Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022060.13995.ED
H. Tokuyama, K. Hayashi, H. Matsuda, E. Kubota, M. Honda, K. Okubo, I. Takamatsu, S. Tatematsu, Y. Ozawa, S. Wakino, T. Saruta
The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59±3; clipped, 16±1; nonclipped, 44±2 mL/min;P <0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7±0.1 to 2.0±0.2 pg/mg tissue) and nonclipped kidneys (from 0.6±0.1 to 2.5±0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1±0.6 to 0.8±0.1 pg/mg tissue;P <0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4±0.3 to 1.5±0.2 pg/mg tissue;P <0.05). Finally, [Pro11-d-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.
{"title":"Differential Regulation of Elevated Renal Angiotensin II in Chronic Renal Ischemia","authors":"H. Tokuyama, K. Hayashi, H. Matsuda, E. Kubota, M. Honda, K. Okubo, I. Takamatsu, S. Tatematsu, Y. Ozawa, S. Wakino, T. Saruta","doi":"10.1161/01.HYP.0000022060.13995.ED","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022060.13995.ED","url":null,"abstract":"The present study was undertaken to clarify the role of intrarenal angiotensin (Ang) II and its generating pathways in clipped and nonclipped kidneys of 4-week unilateral renal artery stenosis in anesthetized dogs. After 4 weeks, renal plasma flow (RPF) decreased in clipped and nonclipped kidneys (baseline, 59±3; clipped, 16±1; nonclipped, 44±2 mL/min;P <0.01, n=22). Renal Ang I levels increased only in clipped, whereas intrarenal Ang II contents were elevated in both clipped (from 0.7±0.1 to 2.0±0.2 pg/mg tissue) and nonclipped kidneys (from 0.6±0.1 to 2.5±0.3 pg/mg tissue). Intrarenal ACE activity was increased in nonclipped kidneys but was unaltered in clipped kidneys. An angiotensin receptor antagonist (olmesartan medoxomil) given into the renal artery markedly restored RPF, and dilated both afferent and efferent arterioles (using intravital videomicroscopy). Furthermore, in clipped kidneys, the elevated Ang II was suppressed by a chymase inhibitor, chymostatin (from 2.1±0.6 to 0.8±0.1 pg/mg tissue;P <0.05), but not by cilazaprilat. In nonclipped kidneys, in contrast, cilazaprilat, but not chymostatin, potently inhibited the intrarenal Ang II generation (from 2.4±0.3 to 1.5±0.2 pg/mg tissue;P <0.05). Finally, [Pro11-d-Ala12]Ang I (an inactive precursor that yields Ang II by chymase but not by ACE; 1 to 50 nmol/kg) markedly elevated intrarenal Ang II in clipped, but not in nonclipped, kidneys. In conclusion, renal Ang II contents were elevated in both clipped and nonclipped kidneys, which contributed to the altered renal hemodynamics and microvascular tone. Furthermore, the mechanisms for intrarenal Ang II generation differ, and chymase activity is enhanced in clipped kidneys, whereas ACE-mediated Ang II generation is possibly responsible for elevated Ang II contents in nonclipped kidneys.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"16 1","pages":"34-40"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86444867","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022570.02119.75
E. Baker, A. Duggal, Yanbin Dong, Nicola J. Ireson, M. Wood, N. Markandu, G. MacGregor
The T594M polymorphism of the epithelial sodium channel is found in ≈5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle’s syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89±3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91±4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8±4/2 mm Hg (systolic, P <0.05; diastolic, P <0.01). On restarting amiloride, blood pressure was again controlled to 140/88±6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.
