Gene expression of natriuretic peptides and their receptors type-A and-C after myocardial infarction in rats

The purpose of this study was to investigate myocardial mRNA expression of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in different regions of the heart at three different time points after induction of myocardial infarction (MI) in rats. Furthermore, we examined putative changes in mRNA expression of natriuretic peptide receptors (NPRs), NPR-A and NPR-C, in myocardium and peripheral organs. Substantial increase in the mRNA levels of both BNP and ANP in the infarcted as well as non-infarcted regions were observed after induction of MI. These findings were paralleled by elevated circulating concentrations of ANP, BNP and N-terminal proANP (Nt-proANP). In addition, the mRNA levels of the clearance receptor, NPR-C, were augmented in the infarcted and non-infarcted regions of the left ventricular wall (LV), while it was decreased in the kidneys and lungs 28 days post-MI. Based on these data, we propose that, in addition to increased myocardial secretion of BNP and ANP, reduced peripheral clearance by NPR-C may contribute to the observed increase in circulating plasma concentrations of the natriuretic peptides after induction of MI in rats.     

Gene expression of natriuretic peptides and their receptors type-A and -C after myocardial infarction in rats

The purpose of this study was to investigate myocardial mRNA expression of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in different regions of the heart at three different time points after induction of myocardial infarction (MI) in rats. Furthermore, we examined putative changes in mRNA expression of natriuretic peptide receptors (NPRs), NPR-A and NPR-C, in myocardium and peripheral organs. Substantial increase in the mRNA levels of both BNP and ANP in the infarcted as well as non-infarcted regions were observed after induction of MI. These findings were paralleled by elevated circulating concentrations of ANP, BNP and N-terminal proANP (Nt-proANP). In addition, the mRNA levels of the clearance receptor, NPR-C, were augmented in the infarcted and non-infarcted regions of the left ventricular wall (LV), while it was decreased in the kidneys and lungs 28 days post-MI. Based on these data, we propose that, in addition to increased myocardial secretion of BNP and ANP, reduced peripheral clearance by NPR-C may contribute to the observed increase in circulating plasma concentrations of the natriuretic peptides after induction of MI in rats.     

Improvement of mortality by long-term E4010 treatment in monocrotaline-induced pulmonary hypertensive rats.

We investigated the effects of long-term treatment with a selective phosphodiesterase 5 inhibitor E4010, 4-(3-chloro-4methoxybenzyl)amino-1-(4-hydroxypiperidino)-6-phth alazin ecarbonitrile monohydrochloride, on the survival rate of rats with pulmonary hypertension induced by monocrotaline (MCT). After an s.c. injection of 40 mg/kg MCT (day 0), male Wistar rats of 4 weeks of age were divided into four groups. Vehicle-treated rats (control, n = 8) and MCT-treated rats (n = 32) were fed a commercial diet. E4010-treated rats were given a commercial diet containing 0.01% (E4010 0.01%, n = 32) and 0.1% (E4010 0.1%, n = 32) of E4010, respectively. At day 23, all rats in the control group and 28.1% of those in the MCT group (P <.01 versus control) were alive. Although the survival rate of E4010 0.01%-treated rats was not improved (50%) compared with MCT, those at 0.1% showed a significant difference (84. 4%, P <.01 versus MCT). For MCT rats (n = 9), right ventricle weight and the levels of plasma atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, and cyclic AMP were higher compared with control (n = 8). In E4010 0.1%-treated rats (n = 27), the right ventricular hypertrophy was suppressed, and the increase in plasma cGMP level was amplified compared with MCT without any effects on plasma ANP, BNP, and cyclic AMP levels. Accordingly, we consider that the mechanism of action of E4010 may be related to the decreased pulmonary arterial pressure caused by the augmentation of pulmonary arterial relaxation through an ANP and/or BNP-cGMP system. These results suggest that E4010 will be useful for the treatment of pulmonary hypertension.     

