侧脑室注射血管紧张素Ⅱ促进内源性洋地黄样因子释放

目的 探讨侧脑室注射血管紧张素Ⅱ对内源性洋地黄样因子 (EDLF)释放的影响。方法 大鼠侧脑室注射血管紧张素Ⅱ及侧脑室注射Saralasin或损毁第三脑室前腹区 (AV3V)预处理 ,放射免疫方法测定血清EDLF浓度的变化。结果 侧脑室注射AngⅡ可引起血清EDLF浓度升高 ;Saralasin预处理或海人酸损毁AV3V区可阻断侧脑室注射AngⅡ引起的血清EDLF升高效应。

血管紧张素Ⅱ受体拮抗剂治疗高血压

目前，口服非肽类血管紧张Ⅱ受体阻滞剂已用于治疗的高血压病，充血性心力衰竭和保护肾脏，这类药物具有两种心血管作用。首先，能够阻断血和紧张Ⅱ的缩血管作用，降低高血压患者的血压，减轻心力衰竭患者的后负荷。其次，阻断血管紧张素Ⅱ的生长促进作用，延缓血管肥厚和动脉粥样硬化，消退左心室肥厚，降低肾小球内压，这类药物的作用机制同血管紧张素转换酶抑制剂不一样。ＡＣＥ抑制剂可能没有完全阻断血管紧张素Ⅱ的生成。

盐敏感性高血压病患者血浆心钠素、血管紧张素-Ⅱ和醛固酮水平测定及苯那普利治疗的初步观察

目的 探讨心钠素 (ANP)和肾素 血管紧张素 醛固酮系统 (RAAS)在盐敏感性高血压病发病中的作用及苯那普利的降压作用和ANP的关系。方法 64例高血压病患者分为盐敏感性 (SS ,3 0例 )和非盐敏感性高血压病组 (NSS ,3 4例 ) ,测定盐负荷前与盐负荷期间血浆ANP、血管紧张素Ⅱ(AngⅡ )和醛固酮 (ALD)水平。 3 0例正常人为对照组。SS组患者采用自身对照的方法予以口服安慰剂和苯那普利 ( 10～ 2 0mg/d) ,观察治疗前后血压及血浆ANP水平的变化。结果 ( 1)基础血浆ANP水平 ,SS组显著低于NSS组 ,NSS组显著低于正常组 [分别为 ( 110 2 8± 15 4 0 )pmol/L ,( 14 5 5 2± 2 6 5 3 )pmol/L和 ( 197 74± 2 6 2 0 )pmol/L ,P均 <0 0 1]。盐负荷期SS组和NSS组血浆ANP水平均明显增高[分别为 ( 13 3 5 6± 3 4 0 3 )pmol/L和 ( 169 2 0± 3 5 91)pmol/L ,P均 <0 0 5 ]。增高的百分数两组间差异无显著性 (P >0 0 5 )。但SS组血浆ANP仍低于正常水平。 ( 2 )基础血浆AngⅡ和ALD水平在SS组与NSS组间无明显差异 (P均 >0 0 5 )。盐负荷期SS组和NSS组血浆AngⅡ和ALD水平无明显改变 (P均 >0 0 5 )。 ( 3 )SS组于苯那普利治疗后血压明显降低 (P均 <0 0 1) ,血浆ANP水平 [( 14 6 74± 3 1 86)pmol/L]显著增高

Protective effects of icariin on human umbilical vein endothelial cell injured by angiotensin Ⅱ

To investigate the effects of icariin （ICA） on angiotensin Ⅱ（Ang Ⅱ）-induced injury in human umbilical vein endothelial cells line （ECV-304）. The ECV-304 cells were cultured in vitro. After 24 h incubating with icariin, the model of AngⅡ-induced injury in ECV-304 was established. The cell viability （MTT method）, Lactate dehydrogenase （LDH） release and Nitric oxide （NO） production in the medium, the capacity of scavenging superoxide anion radicals （O2^-） and hydroxyl radicals （.OH） were measured. The activities of superoxide dismutase （SOD）, total nitric oxide synthase （T-NOS）, inducible nitric oxide synthase （iNOS） and constitutive nitric oxide synthase （cNOS） in the cells were determined. Compared with the Ang Ⅱ-treated group, ICA can significantly raise the viability of EC, increase the activities of SOD, T-NOS and cNOS, increase the production of NO, enhance the capacity of scavenging superoxide anion radicals （ O2^- ） and hydroxyl radicals（.OH）, and lower LDH leakage and iNOS activity. The results suggest that ICA can protect endothelial cells （ECV-304） from Ang II-induced injury.