上皮钠通道T594M多态性存在于约5%的非洲裔人群中，并与高血压显著相关。虽然T594M多态性可以通过受影响的通道增加肾脏钠的吸收，但这种多态性是否导致高血压尚不清楚。阿米洛利特特异性抑制过度活跃的钠通道，有效控制Liddle综合征的血压，Liddle综合征的高血压是由单独的上皮钠通道突变引起的。本研究的目的是确定阿米洛利是否能有效降低T594M多态性个体的血压。在一项开放、对照研究中，14例T594M多态性黑人高血压患者停用常规药物，并用阿米洛利治疗。在研究开始时，服用两种药物的人的平均血压为142/89±3/3 mm Hg，单独使用阿米洛利(10 mg BID)有效地将血压控制在140/91±4/2 mm Hg的水平。停用阿米洛利2周后，血压显著升高17/8±4/2 mm Hg(收缩压，P <0.05;舒张期，P <0.01)。重新启动阿米洛利后，血压再次控制在140/88±6/2 mm Hg。这些结果表明，10 mg BID阿米洛利对T594M多态性的非洲裔高血压个体有效控制血压。我们的研究支持了T594M多态性有助于血压升高的概念，并建议应考虑在受影响的个体中使用阿米洛利。
{"title":"Amiloride, a Specific Drug for Hypertension in Black People With T594M Variant?","authors":"E. Baker, A. Duggal, Yanbin Dong, Nicola J. Ireson, M. Wood, N. Markandu, G. MacGregor","doi":"10.1161/01.HYP.0000022570.02119.75","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022570.02119.75","url":null,"abstract":"The T594M polymorphism of the epithelial sodium channel is found in ≈5% of people of African origin and is significantly associated with high blood pressure. Although the T594M polymorphism could increase renal sodium absorption through affected channels, it is not known whether this polymorphism causes hypertension. Amiloride specifically inhibits overactive sodium channels and effectively controls blood pressure in Liddle’s syndrome, in which hypertension is caused by separate epithelial sodium channel mutations. The aim of this study was to determine whether amiloride was effective in lowering blood pressure in individuals with the T594M polymorphism. In an open, controlled study, 14 black hypertensive individuals with the T594M polymorphism were withdrawn from their usual medication and treated with amiloride. On entry to the study, individuals taking a mean of 2 drugs had blood pressure of 142/89±3/3 mm Hg. Amiloride alone (10 mg BID) controlled blood pressure effectively to the same level (140/91±4/2 mm Hg). When amiloride was withdrawn for 2 weeks, there was a large increase in blood pressure of 17/8±4/2 mm Hg (systolic, P <0.05; diastolic, P <0.01). On restarting amiloride, blood pressure was again controlled to 140/88±6/2 mm Hg. These results demonstrate that 10 mg BID amiloride is effective in controlling blood pressure in hypertensive individuals of African origin who have the T594M polymorphism. Our study supports the concept that the T594M polymorphism contributes to the elevation of blood pressure and suggests that consideration should be given to the use of amiloride in affected individuals.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"5 1","pages":"13-17"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85590814","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000021747.43346.95
F. Trabold, S. Pons, A. Hagège, M. Bloch-Faure, F. Alhenc-Gelas, J. Giudicelli, Christine Richer-Giudicelli, P. Meneton
To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B2 receptor–deficient (B2−/−) and tissue kallikrein–deficient (TK−/−) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B2−/−, TK−/−, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dtmax) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B2−/− mice compared with TK−/− and WT mice. In addition, B2−/− mice, but not TK−/− mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2−/− mice were significantly more sensitive than were TK−/− mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B2−/− mice and smaller in TK−/− mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK−/− and B2−/− mice could be underlain by tissue kallikrein kinin–independent effect and/or kinin B1 receptor activation.