神经激肽-1受体在急性坏死性胰腺炎肺损害中的作用

目的 :研究神经激肽 1受体 (NK 1R)在急性坏死性胰腺炎 (ANP)大鼠肺组织中的表达 ,探讨该受体在 ANP肺损害中的作用。方法 :健康成年 Sprague Dawley大鼠按抽签法随机分为 ANP组 (90只 )和正常对照组 (30只 )。正常对照组开腹后只翻动胰腺 ,ANP组大鼠经胰胆管恒速逆行注射质量分数为 5 %的牛磺胆酸钠 (0 .1ml/ kg)制成 ANP大鼠模型。检测肺脏髓过氧化物酶 (MPO)的活性和肺脏毛细血管通透性 (L CP)。应用逆转录聚合酶链反应 (RT PCR)检测肺组织中 NK 1R m RNA水平 ,应用 Western Blot技术检测NK 1R的蛋白水平 ,以免疫组织化学方法进行 NK 1R的组织学定位。结果 :ANP组 6 h后肺组织 MPO和L CP水平即明显高于正常对照组。与正常对照组相比 ,ANP肺组织中 NK 1R m RNA和蛋白都过度表达 ;NK 1R m RNA表达分别与 MPO(r=0 .83,P<0 .0 1)和 L CP(r=0 .79,P<0 .0 1)水平相关。免疫组织化学检测显示 ,NK 1R的表达主要位于肺泡隔血管内皮细胞表面及部分肺泡 型、 型上皮细胞表面等处。结论 :ANP肺组织中 NK 1R的表达水平明显上调 ,导致中性粒细胞等炎性细胞聚集 ,加剧 ANP时的肺损害。     

Novel analog of atrial natriuretic peptide selective for receptor-A produces increased diuresis and natriuresis in rats.

Atrial natriuretic peptide (ANP) binds to natriuretic peptide receptor-A (NPR-A), a membrane guanylyl cyclase, and to natriuretic peptide receptor-C (NPR-C), which plays a role in peptide clearance. Rat ANP (rANP) mutants that bind rat NPR-A selectively over rat NPR-C were isolated from randomized libraries of rANP-display phage by differential panning. One variant was identified with reduced NPR-C binding; rANP (G16R, A17E, Q18A) [rANP(REA18)]. Synthetic rANP(REA18) was equipotent with rANP in stimulating cGMP production from cloned rat NPR-A (ED50 = 1.8 nM) and was reduced in NPR-C binding by approximately 200-fold. When infused into conscious rats at 0.325 microg/min for 30 min rANP elicited an identical decrease in blood pressure compared with 0.25 microg/min of rANP(REA18), however the natriuretic (P < 0.05) and diuretic (P = 0.07) responses to rANP(REA18) were greater. These data are consistent with a role for NPR-C as a local decoy receptor attenuating NPR-A effects in the kidney, where these receptors are coexpressed. Improved NPR-A specificity could provide more effective natriuretic peptides for treatment of acute renal failure or heart failure.     

Increased plasma concentrations of brain natriuretic peptide in patients with acute lung injury

: This study was performed to elucidate the pathophysiological role of brain natriuretic peptide (BNP) and atrial natriuretic peptide (ANP) in acute lung injury. : We sequentially measured plasma concentrations of immunoreactive BNP and ANP in 10 patients (mean age, 63 years) with acute lung injury and compared those with hemodynamic parameters and pulmonary functions. : Plasma concentrations of immunoreactive BNP and ANP were markedly elevated at entry into the study. Plasma BNP concentrations during the early course (3 days) showed significant (P < .01) positive correlations with systemic vascular resistance index (r = .708) and pulmonary vascular resistance index (r = .573), but a negative correlation with cardiac index (r = −.608). Plasma ANP concentrations showed a significant (P < .05) positive correlation with pulmonary capillary wedge pressure (r = .398). Plasma BNP in 4 patients who died and 1 patient with acute renal failure remained elevated during the entire hospital length of stay (12 days). : These findings suggest that circulating BNP plays an important role in acute lung injury along with ANP as a compensatory mechanism for cardiac dysfunction accompanied by increased systemic vascular resistance index and pulmonary vascular resistance index. Circulating BNP may be a sensitive humoral marker for the degree of ventricular dysfunction associated with acute lung injury.     

Heart specific up-regulation of genes for B-type and C-type natriuretic peptide receptors in diabetic mice

BACKGROUND: Diabetes may cause cardiomyopathy characterized by cardiac fibrosis. Recent studies of genetically modified mice have elucidated a role of the natriuretic peptides (NP), type-A and type-B (ANP and BNP), and their common receptor [natriuretic peptide receptor (NPR), type-A] in development of cardiac fibrosis. The role of NP type-C (CNP) and NPR type-B (NPR-B) in the heart is less well established. In this study we examined if diabetes alters heart expression of the genes encoding the NP and its receptors. MATERIALS AND METHODS: Cardiac mRNA was quantified by real-time PCR in diabetic streptozotocin (STZ)-treated and ob/ob-mice and nondiabetic control mice. RESULTS: The ob/ob-mice with type-II diabetes displayed highly significant increases of the cardiac mRNA expression of NPR-B and NPR-C while the expression levels of NPR-A, ANP, BNP, and CNP mRNA were similar in ob/ob-mice and controls. Mice with STZ-induced type-I diabetes also showed an increase of heart NPR-B mRNA expression at 12 weeks, but not at 3, 6 or 9 weeks after STZ-treatment. The ANP and NPR-C mRNA expressions were only altered after 3 weeks, whereas BNP, CNP and NPR-A mRNA expressions were not altered in STZ-treated-mouse hearts at any of the time points. CONCLUSIONS: The results show that diabetes in mice confers increased NPR-B gene expression in the heart, suggesting that increased NPR-B signalling may affect development of diabetic cardiomyopathy.     

The atrial natriuretic peptide as a regulator of Kupffer cell functions

Kupffer cells (KCs), the resident macrophages of the liver, contribute prominently to liver injury by inflammatory mediators. Pre-conditioning with the atrial natriuretic peptide (ANP), known also as a regulator of macrophage functions, attenuates hepatic ischemia-reperfusion injury. Therefore, the aim of this study was to determine the presence of functional ANP receptors on isolated KCs and to investigate whether this hepatoprotective hormone influences the activation of KCs. KCs were isolated by collagenase/pronase digestion followed by elutrial centrifugation and cultured for 1 to 3 days. Intracellular cyclic guanosine 3'5'-monophosphate (cGMP) concentrations were measured by radioimmunoassay after treating the cells with sodium nitroprusside or ANP. KCs were stimulated with bacterial lipopolysaccharide in the presence or absence of ANP, and inflammatory mediators were determined. Phagocytosis was assayed using Coumarin-labeled latex particles and flow cytometric analysis. Treatment of KCs with ANP but not with sodium nitroprusside resulted in a significant elevation of intracellular cGMP levels indicating functional type A natriuretic peptide receptors (NPR-As). ANP significantly reduced lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNFalpha) secretion, paralleled by an increased cell-associated TNFalpha. LPS-induced TNFalpha mRNA expression was not affected. ANP significantly increased phagocytotic activity of KCs via NPR-A. No effect of ANP on LPS-activated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 protein levels, iNOS mRNA expression, nitric oxide, and PGE2-production was observed. We demonstrated functional cGMP-dependent ANP receptors in isolated rat KCs. ANP reduced TNFalpha release possibly by influencing post-translational processing of TNFalpha in LPS-activated KCs. In addition, we demonstrated that ANP enhances phagocytosis in KCs. These effects may contribute to the hepatoprotective actions of ANP.     