The angiotensin Ⅱ type 1 receptor and receptor-associated proteins

The mechanisms of regulation, activation and signal transduction of the angiotensin II (Ang II) type 1 (AT1) receptor have been studied extensively in the decade after its cloning. The AT1 receptor is a major component of the renin-angiotensin system (RAS). It mediates the classical biological actions of Ang II. Among the structures required for regulation and activation of the receptor, its carboxyl- terminal region plays crucial roles in receptor internalization, desensitization and phosphorylation. The mechanisms involved in heterotrimeric G-protein coupling to the receptor, activation of the downstream signaling pathway by G proteins and the Ang II signal transduction pathways leading to specific cellular responses are discussed. In addition, recent work on the identification and characterization of novel proteins associated with carboxy1-terminus of the AT1 receptor is presented. These novel proteins will advance our understanding of how the receptor is internalized and recycled as they provide molecular mechanisms for the activation and regulation of G-protein-coupled receptors.

Effects of angiotensin Ⅱ receptor antagonist, Losartan on the apoptosis, proliferation and migration of the human pancreatic stellate cells

AIM： To investigate the effects of AT, （Type 1 angiotensin Ⅱ receptor） antagonist （Losartan） on the apoptosis, proliferation and migration of the human pancreatic stellate cells （hPSCs）. METHODS： hPSCs were isolated from pancreatic sample of patients with pancreatic carcinoma using radioimmunoassay （RIA） technique to detect the concentration of AngⅡ in culture media and cell homogenate. Immunocytochemistry （ICC） and in situ hybridization （ISH） methods were utilized to test AT1 expression in hPSCs. Effects of Losartan on hPSCs proliferation, apoptosis and migration were investigated using BrdU incorporation, TUNEL, flow cytometry （FCM）, and phase-contrast microscope separately when cells treated with Losartan. Immunofluorescence and Western blot were applied to quantify the expression of type Ⅰ collagen in hPSCs. RESULTS： There exists AT1 expression in hPSCs, while no AngⅡ was detected in culture media and cell homogenate. Losartan induces cell apoptosis in a doseand time-dependent manner （apparently at 10^-5 mol/L）, no pro-proliferative effect was observed in the same condition. Corresponding dosage of Losartan can also alleviate the motion capability and type Ⅰ collagen content of hPSCs compared with AngⅡ treatment and non-treatment control groups. CONCLUSION： These findings suggest that paracrine not autocrine functions of AngⅡ may have effects on hPSCs, which was mediated by AT1 expressed on cells, while Losartan may exert anti-fibrotic effects by inhibiting hPSCs motion and partly by inducing apoptosis.

Effect of Microinfusion of Angiotensin Ⅱ into the RVLM in Rats on the Baroreceptor Reflex Sensitivity