{"title":"Cardiovascular Phenotypes of Kinin B2 Receptor– and Tissue Kallikrein–Deficient Mice","authors":"F. Trabold, S. Pons, A. Hagège, M. Bloch-Faure, F. Alhenc-Gelas, J. Giudicelli, Christine Richer-Giudicelli, P. Meneton","doi":"10.1161/01.HYP.0000021747.43346.95","DOIUrl":"https://doi.org/10.1161/01.HYP.0000021747.43346.95","url":null,"abstract":"To clarify the role of the kallikrein-kinin system in cardiovascular homeostasis, the systemic and regional hemodynamics of kinin B2 receptor–deficient (B2−/−) and tissue kallikrein–deficient (TK−/−) mice were compared with their wild-type (WT) littermates on a pure C57BL/6 genetic background. B2−/−, TK−/−, and WT adult mice were normotensive and displayed normal hemodynamic (left ventricular [LV] pressure, cardiac output, total peripheral resistance, dP/dtmax) and echocardiographic (septum and LV posterior wall thickness, LV diameter, LV mass, and LV fractional shortening) parameters. However, heart rate was lower in B2−/− mice compared with TK−/− and WT mice. In addition, B2−/− mice, but not TK−/− mice, exhibited lower coronary and renal blood flows and greater corresponding vascular resistances than did WT mice, indicating a tonic physiological vasodilating effect of bradykinin in these vascular beds. However, maximal coronary vasodilatation capacity, estimated after dipyridamole infusion, was similar in the 3 groups of mice. B2−/− mice were significantly more sensitive than were TK−/− mice to the vasoconstrictor effects of angiotensin II and norepinephrine. Finally, renin mRNA levels were significantly greater in B2−/− mice and smaller in TK−/− mice compared with WT mice. Taken together, these results indicate that under basal conditions, the kinin B2 receptor is not an important determinant of blood pressure in mice but is involved in the control of regional vascular tone in the coronaries and the kidneys. The phenotypic differences observed between TK−/− and B2−/− mice could be underlain by tissue kallikrein kinin–independent effect and/or kinin B1 receptor activation.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"23 1","pages":"90-95"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"82515704","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022659.17774.E4
Hao Wang, F. Leenen
Central infusions of benzamil prevent/reverse salt-induced hypertension in genetic models of salt-sensitive hypertension. Benzamil acts by blockade of ion—presumably sodium—channels. In the present study, we assessed in Dahl salt-sensitive (S) rats on high salt intake whether these channels mediate increases in brain “ouabain” and, thereby, hypertension. Intracerebroventricular (icv) infusions of a low (1.2 &mgr;g/kg per hour) or high (4.0 &mgr;g/kg per hour) dose of benzamil were given to Dahl S rats on high salt diet (1370 &mgr;mol Na+/g food) for 2 or 4 weeks. “Ouabain” content was measured using a specific enzyme-linked immunosorbent assay (ELISA). Systolic blood pressure (BP) in Dahl S rats on high salt for 4 weeks increased markedly (188±10 versus 128±4 mm Hg, n=8, P <0.05). Benzamil fully blocked this increase (131±7 mm Hg after the high dose of benzamil). Hypothalamic and pituitary “ouabain” increased significantly (22±7 versus 12±3 and 151±38 versus 69±6 ng/g tissue, respectively, P <0.05) in Dahl S rats on high salt versus regular salt diet for 2 weeks. Benzamil blocked these increases of brain “ouabain” to high salt intake. Similarly, high salt intake for 4 weeks increased hypothalamic (18±2 versus 13±1 ng/g tissue, P <0.05) and pituitary (183±30 versus 78±8 ng/g tissue, P <0.05) “ouabain.” Benzamil also inhibited these increases of brain “ouabain.” Both hypothalamic and pituitary “ouabain” showed significant positive correlations with BP. In contrast, high salt intake did not affect “ouabain” levels in the adrenal gland or plasma in Dahl S rats on high salt for either 2 or 4 weeks. These findings indicate that in Dahl S rats high salt intake only increases brain and not peripheral “ouabain” and that benzamil-blockable brain sodium channels mediate the increases in brain “ouabain” and the subsequent hypertension.
在盐敏感性高血压遗传模型中，中心输注苯氨苄可预防/逆转盐致高血压。苯扎米通过阻断离子(可能是钠离子)通道起作用。在本研究中，我们在高盐摄入的Dahl盐敏感(S)大鼠中评估了这些通道是否介导脑“瓦巴因”的增加，从而导致高血压。对高盐饮食(1370 mol Na+/g食物)的Dahl S大鼠进行低剂量(1.2 g/kg / h)或高剂量(4.0 g/kg / h)苯甲胺脑室内(icv)输注2或4周。采用特异性酶联免疫吸附试验(ELISA)测定“瓦巴因”含量。高盐治疗4周后，达尔S大鼠收缩压(BP)明显升高(188±10 vs 128±4 mm Hg, n=8, P <0.05)。Benzamil完全阻断了这种增加(高剂量Benzamil后131±7 mm Hg)。高盐饮食2周后，达尔S大鼠下丘脑和垂体“乌阿巴因”显著升高(分别为22±7 ng/g比12±3 ng和151±38 ng/g比69±6 ng/g, P <0.05)。苯扎米阻断了大脑因高盐摄入而增加的“苦瓜碱”。同样，高盐摄入4周增加下丘脑(18±2比13±1 ng/g组织，P <0.05)和垂体(183±30比78±8 ng/g组织，P <0.05)“瓦巴因”。苯扎米还能抑制脑内“瓦巴因”的增加。下丘脑和垂体“沃巴因”均与血压呈显著正相关。相比之下，高盐摄入对高盐摄入2周或4周的达尔S大鼠肾上腺或血浆中的“瓦巴因”水平没有影响。这些发现表明，在达尔S大鼠中，高盐摄入只增加了脑内的“瓦巴因”，而没有增加外周的“瓦巴因”，苯并米可阻断的脑钠通道介导了脑内“瓦巴因”的增加和随后的高血压。
{"title":"Brain Sodium Channels Mediate Increases in Brain “Ouabain” and Blood Pressure in Dahl S Rats","authors":"Hao Wang, F. Leenen","doi":"10.1161/01.HYP.0000022659.17774.E4","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022659.17774.E4","url":null,"abstract":"Central infusions of benzamil prevent/reverse salt-induced hypertension in genetic models of salt-sensitive hypertension. Benzamil acts by blockade of ion—presumably sodium—channels. In the present study, we assessed in Dahl salt-sensitive (S) rats on high salt intake whether these channels mediate increases in brain “ouabain” and, thereby, hypertension. Intracerebroventricular (icv) infusions of a low (1.2 &mgr;g/kg per hour) or high (4.0 &mgr;g/kg per hour) dose of benzamil were given to Dahl S rats on high salt diet (1370 &mgr;mol Na+/g food) for 2 or 4 weeks. “Ouabain” content was measured using a specific enzyme-linked immunosorbent assay (ELISA). Systolic blood pressure (BP) in Dahl S rats on high salt for 4 weeks increased markedly (188±10 versus 128±4 mm Hg, n=8, P <0.05). Benzamil fully blocked this increase (131±7 mm Hg after the high dose of benzamil). Hypothalamic and pituitary “ouabain” increased significantly (22±7 versus 12±3 and 151±38 versus 69±6 ng/g tissue, respectively, P <0.05) in Dahl S rats on high salt versus regular salt diet for 2 weeks. Benzamil blocked these increases of brain “ouabain” to high salt intake. Similarly, high salt intake for 4 weeks increased hypothalamic (18±2 versus 13±1 ng/g tissue, P <0.05) and pituitary (183±30 versus 78±8 ng/g tissue, P <0.05) “ouabain.” Benzamil also inhibited these increases of brain “ouabain.” Both hypothalamic and pituitary “ouabain” showed significant positive correlations with BP. In contrast, high salt intake did not affect “ouabain” levels in the adrenal gland or plasma in Dahl S rats on high salt for either 2 or 4 weeks. These findings indicate that in Dahl S rats high salt intake only increases brain and not peripheral “ouabain” and that benzamil-blockable brain sodium channels mediate the increases in brain “ouabain” and the subsequent hypertension.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"8 1","pages":"96-100"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78877887","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022660.28915.B1
Steven C. Hunt, R. C. Ellison, Larry D. Atwood, J. Pankow, Michael A. Province, Mark F. Leppert
This study presents genome scans for hypertension and blood pressures from 2959 individuals in 500 white families from the National Heart, Lung, and Blood Institute Family Heart Study. Genome scans were performed with different methods of handling the 27% of individuals taking antihypertensive medications. Variance components LOD scores were estimated by assigning medicated hypertensive individuals (1) to have a blood pressure of 140/90; (2) to be missing; and (3) to have a randomly assigned systolic blood pressure between 140 and 160 (N[150,5] distribution) and diastolic blood pressure between 90 and 100 mm Hg (N[95,2.5] distribution). There were 5 regions with heterogeneity LOD scores ≥2.0 for hypertension (unadjusted for multiple models): 2.8 on chromosome 1 (192 cM), 2.6 on chromosome 7 (58 cM), 2.0 on chromosome 7 (127 cM), 2.4 on chromosome 12 (83 cM), and 2.4 on chromosome 15 (103 cM). Diastolic blood pressure had no LOD scores ≥2.0. Only chromosome 6 showed linkage for systolic blood pressure, with a LOD score of 3.3 at 88.7 cM from the initial randomization. Multiple randomizations of medicated subjects’ systolic blood pressures yielded a mean LOD score of 2.8±0.4, whereas setting medicated systolic blood pressures to 140 mm Hg yielded a LOD score of 3.3. Excluding the medicated individuals or using their treated blood pressures reduced the LOD scores to 0.8 and 1.3, respectively, indicating the importance of including the extremes of quantitative trait distributions in linkage analyses. These results overlap other published scans, particularly regions on chromosomes 1 and 6, which have been implicated in familial combined hyperlipidemia.
