There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations o...There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.展开更多
Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrost...Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.展开更多
A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonis...A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.展开更多
Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not...Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts;the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.展开更多
Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immun...Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immunopathogenesis of hypertension and have an agonist effect similar to angiotensin II. Methods Autoantibodies against AT1 receptor were purified from sera of patients with primary hypertension by affinity chromatography. Proliferation of cultured rat vascular smooth muscle cells was detected by bromodeoxyuridine incorporation and activation of signalling molecules detected by Western blotting and electrophoretic mobility shift assay. Results The AT1-RAb caused a significant proliferation similar to the Ang II during first 24 hours. The levels of nuclear factor-KB （NF-KB）, phosphorylated JAK2., phosphorylated STAT1 （pSTAT1） and phosphorylated STAT3 （pSTAT3） molecules were increased in response to the autoantibodies. In contrast, the activations of NF-KB and JAK-STAT were blocked by Iosartan, pyrrolidinedithiocarbamate （a specific inhibitor of NF-KB） and AG490 （a specific inhibitor of the JAK2. tyrosine kinase）. The expressions of NF-KB, pSTAT1 and pSTAT3 reached peak levels at different times. Moreover, the relative densities of electrophoretic bands showed that activation of pSTAT3 was more significant than STAT1 induced by AT1 -RAb. Conclusions These results suggest that the autoantibodies against AT1 receptor have an agonist effect similar to Ang II in proliferation of VSMCs and the NF-KB and JAK-STAT proteins play essential roles. The effect is different from Angll in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.展开更多
The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary ...The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary artery vascular remodeling.Forty Arbor Acres(AA)broilers were randomly divided into four groups(n=10):a control group(deionized water,Og/L NaCl),a freshwater group(FW,deionized water+1 g/L NaCl),highly salinized freshwater group 1(H-SFW-1,deionized water+2.5 g/L NaCl)and highly salinized freshwater group 2(H-SFW-2,deionized water+5 g/L NaCl).The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water(H-SFW-1&H-SFW-2),which significantly increased the content of angiotensin II(Ang II)and the expression of angiotensin II type 1(AT1)receptor protein.Meanwhile,it significantly decreased the expression of dopamine receptor D4(DRD4)protein.The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers,which could be significantly inhibited by DRD4 agonists(D4A,HY-101384A)and enhanced by DRD4 inhibitors(D4I;HY-B0965).In addition,the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers,either at the transcriptional or translational level.At the same time,the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A.The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner.These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers,accompanied by varying degrees of proliferation of pulmonary artery smooth muscle.This mechanism may involve response of its receptor being induced by increased Ang II,while DRD4 can negatively regulate it.展开更多
In order to investigate the immunological damage in rat immunized with AT1-receptor peptide, 18 male Wistar rats were divided into two groups: immunized-group (n=12), each rat was immunized with 150 μg AT 1-receptor...In order to investigate the immunological damage in rat immunized with AT1-receptor peptide, 18 male Wistar rats were divided into two groups: immunized-group (n=12), each rat was immunized with 150 μg AT 1-receptor petide coupled to bovine serum albumin, together with Freund's adjuvant. Control group (n=6), sham-immunized, 'immunized liquid' was same as immunized-group except AT1-receptor peptide. Systolic blood pressure (SBP) was measured by using the tail-cuff technique, antibody against AT1-receptor peptide detected by using ELISA method, and left ventricular myocardium and renal cortex sections were observed under light and electron microscopy. There was no significant difference in SBP and light microscopic observation of the tissue sections between the immunized-group and control group. The O.D. value of anti-AT1-receptor peptide antiserum was significantly higher in the immunized-group than in the rats before immunization and control group (P<0.01). Positive rate in the immunized-group was 100 %, while 0 % in the control group. Ultramicroscopic morphology showed potential myocardial injury, including: increase in number of mitochondria, swelling of many mitochondria with reduction in number or absence of their cristae and cristolysis, disorder of the cardiac myofibrils, and myofibrillar disruption and myocytolysis. And lysosomes were increased in renal tubular epithelia. The AT1-receptor peptide could induce to generate the antibody against AT1-receptor peptide and lead to myocardial and renal damage in rats.展开更多
Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and ...Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca2+]i elevation was abolished in the presence of the ETA receptor blocker BQ123, but was not affected by the ETB receptor blocker BQ788. ET-1-induced an increase in [Ca2+]i, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.展开更多
Objective The study will explore effects of the autoantibodies against AT1 receptor and angiotensin Ⅱ on the refractory hypertension. Methods Seventy-seven patients (46 men and 31 women) with essential hypertension w...Objective The study will explore effects of the autoantibodies against AT1 receptor and angiotensin Ⅱ on the refractory hypertension. Methods Seventy-seven patients (46 men and 31 women) with essential hypertension were divided into groups of refractory hypertension (RH) and hypertension (HT) according to the 1999 WHO-ISH Guidelines for the Management of Hypertension. Forty normotensives (22 men) were recruited as controls. The mean age was 54. 3±13 years old in RH group, 53. 5±9 years old in HT group and 51. 2±11. 9 years old in normotensives (NT) group. The mean blood pressure was 154. 2±9. 4/98. 4± 8. 2 mmHg in RH group and 130. 1±7. 6/80. 5±6. 7 mmHg in HT group after combination drug therapy of hypertension for 4 weeks. Blood pressure in NT group was 120. 8±11. 7/76. 4 ± 7. 2 mmHg. The epitope of the 2nd extracellular loops of AT1 receptor was synthesized and used as antigens to screen the autoantibodies by ELISA. Plasma angiotensin (Ang) II were examined by a radioimmunoassay. Results The autoantibodies against AT1 receptor were positive in 18 (46. 15 %) patients with RH, in 4 (10. 5 % ) hypertension and in 3 (7. 5 % ) normotensives, P < 0. 01. Ang Ⅱwas 57. 01±52. 63 pmol/L in patients with RH. Both the autoantibodies positive and the Ang Ⅱ increasing were 4 (10. 3 % ) cases, both normal were 7 (17. 9 % ) cases, the autoantibodies positive or Ang II increasing was all of 14 (35. 9 % ) cases (x2 = 0. 09, P>0. 05) . There was no relationship between the autoantibodies against AT1 receptor and the angiotensin Ⅱ in refractory hypertension. Conclusion The autoantibodies against AT1 receptor and Ang Ⅱ might be two independent factors in developing of refractory hypertension. The findings suggest that AT1 receptor an-tagnist used in the treatment of refractory hypertension might have an important value.展开更多
文摘There is a pathophysiological correlation between arterial hypertension and diabetes mellitus, established since the pre-diabetic state in the entity known as insulin resistance. It is known that high concentrations of angiotensin-Ⅱ enable chronic activation of the AT1 receptor, promoting sustained vasoconstriction and the consequent development of high blood pressure. Furthermore, the chronic activation of the AT1 receptor has been associated with the development of insulin resistance. From a molecular outlook, the AT1 receptor signaling pathway can activate the JNK kinase. Once activated, this kinase can block the insulin signaling pathway, favoring the resistance to this hormone. In accordance with the previously mentioned mechanisms, the negative regulation of the AT1receptor could have beneficial effects in treating metabolic syndrome and type 2diabetes mellitus. This review explains the clinical correlation of the metabolic response that diabetic patients present when receiving negatively regulatory drugs of the AT1 receptor.
文摘Growing evidence has highlighted that angiotensin-converting enzyme(ACE)-inhibitors(ACEi)/AT1 receptor blockers(ARBs)may influence the complex interplay between dopamine and the renin-angiotensin system in the nigrostriatal pathway,thus affecting the development of levodopa-induced dyskinesia in Parkinson’s disease(PD).In the present study,we analyzed whether the use of this class of medication was associated with a reduced occurrence of levodopa-induced dyskinesia,using electronically-stored information of idiopathic PD patients enrolled at Novara University Hospital“Maggiore della Carità”.We conducted a retrospective case-control study identifying PD patients with dyskinesias(PwD;n=47)as cases.For each PwD we selected a non-dyskinetic control(NoD),nearly perfectly matched according to sex,Unified Parkinson’s Disease Rating Scale(UPDRS)part III score,and duration of antiparkinsonian treatment.Binary logistic regression was used to evaluate whether dyskinesias were associated with ACEi/ARBs use.Ninety-four PD patients were included,aged 72.18±9 years,with an average disease duration of 10.20±4.8 years and 9.04±4.9 years of antiparkinsonian treatment.The mean UPDRS part III score was 18.87±7.6 and the median HY stage was 2.In the NoD group,25(53.2%)were users and 22(46.8%)non-users of ACEi/ARBs.Conversely,in the PwD group,11(23.4%)were users and 36 non-users(76.6%)of this drug class(Pearson chi-square=8.824,P=0.003).Concerning general medication,there were no other statistically significant differences between groups.After controlling for tremor dominant phenotype,levodopa equivalent daily dose,HY 3-4,and disease duration,ACEi/ARBs use was a significant predictor of a lower occurrence of dyskinesia(OR=0.226,95%CI:0.080-0.636,P=0.005).Therefore,our study suggests that ACEi/ARBs may reduce levodopa-induced dyskinesia occurrence and,thanks to good tolerability and easy management,represent a feasible choice when dealing with the treatment of hypertension in PD patients.The study was approved by the Ethics Committee of Novara University Hospital“Maggiore della Carità”(CE 65/16)on July 27,2016.
基金We are thankful to the National Natural Science Foundation of China(No.30371688)Key Fund of Ministry of Education of China(No.03089)for financial support.
文摘A series of 2-alkylbenzimidazole derivatives 9a-n have been designed and synthesized as a novel class of non-peptide angiotensin H AT1 receptor antagonists. The synthesized compounds were evaluated for their antagonism of angiotensin H, induced contraction in the rabbit thoracic aortic ring and the results showed that compounds 9a, 9g and 9j exhibited potent antagonistic activity of AT1 receptor.
文摘Angiotensin II (Ang II) is known to elicit cardiac fibrosis by activating the AT1 receptor and CD44 expression in the in vivo model. However, the cellular/molecular mechanisms underlying cardiac fibrosis are still not well understood. This study examines the roles of the AT1 receptor and CD44 gene expression in collagen synthesis through Ang II stimulated cardiac fibroblasts. Fibroblasts were isolated from the neonatal rat hearts;the activation of fibroblasts was evaluated using the assays of cell viability and migration, and silencing of CD44 gene expression was conducted with small interfering RNA (siRNA). Results showed that Ang II significantly increases the cell proliferation and migration in a dose-dependent manner. Upon activation, the protein levels of TGF-β1, Smad2, Smad4 and collagen I were significantly increased (all p < 0.05 vs. unstimulated cells), but these changes were significantly downregulated by the AT1 receptor blocker, telmisartan (all p < 0.05 vs. Ang II activated cells). Furthermore, mRNA and protein level of CD44 were upregulated, and there was a linear correlation between CD44 and TGF-β1 as demonstrated by Pearson correlation analysis (r = 0.955, p < 0.01). Gene transfection of fibroblasts with Ad-CD44 siRNA, as evidenced by low levels of CD44 mRNA and protein, significantly reduced the production of collagen I. In summary, these results indicate that the proliferation, migration and collagen production from Ang II activated cardiac fibroblasts are potentially mediated by the AT1 receptor and CD44. Such a signaling mechanism could be crucial for the production of collagen and the development of tissue fibrosis in the heart.
基金The first two authors contributed equally to this work. This study was supported by a grant from National Natural Science Foundation of China （No. G30300/33）.
文摘Background Autoantibodies against angiotensin AT1 receptor have been discovered in patients with preeclampsia or malignant hypertension. Some studies have demonstrated that the autoantibodies are involved in the immunopathogenesis of hypertension and have an agonist effect similar to angiotensin II. Methods Autoantibodies against AT1 receptor were purified from sera of patients with primary hypertension by affinity chromatography. Proliferation of cultured rat vascular smooth muscle cells was detected by bromodeoxyuridine incorporation and activation of signalling molecules detected by Western blotting and electrophoretic mobility shift assay. Results The AT1-RAb caused a significant proliferation similar to the Ang II during first 24 hours. The levels of nuclear factor-KB （NF-KB）, phosphorylated JAK2., phosphorylated STAT1 （pSTAT1） and phosphorylated STAT3 （pSTAT3） molecules were increased in response to the autoantibodies. In contrast, the activations of NF-KB and JAK-STAT were blocked by Iosartan, pyrrolidinedithiocarbamate （a specific inhibitor of NF-KB） and AG490 （a specific inhibitor of the JAK2. tyrosine kinase）. The expressions of NF-KB, pSTAT1 and pSTAT3 reached peak levels at different times. Moreover, the relative densities of electrophoretic bands showed that activation of pSTAT3 was more significant than STAT1 induced by AT1 -RAb. Conclusions These results suggest that the autoantibodies against AT1 receptor have an agonist effect similar to Ang II in proliferation of VSMCs and the NF-KB and JAK-STAT proteins play essential roles. The effect is different from Angll in that STAT3 is the main downstream activating molecule in JAK-STAT signalling pathway.
基金This research was funded by the Fundamental Research Funds for the Central Universities(Grant No.2662020DKPY013)the National Natural Science Foundation of China(Grant No.31972748)the Huazhong Agricultural University 2020 College Student Science and Technology Innovation Fund(SRF).
文摘The major cause of pulmonary vascular remodeling in broilers is abnormal proliferation of vascular smooth muscle cells(VSMCs),and one of the main causes of pulmonary hypertension syndrome(PHS)in broilers is pulmonary artery vascular remodeling.Forty Arbor Acres(AA)broilers were randomly divided into four groups(n=10):a control group(deionized water,Og/L NaCl),a freshwater group(FW,deionized water+1 g/L NaCl),highly salinized freshwater group 1(H-SFW-1,deionized water+2.5 g/L NaCl)and highly salinized freshwater group 2(H-SFW-2,deionized water+5 g/L NaCl).The results of in vivo experiments showed that vascular smooth muscle of the broilers could be significantly proliferated by intake of high-salinity fresh water(H-SFW-1&H-SFW-2),which significantly increased the content of angiotensin II(Ang II)and the expression of angiotensin II type 1(AT1)receptor protein.Meanwhile,it significantly decreased the expression of dopamine receptor D4(DRD4)protein.The results of in vitro experiments showed that exogenous Ang II induced the proliferation of primary VSMCs in broilers,which could be significantly inhibited by DRD4 agonists(D4A,HY-101384A)and enhanced by DRD4 inhibitors(D4I;HY-B0965).In addition,the results of immunoblotting and fluorescence quantitative PCR showed that AT1 receptors could be negatively regulated by DRD4 in VSMCs of broilers,either at the transcriptional or translational level.At the same time,the expression of AT1 receptor could be increased by DRD4 inhibition by D4I and decreased by DRD4 activation by D4A.The negative regulatory effect of DRD4 on AT1 receptor occurred in a dose-dependent manner.These results indicate that long-term intake of highly salinized fresh water can cause PHS in broilers,accompanied by varying degrees of proliferation of pulmonary artery smooth muscle.This mechanism may involve response of its receptor being induced by increased Ang II,while DRD4 can negatively regulate it.
文摘In order to investigate the immunological damage in rat immunized with AT1-receptor peptide, 18 male Wistar rats were divided into two groups: immunized-group (n=12), each rat was immunized with 150 μg AT 1-receptor petide coupled to bovine serum albumin, together with Freund's adjuvant. Control group (n=6), sham-immunized, 'immunized liquid' was same as immunized-group except AT1-receptor peptide. Systolic blood pressure (SBP) was measured by using the tail-cuff technique, antibody against AT1-receptor peptide detected by using ELISA method, and left ventricular myocardium and renal cortex sections were observed under light and electron microscopy. There was no significant difference in SBP and light microscopic observation of the tissue sections between the immunized-group and control group. The O.D. value of anti-AT1-receptor peptide antiserum was significantly higher in the immunized-group than in the rats before immunization and control group (P<0.01). Positive rate in the immunized-group was 100 %, while 0 % in the control group. Ultramicroscopic morphology showed potential myocardial injury, including: increase in number of mitochondria, swelling of many mitochondria with reduction in number or absence of their cristae and cristolysis, disorder of the cardiac myofibrils, and myofibrillar disruption and myocytolysis. And lysosomes were increased in renal tubular epithelia. The AT1-receptor peptide could induce to generate the antibody against AT1-receptor peptide and lead to myocardial and renal damage in rats.
基金Supported by the National Natural Science Foundation of China (Grant No. 200830870910).
文摘Using fura-2-acetoxymethyl ester (AM) fluorescence imaging and patch clamp techniques, we found that endothelin-1 (ET-1) significantly elevated the intracellular calcium level ([Ca2+]i) in a dose-dependent manner and activated the L-type Ca2+ channel in cardiomyocytes isolated from rats. The effect of ET-1 on [Ca2+]i elevation was abolished in the presence of the ETA receptor blocker BQ123, but was not affected by the ETB receptor blocker BQ788. ET-1-induced an increase in [Ca2+]i, which was inhibited 46.7% by pretreatment with a high concentration of ryanodine (10 μmol/L), a blocker of the ryanodine receptor. The ET-1-induced [Ca2+]i increase was also inhibited by the inhibitors of protein kinase A (PKA), protein kinase C (PKC) and angiotensin type 1 receptor (AT1 receptor). We found that ET-1 induced an enhancement of the amplitude of the whole cell L-type Ca2+ channel current and an increase of open-state probability (NPo) of an L-type single Ca2+ channel. BQ123 completely blocked the ET-1-induced increase in calcium channel open-state probability. In this study we demonstrated that ET-1 regulates calcium overload through a series of mechanisms that include L-type Ca2+ channel activation and Ca2+-induced Ca2+ release (CICR). ETA receptors, PKC, PKA and AT1 receptors may also contribute to this pathway.
文摘Objective The study will explore effects of the autoantibodies against AT1 receptor and angiotensin Ⅱ on the refractory hypertension. Methods Seventy-seven patients (46 men and 31 women) with essential hypertension were divided into groups of refractory hypertension (RH) and hypertension (HT) according to the 1999 WHO-ISH Guidelines for the Management of Hypertension. Forty normotensives (22 men) were recruited as controls. The mean age was 54. 3±13 years old in RH group, 53. 5±9 years old in HT group and 51. 2±11. 9 years old in normotensives (NT) group. The mean blood pressure was 154. 2±9. 4/98. 4± 8. 2 mmHg in RH group and 130. 1±7. 6/80. 5±6. 7 mmHg in HT group after combination drug therapy of hypertension for 4 weeks. Blood pressure in NT group was 120. 8±11. 7/76. 4 ± 7. 2 mmHg. The epitope of the 2nd extracellular loops of AT1 receptor was synthesized and used as antigens to screen the autoantibodies by ELISA. Plasma angiotensin (Ang) II were examined by a radioimmunoassay. Results The autoantibodies against AT1 receptor were positive in 18 (46. 15 %) patients with RH, in 4 (10. 5 % ) hypertension and in 3 (7. 5 % ) normotensives, P < 0. 01. Ang Ⅱwas 57. 01±52. 63 pmol/L in patients with RH. Both the autoantibodies positive and the Ang Ⅱ increasing were 4 (10. 3 % ) cases, both normal were 7 (17. 9 % ) cases, the autoantibodies positive or Ang II increasing was all of 14 (35. 9 % ) cases (x2 = 0. 09, P>0. 05) . There was no relationship between the autoantibodies against AT1 receptor and the angiotensin Ⅱ in refractory hypertension. Conclusion The autoantibodies against AT1 receptor and Ang Ⅱ might be two independent factors in developing of refractory hypertension. The findings suggest that AT1 receptor an-tagnist used in the treatment of refractory hypertension might have an important value.
