Preservation of diastolic function in monocrotaline-induced right ventricular hypertrophy in rats

During ischemic heart diseases and when heart failure progresses depletion of myocardial energy stores occurs. D-Ribose (R) has been shown to improve cardiac function and energy status after ischemia. Folic acid (FA) is an essential cofactor in the formation of adenine nucleotides. Therefore, we assessed whether chronic R-FA administration during the development of hypertrophy resulted in an improved cardiac function and energy status. In Wistar rats (n = 40) compensatory right ventricular (RV) hypertrophy was induced by monocrotaline (30 mg/kg; MCT), whereas saline served as control. Both groups received a daily oral dose of either 150 mg.kg(-1).day(-1) dextrose (placebo) or R-FA (150 and 40 mg.kg(-1).day(-1), respectively). In Langendorff-perfused hearts, RV and left ventricular (LV) pressure development and collagen content as well as total RV adenine nucleotides (TAN), creatine content, and RV and LV collagen content were determined. In the control group R-FA had no effect. In the MCT-placebo group, TAN and creatine content were reduced, RV and LV diastolic pressure-volume relations were steeper, RV systolic pressures were elevated, RV and LV collagen content was increased, and RV-LV diastolic interaction was altered compared with controls. In the MCT-R-FA group, TAN, RV and LV diastolic stiffness, RV and LV collagen content, and RV-LV diastolic interaction were normalized to the values in the control group while creatine content remained depressed and RV systolic function remained elevated. In conclusion, the depression of energy status in compensated hypertrophic myocardium observed was partly prevented by chronic R-FA administration and accompanied by a preservation of diastolic function and collagen deposition.     

Characterization of right ventricular function after monocrotaline-induced pulmonary hypertension in the intact rat

We characterized hemodynamics and systolic and diastolic right ventricular (RV) function in relation to structural changes in the rat model of monocrotaline (MCT)-induced pulmonary hypertension. Rats were treated with MCT at 30 mg/kg body wt (MCT30, n = 15) and 80 mg/kg body wt (MCT80, n = 16) to induce compensated RV hypertrophy and RV failure, respectively. Saline-treated rats served as control (Cont, n = 13). After 4 wk, a pressure-conductance catheter was introduced into the RV to assess pressure-volume relations. Subsequently, rats were killed, hearts and lungs were rapidly dissected, and RV, left ventricle (LV), and interventricular septum (IVS) were weighed and analyzed histochemically. RV-to-(LV + IVS) weight ratio was 0.29 +/- 0.05 in Cont, 0.35 +/- 0.05 in MCT30, and 0.49 +/- 0.10 in MCT80 (P < 0.001 vs. Cont and MCT30) rats, confirming MCT-induced RV hypertrophy. RV ejection fraction was 49 +/- 6% in Cont, 40 +/- 12% in MCT30 (P < 0.05 vs. Cont), and 26 +/- 6% in MCT80 (P < 0.05 vs. Cont and MCT30) rats. In MCT30 rats, cardiac output was maintained, but RV volumes and filling pressures were significantly increased compared with Cont (all P < 0.05), indicating RV remodeling. In MCT80 rats, RV systolic pressure, volumes, and peak wall stress were further increased, and cardiac output was significantly decreased (all P < 0.05). However, RV end-systolic and end-diastolic stiffness were unchanged, consistent with the absence of interstitial fibrosis. MCT-induced pressure overload was associated with a dose-dependent development of RV hypertrophy. The most pronounced response to MCT was an overload-dependent increase of RV end-systolic and end-diastolic volumes, even under nonfailing conditions.     