Objective: The present study was designed to investigate the effect of microinfusion angiotensin Ⅱ(Ang Ⅱ),Ang Ⅱ type 1(AT_1)receptor antagonist losartan into the rostral ventrolateral medulla(RVLM)on the baroreceptor reflex sensitivity(BRS)in urethane-anesthetized rats. Methods: Reflex changes in heart rate(HR)were elicited by bolus intravenous injection of phenylephrine before and during RVLM microinfusion of saline(0.5 μl/h),Ang Ⅱ (1.5 nmol/h),losartan(250 nmol/h),and Ang Ⅱ(1.5 nmol/h)pretreated with microinjection of losartan (50 nmol/0.51 μl)into the RVLM.The average ratio between changes in HR in beats per minute(beats·min -1)and changes in mean arterial pressure [MAP,mmHg(1 mmHg=0.133 kPa)] was used as an index of BRS. Results: Ang Ⅱ resulted in a significant decrease in the BRS for reflex bradycardia compared with control(-2.1±0.1 vs-3.9±0.4 beats·min -1·mmHg -1).Microinfusion of losartan had no significant effect on BRS for reflex bradycardia.The effect of Ang Ⅱ was almost completely abolished by pretreatment with microinjection of losartan. Conclusion:These results showed that the exogenous Ang Ⅱ in the RVLM produces inhibitory modulation of BRS,which is mediated by AT_1 receptor.However,AT_1 receptor in the RVLM is not involved in the tonic control of BRS.

REGULATING EFFECTS OF VASCULAR ENDOTHELIAL GROWTH FACTOR AND ANG Ⅱ ON FROG'S PERICARDIAL STOMATA, MESOTHELIUM AND ANGIOGENESIS

To observe the regulating effects of vascular endothelial growth factor (VEGF) and angiotensinⅡ (ANG II) on the frog’s pericardium, lymphatic stomata and angiogenesis so as to reveal their effects and mechanism on the mesothelial permeability, lymphatic stoma regulation and myocardial hypertrophy. Methods. VEGF and ANGⅡ were injected into the frog’s peritoneal cavity so as to examine the changes of the pericardial stromata by using transmission electron microscopy, scanning electron microscopy and computerized imaging analysis. Results. Scattered distributed pericardial stomata were found on the parietal pericardium of the frog with a few sinusoid mesothelial cells, whose blood supply was directly from the cardiac chambers flowing into the trabecular spaces of the myocardium (because there are no blood vessels in the myocardium of the frog). The average diameters of the pericardial stomata in VEGF and ANGⅡ groups were 1.50μ m and 1.79μ m respectively, which were much larger than those in the control group (0.72μ m, P Conclusions. VEGF and ANGⅡ could strongly regulate the pericardial stomata by increasing their numbers and openings with larger diameters and higher distribution density. They could also increase the sinusoid areas with the result of the higher permeability of the pericardium, which clearly indicated that VEGF and ANGⅡ could speed up the material transfer of the pericardial cavity and play an important role in preventing myocardial interstitial edema. Yet there was no strong evidence to show the angiogenesis in the myocardium.

Expression of Angiotensin Ⅱ and Aldosterone in Radiation-induced Lung Injury

Objective Radiation-induced lung injury （RILl） is the most common, dose-limiting complication in thoracic malignancy radiotherapy. Considering its negative impact on patients and restrictions to efficacy, the mechanism of RILl was studied. Methods Wistar rats were locally irradiated with a single dose of 0, 16, and 20 Gy to the right half of the lung to establish a lung injury model. Two and six months after irradiation, the right half of the rat lung tissue was removed, and the concentrations of TGF-[31, angiotensin II, and aldosterone were determined via enzyme-linked immunosorbent assay. Results Statistical differences were observed in the expression levels of angiotensin II and aldosterone between the non-irradiation and irradiation groups. Moreover, the expression level of the angiotensin II-aldosterone system increased with increasing doses, and the difference was still observed as time progressed. Conclusions Angiotensin II-aldosterone system has an important pathophysiological function in the progression of RILI.

Suppression of angiotensin Ⅱ stimulated responses in aortic vascular smooth muscle cells of experimental cirrhotic rats

Functional responses to angiotensin Ⅱ (AT-Ⅱ) were determined in aortic vascular smooth muscle cells (VSMCs) from experimental cirrhotic rats. Our data showed that AT-Ⅱ-stimulated extracellular acidification rate (ECAR), which was measured by Cytosensor microphysiometry, was significantly reduced in the aortic VSMCs from the cirrhotic rats as compared to those from the control animals. The ability of AT-Ⅱ to promote formation of inositol phosphates, the second messenger produced by the activation of Gq-coupled receptors, was also considerably suppressed in the cirrhotic VSMCs. Furthermore, the maximal p42/44 MAPK phosphorylation stimulated by AT-Ⅱ was significantly reduced in the cirrhotic VSMCs in contrast to that in the normal VSMCs. Taken together, our data clearly demonstrated that the functional responses to AT-Ⅱ was severely suppressed in aortic VSMCs in cirrhosis, indicating the impairment of general Gq-coupled receptor signaling and subsequent biological function in the cirrhotic VSMCs.