{"title":"Genome Scans for Blood Pressure and Hypertension: The National Heart, Lung, and Blood Institute Family Heart Study*","authors":"Steven C. Hunt, R. C. Ellison, Larry D. Atwood, J. Pankow, Michael A. Province, Mark F. Leppert","doi":"10.1161/01.HYP.0000022660.28915.B1","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022660.28915.B1","url":null,"abstract":"This study presents genome scans for hypertension and blood pressures from 2959 individuals in 500 white families from the National Heart, Lung, and Blood Institute Family Heart Study. Genome scans were performed with different methods of handling the 27% of individuals taking antihypertensive medications. Variance components LOD scores were estimated by assigning medicated hypertensive individuals (1) to have a blood pressure of 140/90; (2) to be missing; and (3) to have a randomly assigned systolic blood pressure between 140 and 160 (N[150,5] distribution) and diastolic blood pressure between 90 and 100 mm Hg (N[95,2.5] distribution). There were 5 regions with heterogeneity LOD scores ≥2.0 for hypertension (unadjusted for multiple models): 2.8 on chromosome 1 (192 cM), 2.6 on chromosome 7 (58 cM), 2.0 on chromosome 7 (127 cM), 2.4 on chromosome 12 (83 cM), and 2.4 on chromosome 15 (103 cM). Diastolic blood pressure had no LOD scores ≥2.0. Only chromosome 6 showed linkage for systolic blood pressure, with a LOD score of 3.3 at 88.7 cM from the initial randomization. Multiple randomizations of medicated subjects’ systolic blood pressures yielded a mean LOD score of 2.8±0.4, whereas setting medicated systolic blood pressures to 140 mm Hg yielded a LOD score of 3.3. Excluding the medicated individuals or using their treated blood pressures reduced the LOD scores to 0.8 and 1.3, respectively, indicating the importance of including the extremes of quantitative trait distributions in linkage analyses. These results overlap other published scans, particularly regions on chromosomes 1 and 6, which have been implicated in familial combined hyperlipidemia.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"30 1","pages":"1-6"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83384586","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022063.50739.60
C. Zoccali, F. Mallamaci, G. Tripepi, S. Parlongo, S. Cutrupi, F. Benedetto, A. Cataliotti, L. Malatino
We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (P =0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (P =0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (P ≤0.001) of other cardiovascular risk factors, and in these models, plasma NE ranked as the second correlate of MWT and RWT. Similarly, multiple logistic regression analysis showed that the association of plasma NE with concentric LVH was strong and again independent of other risk factors (P =0.003). Plasma NE is associated to concentric LVH in ESRD patients. These observations constitute a sound basis for testing the effect of anti-adrenergic drugs on left ventricle mass and on cardiovascular outcomes in patients with ESRD.
{"title":"Norepinephrine and Concentric Hypertrophy in Patients With End-Stage Renal Disease","authors":"C. Zoccali, F. Mallamaci, G. Tripepi, S. Parlongo, S. Cutrupi, F. Benedetto, A. Cataliotti, L. Malatino","doi":"10.1161/01.HYP.0000022063.50739.60","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022063.50739.60","url":null,"abstract":"We have recently observed that in patients with end-stage renal disease (ESRD) raised plasma norepinephrine (NE) is an independent predictor of incident cardiovascular events but that its prognostic power is reduced when this sympathetic marker is tested in statistical models including also left ventricular mass. Because left ventricular hypertrophy (LVH) may be a mechanism whereby NE contributes to the high rate of cardiovascular events in ESRD, we examined the relationship between plasma NE and echocardiographic parameters of left ventricle mass in a large group of ESRD patients. Mean wall thickness (MWT) was higher in patients in the third NE tertile than in the other 2 tertiles (P =0.001), and such an increase was paralleled by a rise in relative wall thickness (RWT) (P =0.006). Concentric LVH was more prevalent in patients in the third NE tertile (46%) than in the second (38%) and first (25%) NE tertiles. Multivariate regression analysis confirmed that the association of plasma NE with the muscular component of left ventricle (MWT) and with RWT was independent (P ≤0.001) of other cardiovascular risk factors, and in these models, plasma NE ranked as the second correlate of MWT and RWT. Similarly, multiple logistic regression analysis showed that the association of plasma NE with concentric LVH was strong and again independent of other risk factors (P =0.003). Plasma NE is associated to concentric LVH in ESRD patients. These observations constitute a sound basis for testing the effect of anti-adrenergic drugs on left ventricle mass and on cardiovascular outcomes in patients with ESRD.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"22 1","pages":"41-46"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80830333","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022571.86090.F3
C. Giannattasio, A. Piperno, M. Failla, A. Vergani, G. Mancia
Endothelial function is noninvasively assessed by measuring nitric oxide–dependent increase in radial artery diameter accompanying the elevation in shear stress induced by increasing blood flow through a short-lasting ischemia of the hand. However, shear stress also depends on blood viscosity, whose changes might thus affect nitric oxide increase in a manner that is not properly reflected by blood flow changes. In 12 subjects with hemochromatosis, we measured ultrasonographically radial artery diameter and blood flow responses to a 4-minute ischemia of the hand. This was done also after removing 500 mL of blood (and concomitantly infusing 500 mL of saline), which significantly (P <0.01) reduced hemoglobin concentration and hematocrit. The increase in blood flow induced by the 4-minute ischemia was similar before and after blood removal (+76% and +80%), which, in contrast, markedly attenuated the accompanying increase in radial artery diameter (+25% versus +13%, P <0.01). Thus, in humans, blood viscosity is involved in the endothelial response to an increase in shear stress. This implies that this response may not be accurately assessed and compared by quantifying the stimulus only through an increase in blood flow.