银杏叶提取物对野百合碱诱导的大鼠右心室心肌肥厚的干预作用及其机制*

目的: 探讨银杏叶提取物对大鼠右心室心肌肥厚的干预作用及其机制。方法: 72 只SD 大鼠随机分为3 组,每组24只: 对照组(CON组)、野百合碱诱导右心室心肌肥厚组(MCT组)、银杏叶提取物干预组(EGB组)。MCT组与EGB组首日均以2%MCT按60 mg/kg 剂量腹腔注射,注射后第2日开始,MCT组每日予2 ml 0.9% NaCl灌胃,EGB组以60 mg/kg银杏叶提取物灌胃,对照组SD大鼠首日一次性腹腔注射2 ml 0.9%NaCl注射液。3周后检测各组大鼠心脏血流动力学变化、计算心脏重量指数、HE染色观察心肌病理形态学变化、RT-PCR法检测TRPC6 mRNA表达和Western blot法检测蛋白的表达水平。结果: 与对照组比较,MCT组反映右心室肥厚程度的指标如RVSP、RV±dp/dt_max及RVMI显著增加(P＜0.01),而EGB早期干预组虽然与MCT组的各项指标有相同趋势的变化,但是EGB组各项指标变化的幅度均显著降低(P＜0.01),且EGB组的心肌肥厚指数均显著低于MCT组(P＜ 0.01);HE染色观察心肌形态学变化结果:MCT组呈典型心肌肥厚表现;EGB组右心室心肌细胞较MCT组有显著改善;MCT组及EGB组SD大鼠右心室TRPC6 mRNA及蛋白相对表达水平升高(P＜0.05),而EGB组较MCT组显著降低(P＜0.05)。结论: 银杏叶提取物可能通过降低TRPC6的表达阻碍心肌细胞中CaN／NFAT信号路径而发挥对心肌肥厚的早期保护作用。     

Progressive development of pulmonary hypertension leading to right ventricular hypertrophy assessed by echocardiography in rats.

The present study aimed to evaluate the development of pulmonary hypertension by serial echocardiography, including measurements of pulmonary artery (PA) flow velocities, and correlate echocardiographic indices with pathological findings in rats administered monocrotaline (MCT). MCT (60 mg/kg body weight) or physiologic saline was administered to a total of 9 male Wistar rats at the age of 4 weeks (MCT group: n = 4, control group: n = 5, respectively). Echocardiography was performed serially until the age of 8 weeks. The ratio of right ventricular (RV) outflow tract dimensions to aortic dimensions increased progressively in the MCT group and became significantly greater than that of the control group after the age of 6 weeks. Peak PA velocity (Peak V) in the MCT group was significantly less than that of the control group at the ages of 7 and 8 weeks. The ratio of acceleration time to ejection time (AT/ET) in PA flow waveforms declined progressively and was significantly less than that of the control group after the age of 6 weeks. The ratio of RV weight to body weight (RVW/BW) in the MCT group was significantly greater than that of the control group. Both AT/ET ratio and Peak V were significantly inversely correlated with RVW/BW ratio. Furthermore, these echocardiographic findings were also significantly inversely correlated with the mean cross-sectional RV myocyte area. In conclusion, the progressive development of pulmonary hypertension leading to RV hypertrophy can be evaluated appropriately by echocardiography including PA flow Doppler indices in rats.     

Oxymatrine prevents hypoxia- and monocrotaline-induced pulmonary hypertension in rats

Pulmonary hypertension is a progressive disease characterized by marked pulmonary arterial remodeling and increased vascular resistance. Inflammation and oxidative stress promote the development of pulmonary hypertension. Oxymatrine, one of the main active components of the Chinese herb Sophora flavescens Ait. (Kushen), plays anti-inflammatory and antioxidant protective roles, which effects on pulmonary arteries remain unclear. This study aimed to investigate the effects of oxymatrine on pulmonary hypertension development. Sprague–Dawley rats were exposed to hypoxia for 28 days or injected with monocrotaline, to develop pulmonary hypertension, along with administration of oxymatrine (50 mg/kg/day). Hemodynamics and pulmonary arterial remodeling data from the rats were then obtained. The antiproliferative effect of oxymatrine was verified by in vitro assays. The inflammatory cytokine mRNA levels and leukocyte and T cell accumulation in lung tissue were detected. The antioxidative effects of oxymatrine were explored in vitro. Our study shows that oxymatrine treatment attenuated right-ventricular systolic pressure and pulmonary arterial remodeling induced by hypoxia or monocrotaline and inhibited proliferation of pulmonary arterial smooth muscle cells (PASMCs). Increased expression of inflammatory cytokine mRNA and accumulation of leukocytes and T cells around the pulmonary arteries were suppressed with oxymatrine administration. Under hypoxic conditions, oxymatrine significantly upregulated Nrf2 and antioxidant protein SOD1 and HO-1 expression, but downregulated hydroperoxide levels in PASMCs. In summary, this study indicates that oxymatrine may prevent pulmonary hypertension through its antiproliferative, anti-inflammatory, and antioxidant effects, thus providing a promising pharmacological avenue for treating pulmonary hypertension.     

N-acetylcysteine improves established monocrotaline-induced pulmonary hypertension in rats

Background

The outcome of patients suffering from pulmonary arterial hypertension (PAH) are predominantly determined by the response of the right ventricle to the increase afterload secondary to high vascular pulmonary resistance. However, little is known about the effects of the current available or experimental PAH treatments on the heart. Recently, inflammation has been implicated in the pathophysiology of PAH. N-acetylcysteine (NAC), a well-known safe anti-oxidant drug, has immuno-modulatory and cardioprotective properties. We therefore hypothesized that NAC could reduce the severity of pulmonary hypertension (PH) in rats exposed to monocrotaline (MCT), lowering inflammation and preserving pulmonary vascular system and right heart function.

Methods

Saline-treated control, MCT-exposed, MCT-exposed and NAC treated rats (day 14–28) were evaluated at day 28 following MCT for hemodynamic parameters (right ventricular systolic pressure, mean pulmonary arterial pressure and cardiac output), right ventricular hypertrophy, pulmonary vascular morphometry, lung inflammatory cells immunohistochemistry (monocyte/macrophages and dendritic cells), IL-6 expression, cardiomyocyte hypertrophy and cardiac fibrosis.

Results

The treatment with NAC significantly decreased pulmonary vascular remodeling, lung inflammation, and improved total pulmonary resistance (from 0.71 ± 0.05 for MCT group to 0.50 ± 0.06 for MCT + NAC group, p < 0.05). Right ventricular function was also improved with NAC treatment associated with a significant decrease in cardiomyocyte hypertrophy (625 ± 69 vs. 439 ± 21 μm² for MCT and MCT + NAC group respectively, p < 0.001) and heart fibrosis (14.1 ± 0.8 vs. 8.8 ± 0.1% for MCT and MCT + NAC group respectively, p < 0.001).

Conclusions

Through its immuno-modulatory and cardioprotective properties, NAC has beneficial effect on pulmonary vascular and right heart function in experimental PH.     

Contractile reserve but not tension is reduced in monocrotaline-induced right ventricular hypertrophy

The objective of this study was to evaluate the role of right ventricular hypertrophy on developed tension (F(dev)) and contractile reserve of rat papillary muscle by using a model of monocrotaline (Mct)-induced pulmonary hypertension. Calcium handling and the influence of bicarbonate (HCO(3)(-)) were also addressed with the use of two different buffers (HCO(3)(-) and HEPES). Wistar rats were injected with either Mct (40 mg/kg sc) or vehicle control (Con). Isometrically contracting right ventricular papillary muscles were studied at 80% of the length of maximal developed force. Contractile reserve (1 - F(dev)/F(max)) was calculated from F(dev) and maximal tension (F(max)). Calcium recirculation was determined with postextrasystolic potentiation. Both groups of muscles were superfused with either HCO(3)(-) (Con-B and Mct-B, both n = 6) or HEPES (Con-H and Mct-H, both n = 6) buffer. With hypertrophy, contractions were slower but F(dev) was not changed. However, F(max) was decreased (P < 0.05). With HCO(3)(-), F(max) decreased from 23.8 +/- 6.5 mN.mm(-2) in Con-B, to 13.7 +/- 3.3 mN.mm(-2) in Mct-B. With HEPES, it decreased from 16.3 +/- 3.5 mN.mm(-2) (n = 6, Con-H) to 8.3 +/- 1.6 mN.mm(-2) (Mct-H). Contractile reserve during hypertrophy was therefore also decreased (P < 0.05). With HCO(3)(-), it decreased from 0.73 +/- 0.03 (Con-B) to 0.55 +/- 0.04 (Mct-B). With HEPES, it decreased (P < 0.001) from 0.64 +/- 0.07 (Con-H) to 0.19 +/- 0.06 (Mct-H). The recirculation fraction decreased (P < 0.05) from 0.59 +/- 0.04 in Con-B to 0.44 +/- 0.04 in Mct-B. We conclude that contractile reserve and recirculation fraction are impaired during hypertrophy, with a stronger effect under HEPES than HCO(3)(-) superfusion.     

Rosuvastatin provides pleiotropic protection against pulmonary hypertension, right ventricular hypertrophy, and coronary endothelial dysfunction in rats

We recently reported that increased vascular endothelial nitric oxide production could protect against the development of monocrotaline (MCT)-induced pulmonary arterial hypertension (PAH) and right ventricular hypertrophy (RVH) in rats (32). The present study investigated whether the pleiotropic action of 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in upregulating endothelial function could also protect against the MCT-induced end-organ damages. Rosuvastatin (2 mg kg(-1) day(-1) via oral gavage) or placebo was initiated 1 wk before or 1 wk after MCT (60 mg/kg ip) administration. One month after MCT, significant PAH developed in the placebo rats, which were accompanied by histological evidence of pulmonary vascular thickening and right ventricular hypertrophy. The coronary endothelial vasodilatory function, assessed with endothelial/nitric oxide-dependent responses to acetylcholine and N(G)-nitro-L-arginine methyl ester (L-NAME), was depressed, while the constrictory responses to known coronary constrictors was enhanced. In rats that received rosuvastatin treatment 1 wk before MCT administration, a significantly reduced PAH and RVH was observed, as well as reduced pulmonary vascular and right ventricular remodelings. Rosuvastatin 1-wk posttreatment had no effect on PAH, but inhibited RVH. Right coronary endothelial dysfunction, which was shown in placebo rats, was effectively prevented by both pre- and postrosuvastatin treatment, while this effect was more dramatic in the pretreated group. Left coronary endothelial function, which was not affected by MCT, also showed an upregulation by rosuvastatin. Taken together, our results demonstrated the pleiotropic protection of rosuvastatin against the development of PAH and RVH and confirmed our previous finding that the targeted preservation of coronary endothelial function and vasoactivity may provide a novel approach to protect against cardiac remodeling.     

Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats

Hill, Nicholas S., Rod R. Warburton, Linda Pietras, andJames R. Klinger. Nonspecific endothelin-receptor antagonist blunts monocrotaline-induced pulmonary hypertension in rats.J. Appl. Physiol. 83(4):1209-1215, 1997.Endothelin-1 (ET-1), a potent vasoactive andmitogenic peptide, has been implicated in the pathogenesis ofseveral forms of pulmonary hypertension. We hypothesized thatnonspecific blockade of ET receptors would blunt the development ofmonocrotaline (MCT)-induced pulmonary hypertension in rats. Asingle dose of the nonspecific ET blocker bosentan (100 mg/kg) given tointact rats by gavage completely blocked the pulmonary vasoconstrictoractions of Big ET-1 and partially blunted hypoxic pulmonaryvasoconstriction. After 3 wk, MCT-injected (105 mg/kg sc) rats gavagedonce daily with bosentan (200 mg/kg) had lower right ventricular (RV)systolic pressure (RVSP), RV-to-body weight (RV/BW) andRV-to-left ventricular (LV) plus septal (S) weight [RV/(LV+S)] ratiosand less percent medial thickness of small pulmonary arteries thancontrol MCT-injected rats. Lower dose bosentan (100 mg/kg) had noeffect on these parameters after MCT or saline injection. Bosentanraised plasma ET-1 levels but had no effect on lung ET-1 levels.Bosentan (200 mg/kg) also had no effect on wet-to-dry lung weightratios 6 days after MCT injection. When given during the last 10 days,but not the first 11 days of a 3-wk period after MCT injection,bosentan reduced RV/(LV+S) compared with MCT-injected controls. Weconclude that ET-1 contributes to the pathogenesis of MCT-inducedpulmonary hypertension and acts mainly during the later inflammatoryrather than the acute injury phase after injection.

     

Involvement of mast cells in monocrotaline-induced pulmonary hypertension in rats

Background

Mast cells (MCs) are implicated in inflammation and tissue remodeling. Accumulation of lung MCs is described in pulmonary hypertension (PH); however, whether MC degranulation and c-kit, a tyrosine kinase receptor critically involved in MC biology, contribute to the pathogenesis and progression of PH has not been fully explored.

Methods

Pulmonary MCs of idiopathic pulmonary arterial hypertension (IPAH) patients and monocrotaline-injected rats (MCT-rats) were examined by histochemistry and morphometry. Effects of the specific c-kit inhibitor PLX and MC stabilizer cromolyn sodium salt (CSS) were investigated in MCT-rats both by the preventive and therapeutic approaches. Hemodynamic and right ventricular hypertrophy measurements, pulmonary vascular morphometry and analysis of pulmonary MC localization/counts/activation were performed in animal model studies.

Results

There was a prevalence of pulmonary MCs in IPAH patients and MCT-rats as compared to the donors and healthy rats, respectively. Notably, the perivascular MCs were increased and a majority of them were degranulated in lungs of IPAH patients and MCT-rats (p < 0.05 versus donor and control, respectively). In MCT-rats, the pharmacological inhibitions of MC degranulation and c-kit with CSS and PLX, respectively by a preventive approach (treatment from day 1 to 21 of MCT-injection) significantly attenuated right ventricular systolic pressure (RVSP) and right ventricular hypertrophy (RVH). Moreover, vascular remodeling, as evident from the significantly decreased muscularization and medial wall thickness of distal pulmonary vessels, was improved. However, treatments with CSS and PLX by a therapeutic approach (from day 21 to 35 of MCT-injection) neither improved hemodynamics and RVH nor vascular remodeling.

Conclusions

The accumulation and activation of perivascular MCs in the lungs are the histopathological features present in clinical (IPAH patients) and experimental (MCT-rats) PH. Moreover, the accumulation and activation of MCs in the lungs contribute to the development of PH in MCT-rats. Our findings reveal an important pathophysiological insight into the role of MCs in the pathogenesis of PH in MCT- rats.     

Interleukin 1 bioactivity in the lungs of rats with monocrotaline-induced pulmonary hypertension

A single subcutaneous injection of monocrotaline in rats provokes lung injury, inflammation, and progressive pulmonary hypertension. The specific mediators of the lung injury and inflammation and the relation of these events to the ensuing hypertensive pulmonary vascular disease are not understood. Since the monokine interleukin 1 (IL-1) has been implicated in acute inflammatory reactions, the present study tested the hypotheses that monocrotaline promotes the appearance of IL-1 in the bronchoalveolar spaces of treated rats and that accumulation of the monokine coincides temporally with development of lung injury, inflammation, and/or pulmonary hypertension. As expected, monocrotaline administration was associated with an early phase of pulmonary edema, manifest at Day 7 post-treatment as an increase in the lung wet-to-dry weight ratio, followed at Day 14 post-treatment by development of pulmonary hypertension as evidenced by progressive right ventricular hypertrophy. Lung inflammation also was present at Days 14 and 21 after monocrotaline as indicated by the accumulation of leukocytes in the bronchoalveolar lavage fluid and by an increase in the lung tissue activity of the granulocyte-specific enzyme myeloperoxidase. Interleukin 1, bioassayed in bronchoalveolar lavage fluid using the standard D10 T-cell assay system, was increased slightly at Day 4 postmonocrotaline, returned to baseline at Day 7, and was markedly elevated at Days 14 and 21 after monocrotaline treatment. These observations indicate that increases in the bronchoalveolar lavage fluid content of IL-1 bioactivity are temporally related to the evolution of monocrotaline-induced lung injury, inflammation, and pulmonary hypertension and suggest that the monokine may play a pathogenetic role in these events.     

Sharp increase in density of pulmonary and pericardial mast cells in monocrotaline-induced pulmonary hypertension in rats

Multifunctional granular mast cells (MCs) are involved in various pathological processes. The response of the MC population in the myocardium, pericardium, and lungs to pulmonary hypertension (PH) has been studied 8 weeks after the injection of monocrotaline. Five intact and five experimental rats were used. The density of MCs of different degrees of maturity was estimated in paraffin sections stained with Alcian blue and Safranin. The expression of PH was estimated by functional parameters using an echocardiogram and morphological markers. The MC density in the myocardium of intact and experimental rats was relatively low, i.e., 2–4 cells/mm². In the pericardia of intact rats, the MC density was 14 times higher than in the myocardia and increased by a factor of three in PH. In the myocardia and pericardia of intact and experimental rats, mature, Safranin-positive cells predominated (70–80%). In the lungs of intact rats, the MC density was about 30 cells/mm² and 98% of the cells were immature Alcian-positive cells. In lungs of rats with PH the mean density of MCs increased 5.6 times. In lungs of rats with severe pathologies, mature Safranin-positive cells appeared. The highest number of MCs in lungs was found in rats with distinctly pronounced disorders of myocardial function and marked histolological damages of myocardium and lung. The findings show the active reaction of the MC population to monocrotaline-induced PH, which stimulates the migration of immature MCs to the pericardium and lungs from the outside. The connection of cellular mechanisms of the development of PH with the function of MCs is not yet clear; however, the results of the present work indicate the important role of MCs in the pathogenesis of PH.     

Supplemental oxygen reduces right ventricular hypertrophy in monocrotaline-injected rats

We evaluated the possible contributory role of hypoxia in the development of monocrotaline-induced pulmonary hypertension. Male Sprague-Dawley rats were injected subcutaneously with monocrotaline (60 mg/kg) or saline in controls and were kept in oxygen-enriched (inspired O2 fraction of 0.35) or compressed air chambers. After 21 days, rats were anesthetized while spontaneously breathing room air, hemodynamic parameters and arterial blood gases were measured, and animals were killed. Right ventricular peak systolic pressures (RVPP), right ventricular-to-left ventricular plus septal weight ratios (RV/LV + S), hematocrits, lung dry weight-to-body weight ratios, and medial thickness of pulmonary arteries were significantly reduced in monocrotaline-injected rats exposed to mild hyperoxia compared with air. The air-exposed monocrotaline-injected rats had significantly more arterial hypoxemia than the other groups, and mild hyperoxia had no effect on any of the measured variables in saline-injected rats. To determine whether the effects of mild hyperoxia occurred early or late after monocrotaline injection, we moved separate groups of rats from air to mild hyperoxia and vice versa 10 days after monocrotaline injection. After 21 days, significant reductions in RVPP and RV/LV + S occurred only in rats exposed to mild hyperoxia during the latter 11 days after injection. Our findings suggest that hypoxia contributes to the development of pulmonary hypertension relatively late after monocrotaline injection in rats but that it does not influence the early injury.     

Quantification of right ventricular afterload in patients with and without pulmonary hypertension