Direct comparison of relaxation and cGMP production in human coronary by-pass grafts in response to stimulation with natriuretic peptides and a nitric oxide donor

In the present study, we investigated the vasodilator properties of A-type, B-type and C-type natriuretic peptides (ANP, BNP and CNP respectively) and the NO (nitric oxide) donor sin-1 (3-morpholino-sydnonimine) in human by-pass grafts. In contrast with previous studies, the same vessel was used to demonstrate a direct link between cGMP production and functional relaxation. Remnants of the IMA (internal mammary artery) and SV (saphenous vein) were obtained from 82 patients undergoing coronary artery by-pass grafting. The responses to cumulative concentrations of ANP, BNP, CNP and sin-1 in vessel rings pre-contracted with a thromboxane A2 agonist (U46619) were measured in an organ bath. Additionally, intracellular cGMP production after single submaximal dose application of these drugs to vessel rings was determined by a RIA. ANP (P=0.001) and sin-1 (P<0.001) caused significant concentration-dependent relaxation of the IMA. In the SV, only sin-1 (P<0.001) induced marked concentration-dependent relaxation. At a single submaximal concentration, significant relaxation as well as intracellular cGMP production were found in response to ANP, BNP and sin-1 in the IMA. In contrast, in the SV, only sin-1 significantly induced cGMP production and relaxation. There was a moderate, but significant, correlation between intracellular cGMP net production and net relaxation in the IMA. In conclusion, ANP, as the most powerful relaxant of all the natriuretic peptides tested on the IMA, may be a possible alternative vasorelaxant to overcome peri-operative vasospasm in this artery. In contrast with sin-1, ANP and BNP were not effective vasorelaxants of the SV. Net relaxation in response to natriuretic peptides correlated with cGMP net concentrations in the IMA.     

Pretreatment with cationic lipid-mediated transfer of the Na+K+-ATPase pump in a mouse model in vivo augments resolution of high permeability pulmonary oedema

Resolution of pulmonary oedema is mediated by active absorption of liquid across the alveolar epithelium. A key component of this process is the sodium-potassium ATPase (Na+K+-ATPase) enzyme located on the basolateral surface of epithelial cells and up-regulated during oedema resolution. We hypothesised that lung liquid clearance could be further up-regulated by lipid-mediated transfer and expression of exogenous Na+K+-ATPase cDNA. We demonstrate proof of this principle in a model of high permeability pulmonary oedema induced by intraperitoneal injection of thiourea (2.5 mg/kg) in C57/BL6 mice. Pretreatment of mice (24 h before thiourea) by nasal sniffing of cationic liposome (lipid #67)-DNA complexes encoding the alpha and beta subunits of Na+K+-ATPase (160 microg per mouse), significantly (P<0.01) decreased the wet:dry weight ratios measured 2 h after thiourea injection compared with control animals, pretreated with an equivalent dose of an irrelevant gene. Whole lung Na+K+-ATPase activity was significantly (P<0.05) increased in mice pretreated with Na+K+-ATPase cDNA compared both with untreated control animals as well as animals pretreated with the irrelevant gene. Nested RT-PCR on whole lung homogenates confirmed gene transfer by detection of vector-specific mRNA in three of four mice studied 24 h after gene transfer. This demonstration of a significant reduction in pulmonary oedema following in vivo gene transfer raises the possibility of gene therapy as a novel, localised approach for pulmonary oedema in clinical settings such as ARDS and lung transplantation.     

Natriuretic peptide-induced relaxation of myometrium from the pregnant guinea pig is not mediated by guanylate cyclase activation

We tested both relaxation and cGMP generation by atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) in oxytocin-stimulated myometrium from near-term pregnant guinea pigs to investigate the ability and mechanism of natriuretic peptides to inhibit myometrial contractility. Myometrial strips were contracted by 10(-8) M oxytocin, and relaxation to the cumulative addition (10(-9)-10(-6) M) of the natriuretic peptides measured. Maximal relaxation to BNP was significantly greater than to ANP (52 versus 32% respectively; p < 0.05), whereas CNP failed to produce relaxation. However, the increase in cGMP produced by BNP (10(-7) M) was significantly less than that produced by ANP (10(-7) M) (4.5 versus 7.0 times basal; p < 0.05); CNP did not increase myometrial cGMP. Anantin, a competitive blocker of the guanylate cyclase A receptor, significantly reduced the increase in cGMP produced by ANP and BNP, but had no effect on relaxation induced by either peptide. Rp-8-Br-cGMP, an inhibitor of the cGMP-dependent protein kinase, did not alter BNP-induced relaxation. The atrial natriuretic peptide-fragment 4-23 amide, a natriuretic peptide clearance receptor agonist, failed to inhibit oxytocin-stimulated myometrial contraction. We conclude that natriuretic peptide induced relaxation of oxytocin-stimulated myometrium from the pregnant guinea pig is not mediated by either guanylate cyclase A or B activation, is independent of the cGMP pathway, and does not involve clearance receptor activation. Our results suggest that natriuretic peptide-induced relaxation of pregnant myometrium is mediated via a novel mechanism.     

博莱霉素致小鼠肺纤维化模型的动态演变及其发生机制

目的 了解小鼠肺纤维化模型的动态演变，探讨博莱霉素致肺纤维化的作用机制。方法 36只雄性ICR小鼠，按随机数字表法分为阴性对照组（NC组）和肺纤维化模型组（FMA、FMB、FMC、FMD、FME组），每组6只。除NC组外，其余各组经鼻滴入博莱霉素建立肺纤维化模型。分别于6、14、21、28和35d处死各组小鼠，取外周血经流式细胞仪测定T细胞亚群Th1／Th2和Tc1／Tc2，计数支气管肺泡灌洗液（BALF）中总细胞数和细胞分类，右肺行苏木素-伊红（HE）及Masson染色，测定左肺组织中羟脯氨酸（HYP）的含量；并提取左肺组织总RNA，采用半定量逆转录-聚合酶链反应（RT—PCR）了解肺组织中多种细胞因子的表达。测定35d处死小鼠的潮气量（Vt）、0．1秒用力呼气容积／用力肺活量（FEV0．1／FVC）和静态肺顺应性（Cst）。结果 ①肺纤维化各组小鼠BALF中细胞总数与NC组比较均显著增高（P均〈O．01），且其肺组织中HYP含量除FMA组外均显著升高（P均〈0．01）。②FME组VT和Cst均较NC组明显降低（P均〈0．01），FEV0．1／FVC则显著升高（P〈O．05）。③在肺纤维化模型炎症期（FMA组），T细胞Th1／Th2和Tc1／Tc2之间的平衡呈Th1、Tc1优势表达为主；在纤维化形成期（FMB、FMC组），则以Th2、Tc2优势表达；在肺纤维化形成后，Th1、Tc1再度呈优势表达的状态。④肺纤维化模型组中转化生长因子-β1（TGF—β1）和金属蛋白酶组织抑制因子-1（TIMP-1）均较NC组显著升高（P均〈0．01）。结论 博莱霉素致肺纤维化小鼠肺功能为限制性通气功能障碍，Th2、Tc2及促纤维化生成因子在肺纤维化形成过程中发挥重要作用。     

Adenovirus-mediated atrial natriuretic protein expression in the lung protects rats from hypoxia-induced pulmonary hypertension

Endogenous as well as exogenous atrial natriuretic peptide (ANP) attenuates the development of chronic hypoxic pulmonary hypertension (CHPH) in rats. We built a recombinant adenovirus type 5 containing ANP cDNA under the control of the Rous sarcoma virus long terminal repeat (Ad.ANP). The efficiency of this vector in delivering the ANP gene was first examined in rat primary cultures of pulmonary vessel smooth muscle cells (SMCs) in comparison with Ad.beta GAL. Conditioned medium collected from Ad.ANP-infected cells (1000 TCID(50)/cell) contained 5 x 10(9) M immunoreactive ANP and elicited relaxation of isolated rat pulmonary arteries preconstricted with phenylepinephrine. To examine the effects of adenovirus-mediated ANP expression in the CHPH rat lung, Ad.ANP or Ad.beta GAL was administered via the tracheal route. Immunoreactive ANP was detected in bronchoalveolar fluid as early as 4 days and until 10-17 days after Ad.ANP administration (5 x 10(8) TCID(50)). Lung ANP immunostaining was mainly localized in bronchial and alveolar epithelial cells. As compared with Ad.beta GAL-treated controls, rats given Ad.ANP (5 x 10(8) TCID(50)) on the day before a 2-week exposure to hypoxia (10% O(2)) had lower values for pulmonary artery pressure (32.1 +/- 1.93 vs. 35.5 +/- 2 mmHg, p < 0.01) and Fulton's index (0.52 +/- 0.089 vs. 0.67 +/- 0.12, p < 0.001) and less severe right ventricular hypertrophy and distal vessel muscularization. These results suggest that induction of ANP expression in the lung may hold promise in the treatment of pulmonary hypertension.     

RNA结合蛋白QKI在心肌肥大中的作用

目的探讨RNA结合蛋白QKI在血管紧张素Ⅱ诱导的心肌细胞肥大中的作用。方法将H9C2细胞分为对照组与心肌肥大组(AngⅡ组),AngⅡ组采用血管紧张素Ⅱ(10-7 mol/L)刺激H9C2细胞建立肥大模型;2组均采用转染小干扰RNA抑制QKI的表达,腺病毒感染H9C2细胞过表达QKI5和QKI6,应用Western blot检测H9C2细胞中QKI水平,应用实时定量RCR检测对照组及AngⅡ组作用6,12,18,24,36h时心房利钠多肽表达水平。结果与对照组比较,AngⅡ组作用12h总QKI增加,其中QKI6升高明显(P<0.05);AngⅡ+siQKI组心房利钠多肽水平较AngⅡ+NC组增加(P<0.05);AngⅡ+Ad-QKI5组心房利钠多肽水平与AngⅡ+Ad-Ctrl组比较差异无统计学意义(P>0.05),AngⅡ+Ad-QKI6组心房利钠多肽水平较AngⅡ+Ad-Ctrl组降低(P<0.05)。结论 QKI6可抑制心肌肥大。     

高频振荡通气联合肺表面活性物质对吸入性损伤肺组织天冬氨酸特异性半胱氨酸蛋白酶-3和p73的影响

目的 探讨高频振荡通气(HFOV)联合肺表面活性物质(PS)对吸人性损伤兔肺组织细胞凋亡的影响.方法 采用兔蒸汽吸人性损伤模型,将32只兔按不同通气治疗方式分为常规控制机械通气(CMV)组、HFOV组、CMV+PS组及HFOV+PS组4组,每组8只.治疗4 h后处死动物,取右肺中叶组织,分别检测天冬氨酸特异性半胱氨酸蛋白酶-3(caspase-3)、p73的含量及其mRNA表达水平.结果 ①HFOV组和HFOV+PS组肺组织caspase-3和p73的含量分别较CMV组和CMV+PS组明显减少,差异有统计学意义(P<0.05或P<0.01);加入外源性PS后,CMV+PS组和HFOV+PS组的caspase-3和p73含量也较相应未加入组明显减少,差异也有统计学意义(P均<0.05).②HFOV组和HFOV+PS组caspase-3 mRNA和p73 mRNA表达分别较CMV组和CMV+PS组明显减少,差异有统计学意义(P均<0.01);加入外源性PS后,CMV+PS组和HFOV+PS组肺组织caspase-3 mRNA和p73 mRNA的表达也明显低于相应未加入组,差异也有统计学意义(P均<0.05).结论 与CMV或CMV+PS比较,HFOV或HFOV+PS能减少吸入性损伤肺组织细胞中caspase-3、p73的含量及其mRNA表达,从而可能减少通气肺的肺细胞凋亡.     

No Correlation Between Atrial Natriuretic Peptide Concentrations and Echocardiographic Measurements of Left Atrial Size or Left Ventricular Size and Function in Patients with Persistent Atrial Fibrillation

Atrial fibrillation (AF) may be associated with activation of atrial natriuretic peptide (ANP). The exact trigger for the release of ANP is still being debated. Atrial volume, pressure, and wall stretch are considered to be the main determinants of ANP activation. The aim of the study was to evaluate plasma ANP concentrations in patients with persistent AF and to analyze the echocardiographic determinants of ANP concentration in this group. The study population included 67 patients, 59 ± 7 years of age, with a median AF duration of 5.5 months (range 0.1–12). The relationship between plasma ANP concentrations and echocardiographic left atrial (LA) diameter and volume, and left ventricular (LV) diameter and ejection fraction (EF) was analyzed by logistic regression analysis. The median baseline plasma ANP concentration was 63 pg/mL (range 21–126) in the study group versus 34 pg/mL (range 16–73) in a control group. The mean left antero-posterior atrial dimension, LA volume, LV enddiastolic diameter, and LVEF were 48 mm, 104 mL, 52 mm, and 54%, respectively. A significant linear positive correlation was found between plasma ANP concentration and maximal LA volume (r = 0.62, P < 0.01). A negative correlation was found between LVEF and plasma ANP concentration (r =−0.42, P = 0.01). However, by multivariate regression analysis, no echocardiographic parameter was an independent predictor of plasma ANP concentration. Plasma ANP concentrations were independent of echocardiographic measurements of LA size or LV size and function in patients with persistent AF.     

Effect of isosorbide-5-mononitrate on plasma and urine levels of cyclic GMP in relation to exercise in coronary patients compared with control subjects

Abstract. Nitric oxide (NO) and atrial natriuretic peptide (ANP) relax vascular smooth muscle increasing levels of cyclic guanosine 3': 5' monophosphate (cGMP). Nitrovasodilators act as exogenous nitric oxide donors. The aim of this study was to ascertain the response of cGMP to exercise without medication and after the administration of 20 mg of isosorbide-5-mononitrate (IS-5-MN) in coronary patients ( n = 8) and healthy control subjects ( n = 9). A third group of 10 normal volunteers was studied to test plasma cGMP response to second exercise test without IS-5-MN administration. Plasma cGMP increased significantly in both patients ( P <0.02) and controls ( P <0.01) after the first ergometry. After IS-5-MN administration, plasma cGMP did not increase either before or after exercise. In normal volunteers without IS-5-MN plasma cGMP increased significantly after first ( P < 0.004) and second ( P < 0.0008) exercise test. In conclusion, plasma cGMP increases during exercise. Administration of IS-5-MN does not raise plasma cGMP and neither does performance of further exercise after its administration.     

Impaired vasodilator responses to atrial natriuretic peptide in essential hypertension

BACKGROUND: Atrial natriuretic peptide (ANP) has vasodilating and diuretic/natriuretic properties, both of which contribute to lower blood pressure. These effects are mediated by binding of ANP to a cell-surface receptor [type A guanylyl cyclase (GC-A)]. It has been demonstrated by studies in monogenetic mouse models that the ANP/GC-A system participates in the maintenance of blood pressure homeostasis. METHODS: In male patients with essential hypertension (EH; n = 36) as the only cardiovascular risk factor and normotensive controls (n = 12), blood flow was measured in the forearm circulation in response to i.a. infusion of synthetic human ANP, acetylcholine, orciprenaline, and sodium nitroprusside by strain-gauge venous plethysmography. In blood samples, cyclic guanosine'5-monophosphate (cGMP) and ANP concentrations were measured at resting conditions and during exogenous ANP infusion. In 200 patients with EH, genomic DNA was screened for an inhibitory deletion mutation of the GC-A gene, which has been recently linked to EH in a Japanese cohort. RESULTS: The vasodilatations in response to ANP and acetylcholine were impaired in the forearm circulation of patients with EH, whereas the responses to orciprenaline and nitroprusside were preserved. Plasma ANP and cGMP concentrations were increased in the patients with EH both at resting conditions and during ANP infusion; the resting plasma cGMP levels correlated significantly with the plasma ANP levels (r = 0.68). A specific deletion mutation of the GC-A gene did not account for the diminished relaxant effects of ANP in our study population. CONCLUSIONS: The vascular ANP/GC-A pathway is altered in patients with EH, in addition to the known defects on the nitric oxide/cGMP pathway. Attenuation of the vasodilative responses to ANP suggests impaired receptor or postreceptor responsiveness of GC-A. It is possible that this dysfunction participates in the pathomechanism of EH.     

