摘要:

&NA;Different family and case‐control studies support genetic linkage and association at the human angiotensinogen (AGT) locus with essential hypertension. To extend these previous observations, a European collaborative study of nine centers was set up to create a large resource of affected sibling pairs. The AGT locus was studied using a highly polymorphic dinucleotide repeat in the 3′‐flanking region of the gene in 350 European families, comprising 630 affected sibling pairs. Statistical analyses using two different methods did not show any evidence for linkage either in the whole panel or in family subsets selected for severity or early onset of disease. Although several arguments from association studies suggest a role of the AGT gene in essential hypertension, this large family study did not replicate the initial linkage reported in smaller studies. Our results highlight the difficulty of identifying susceptibility genes by linkage analysis in complex diseases. (Hypertension. 1998;31:725‐729.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Significant linkage and association of alpha‐adducin, a cytoskeleton protein involved in transmembrane ion transport, with essential hypertension were recently shown in Caucasian populations, especially in relation to salt sensitivity. The present study investigated the relevance of this candidate gene to hypertension in a well‐characterized Japanese population. A total number of 507 individuals were selected from clinic outpatients. Hypertensive subjects were defined on the basis of the individual's blood pressure readings before starting medications; the criteria included systolic blood pressure >or= to 160 mm Hg and/or diastolic blood pressure >or= to 95 mm Hg. Patients with diabetes mellitus, renal failure, and secondary forms of hypertension had been excluded. Control subjects had blood pressure values < 130/85 mm Hg. The allele frequency of a genetic variant at amino acid residue 460 of alpha‐adducin (460Trp) was compared between cases and control subjects with chi squared statistics; in addition, the association was tested with blood pressure as a continuous variable. No significant association was found in either of the statistics tested. The 460Trp variant appeared to be relatively common in the Japanese (54% to 60%) compared with a reported prevalence of 13% to 23% in Caucasians. The present study brought up an important issue concerning the pathophysiological role of alpha‐adducin in non‐Caucasian populations, given the likely ethnic variation in the nature of genetic susceptibility loci. The 460Trp variant of the alpha‐adducin gene is unlikely to have a major effect on susceptibility to hypertension in the Japanese population studied, although the present study does not exclude the involvement of alpha‐adducin in the pathogenesis of hypertension. (Hypertension. 1998;31:730‐733.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Previous researchers have identified two sequences present upstream (angiotensinogen gene‐activating element [AGE2]) and downstream (d61‐2) of the human angiotensinogen gene that act as cell‐specific enhancers of transcription in transiently transfected HepG2 cells. To examine the importance of these two sequences in regulating tissue‐ and cell‐specific expression of the gene in vivo, we generated transgenic mice containing the mutations in the context of a genomic transgene previously shown to exhibit appropriate tissue and cell specificity. The ability of these sequences to enhance transcription of a basal human angiotensinogen promoter was confirmed in transient transfection assays in HepG2 cells, and mutations within the AGE2 and d61‐2 sequences abolished transactivation of the promoter. Tissue‐ and cell‐specific expression was examined in three lines of transgenic mice carrying the d61‐2 mutation, two lines of transgenic mice carrying the AGE2 mutation, and three founder transgenic mice carrying a double‐mutant construct. Although the absolute levels of expression varied among lines, the pattern of tissue‐specific expression was essentially unaltered by the mutations. In situ hybridization confirmed that the mutations were also dispensable for proximal tubule‐specific expression within the kidney. Finally, a comparison of transgene expression with transgene copy number revealed a direct proportionality in liver (R = .77, P = .0014) and kidney (R = .76, P = .0024). These results clearly demonstrate that these sites, which strongly induce promoter activity in cells in culture, are not required for appropriate expression of the gene when present in a genomic construct in vivo. (Hypertension. 