内皮功能是通过测量一氧化氮依赖的桡动脉直径的增加，并伴随短时间缺血引起的血流量增加而引起的剪切应力升高来无创评估的。然而，剪切应力也取决于血液粘度，因此，血液粘度的变化可能会影响一氧化氮的增加，而血流的变化无法正确反映这种增加。在12名血色素沉着症患者中，我们测量了超声桡动脉直径和手部缺血4分钟后的血流反应。在抽取500 mL血液(并同时注入500 mL生理盐水)后，也进行了这项研究，这显著(P <0.01)降低了血红蛋白浓度和红细胞压积。4分钟缺血引起的血流量增加在取血前后相似(+76%和+80%)，明显减弱了桡动脉直径的增加(+25% vs +13%， P <0.01)。因此，在人类中，血液粘度参与了内皮细胞对剪切应力增加的反应。这意味着，仅通过血流量的增加来量化刺激，可能无法准确地评估和比较这种反应。
{"title":"Effects of Hematocrit Changes on Flow-Mediated and Metabolic Vasodilation in Humans","authors":"C. Giannattasio, A. Piperno, M. Failla, A. Vergani, G. Mancia","doi":"10.1161/01.HYP.0000022571.86090.F3","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022571.86090.F3","url":null,"abstract":"Endothelial function is noninvasively assessed by measuring nitric oxide–dependent increase in radial artery diameter accompanying the elevation in shear stress induced by increasing blood flow through a short-lasting ischemia of the hand. However, shear stress also depends on blood viscosity, whose changes might thus affect nitric oxide increase in a manner that is not properly reflected by blood flow changes. In 12 subjects with hemochromatosis, we measured ultrasonographically radial artery diameter and blood flow responses to a 4-minute ischemia of the hand. This was done also after removing 500 mL of blood (and concomitantly infusing 500 mL of saline), which significantly (P <0.01) reduced hemoglobin concentration and hematocrit. The increase in blood flow induced by the 4-minute ischemia was similar before and after blood removal (+76% and +80%), which, in contrast, markedly attenuated the accompanying increase in radial artery diameter (+25% versus +13%, P <0.01). Thus, in humans, blood viscosity is involved in the endothelial response to an increase in shear stress. This implies that this response may not be accurately assessed and compared by quantifying the stimulus only through an increase in blood flow.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"22 1","pages":"74-77"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83788320","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022880.45113.C9
T. Ogihara, T. Asano, K. Ando, H. Sakoda, M. Anai, N. Shojima, Hiraku Ono, Y. Onishi, M. Fujishiro, Miho Abe, Y. Fukushima, M. Kikuchi, T. Fujita
A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.
{"title":"High-Salt Diet Enhances Insulin Signaling and Induces Insulin Resistance in Dahl Salt-Sensitive Rats","authors":"T. Ogihara, T. Asano, K. Ando, H. Sakoda, M. Anai, N. Shojima, Hiraku Ono, Y. Onishi, M. Fujishiro, Miho Abe, Y. Fukushima, M. Kikuchi, T. Fujita","doi":"10.1161/01.HYP.0000022880.45113.C9","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022880.45113.C9","url":null,"abstract":"A high-salt diet, which is known to contribute to the pathogenesis of hypertension, is also reportedly associated with insulin resistance. We investigated the effects of a high-salt diet on insulin sensitivity and insulin signaling in salt-sensitive (Dahl-S) and salt resistant (Dahl-R) strains of the Dahl rat. Evaluation of hyperinsulinemic-euglycemic clamp studies and glucose uptake into the isolated soleus muscle revealed that salt loading (8% NaCl) for 4 weeks induced hypertension and significant insulin resistance in Dahl-S rats, whereas no significant effects were observed in Dahl-R rats. Despite the presence of insulin resistance, insulin-induced tyrosine phosphorylation of the insulin receptor and insulin receptor substrates, activation of phosphatidylinositol 3-kinase, and phosphorylation of Akt were all enhanced in Dahl-S rats fed a high-salt diet. The mechanism underlying this form of insulin resistance thus differs from that previously associated with obesity and dexamethasone and is likely due to the impairment of one or more metabolic steps situated downstream of phosphatidylinositol 3-kinase and Akt activation. Interestingly, supplementation of potassium (8% KCl) ameliorated the changes in insulin sensitivity in Dahl-S rats fed a high-salt diet; this was associated with a slight but significant decrease in blood pressure. Evidence presented suggest that there is an interdependent relationship between insulin sensitivity and salt sensitivity of blood pressure in Dahl-S rats, and it is suggested that supplementing the diet with potassium may exert a protective effect against both hypertension and insulin resistance in salt-sensitive individuals.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"084 1","pages":"83-89"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91158003","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022805.11288.7F
Tsung-Ming Lee, S. Su, Chang‐Her Tsai
Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well-controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period. Pravastatin lowered proteinuria after 6 months by 54% (P <0.0001). Creatinine clearance was stable throughout the study in the 2 groups. Despite unchanged plasma endothelin-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with improvement in urinary protein excretion in pravastatin-treated patients (r =0.64, P =0.001). The urinary excretion of retinol-binding protein decreased after pravastatin administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of IgG did not change significantly throughout the study in either group. Multivariate analysis revealed that proteinuria was only significantly correlated with statin use (P <0.0001, R2= 0.66). Linear regression analysis in the statin-treated group did not show any correlation between changes in lipid profiles and proteinuria regression. Thus, in addition to their primary function of antilipidemia, the addition of pravastatin to treatment for well-controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and lipid-lowering effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.
蛋白尿是心血管和肾脏发病率和死亡率的重要危险因素。3-羟基-3-甲基戊二酰辅酶A还原酶抑制剂(他汀类药物)治疗对控制良好的正常血脂高血压患者蛋白尿的影响尚未研究。共有63例正常血脂(总胆固醇<240 mg/dL)和蛋白尿(300 ~ 3000 mg/d)且血压控制良好的患者(<140/90 mm Hg)被随机分为安慰剂组(n=32)或普伐他汀组(10 mg/d;N =31)，经过3个月的安慰剂期。普伐他汀降低6个月后蛋白尿54% (P <0.0001)。在整个研究过程中，两组的肌酐清除率稳定。尽管在整个研究过程中血浆内皮素-1水平没有变化，但普伐他汀治疗的患者尿中肽的排泄减少，并与尿蛋白排泄改善显著相关(r =0.64, P =0.001)。服用普伐他汀后，尿中视黄醇结合蛋白的排泄量减少，可能反映了小管功能的改善。相比之下，在整个研究过程中，两组的尿中IgG的排泄没有明显变化。多因素分析显示，蛋白尿仅与他汀类药物使用显著相关(P <0.0001, R2= 0.66)。他汀类药物治疗组的线性回归分析未显示脂质谱变化与蛋白尿回归之间的任何相关性。因此，除了其抗血脂的主要功能外，普伐他汀治疗控制良好的高血压可能具有独立于血流动力学和降脂作用的降低蛋白尿的附加作用，可能通过抑制肾内皮素-1合成和改善小管功能。
{"title":"Effect of Pravastatin on Proteinuria in Patients With Well-Controlled Hypertension","authors":"Tsung-Ming Lee, S. Su, Chang‐Her Tsai","doi":"10.1161/01.HYP.0000022805.11288.7F","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022805.11288.7F","url":null,"abstract":"Proteinuria is an important risk factor for cardiovascular and renal morbidity and mortality. The effects of 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitor (statin) therapy on proteinuria in normolipidemic patients with well-controlled hypertension have not been studied. A total of 63 normolipidemic (total cholesterol <240 mg/dL) and proteinuric (300 to 3000 mg/d) patients with well-controlled blood pressure (<140/90 mm Hg) were randomized to receive either placebo (n=32) or pravastatin (10 mg/d; n=31) after a 3-month placebo period. Pravastatin lowered proteinuria after 6 months by 54% (P <0.0001). Creatinine clearance was stable throughout the study in the 2 groups. Despite unchanged plasma endothelin-1 levels throughout the study, urinary excretion of the peptide was decreased and significantly correlated with improvement in urinary protein excretion in pravastatin-treated patients (r =0.64, P =0.001). The urinary excretion of retinol-binding protein decreased after pravastatin administration, probably reflecting an improvement in tubular function. In contrast, the urinary excretion of IgG did not change significantly throughout the study in either group. Multivariate analysis revealed that proteinuria was only significantly correlated with statin use (P <0.0001, R2= 0.66). Linear regression analysis in the statin-treated group did not show any correlation between changes in lipid profiles and proteinuria regression. Thus, in addition to their primary function of antilipidemia, the addition of pravastatin to treatment for well-controlled hypertension may have an additive effect on reducing proteinuria independent of hemodynamics and lipid-lowering effects, possibly through inhibiting renal endothelin-1 synthesis and improving tubular function.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"66 1","pages":"67-73"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90061818","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}
Pub Date : 2002-07-01DOI: 10.1161/01.HYP.0000022606.52221.2F
M. Naruse, A. Tanabe, A. Sato, S. Takagi, K. Tsuchiya, T. Imaki, K. Takano
Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 &mgr;g/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.
醛固酮突破在ACE抑制剂治疗期间有报道。本研究探讨高血压大鼠长期血管紧张素II型1 (AT1)受体拮抗剂(AT1A)治疗期间血浆醛固酮浓度(PAC)的变化及其机制和对靶器官损伤的影响。从4周龄开始，对有卒中倾向的自发性高血压大鼠给予AT1A(坎地沙坦，1mg /kg / d PO)，持续34周。PAC在前4周明显降低，但在AT1A给药8周后醛固酮出现突破。血浆血管紧张素II浓度显著升高，而血浆ACTH和血清钾未见变化。通过在24周AT1A治疗期的最后一周给予高剂量坎地沙坦(3 mg/kg /天PO)、地塞米松(200 mg/kg /天IP)或AT2拮抗剂(PD123319, 10 mg/kg /天SC)来研究醛固酮突破的机制。地塞米松和AT2拮抗剂而非高剂量AT1A均能显著降低PAC，其中AT2拮抗剂降低幅度更大。为了阐明残留醛固酮的影响，研究了低剂量螺内酯(10mg /kg / day SC)对左心室肥厚和脑利钠肽mRNA表达的影响。螺内酯是一种醛固酮拮抗剂。低剂量螺内酯进一步改善左心室肥厚和脑利钠肽mRNA表达，但没有额外的抑制作用。这些结果表明，醛固酮突破发生在长期AT1A治疗期间，主要是通过at2依赖机制。残余醛固酮可能减弱AT1A的心脏保护作用。
{"title":"Aldosterone Breakthrough During Angiotensin II Receptor Antagonist Therapy in Stroke-Prone Spontaneously Hypertensive Rats","authors":"M. Naruse, A. Tanabe, A. Sato, S. Takagi, K. Tsuchiya, T. Imaki, K. Takano","doi":"10.1161/01.HYP.0000022606.52221.2F","DOIUrl":"https://doi.org/10.1161/01.HYP.0000022606.52221.2F","url":null,"abstract":"Aldosterone breakthrough during ACE inhibitor therapy has been reported. This study investigates changes in plasma aldosterone concentration (PAC) and its mechanism and effects on target organ damage during long-term angiotensin II type 1 (AT1) receptor antagonist (AT1A) therapy in hypertensive rats. An AT1A (candesartan, 1 mg/kg per day PO) was administered in stroke-prone spontaneously hypertensive rats from 4 weeks of age for 34 weeks. PAC was significantly decreased during the first 4 weeks but showed aldosterone breakthrough after 8 weeks of AT1A administration. Plasma angiotensin II concentration was significantly elevated, whereas no change was seen in plasma ACTH or serum potassium. The mechanism(s) of aldosterone breakthrough were investigated by giving high doses of candesartan (3 mg/kg per day PO), dexamethasone (200 &mgr;g/kg per day IP), or the AT2 antagonist (PD123319, 10 mg/kg per day SC) during the last week of the 24-week AT1A treatment period. Dexamethasone and AT2 antagonist but not high-dose AT1A produced a significant decrease in PAC, with a larger decrease produced by the AT2 antagonist. To clarify the effects of the residual aldosterone, effects of coadministration of low-dose spironolactone (10 mg/kg per day SC), an aldosterone antagonist, on left ventricular hypertrophy and expression of brain natriuretic peptide mRNA were determined. Low-dose spironolactone further improved left ventricular hypertrophy and brain natriuretic peptide mRNA expression despite no additional depressor effect. These results suggest that aldosterone breakthrough occurs during long-term AT1A therapy, mainly by an AT2-dependent mechanism. Residual aldosterone may attenuate the cardioprotective effects of AT1A.","PeriodicalId":13233,"journal":{"name":"Hypertension: Journal of the American Heart Association","volume":"48 1","pages":"28-33"},"PeriodicalIF":0.0,"publicationDate":"2002-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90364317","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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