Multiple templates-based homology modeling and docking analysis of angiotensin Ⅱ type 1 receptor

Using the latest reported homologous Chemokine receptors （PDB ID： 3ODU, 3OE0 and 3OE6） as templates, twenty models of angiotensin II （Ang II） type 1 （AT1） receptor （known as p30556） were generated by multiple templates homology modeling. According to the results of the initial validation of these twenty models, the model 0020 was finally chosen as the best one for further studies. Then, a 2 ns molecular dynamic （MD） simulation for model 0020 was conducted in normal saline （0.9%, w/F） under periodical boundary conditions, which was followed by docking studies of model 0020 with several existing AT1 receptor blockers （ARBs）. The docking results reveal that model 0020 possesses good affinities with these docked ARBs which are in accordance with both the IC50 inhibitor values and their curative effects. The results also show more potent interactions between the model 0020 and its ARBs than those of ever reported results, such as hydrogen bonds, hydrophobic interactions, and especially cation-n interactions and π-π interactions which have never been reported before. This may reveal that the structure of the model 0020 is quite close to its real crystal structure and the model 0020 may have the potential to be used for structure based drug design：

高温、噪声、振动复合应激时人体血压和缩血管激素的变化

目的为了给航卫保障和座舱环控系统设计提供依据，我们探讨了高温、噪声、振动复合应激时人体血压和缩血管激素的改变。方法按均匀设计，１１名健康男性青年完成１９次试验。每次试验１２０ｍｉｎ。由专人检测试验前后的收缩压、舒张压和４种缩血管激素。结果复合应激使受试者的舒张压、血管紧张素Ⅱ显著增加。肾素、醛固酮和内皮素则无显著性变化。结论①血管紧张素Ⅱ是引起受试者血压增高的重要因素。②噪声与高温、振动强度、振动频率之间对舒张压和血管紧张素Ⅱ有交互作用，噪声均为主效应。③高温对舒张压的作用为拮抗效应。高温和振动强度＋振动频率对血管紧张素Ⅱ均表现为协同效应。

Effects of combination of irbesartan and perindopril on calcineurin expression and sarcoplasmic reticulum Ca^(2+)-ATPase activity in rat cardiac pressure-overload hypertrophy

Aim： To observe effects of angiotensin （Ang） II receptor antagonist （ATI） irbesartan and angiotensin-converting enzyme （ACE） inhibitor perindopril on rat myocardium calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity in the model of pressure-overload cardiac hypertrophy. Methods： Forty male adult Sprague Dawley rats were divided into 5 groups One group was treated by sham operation; four groups were myocardium hypertrophy cases caused by banding aortic above renal artery. Drugs were given one week after operation. Group 1： sham group, rats （n=8） were gavaged with normal saline 2 ml/（kg·d） （ig）; Group 2： control group, rats （n=8） were treated with normal saline 2 ml/（kg·d） （ig）; Group 3： rats （n=8） were given perindopril 2 mg/（kg·d） （ig）; Group 4： rats （n=8） were treated with irbesartan 20 mg/（kg·d） （ig）; Group 5： rats （n=8） were given irbesartan 20 mg/（kg·d） plus perindopril 2 mg/（kg·d） （ig）. Morphometric determination, calcineurin expression and sarcoplasmic reticulum Ca^2＋-ATPase activity were done at the end of 6 week of drug intervention. Expression of calcineurin in myocardium was detected by immunohistochemistry. Results： Left ventricular mass index （LVMI）, transverse diameter of myocardial cell （TDM）, calcineurin activity were remarkably decreased after drug intervention and this decrease was most remarkable in the combination drug therapy group. Sarcoplasmic reticulum Ca^2＋-ATPase activity was increased after drug intervention, especially in the combined drug therapy group. Calcineurin expression in myocardium was remarkably decreased after drug intervention. LVMI was positively correlated with TDM and calcineurin, negatively correlated with sarcoplasmic reticulum Ca^2＋-ATPase. Conclusion： These data suggest that irbesartan and perindopril inhibit cardiac hypertrophy through the increased activity of sarcoplasmic reticulum Ca^2＋-ATPase and decreased expression of calcineurin. Their combination had better effects on regressing of ventricular hypertrophy.