1998;31:734‐740.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Cardiac hypertrophy is a common but not inevitable complication of hypertension. Variation in heart size in hypertensives may reflect independent genetic susceptibility to cardiac hypertrophy. Using an experimental genetic model, we determined the location of quantitative trait loci responsible for cardiac hypertrophy and/or hypertension. We studied 182 F2male animals derived from a cross of the spontaneously hypertensive rat and normotensive Donryu rats. Direct mean arterial pressure (MAP) and left ventricular (LV) mass were measured at 20 weeks of age, and DNA was obtained for linkage analysis. The estimated heritability of MAP was 62% and for LV mass expressed per unit of body weight (relative LV mass) was 76%. We used 185 polymorphic markers, with an average intermarker distance of 12.3 centimorgans for a genome‐wide scan in a representative subgroup of 46 animals to identify preliminary quantitative trait loci, which were then mapped in all 182 male F2rats. Two loci showed logarithm of the odds scores of > 4.0. One on chromosome 2, Lvm‐1, was linked to relative LV mass but showed no evidence of linkage to MAP. Another locus on chromosome 1, was linked to MAP. In the same region, a locus Lvm‐2 was linked with relative LV mass. These data indicate the existence of a genetic locus on chromosome 2 of the spontaneously hypertensive rat that affects relative LV mass independently of blood pressure. (Hypertension. 1998;31:741‐746.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Inhibition of the renin‐angiotensin system has been shown to improve symptoms and prognosis in heart failure. We compared the effects of inhibition of angiotensin‐converting enzyme or blockade of angiotensin II type 1 (AT1) receptors in a model with renin‐induced hypertension that is known to exhibit similar changes in sympathetic activation and beta‐adrenergic desensitization, as observed in heart failure. Treatment with captopril (100 mg/kg of feed) or the AT1‐antagonist Bay 10‐6734 (100 mg/kg of feed) was performed in transgenic rats harboring the mouse renin 2dgene [TG(mREN2)27]. Neuropeptide Y and angiotensin II levels, adenylyl cyclase activity, beta‐adrenergic receptors, Gsalpha, and Gialpha were investigated. TG(mREN2)27 showed a depletion of myocardial neuropeptide Y stores and an increase in myocardial angiotensin II concentrations. Isoprenaline‐ and guanylylimidodiphosphate‐stimulated adenylyl cyclase activities and beta‐adrenergic receptor density were reduced, whereas the catalyst and Gsalpha ‐function were unchanged. Gialpha protein and mRNA concentrations were increased. All alterations were normalized by both treatments. Systolic left ventricular pressures, plasma atrial natriuretic peptide, and myocardial steady state atrial natriuretic peptide mRNA concentrations and heart weights were similarly reduced by both treatments. Sympathetic neuroeffector defects are similarly reversed by angiotensin‐converting enzyme inhibition or AT1antagonism. The data support the concept that pharmacological interventions in the myocardial renin‐angiotensin system significantly reverse local sympathetic neuroeffector defects. This could be important for the beneficial effects of these agents. (Hypertension. 1998;31:747‐754.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;In patients with congestive heart failure (CHF) receiving therapy with angiotensin‐converting enzyme (ACE) inhibition, institution of calcium channel antagonism with amlodipine provided favorable effects. The goal of the present study was to define potential mechanisms for these effects by measuring left ventricular function, hemodynamics, and neurohormonal system activity in a model of CHF in which amlodipine treatment had been instituted either as a monotherapy or in combination with ACE inhibition. Thirty‐two pigs were instrumented to allow measurement of cardiac index, total systemic resistance index, and neurohormonal activity in the conscious state and assigned to one of four groups: (1) rapid atrial pacing (240 bpm) for 3 weeks (n = 8), (2) amlodipine (1.5 mg [center dot] kg‐1[center dot] d‐1) and pacing (n = 8), (3) ACE inhibition (fosinopril 1.0 mg/kg BID) and pacing (n = 8), and (4) amlodipine and ACE inhibition (1.0 mg [center dot] kg (‐1) [center dot] d‐1and 1.0 mg/kg BID, respectively) and pacing (n = 8). Measurements were obtained in the normal control state and after the completion of the treatment protocols. With rapid pacing, basal resting cardiac index was reduced compared with control values (2.7 +/− 0.2 versus 4.7 +/− 0.1 L [center dot] min‐1[center dot] m (‐2), respectively, P < .05) and increased from rapid pacing‐only values with either amlodipine or combination therapy (3.7 +/− 0.3 and 4.4 +/− 0.5 L [center dot] min‐1[center dot] m‐2, respectively, P < .05). Basal resting total systemic resistance index was higher in the rapid pacing‐only group compared with control values (2731 +/− 263 versus 1721 +/− 53 dyne [center dot] s [center dot] cm‐5[center dot] m2, respectively, P < .05), was reduced with either amlodipine treatment or ACE inhibition (2125 +/− 226 and 2379 +/− 222 dyne [center dot] s [center dot] cm‐5[center dot] m2, respectively, P < .05), and was normalized with combination therapy. Plasma catecholamines, renin activity, and endothelin levels were increased threefold with rapid pacing. Amlodipine, either as a monotherapy or in combination with ACE inhibition, did not result in increased plasma catecholamines and renin activity compared with the rapid pacing‐only group. Furthermore, combination therapy reduced steady state norepinephrine and normalized epinephrine levels. The results of the present study demonstrated that monotherapy with either amlodipine or ACE inhibition provides beneficial effects in this pacing model of CHF. Combined amlodipine and ACE inhibition provided greater benefit with respect to vascular resistance properties and neurohormonal system activity compared with either monotherapy. (Hypertension. 1998;31:755‐765.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Endothelin‐1 (ET‐1) is a cardiovascular peptide that binds to two distinct receptors, ETAand ETB, resulting in systemic and regional vasoconstriction, alteration in sodium excretion, mitogenesis, and release of other vasoactive peptides such as atrial natriuretic peptide (ANP). A role for ET‐1 has been proposed in congestive heart failure (CHF) based on the increase in circulating ET‐1 in this cardiovascular disease state. The present study determined the cardiorenal and endocrine responses to chronic selective oral ETAantagonism in experimental CHF. Two groups of conscious dogs underwent 21 days of pacing‐induced CHF. These groups included a control untreated group (n = 6) and a group that received an orally active ETAreceptor antagonist (A‐127722, Abbott Pharmaceuticals, 5mg/kg PO bid, n = 6). Each group was studied at baseline before the onset of CHF and after 14 and 21 days of CHF. Compared with the CHF control group, the ET (A) receptor antagonism group at 14 days of CHF showed lower mean arterial pressure and systemic vascular resistance. Similarly, ETAreceptor antagonism markedly attenuated the increase in circulating ANP despite similar atrial pressures. At 21 days of CHF, ETAreceptor antagonism lowered pulmonary artery pressure, pulmonary vascular resistance, and systemic vascular resistance in association with a higher cardiac output. Plasma ANP remained suppressed. Despite the lower mean arterial pressure and circulating ANP in the ETAreceptor antagonist group, the absolute decrease in sodium excretion from baseline was less compared with the untreated CHF control group. The present investigation supports the conclusion that endogenous ET‐1 participates in the systemic and pulmonary vasoconstriction, the elevation of ANP, and the sodium retention that characterize this model of experimental CHF, suggesting a potential therapeutic role for ETAreceptor antagonism in CHF. (Hypertension. 1998;31:766‐770.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;There is continuing uncertainty about whether morbidity and mortality of treated hypertensive patients depends on the drug(s) used to treat or only on the level of blood pressure achieved. This study was undertaken in a sample of special Veterans Administration hypertension clinics to determine which antihypertensive drugs were selected by the involved healthcare providers and how effective they were in achieving normotension. Hypertensive veterans (n = 6100) were followed in six VA Hypertension Screening and Treatment Program clinics for 46 months beginning in May 1989. Their average age was 60.7 years; 53% lived in the Stroke Belt; 46% had target organ damage, 36% were black, 23% smoked, and 10% had diabetes mellitus. Antihypertensive regimens were divided into 12 all‐inclusive categories. Blood pressures were averaged at the last study visit for all patients on a regimen. The regimens of diuretic or diuretic plus beta‐blocker gave the lowest average pressures (140.6/82.3 mm Hg) and calcium antagonist the highest (149.0/86.5 mm Hg). ANOVA indicated that differences between seven common regimens and also between the four single drug regimens were highly significant (P < .0001). This pattern of low treated pressure with the “old” agents and higher treated pressure with newer agents was reflected in the percentage of patients controlled below 140/90 mm Hg and the percentage uncontrolled above 159/94 mm Hg. Blacks and patients with target organ damage resembled the entire cohort in average treated diastolic blood pressure, but the former had lower and the latter had higher treated systolic blood pressure than the entire cohort. (Hypertension. 