Right ventricular (RV) afterload is commonly defined as pulmonary vascular resistance, but this does not reflect the afterload to pulsatile flow. The purpose of this study was to quantify RV afterload more completely in patients with and without pulmonary hypertension (PH) using a three-element windkessel model. The model consists of peripheral resistance (R), pulmonary arterial compliance (C), and characteristic impedance (Z). Using pulmonary artery pressure from right-heart catheterization and pulmonary artery flow from MRI velocity quantification, we estimated the windkessel parameters in patients with chronic thromboembolic PH (CTEPH; n = 10) and idiopathic pulmonary arterial hypertension (IPAH; n = 9). Patients suspected of PH but in whom PH was not found served as controls (NONPH; n = 10). R and Z were significantly lower and C significantly higher in the NONPH group than in both the CTEPH and IPAH groups (P < 0.001). R and Z were significantly lower in the CTEPH group than in the IPAH group (P < 0.05). The parameters R and C of all patients obeyed the relationship C = 0.75/R (R(2) = 0.77), equivalent to a similar RC time in all patients. Mean pulmonary artery pressure P and C fitted well to C = 69.7/P (i.e., similar pressure dependence in all patients). Our results show that differences in RV afterload among groups with different forms of PH can be quantified with a windkessel model. Furthermore, the data suggest that the RC time and the elastic properties of the large pulmonary arteries remain unchanged in PH.     

Effect of chronic administration of aminoguanidine on the reactivity of pulmonary vessels in rats with monocrotaline-induced pulmonary hypertension

Monocrotaline (MCT)-induced pulmonary hepertension (PH) is associated with impaired endothelium-dependent relaxation and increased activity of inducible NO-synthase (iNOS). To examine the role of iNOS in MCT-induced PH, we used iNOS inhibitor: aminoguanidine (AG). The PH was simulated with a subcutaneous injection of 60 mg/kg MCT to Wistar rats; control rats were injected with saline. Then each group was separated into 2 subgroups: the 1st one was given drinking water (MCT-C and C-C groups) whereas the 2nd one was given AG in drinking water (15 mg/(kg(-1) x day(-1)) (MCT-AG and C-AG groups). In 4 weeks, the perfusion pressure (PP) responses of isolated pulmonary arteries to acetylcholine (Ach) and activator of soluble guanylate cyclase (sGC), FPTO, were examined. In the MCT-C group, a decrease of relative PP to perfusion of 1 x 10(-8) M and 5 x 10(-8) M Ach and 1 x 10(-8) M FPTO was diminished. This reduction of relaxant responses in MCT-treated rats was prevented by AG treatment. The findings suggest that AG administration restores the impaired endothelium-dependent and sGC-dependent relaxation of the pulmonary artery at MCT-induced PH.     

Attenuation of the extract from Moringa oleifera on monocrotaline-induced pulmonary hypertension in rats

The purpose of this study was to determine the effects of an extract from Moringa oleifera (MO) on the development of monocrotaline (MCT)-induced pulmonary hypertension (PH) in Wistar rats. An ethanol extraction was performed on dried MO leaves, and HPLC analysis identified niaziridin and niazirin in the extract. PH was induced with a single subcutaneous injection of MCT (60 mg/kg) which resulted in increases in pulmonary arterial blood pressure (Ppa) and in thickening of the pulmonary arterial medial layer in the rats. Three weeks after induction, acute administration of the MO extract to the rats decreased Ppa in a dose-dependent manner that reached statistical significance at a dose of 4.5 mg of freeze-dried extract per kg body weight. The reduction in Ppa suggested that the extract directly relaxed the pulmonary arteries. To assay the effects of chronic administration of the MO extract on PH, control, MCT and MCT+MO groups were designated. Rats in the control group received a saline injection; the MCT and MCT+MO groups received MCT to induce PH. During the third week after MCT treatment, the MCT+MO group received daily i.p. injections of the MO extract (4.5 mg of freeze-dried extract/kg of body weight). Compared to the control group, the MCT group had higher Ppa and thicker medial layers in the pulmonary arteries. Chronic treatments with the MO extract reversed the MCT-induced changes. Additionally, the MCT group had a significant elevation in superoxide dismutase activity when normalized by the MO extract treatments. In conclusion, the MO extract successfully attenuated the development of PH via direct vasodilatation and a potential increase in antioxidant activity.     