Changes in Plasma Angiotensin II and Circadian Rhythm of Blood Pressure in Hypertensive Patients with Sleep Apnea Syndrome Before and After Treatment

Objective To explore the changes in plasma angiotensin II （Ang Ⅱ） and circadian rhythm of blood pressure among hypertensive patients with sleep apnea syndrome （SAS） before and after continuous positive airway pressure （CPAP） or surgical treatment. Methods A total of 180 essential hypertension patients were enrolled in our study. The determination of plasma Ang Ⅱ concentration, ambulatory blood pressure （ABP）, and polysomnography （PSG） monitoring were performed before and 3 months after CPAP or surgical treatment. Results Patients were classified into three groups by their apnea-hypopnea index （AHI）： essential hypertension group （EH group, n=72; AHI〈5）, essential hypertension with mild SAS group （EH＋mild SAS group, n=60, 5≤AHI〈20）, and essential hypertension with moderate and severe SAS group （EH＋moderate-severe SAS group, n=48, AHI_〉20）. The concentrations of plasma AngⅡ in the above three groups were 13.42±3.27, 16.17±3.82, and 18.73±4.05 ng/mL respectively before treatment, and AngⅡ concentration in EH patients combined with SAS was significantly higher than that in EH group （all P〈0.05）. After treatment the values in the latter two groups significantly decreased to 14.67±2.56 and 15.03±3.41 ng/mL respectively （P〈0.05）. The incidence of non-dipper blood pressure curve in EH patients was 31.9%, and those in hypertensive patients with mild SAS and moderate-severe SAS were 51.7% and 58.3%, respectively before treatment. The incidence of non-dipper blood pressure curve in the EH patients with mild SAS was significantly higher than that of patients with EH alone （P〈0.05）. After CPAP treatment or surgery, the incidence of non-dipper blood pressure curve in the two SAS groups was significantly decreased to 38.3% and 39.6%, respectively （P〈0.05）. Conclusions Ang Ⅱ might play a role in blood pressure variability in patients with obstructive SAS. CPAP or surgical treatment can improve blood pressure disorder and decrease plasma Ang Ⅱ level in patients with obstructive SAS.

Angiotensin-receptor blockers as therapy for mild-to-moderate hypertension-associated non-alcoholic steatohepatitis

AIM： TO evaluate insulin resistance, cytolysis and nonalcoholic steatohepatitis （NASH） score （NAS） using the Kleiner and Brunt criteria in 54 patients with NASH and mild-to-moderate hypertension, treated with telmisartan vs valsartan for 20 mo. METHODS： All patients met the NCEP-ATP Ⅲ criteria for metabolic syndrome. Histology confirmed steatohepatitis, defined as a NAS greater than five up to 3 wk prior inclusion, using the current criteria. Patients with viral hepatitis, chronic alcohol intake, drug abuse or other significant immune or metabolic hepatic pathology were excluded. Subjects were randomly assigned either to the valsartan （V） group （standard dose 80 mg o.d., n = 26）, or to the telmisartan （T） group （standard dose 20 mg o.d., n = 28）. Treatment had to be taken daily at the same hour with no concomitant medication or alcohol consumption allowed. Neither the patient nor the medical staff was aware of treatment group allocation. Paired liver biopsies obtained at inclusion （visit 1） and end of treatment （EOT） were assessed by a single blinded pathologist, not aware of patient or treatment group. Blood pressure, BMI, ALT, AST, HOMA-IR, plasma triglycerides （TG） and total cholesterol （TC） were evaluated at inclusion and every 4 mo until EOT （visit 6）. RESULTS： At EOT we noticed a significant decrease in ALT levels vs inclusion in all patients and this decrease did not differ significantly in group T vs group V. HOMA-IR significantly decreased at EOT vs inclusion in all patients but in group T, the mean HOMA-IR decrease per month was higher than in group V. NAS significantly diminished at EOT in all patients with a higher decrease in group T vs group V. CONCLUSION： Angiotensin receptor blockers seem to be efficient in hypertension-associated NASH. Telmisartan showed a higher efficacy regarding insulin resistance and histology, perhaps because of its specific PPAR-gamma ligand effect.

