腹主动脉缩窄术建立幼鼠CHF模型,术后4周随机分3组:假手术对照组、CHF组、卡维地洛组.直接灌胃给药,8周后行血流动力学、心肌病理分析、心肌细胞凋亡及其相关基因Bcl-2、p53蛋白表达水平和检测血清中脂质过氧化物(LPO)和超氧化物歧化酶(SOD)含量.结果:与假手术组比较,CHF组收缩压(SBP)、舒张压(DBP)、左室收缩压(LVSP)、左室舒张末压(LVEDP)、左右心室相对重量(LVRW,RVRW)、LPO、凋亡指数(AI)、p53基因蛋白表达水平显著升高(P<0.01),左室内压最大收缩率( dp/dtmax)、左室内压最大舒张率(-dp/dtmax)、SOD、Bcl-2基因蛋白表达水平均显著降低(P<0.01).与CHF组比较,卡维地洛组SBP、DBP、LVSP、LVEDP、LVRW、RVRW、LPO、AI、p53基因蛋白表达水平下降, dp/dtmax,-dp/dtmax,SOD,Bcl-2基因蛋白表达水平显著升高(P<0.01).结论:卡维地洛能有效抑制CHF幼鼠心室重构的发展,而抗凋亡、抗氧化、改善血流动力学是其治疗心室重构的重要机制.     

醛固酮受体拮抗剂对心肌细胞凋亡的影响

目的研究醛固酮受体拮抗剂螺内酯对急性心肌梗死心肌细胞凋亡及相关基因Bcl-2、Bax蛋白表达的作用。方法通过结扎左冠状动脉前降支造成大鼠左室大面积心肌梗死模型。SD大鼠随机分为心肌梗死对照组(AMI组,0.9%氯化钠溶液2ml/d灌胃,n=24)和螺内酯治疗组(Spi组,螺内酯20mg/kg/d,2ml灌胃,n=24),另设假手术组(Sham组,0.9%氯化钠溶液,2ml/d灌胃,n=24)。分别于术后2、7、14、21d观察下列指标:用流式细胞学方法测定非梗死心肌细胞凋亡率及Bcl-2、Bax蛋白表达。结果与Sham组相比较,AMI组大鼠和Spi组非梗死区心肌细胞凋亡率显著升高(P<0.01);BCL-2蛋白表达降低(P<0.05),Bax蛋白表达升高(P<0.05);与AMI组比较,大鼠心肌细胞凋亡率和非梗死区心肌细胞BCL-2蛋白表达在2d、7d差异无统计学意义(P>0.05),14d、21d有所升高(P<0.05)。Bax蛋白表达在2d、7d差异无统计学意义(P>0.05),14d、21d有所降低(P<0.05)。结论螺内酯治疗可减少心肌细胞凋亡,同时增加凋亡相关基因Bcl-2蛋白的表达和减弱Bax蛋白的表达。     

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

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