高血压大鼠心肌肥大及逆转过程中相关因素的探讨

目的：探讨在心肌肥大及逆转过程中收缩压(SBP)、舒张压(DBP)、平均动脉压(MAP)、神经肽Y(NPY)等与左心室肥大的关系。方法：血压和心率用生物信号分析系统记录;NPY用放射免疫法测定,用SPSS软件求出了相关系数和回归方程。结果：SBP、DBP、MAP、心肌匀浆中NPY与心系数(LVW／BW)呈正相关,血液中NPY和心率(HR)与心系数不相关。结论：血压升高是导致左室肥大的因素之一,收缩压的影响大于舒张压;SBP、DBP、MAP、心肌匀浆中NPY与心系数(LVW/BW)有相关的趋势。     

Selective right, but not left, coronary endothelial dysfunction precedes development of pulmonary hypertension and right heart hypertrophy in rats

We investigated a causal role for coronary endothelial dysfunction in development of monocrotaline (MCT)-induced pulmonary hypertension and right heart hypertrophy in rats. Significant increases in pulmonary pressure and right ventricular weight did not occur until 3 wk after 60 mg/kg MCT injection (34 +/- 4 vs. 19 +/- 2 mmHg and 37 +/- 2 vs. 25 +/- 1% septum + left ventricular weight in controls, respectively). Isolated right coronary arteries (RCA) showed significant decreases in acetylcholine-induced NO dilation in both 1-wk (33 +/- 3% with 0.3 microM; n = 5) and 3-wk (18 +/- 3%; n = 11) MCT rats compared with control rats (71 +/- 8%, n = 10). Septal coronary arteries (SCA) showed a smaller decrease in acetylcholine dilation (55 +/- 8% and 33 +/- 7%, respectively, vs. 73 +/- 8% in controls). No significant change was found in the left coronary arteries (LCA; 88 +/- 6% and 81 +/- 6%, respectively, vs. 87 +/- 3% in controls). Nitro-L-arginine methyl ester-induced vasoconstriction, an estimate of spontaneous endothelial NO-mediated dilation, was not significantly altered in MCT-treated SCA or LCA but was increased in RCA after 1 wk of MCT (-41 +/- 6%) and decreased after 3 wk (-18 +/- 3% vs. -27 +/- 3% in controls). A marked enhancement to 30 nM U-46619-induced constriction was also noted in RCA of 3-wk (-28 +/- 6% vs. -9 +/- 2% in controls) but not 1-wk (-12 +/- 7%) MCT rats. Sodium nitroprusside-induced vasodilation was not different between control and MCT rats. Together, our findings show that a selective impairment of right, but not left, coronary endothelial function is associated with and precedes development of MCT-induced pulmonary hypertension and right heart hypertrophy in rats.     

Myocardial fibrosis and right ventricular function of heterotopically transplanted hearts in rats treated with cyclosporin

The aim was to determine whether treatment of rats with cyclosporin A (CsA) leads to deleterious side effects on heterotopically iso- or allotransplanted hearts when compared with recipient native in situ hearts. Four experimental groups were employed: inbred (Lewis) rats receiving either no immunosuppression or CsA at a dose of 15 mg.kg^–1 per day for 7 days after surgery, and outbred (Wistar) rats receiving CsA at the same daily dose for either 7 or 21 days. One month following surgery, the mass of all transplanted hearts decreased and resulting atrophy was associated with relative myocardial fibrosis. Treatment with CsA significantly increased the concentration and content of collagen in the right and left ventricles of all transplanted and recipient hearts. No appreciable difference was observed between corresponding hearts of inbred and outbred groups receiving the identical dose of CsA, and between hearts in outbred groups treated for either 7 or 21 days. No signs of right ventricular mechanical dysfunction, as assessed on the isolated perfused working preparation, were observed after CsA treatment in both transplanted and recipient hearts. The maximal steady state developed pressure (RVDevP) and the rate of its development [(+dP/dt)_max] were slightly higher in transplants than in the corresponding recipients, and in CsA-treated versus untreated hearts, while the index of contractile state [(+dP/dt)/P] was similar in all groups. The data suggest that treatment of rats with CsA can induce a similar degree of fibrosis both in heterotopic cardiac transplants and in recipient native hearts without impairment of their contractile performance.