INTERLEUKIN 10 INHIBITS THE RAT VSMC PROLIFERATION AND COLLAGEN SECRETION STIMULATED BY ANGIOTENSIN II

Objective. To study the effect of interleukin 10 (IL- 10) on the angiotensin II (AngII) stimulated rat VSMC proliferation and collagen secretion, and furthermore, explore its mechanism. Methods. On cultured VSMC of rat, 3H- thymine (3H- TdR) and 3H- proline incorporations were used to evaluate the DNA and collagen synthesis, respectively. Western blot and immunoprecipitation were applied to assay the expression and activity of focal adhesion kinase (FAK), respectively. Results. IL- 10 (10－ 8～ 10－ 10g/ml) inhibited the increase of 3H- TdR and 3H- proline incorporation as well as FAK activity, which was induced by 10－ 7mol/L AngII (P< 0.05 or P< 0.01). IL- 10 also obviously downregulated the synthesis and secretion of collagen by AngII stimulated VSMC. But there was no difference in the protein expression of FAK among all the groups (P >0.05). Conclusion. IL- 10 antagonizes the VSMC proliferation and collagen synthesis by regulating FAK activity stimulated by AngII.

Total Glycosides of Ranunculus Japonius Prevent Hypertrophy in Cardiomyocytes via Alleviating Chronic Ca^(2+) Overload

Objective To evaluate the in vitro anti-hypertrophic effect of total Glycosides of Ranunculus Japonius （TGRJ）. Methods Neonatal rat cardiomyocytes were cultured and hypertrophy was induced by adminis- trating isoproterenol （ISO, 10 gmol/L） or angiotensin Ⅱ （AngⅡ, 1 gmol/L） for 48 hours. In the treatment groups, cells were pretreated with TGRJ （0.3 g/L） for 30 minutes prior to hypertrophic stimuli. The anti-hypertrophic effects of TGRJ were examined by measuring cell size, total protein content, and protein synthesis. Intracellular free Ca2＋ concentration （[Ca2＋]i） was evaluated using fluorescence dye Fura-2/AM. Sacroplasmic/endoplasmic reticulum Ca2＋ ATPase 2a （SERCA2a）, atrial natriuretic peptide （ANP）, B-type natriuretic peptide （BNP）, and beta-myosin heavy chain （β-MHC） protein expression levels were measured by Western blotting. SERCA2a activity was assayed by p-nitrophenal phosphate disodium salt hexahydrate method. Results Increased cell size, total protein content, and protein synthesis following ISO or Ang II stimulation were significantly inhibited by pretreatment with TGRJ （all P〈0.05）. This anti-hypertrophic effect of TGRJ was confirmed by its suppressing effect on elevated expression of the three hypertrophic related genetic markers, ANP, BNP, and ^-MHC. In addition, TGRJ inhibited ISO or Ang Ⅱ induced up-regulation of [Ca2＋] under chronic but not acute conditions. And ISO or Ang Ⅱ induced down-regulation of SERCA2a expression and activity was also effectively rectified byTGRJ pretreatment. Conclusions The results of present study suggested that TGRJ could prevent ISO or Ang Ⅱ induced cardiac hypertrophy through improving chronic [Ca2＋]i disorder, might via normalizing SERCA2a expression and activity.

ROLE OF CALCINEURIN IN ANGIOTENSIN II- INDUCED CARDIAC MYOCYTE HYPERTROPHY OF RATS

The present study investigated the role of calcineurin in angiotensin II(AngII)- induced cardiac myocyte hypertrophy of rats. Method. The primary cardiac myocytes were cultured under the standard conditions. The calcineurin activity in AngII- treated cardiomyocytes was tested by using PNPP;protein synethsis rate was assessed by 3H- leucine incorporation; atrial natriuretic factor(ANF) mRNA level was determined by Northern blot analysis. Cell viability was estimated by lactate dehydrogenase(LDH) levels in cultured medium and by dyed cell numbers. Result. After stimulation of 10,100 and 1 000nmol/L of AngII, calcineurin activities in the cardiomyocytes were increased by 13％ ,57％ (P Conclusion. During AngII- induced cardiac myocyte hypertrophy, calcineurin signal pathway is activated, and inhibition of the pathway can attenuate AngII- induced cardiac myocyte hypertrophy, which suggests that the calcineurin signal pathway may play an important role in AngII- induced myocardial hypertrophy of rats.

EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty- four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit＋ bosentan group and Nit＋ losartan group. Nitroglycerin tolerance was induced by 2- day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg－ 1· d－ 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg－ 1· d－ 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit＋ losartan group and Nit＋ bosentan group compared with Nit group [(31.95± 4.45 )％ vs (21.00± 3.69 )％ , P< 0.01 and (33.18± 6.16 )％ vs (21.00± 3.69 )％ , P< 0.01 ,respectively]. The maximal vessel relaxation induced by SNP was the same in 4 different groups but the highest EC50 (concentration which produces 50％ of the maximal response to SNP) was found in tolerant group[(34± 10) nmol/ L,P < 0.01 .The ET- 1 amounts in plasma and vascular tissue were markedly increased by 54％ and 60％ in Nit group compared with those in control group(P< 0.01).The ET- 1 amounts in plasma and vascular tissue were decreased by 30％ and 37％ in Nit＋ losartan group compared with those in Nit group (P< 0.01). Conclusion. Endothelin receptor antagonist and angiotensinⅡ receptor antagonist could prevent against the Nit tolerance .

GPCR-CARMA3-NF-kappaB Signaling Axis： A Novel Drug Target for Cancer Therapy

G protein-coupled receptors （GPCRs） play pivotal roles in regulating various cellular functions. It has been well established that GPCR activates NF-κB and aberrant regulation of GPCR-NF-κB signaling axis leads to cancers. However, how GPCRs induce NF-κB activation remains largely elusive. Recently, it has been shown that a novel scaffold protein, CARMA3, is indispensable in GPCR-induced NF-κB activation. In CARMA3-deficient mouse embryonic fibroblast cells, some GPCR ligand-, like lysophosphatidic acid （LPA）, induced NF-κB activation is completely abolished. Mechanistically, upon GPCR activation, CARMA3 is linked to the membrane by β-arrestin 2 and phosphorylated by some PKC isoform. Phosphorylation of CARMA3 unfolds its steric structure and recruits its downstream effectors, which in turn activate the IKK complex and NF-κB. Interestingly, GPCR （LPA）-CARMA3-NF-κB signaling axis also exists in ovarian cancer cells, and knockdown of CARMA3 results in attenuation of ovarian cancer migration and invasion, suggesting a novel target for cancer therapy. In this review, we summarize the biology of CARMA3, discuss the GPCR （LPA）-CARMA3-NF-κB signaling axis in ovarian cancer and speculate its potential role in other types of cancers. With a strongly increasing tendency to identify more LPA-like ligands, such as endothelin-1 and angiotensin II, which also activate NF-κB through CARMA3 and contribute to myriad diseases, GPCR-CARMA3-NF-κB signaling axis is emerging as a novel drug target for various types of cancer and other myriad diseases.