WY14643对急性肺损伤大鼠肺组织PPAR-α表达的影响及其机制研究

目的 探讨WY14643对急性肺损伤（ALI）大鼠肺组织中过氧化物酶增殖体激活受体-α（PPAR-α）表达的影响及其可能机制。方法 将104只雄性Wistar大鼠随机分为对照组、脂多糖（LPS）致伤组（ALI组）、1mg／kgPPAR-α激活剂WY14643治疗组（LW 1mg组）和3mg／kg WY14643治疗组（LW3mg组）。用LPS（5mg／kg）静脉注射复制大鼠ALI模型，注射LPS 15min后再次分组按剂量静脉注射WY14643。分别于制模后1、2、4和8h活杀大鼠，观察肺组织病理变化；采用逆转录-聚合酶链反应（RT—PCR）检测肺组织中PPAR-α mRNA表达；蛋白质免疫印迹法（Western blot）检测肺组织PPAR-α蛋白表达。结果 ALI组PPAR-α mRNA表达均较对照组降低，差异有显著性（P均〈0．05）；LW 1mg组在2h和4h、LW 3mg组在2、4和8h PPAR-α mRNA表达均较ALI组相应时间点升高，差异均有显著性（P均〈0．01）；而LW 1mg组与LW 3mg组在1、2、4和8hPPAR-α蛋白表达均较ALI组相应时间点显著升高（P均〈0．01）；LW 1mg组在4hL和8h与LW 3mg组在2、4和8h PPAR-α蛋白表达均较对照组升高，差异有显著性（P〈0．01）；LW 1mg与LW 3mg组间比较其作用差异也有显著性（P〈0．05）。结论 ALI大鼠肺组织PPAR-α和蛋白表达均明显下降；WY14643对PPAR-α具有较明显的上调作用。     

丹参对大鼠急性坏死性胰腺炎并发肺损伤的影响

目的 探讨急性坏死性胰膜炎（ANP）时肺微循环改变对肺损伤的影响及其丹参的保护作用。方法 SD大鼠192只，随机分为对照组（C组）、胰腺炎组（P组）和治疗组（T组）。5％牛磺胆酸钠胰腺被膜下均匀注射制作ANP模型。采用放射生物微球技术测定制模后0.5、2、6及12h的肺组织血流量，同时观察血清磷脂酶A2（PLA2）活性、血栓素A2（TXA2）与前列环素（PGI2）比值及肺组织学改变。结果 与C组比较，P组各时相肺组织学损伤明显加重（P＜0．01），肺血流量明显降低（P＜0．05），PLA2活性明显增高（P＜0．001），TXA2／PGI2自2h起明显增高（P＜0．05）。与P组比较，自2h起，T组肺组织学损伤明显减轻（P＜0．05），肺血流量明显增加（P＜0．05）；自6h起，PLA2活性、TXA2／PGI2明显降低（P＜0．05）。结论 ANP大鼠肺微循环障碍及相关炎症介质的升高是ANP早期肺损伤的重要原因，丹参对ANP肺损伤具有保护作用。