1998;31:771‐779.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;Recent findings of a linkage between high blood pressure (BP) and later development of dementia have given new prospects on cerebral target‐organ damage in hypertension and have added substance to the concept of “preventable senility.” The aim of this study was to analyze the impact of hypertension, circadian BP profile, and disturbed glucose metabolism on cognitive function. The study population consisted of 999 seventy‐year‐old men from a population‐based cohort study in Uppsala, Sweden, followed with respect to cardiovascular risk factors since the age of 50 years. At the age of 70, 24‐hour ambulatory BP was monitored together with measurements of insulin sensitivity, glucose tolerance, serum lipids, and lipoproteins. Cognitive function was assessed by the Mini‐Mental State Examination and the Trail‐Making Test. High diastolic BP at baseline predicted later impaired cognitive performance, even after excluding men with a previous stroke (n = 70). Cross‐sectional measurements at age 70 showed that high 24‐hour BP, nondipping, insulin resistance, and diabetes all were related to low cognitive function. The relationships between hypertension and cognitive impairment were strongest in untreated men. These data from a general population of healthy elderly men indicate that hypertension and associated metabolic disturbances might be susceptibility factors for cognitive disorders. The findings add support to possibilities of intervention in early stages in cognitive decline, ie, before manifest dementia. (Hypertension. 1998;31:780‐786.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

&NA;A myogenic vasoconstriction may amplify the effects of circulating vasoconstrictors. In cremaster arterioles, the contribution of a myogenic component to the constriction on intravenous infusion of norepinephrine (NE) or angiotensin II (Ang II) was studied. Second, the role of endothelium‐derived nitric oxide (NO) in the control of these myogenic constrictions and its site of action in the resistance vascular bed was investigated. In 30 anesthetized (pentobarbital) hamsters, the cremaster was prepared for intravital microscopy, and a pneumatic vessel occluder was placed around the aorta to vary blood pressure in the hindquarter of the animal. Intravenous infusion of NE (0.5 nmol/min) increased the systemic blood pressure by 52 +/− 2 mm Hg. Simultaneously, constrictions of up to 33 +/− 6% were observed in the small arterioles (SAs; maximal inner diameter, 36 to 65 micro meter). The constrictions were not significantly altered by a local adrenergic blockade but were abolished when the pressure elevation in the cremaster arterioles was blocked by partial occlusion of the abdominal aorta. Diameters in large arterioles (LAs; maximal inner diameter, 65 to 127 micro meter), however, did not change significantly on NE infusion. Similar responses in the arterioles were observed when the local pressure was increased stepwise from 60 to 120 mm Hg by partial opening of the aortic occluder. However, after treatment of the cremaster tissue with the inhibitor of the NO synthase, NG‐nitro‐L‐arginine (L‐NNA, 30 micro mol/L), a significant pressure‐induced constriction of up to 16 +/− 3% occurred in LAs, whereas the magnitude of the constriction in SAs remained unchanged. L‐NNA also abolished the increases in blood flow that were observed with increments in pressure in control animals. Similar results were obtained when Ang II was used to increase blood pressure. We conclude that a myogenic constriction of SAs contributes markedly to the overall response of cremaster arterioles to circulating vasoconstrictors. NO effectively opposes the myogenic response in LAs, thus preventing myogenic constrictions in a vascular region where constriction cannot be fully controlled by metabolic dilation. If this attenuating effect of NO on myogenic constriction also takes place in other organs, it might be a decisive mechanism in controlling changes of total peripheral vascular resistance elicited by vasoconstrictors. (Hypertension. 1998;31:787‐794.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID