Recent studies have shown that angiotensin-(1-7) (Ang-[1-7]), which is generated endogenously from both Ang I and II, is a bioactive component of the renin-angiotensin system and may play an important role in the regulation of blood pressure. However, little is known about its role in regulating the reactivity of the afferent arteriole or the mechanism(s) involved. We hypothesized that Ang-(1-7), acting on specific receptors, participates in the control of afferent arteriole tone. We first examined the direct effect of Ang-(1-7) on rabbit afferent arterioles microperfused in vitro, and we tested whether endothelium-derived relaxing factor/NO and cyclooxygenase products are involved in its actions. To assess the vasodilator effect of Ang-(1-7), afferent arterioles were preconstricted with norepinephrine, and increasing concentrations of Ang-(1-7) were added to the lumen. We found that 10−10 to 10−6 mol/L Ang-(1-7) produced dose-dependent vasodilatation, increasing luminal diameter from 8.9±1.0 to 16.3±1.1 &mgr;m (P <0.006). Indomethacin had no effect on Ang-(1-7)–induced dilatation. NG-nitro-l-arginine methyl ester, a NO synthesis inhibitor, abolished the dilatation induced by Ang-(1-7). We attempted to determine which angiotensin receptor subtype is involved in this process. We found that 10−6 mol/L [d-Ala7]–Ang-(1-7), a potent and selective Ang-(1-7) antagonist, abolished the dilatation induced by Ang-(1-7). An angiotensin II type 1 receptor antagonist (L158809) and an angiotensin II type 2 receptor antagonist (PD 123319) at 10−6 mol/L had no effect on Ang-(1-7)–induced dilatation. Our results show that Ang-(1-7) causes afferent arteriole dilatation. This effect may be due to production of NO, but not the action of cyclooxygenase products. Ang-(1-7) has a receptor-mediated vasodilator effect on the rabbit afferent arteriole. This effect may be mediated by Ang-(1-7) receptors, because angiotensin type 1 and type 2 receptor antagonists could not block Ang-(1-7)–induced dilatation. Thus, our data suggest that Ang-(1-7)opposes the action of Ang II and plays an important role in the regulation of renal hemodynamics.
{"title":"Vasodilator Action of Angiotensin-(1-7) on Isolated Rabbit Afferent Arterioles","authors":"Yilin Ren, J. Garvin, O. Carretero","doi":"10.1161/HY0302.104673","DOIUrl":"https://doi.org/10.1161/HY0302.104673","url":null,"abstract":"Recent studies have shown that angiotensin-(1-7) (Ang-[1-7]), which is generated endogenously from both Ang I and II, is a bioactive component of the renin-angiotensin system and may play an important role in the regulation of blood pressure. However, little is known about its role in regulating the reactivity of the afferent arteriole or the mechanism(s) involved. We hypothesized that Ang-(1-7), acting on specific receptors, participates in the control of afferent arteriole tone. We first examined the direct effect of Ang-(1-7) on rabbit afferent arterioles microperfused in vitro, and we tested whether endothelium-derived relaxing factor/NO and cyclooxygenase products are involved in its actions. To assess the vasodilator effect of Ang-(1-7), afferent arterioles were preconstricted with norepinephrine, and increasing concentrations of Ang-(1-7) were added to the lumen. We found that 10−10 to 10−6 mol/L Ang-(1-7) produced dose-dependent vasodilatation, increasing luminal diameter from 8.9±1.0 to 16.3±1.1 &mgr;m (P <0.006). Indomethacin had no effect on Ang-(1-7)–induced dilatation. NG-nitro-l-arginine methyl ester, a NO synthesis inhibitor, abolished the dilatation induced by Ang-(1-7). We attempted to determine which angiotensin receptor subtype is involved in this process. We found that 10−6 mol/L [d-Ala7]–Ang-(1-7), a potent and selective Ang-(1-7) antagonist, abolished the dilatation induced by Ang-(1-7). An angiotensin II type 1 receptor antagonist (L158809) and an angiotensin II type 2 receptor antagonist (PD 123319) at 10−6 mol/L had no effect on Ang-(1-7)–induced dilatation. Our results show that Ang-(1-7) causes afferent arteriole dilatation. This effect may be due to production of NO, but not the action of cyclooxygenase products. Ang-(1-7) has a receptor-mediated vasodilator effect on the rabbit afferent arteriole. This effect may be mediated by Ang-(1-7) receptors, because angiotensin type 1 and type 2 receptor antagonists could not block Ang-(1-7)–induced dilatation. Thus, our data suggest that Ang-(1-7)opposes the action of Ang II and plays an important role in the regulation of renal hemodynamics.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"47 1","pages":"799-802"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75877411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Y. Makino, H. Hosoda, K. Shibata, I. Makino, M. Kojima, K. Kangawa, T. Kawarabayashi
Ghrelin, an endogenous ligand for the growth hormone secretagogues, was originally isolated from rat stomach. It stimulates the release of growth hormone from primary pituitary cell cultures. We investigated the plasma concentration of ghrelin peptide in 16 nonpregnant women, 18 normal pregnant women, 20 patients with pregnancy-induced hypertension, and 10 postpartum women. The plasma concentration of ghrelin in nonpregnant women was 239.5±16.9 fmol/mL. The plasma concentration of ghrelin in normal pregnant women at the third trimester was 127.1±5.6 fmol/mL. There was negative correlation between plasma ghrelin concentration and systemic blood pressure in normal pregnant women (systolic:r =−0.564, P <0.05; diastolic:r =−0.610, P <0.01). Pregnant women with pregnancy-induced hypertension (177.9±14.6 fmol/mL, P <0.05) also had significantly higher levels of ghrelin compared with those of normal pregnant women. In addition, there was a significant correlation between plasma ghrelin levels and systemic blood pressure (systolic:r =−0.482, P <0.05; diastolic:r =−0.466, P <0.05). These results suggest for the first time that ghrelin might have some role in cardiovascular control during normal pregnancy and in pathophysiological conditions in pregnancy, such as pregnancy-induced hypertension.
生长素(Ghrelin)是生长激素促分泌剂的内源性配体，最初是从大鼠胃中分离出来的。它能刺激垂体细胞培养中生长激素的释放。我们对16例未妊娠妇女、18例正常妊娠妇女、20例妊娠高血压患者和10例产后妇女的血浆ghrelin肽浓度进行了测定。未妊娠妇女ghrelin血药浓度为239.5±16.9 fmol/mL。正常妊娠晚期胃饥饿素血药浓度为127.1±5.6 fmol/mL。正常孕妇血浆ghrelin浓度与全身血压呈负相关(收缩压:r = - 0.564, P <0.05;舒张期:r = - 0.610, P <0.01)。妊娠高血压孕妇ghrelin水平(177.9±14.6 fmol/mL, P <0.05)明显高于正常孕妇。血浆ghrelin水平与全身血压有显著相关性(收缩压:r = - 0.482, P <0.05;舒张期:r = - 0.466, P <0.05)。这些结果首次表明，胃饥饿素可能在正常妊娠和妊娠病理生理状况(如妊娠高血压)中有一定的心血管控制作用。
{"title":"Alteration of Plasma Ghrelin Levels Associated With the Blood Pressure in Pregnancy","authors":"Y. Makino, H. Hosoda, K. Shibata, I. Makino, M. Kojima, K. Kangawa, T. Kawarabayashi","doi":"10.1161/HY0302.105221","DOIUrl":"https://doi.org/10.1161/HY0302.105221","url":null,"abstract":"Ghrelin, an endogenous ligand for the growth hormone secretagogues, was originally isolated from rat stomach. It stimulates the release of growth hormone from primary pituitary cell cultures. We investigated the plasma concentration of ghrelin peptide in 16 nonpregnant women, 18 normal pregnant women, 20 patients with pregnancy-induced hypertension, and 10 postpartum women. The plasma concentration of ghrelin in nonpregnant women was 239.5±16.9 fmol/mL. The plasma concentration of ghrelin in normal pregnant women at the third trimester was 127.1±5.6 fmol/mL. There was negative correlation between plasma ghrelin concentration and systemic blood pressure in normal pregnant women (systolic:r =−0.564, P <0.05; diastolic:r =−0.610, P <0.01). Pregnant women with pregnancy-induced hypertension (177.9±14.6 fmol/mL, P <0.05) also had significantly higher levels of ghrelin compared with those of normal pregnant women. In addition, there was a significant correlation between plasma ghrelin levels and systemic blood pressure (systolic:r =−0.482, P <0.05; diastolic:r =−0.466, P <0.05). These results suggest for the first time that ghrelin might have some role in cardiovascular control during normal pregnancy and in pathophysiological conditions in pregnancy, such as pregnancy-induced hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"36 1","pages":"781-784"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79448189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
E. Gerdts, L. Oikarinen, V. Palmieri, J. Otterstad, K. Wachtell, K. Boman, B. Dahlöf, R. Devereux
Left ventricular hypertrophy has been suggested to mediate the relation between hypertension and left atrial enlargement, with associated risks of atrial fibrillation and stroke. However, less is known about correlates of left atrial size in hypertensive patients with left ventricular hypertrophy. We assessed left atrial size by echocardiography in 941 hypertensive patients, age 55 to 80 (mean, 66) years, with electrocardiographic left ventricular hypertrophy at baseline in the Losartan Intervention For Endpoint reduction in hypertension study. Enlarged left atrial diameter (women, >3.8 cm; men, >4.2 cm) was present in 56% of women and 38% of men (P <0.01). Compared with the 512 patients with normal left atrial size, the 429 patients with enlarged left atrium more often had mitral regurgitation, atrial fibrillation, and echocardiographic left ventricular hypertrophy. They also had higher age, systolic blood pressure, pulse pressure, weight, body mass index, left ventricular internal chamber dimension, stroke volume, and mass and lower relative wall thickness and ejection fraction (all, P <0.05). In logistic regression analysis, left atrial enlargement was related to left ventricular hypertrophy and eccentric geometry; greater body mass index, systolic blood pressure, and age; female gender; mitral regurgitation; and atrial fibrillation (all, P <0.05). Thus, left atrial size in hypertensive patients with electrocardiographic left ventricular hypertrophy is influenced by gender, age, obesity, systolic blood pressure, and left ventricular geometry independently of left ventricular mass and presence of mitral regurgitation or atrial fibrillation.
{"title":"Correlates of Left Atrial Size in Hypertensive Patients With Left Ventricular Hypertrophy: The Losartan Intervention For Endpoint Reduction in Hypertension (LIFE) Study","authors":"E. Gerdts, L. Oikarinen, V. Palmieri, J. Otterstad, K. Wachtell, K. Boman, B. Dahlöf, R. Devereux","doi":"10.1161/HY0302.105683","DOIUrl":"https://doi.org/10.1161/HY0302.105683","url":null,"abstract":"Left ventricular hypertrophy has been suggested to mediate the relation between hypertension and left atrial enlargement, with associated risks of atrial fibrillation and stroke. However, less is known about correlates of left atrial size in hypertensive patients with left ventricular hypertrophy. We assessed left atrial size by echocardiography in 941 hypertensive patients, age 55 to 80 (mean, 66) years, with electrocardiographic left ventricular hypertrophy at baseline in the Losartan Intervention For Endpoint reduction in hypertension study. Enlarged left atrial diameter (women, >3.8 cm; men, >4.2 cm) was present in 56% of women and 38% of men (P <0.01). Compared with the 512 patients with normal left atrial size, the 429 patients with enlarged left atrium more often had mitral regurgitation, atrial fibrillation, and echocardiographic left ventricular hypertrophy. They also had higher age, systolic blood pressure, pulse pressure, weight, body mass index, left ventricular internal chamber dimension, stroke volume, and mass and lower relative wall thickness and ejection fraction (all, P <0.05). In logistic regression analysis, left atrial enlargement was related to left ventricular hypertrophy and eccentric geometry; greater body mass index, systolic blood pressure, and age; female gender; mitral regurgitation; and atrial fibrillation (all, P <0.05). Thus, left atrial size in hypertensive patients with electrocardiographic left ventricular hypertrophy is influenced by gender, age, obesity, systolic blood pressure, and left ventricular geometry independently of left ventricular mass and presence of mitral regurgitation or atrial fibrillation.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"4 1","pages":"739-743"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81506316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Methylglyoxal can yield advanced glycation end products via nonenzymatic glycation of proteins. Whether methylglyoxal contributes to the pathogenesis of hypertension has not been clear. The aim of the present study was to investigate whether the levels of methylglyoxal and methylglyoxal-induced advanced glycation end products were enhanced and whether methylglyoxal increased oxidative stress, activated nuclear factor–&kgr;B (NF-&kgr;B), and increased intracellular adhesion molecule-1 (ICAM-1) content in vascular smooth muscle cells from spontaneously hypertensive rats. Basal cellular levels of methylglyoxal and advanced glycation end products were more than 2-fold higher (P <0.05) in cells from hypertensive rats than from normotensive Wistar-Kyoto rats. This correlated with levels of oxidative stress and oxidized glutathione that were significantly higher in cells from hypertensive rats, whereas levels of glutathione and activities of glutathione reductase and glutathione peroxidase were significantly lower. Basal levels of nuclearly localized NF-&kgr;B p65 and ICAM-1 protein expression were higher in cells from hypertensive rats than from normotensive rats. Addition of exogenous methylglyoxal to the cultures induced a greater increase in oxidative stress and advanced glycation end products in cells from hypertensive rats compared with normotensive rats and significantly decreased the activities of glutathione reductase and glutathione peroxidase in cells of both rat strains. Methylglyoxal activated NF-&kgr;B p65 and increased ICAM-1 expression in hypertensive cells, which was inhibited by N-acetylcysteine. Our study demonstrates an elevated methylglyoxal level and advanced glycation end products in cells from hypertensive rats, and methylglyoxal increases oxidative stress, activates NF-&kgr;B, and enhances ICAM-1 expression. Our findings suggest that that elevated methylglyoxal and associated oxidative stress possibly contribute to the pathogenesis of hypertension.
{"title":"Increased Methylglyoxal and Oxidative Stress in Hypertensive Rat Vascular Smooth Muscle Cells","authors":"Lingyun Wu, B. Juurlink","doi":"10.1161/HY0302.105207","DOIUrl":"https://doi.org/10.1161/HY0302.105207","url":null,"abstract":"Methylglyoxal can yield advanced glycation end products via nonenzymatic glycation of proteins. Whether methylglyoxal contributes to the pathogenesis of hypertension has not been clear. The aim of the present study was to investigate whether the levels of methylglyoxal and methylglyoxal-induced advanced glycation end products were enhanced and whether methylglyoxal increased oxidative stress, activated nuclear factor–&kgr;B (NF-&kgr;B), and increased intracellular adhesion molecule-1 (ICAM-1) content in vascular smooth muscle cells from spontaneously hypertensive rats. Basal cellular levels of methylglyoxal and advanced glycation end products were more than 2-fold higher (P <0.05) in cells from hypertensive rats than from normotensive Wistar-Kyoto rats. This correlated with levels of oxidative stress and oxidized glutathione that were significantly higher in cells from hypertensive rats, whereas levels of glutathione and activities of glutathione reductase and glutathione peroxidase were significantly lower. Basal levels of nuclearly localized NF-&kgr;B p65 and ICAM-1 protein expression were higher in cells from hypertensive rats than from normotensive rats. Addition of exogenous methylglyoxal to the cultures induced a greater increase in oxidative stress and advanced glycation end products in cells from hypertensive rats compared with normotensive rats and significantly decreased the activities of glutathione reductase and glutathione peroxidase in cells of both rat strains. Methylglyoxal activated NF-&kgr;B p65 and increased ICAM-1 expression in hypertensive cells, which was inhibited by N-acetylcysteine. Our study demonstrates an elevated methylglyoxal level and advanced glycation end products in cells from hypertensive rats, and methylglyoxal increases oxidative stress, activates NF-&kgr;B, and enhances ICAM-1 expression. Our findings suggest that that elevated methylglyoxal and associated oxidative stress possibly contribute to the pathogenesis of hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"29 1","pages":"809-814"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74885528","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M. Suo, N. Hautala, G. Földes, I. Szokodi, M. Tóth, H. Leskinen, P. Uusimaa, O. Vuolteenaho, M. Nemer, H. Ruskoaho
B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II–induced hypertension by injecting DNA constructs containing the BNP promoter (−2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (P <0.001) at 2 hours and peaked at 12 hours (5.2-fold, P <0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, P <0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (P <0.05) at 2 hours and remained upregulated up to 2 weeks (2.8-fold, P <0.05) during Ang II infusion, except at 12 hours. These results indicate that posttranscriptional control plays a major role in the regulation of ventricular BNP gene expression in Ang II–induced hypertension.
{"title":"Posttranscriptional Control of BNP Gene Expression in Angiotensin II–Induced Hypertension","authors":"M. Suo, N. Hautala, G. Földes, I. Szokodi, M. Tóth, H. Leskinen, P. Uusimaa, O. Vuolteenaho, M. Nemer, H. Ruskoaho","doi":"10.1161/HY0302.105214","DOIUrl":"https://doi.org/10.1161/HY0302.105214","url":null,"abstract":"B-type natriuretic peptide (BNP) plasma concentrations are raised in patients with heart failure. In several experimental models of cardiac overload, however, BNP mRNA and plasma BNP peptide levels are normal, despite the persistent increase in blood pressure and ventricular hypertrophy. In this study, the role of transcriptional mechanisms in the regulation of BNP gene expression were studied in angiotensin (Ang) II–induced hypertension by injecting DNA constructs containing the BNP promoter (−2200 to 75 bp of the transcriptional start site) linked to luciferase reporter into rat myocardium. Ang II was administered to conscious rats via intravenous infusion for 2 hours or by subcutaneous minipumps for 6 hours, 12 hours, 3 days, 1 week, and 2 weeks. Ang II increased blood pressure and cardiac mass and induced changes in diastolic function. The left ventricular BNP mRNA levels increased 2.2-fold (P <0.001) at 2 hours and peaked at 12 hours (5.2-fold, P <0.001). Thereafter, BNP mRNA levels decreased (1.8-fold induction at 3 days, P <0.05) and returned to control levels at 1 week, despite persistent hypertension and myocardial hypertrophy. Left ventricular BNP peptide concentrations followed the changes in BNP mRNA levels. The BNP promoter was activated 2.7-fold (P <0.05) at 2 hours and remained upregulated up to 2 weeks (2.8-fold, P <0.05) during Ang II infusion, except at 12 hours. These results indicate that posttranscriptional control plays a major role in the regulation of ventricular BNP gene expression in Ang II–induced hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"156 1","pages":"803-808"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75171931","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
R. Tamarat, J. Silvestre, N. Kubis, J. Bénessiano, M. Duriez, M. Degasparo, D. Henrion, Bernard I Levy
We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II–treated (5 ng/kg per min), and in Ang II and valsartan–treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II–treated rats compared with controls (P <0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 &mgr;g IP, twice a week) in Ang II–treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P <0.01). Conversely, no significant changes were observed in Ang II–treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.
{"title":"Endothelial Nitric Oxide Synthase Lies Downstream From Angiotensin II–Induced Angiogenesis in Ischemic Hindlimb","authors":"R. Tamarat, J. Silvestre, N. Kubis, J. Bénessiano, M. Duriez, M. Degasparo, D. Henrion, Bernard I Levy","doi":"10.1161/HY0302.104671","DOIUrl":"https://doi.org/10.1161/HY0302.104671","url":null,"abstract":"We assessed the role of angiotensin (Ang) II in ischemia-induced angiogenesis and analyzed the molecular pathways involved in such an effect. Ischemia was produced by unilateral artery femoral occlusion in control, in valsartan-treated (Ang II receptor type I antagonist, 20 mg/kg per day), in Ang II–treated (5 ng/kg per min), and in Ang II and valsartan–treated rats. After 28 days, angiogenesis was assessed by microangiography and capillary density measurement in hindlimbs. The ischemic/nonischemic leg ratio for angiographic score and capillary number increased by 2.6- and 2-fold, respectively, in Ang II–treated rats compared with controls (P <0.01). This was associated with an increase in vascular endothelial growth factor (VEGF; 1.6-fold) and endothelial NO synthase (eNOS; 1.8-fold) protein content within the ischemic leg, assessed by Western blot. Angiotensin type 1 receptor blockade and administration of VEGF neutralizing antibody (2.5 &mgr;g IP, twice a week) in Ang II–treated rats completely prevented such Ang II angiogenic effects. The key role of eNOS was then emphasized by using mice deficient in gene encoding for eNOS. In wild-type mice, Ang II (0.3 mg/kg per min) treatment increased by 1.7- and 1.6-fold the ischemic/nonischemic leg for angiographic score and blood perfusion (assessed by laser Doppler perfusion imaging) ratios, respectively (P <0.01). Conversely, no significant changes were observed in Ang II–treated mice deficient in gene encoding for eNOS. Subhypertensive dose of Ang II enhanced angiogenesis associated with tissue ischemia through angiotensin type 1 receptor activation that involved the VEGF/eNOS-dependent pathway.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"28 1","pages":"830-835"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83590092","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Renhui Yang, A. Ogasawara, T. F. Zioncheck, Z. Ren, G. He, G. DeGuzman, N. Pelletier, Ben-Quan Shen, S. Bunting, Hongkui Jin
Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics, and release of NO and prostaglandin I2 (PGI2) in vivo and on vasorelaxation of mesentery artery rings in vitro in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2 hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY (P <0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (P <0.01). Circulating NO and PGI2 levels after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater hypotension (P <0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia in response to VEGF, which was independent of NO and PGI2. The exaggerated hypotensive response to VEGF in SHR may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more caution should be taken when VEGF is administered in patients with hypertension.
{"title":"Exaggerated Hypotensive Effect of Vascular Endothelial Growth Factor in Spontaneously Hypertensive Rats","authors":"Renhui Yang, A. Ogasawara, T. F. Zioncheck, Z. Ren, G. He, G. DeGuzman, N. Pelletier, Ben-Quan Shen, S. Bunting, Hongkui Jin","doi":"10.1161/HY0302.105398","DOIUrl":"https://doi.org/10.1161/HY0302.105398","url":null,"abstract":"Vascular endothelial growth factor (VEGF) induces hypotension in normotensive subjects, which is considered to be a major side effect for treatment of ischemic diseases. However, the hypotensive effect of VEGF has not been investigated in the setting of hypertension. This study determined effects of VEGF on hemodynamics, pharmacokinetics, and release of NO and prostaglandin I2 (PGI2) in vivo and on vasorelaxation of mesentery artery rings in vitro in spontaneously hypertensive rats (SHR) compared with Wistar-Kyoto rats (WKY). Intravenous infusion of VEGF for 2 hours produced a dose-related decrease in arterial pressure, which was enhanced in conscious SHR compared with WKY (P <0.01), and an increase in heart rate in WKY but not in SHR. In response to similar doses of VEGF, compared with WKY, SHR had a higher plasma VEGF level and lower VEGF clearance (P <0.01). Circulating NO and PGI2 levels after VEGF administration were not increased in SHR versus WKY, and VEGF-induced vasorelaxation was blunted in SHR versus WKY in vitro, suggesting endothelial dysfunction in SHR. One-week VEGF infusion also caused greater hypotension (P <0.05) in the absence of tachycardia in SHR compared with WKY controls. Thus, despite blunted vasorelaxation in vitro because of endothelial dysfunction, SHR exhibited exaggerated hypotension without tachycardia in response to VEGF, which was independent of NO and PGI2. The exaggerated hypotensive response to VEGF in SHR may be owing to impaired baroreflex function and reduced VEGF clearance. The data may also suggest that more caution should be taken when VEGF is administered in patients with hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"74 1","pages":"815-820"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85812321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Yasunari, K. Maeda, Munehiro Nakamura, J. Yoshikawa
Because oxidative stress and inflammation are believed to play roles in the pathogenesis of cardiovascular diseases, oxidative stress in polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs) has been measured. A total of 529 subjects participated this study. Intracellular oxidative stress in PMNs and MNCs was measured by gated flow cytometry using carboxyfluorescin diacetate bis-acetoxymethyl ester. C-reacting protein (CRP), insulin action (homeostasis model assessment), and traditional risk factors such as age, gender, body mass index, triglycerides, LDL cholesterol, HDL cholesterol, hemoglobin A1c, and mean blood pressure were also measured. Multiple regression analysis revealed a significant correlation between mean blood pressure and PMN oxidative stress (r =0.104, P =0.018). It also demonstrated a significant correlation between hemoglobin A1c and PMN oxidative stress (r =0.112, P =0.021). A significant correlation was also found between CRP and MNC oxidative stress (r =0.116, P =0.008) by multiple regression analysis. In patients with both hypertension and diabetes, both PMN and MNC oxidative stress was increased (n=21, P =0.022 and P =0.006). These results suggest that both hypertension and diabetes lead to increased oxidative stress of PMNs and MNCs, and that CRP is related to MNC oxidative stress.
由于氧化应激和炎症被认为在心血管疾病的发病机制中发挥作用，因此对多形核白细胞(PMNs)和单核细胞(MNCs)中的氧化应激进行了测量。共有529名受试者参加了本研究。采用门控流式细胞术检测pmn和MNCs细胞内氧化应激。c反应蛋白(CRP)、胰岛素作用(稳态模型评估)和传统的危险因素，如年龄、性别、体重指数、甘油三酯、低密度脂蛋白胆固醇、高密度脂蛋白胆固醇、血红蛋白A1c和平均血压也被测量。多元回归分析显示，平均血压与PMN氧化应激有显著相关性(r =0.104, P =0.018)。血红蛋白A1c与PMN氧化应激有显著相关性(r =0.112, P =0.021)。多元回归分析发现CRP与MNC氧化应激有显著相关性(r =0.116, P =0.008)。合并高血压和糖尿病的患者PMN和MNC氧化应激均升高(n=21, P =0.022和P =0.006)。上述结果提示，高血压和糖尿病均可导致PMNs和MNC氧化应激升高，而CRP与MNC氧化应激有关。
{"title":"Oxidative Stress in Leukocytes Is a Possible Link Between Blood Pressure, Blood Glucose, and C-Reacting Protein","authors":"K. Yasunari, K. Maeda, Munehiro Nakamura, J. Yoshikawa","doi":"10.1161/HY0302.104670","DOIUrl":"https://doi.org/10.1161/HY0302.104670","url":null,"abstract":"Because oxidative stress and inflammation are believed to play roles in the pathogenesis of cardiovascular diseases, oxidative stress in polymorphonuclear leukocytes (PMNs) and mononuclear cells (MNCs) has been measured. A total of 529 subjects participated this study. Intracellular oxidative stress in PMNs and MNCs was measured by gated flow cytometry using carboxyfluorescin diacetate bis-acetoxymethyl ester. C-reacting protein (CRP), insulin action (homeostasis model assessment), and traditional risk factors such as age, gender, body mass index, triglycerides, LDL cholesterol, HDL cholesterol, hemoglobin A1c, and mean blood pressure were also measured. Multiple regression analysis revealed a significant correlation between mean blood pressure and PMN oxidative stress (r =0.104, P =0.018). It also demonstrated a significant correlation between hemoglobin A1c and PMN oxidative stress (r =0.112, P =0.021). A significant correlation was also found between CRP and MNC oxidative stress (r =0.116, P =0.008) by multiple regression analysis. In patients with both hypertension and diabetes, both PMN and MNC oxidative stress was increased (n=21, P =0.022 and P =0.006). These results suggest that both hypertension and diabetes lead to increased oxidative stress of PMNs and MNCs, and that CRP is related to MNC oxidative stress.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"39 1","pages":"777-780"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89353737","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
This study investigated the role of NO in mediating the renal sympathetic nerve–mediated increases in proximal tubular fluid reabsorption (Jva). In inactin-anesthetized Wistar rats, renal sympathetic nerve stimulation (15 V, 2 ms) at 0.75 and 1.0 Hz did not change blood pressure or glomerular filtration rate but did decrease urine flow and sodium excretion in a frequency-related fashion by 40% to 50% at 1.0 Hz (both, P <0.01). Renal nerve stimulation in control animals increased Jva by 11% at 0.75 Hz (P <0.05) and 31% at 1.0 Hz (P <0.01). Intraluminal N&ohgr;-nitro-l-arginine methyl ester (L-NAME) resulted in a higher basal Jva (19%, P <0.05), and renal nerve stimulation had no effect on Jva. When L-NAME plus sodium nitroprusside was present intraluminally, however, there were frequency-dependent increases in Jva that were similar in pattern and magnitude to the control rats. Introduction of the relatively selective nNOS blocker 7-nitroindazole intraluminally, at 10−6 and 10−4 M, raised basal Jva by 18% and 24%, respectively (P <0.01), and renal nerve stimulation did not change Jva. Intraluminal aminoguanidine (10−4 M), a relatively selective iNOS blocker, did not affect basal Jva, which remained unchanged during renal nerve stimulation. These data are consistent with NO exerting a tonic inhibitory action on the basal levels of Jva, which, in part, is caused by NO generated by the nNOS isoform. Moreover, the findings have revealed that the presence of NO is necessary to ensure that renal nerves can stimulate fluid reabsorption by the proximal tubules, requiring NO generated from both nNOS and iNOS.
{"title":"Nitric Oxide Modulation of Neurally Induced Proximal Tubular Fluid Reabsorption in the Rat","authors":"Xiao Chun Wu, E. Johns","doi":"10.1161/HY0302.105681","DOIUrl":"https://doi.org/10.1161/HY0302.105681","url":null,"abstract":"This study investigated the role of NO in mediating the renal sympathetic nerve–mediated increases in proximal tubular fluid reabsorption (Jva). In inactin-anesthetized Wistar rats, renal sympathetic nerve stimulation (15 V, 2 ms) at 0.75 and 1.0 Hz did not change blood pressure or glomerular filtration rate but did decrease urine flow and sodium excretion in a frequency-related fashion by 40% to 50% at 1.0 Hz (both, P <0.01). Renal nerve stimulation in control animals increased Jva by 11% at 0.75 Hz (P <0.05) and 31% at 1.0 Hz (P <0.01). Intraluminal N&ohgr;-nitro-l-arginine methyl ester (L-NAME) resulted in a higher basal Jva (19%, P <0.05), and renal nerve stimulation had no effect on Jva. When L-NAME plus sodium nitroprusside was present intraluminally, however, there were frequency-dependent increases in Jva that were similar in pattern and magnitude to the control rats. Introduction of the relatively selective nNOS blocker 7-nitroindazole intraluminally, at 10−6 and 10−4 M, raised basal Jva by 18% and 24%, respectively (P <0.01), and renal nerve stimulation did not change Jva. Intraluminal aminoguanidine (10−4 M), a relatively selective iNOS blocker, did not affect basal Jva, which remained unchanged during renal nerve stimulation. These data are consistent with NO exerting a tonic inhibitory action on the basal levels of Jva, which, in part, is caused by NO generated by the nNOS isoform. Moreover, the findings have revealed that the presence of NO is necessary to ensure that renal nerves can stimulate fluid reabsorption by the proximal tubules, requiring NO generated from both nNOS and iNOS.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"92 1","pages":"790-793"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77271787","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
K. Matthews, C. Kiefe, C. Lewis, Kiang Liu, S. Sidney, C. Yunis
We assessed the impact of initial socioeconomic status and change in socioeconomic status across 10 years, ie, status trajectories, on the development of essential hypertension among black and white young men and women. Three thousand eight hundred twenty-seven normotensive individuals ages 18 to 30 years at study entry were followed for 10 years, with blood pressure, body mass index, and socioeconomic status characteristics measured at years 0, 2, 5, 7, and 10. Socioeconomic status trajectory measures were a new educational degree earned by year 10; difficulties paying for basics during years 2 to 10; and change in income category from year 5 to 10, defined in relation to year 0 status. Hypertension was defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or antihypertensive medication use at year 10. Reporting difficulties paying for basics at study entry (odds ratio=1.45, 95% confidence interval, 1.05 to 2.02) and continued difficulties during year 2 to 10 follow-up (odds ratio=1.62, 95% confidence interval, 1.04 to 2.53) were independently associated with incident hypertension, adjusted for race-gender group, body mass index, site, age, and initial systolic blood pressure. Decline in income from year 5 to 10 tended to be associated with hypertension, P =0.07, but a new educational degree after study onset was not. Socioeconomic trajectories are independently associated with incidence of hypertension. A dynamic index of socioeconomic status may be a useful concept in understanding the effects of socioeconomic status on the natural history of hypertension.
{"title":"Socioeconomic Trajectories and Incident Hypertension in a Biracial Cohort of Young Adults","authors":"K. Matthews, C. Kiefe, C. Lewis, Kiang Liu, S. Sidney, C. Yunis","doi":"10.1161/HY0302.105682","DOIUrl":"https://doi.org/10.1161/HY0302.105682","url":null,"abstract":"We assessed the impact of initial socioeconomic status and change in socioeconomic status across 10 years, ie, status trajectories, on the development of essential hypertension among black and white young men and women. Three thousand eight hundred twenty-seven normotensive individuals ages 18 to 30 years at study entry were followed for 10 years, with blood pressure, body mass index, and socioeconomic status characteristics measured at years 0, 2, 5, 7, and 10. Socioeconomic status trajectory measures were a new educational degree earned by year 10; difficulties paying for basics during years 2 to 10; and change in income category from year 5 to 10, defined in relation to year 0 status. Hypertension was defined as systolic blood pressure ≥140, diastolic blood pressure ≥90, or antihypertensive medication use at year 10. Reporting difficulties paying for basics at study entry (odds ratio=1.45, 95% confidence interval, 1.05 to 2.02) and continued difficulties during year 2 to 10 follow-up (odds ratio=1.62, 95% confidence interval, 1.04 to 2.53) were independently associated with incident hypertension, adjusted for race-gender group, body mass index, site, age, and initial systolic blood pressure. Decline in income from year 5 to 10 tended to be associated with hypertension, P =0.07, but a new educational degree after study onset was not. Socioeconomic trajectories are independently associated with incidence of hypertension. A dynamic index of socioeconomic status may be a useful concept in understanding the effects of socioeconomic status on the natural history of hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"1 1","pages":"772-776"},"PeriodicalIF":0.0,"publicationDate":"2002-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90462995","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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