ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Essential hypertension probably results from combinations of genetic variations, not necessarily the same in all afflicted persons, which individually may not cause sufficient deviation from normality to be significantly harmful.Genes contributing to hypertension are being sought by analytic experiments aimed at identifying candidate genes associated or segregating with the phenotype in humans and animals and by synthetic experiments in which changes are made in candidate genes in animals and their effects on blood pressure are determined.We have used gene targeting to vary the amounts of angiotensinogen and angiotensin-converting enzyme (ACE) synthesized from their genes (Agt and Ace). These "gene titration" experiments establish that changes in Agt gene expression cause changes in the blood pressures of mice. Surprisingly, quantitative changes in Ace gene expression over a threefold range do not affect blood pressures.Computer simulations with a simple version of the renin-angiotensin system predict that changes in Agt function alter the steady state levels of both angiotensin I (Ang I) and angiotensin II (Ang II). In contrast, modest changes in Ace function alter Ang I levels considerably but scarcely affect Ang II levels. Simulations over the ranges of ACE levels that can be achieved with ACE inhibitors predict that Ang II levels will decrease only when Ang I levels have plateaued.Comparisons of the computer simulations with our genetic experiments and with prior work of others using wide dose ranges of ACE inhibitor show a satisfactory agreement and help reconcile the apparent contradictions between the genetic and pharmacological experiments.(Hypertension. 1997;30:1318-1324.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The angiotensinogen (AGT) gene M235T variant is associated with essential hypertension and elevated plasma AGT concentrations, although the underlying mechanisms are unknown. Recent studies have suggested that AGCE 1 (human AGT gene core promoter element 1) located in the 5' upstream core promoter region (position -25 to -1) of the human AGT gene has an important part in the expression of AGT mRNA by binding with transcription factor AGCF 1 (human AGT gene core promoter element binding factor 1), and a mutation at -20 from adenine to cytosine (A-20C) increases the level of expression of this transcript. We therefore examined subjects with this mutation to study the association with increased plasma AGT concentrations and with essential hypertension. One hundred eighty-eight subjects receiving no antihypertensive medication were examined with regard to the correlation between A-20C and plasma AGT concentrations, and 234 subjects were studied with respect to the association between A-20C and essential hypertension. A-20C was determined by polymerase chain reaction-restriction fragment length polymorphism analysis with EcoOR 109I. Multiple regression analysis showed a weak but significant correlation between A-20C and plasma AGT concentrations (P = .047) and essential hypertension (P = .049). The results suggest that A-20C may underlie the increase in plasma AGT concentrations and be involved in the development of essential hypertension. (Hypertension. 1997;30:1325-1330.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Recently, an allelic variant of the angiotensinogen gene (AGT 235T) has been associated with increased risk of hypertension. However, this finding has not been confirmed by all investigators. A meta-analysis was performed to examine the association between the AGT 235T-allele and hypertension in whites and to identify potential reasons for the controversial results. All relevant articles published between 1992 and 1996 were identified through multiple sources. The studies were methodologically appraised, and the frequency of the AGT 235T-allele was extracted. The 235T-allele frequency was pooled using the common odds ratio (OR) estimator by Mantel-Haenszel. Homogeneity was assessed using the Breslow-Day test. Together these studies present data on 5493 patients. The AGT 235T-allele was significantly associated with hypertension (OR: 1.20; 95% [CI]: 1.11 to 1.29; P < .0001). This association increased in studies with positive family history (OR: 1.42; 95% CI: 1.25 to 1.61, P < .0001), recruitment of cases from referral centers (OR: 1.39; 95% CI: 1.20 to 1.62, P < .0001), and more severe hypertension (OR: 1.34; 95% CI: 1.22 to 1.47, P < .0001). However, the presence of methodological problems in all studies gives rise to serious concerns regarding bias and confounding. Despite a statistically significant, albeit weak, association between the AGT 235T variant and hypertension that has been confirmed through sensitivity analysis, this finding has to be interpreted with caution, as the methodological weaknesses of the individual studies are likely to have biased the outcome of the meta-analysis. Clearly, more rigorous methods need to be applied in association studies on the genetics of human hypertension. (Hypertension. 1997;30:1331-1337.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Fifteen patients with Bartter's syndrome (hyponatremic hypochloremic hypokalemic metabolic alkalosis) were compared with 15 healthy volunteers. Red blood cell Na+/H+and Cl-/HCO3-exchanges were enhanced in all patients with Bartter's syndrome. In calciuric normomagnesemic patients, sensitive to nonsteroidal anti-inflammatory drugs (classic Bartter's syndrome), red blood cell Na (+), K+, 2Cl-cotransport was markedly reduced, calcium-dependent K+permeability was moderately increased, and up to 60% of sodium permeability was represented by cAMP-activated fraction (presumably human analog of beta-isoform of Na+/H+exchange). In noncalciuric hypomagnesemic patients insensitive to indomethacin (Gitelman's syndrome), Na+, K+, 2Cl-cotransport was enhanced, Na+permeability was increased due to calmodulin-dependent fraction, and calcium-dependent K+permeability was markedly enhanced. A new subtype of Bartter-like syndrome ("variant Bartter's syndrome") has been described in which calciuria, hypomagnesemia, and insensitivity to nonsteroidal anti-inflammatory drugs were associated with decreased Na+, K+, 2Cl-cotransport, enhanced calmodulin-activated fraction of Na (+) influx, and reduced calcium-dependent K+permeability. (Hypertension. 1997;30:1338-1341.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

Atrial natriuretic factor (ANF) is expressed in several noncardiac tissues where it may have an autocrine or paracrine function. Such function may be expected of locally synthesized ANF in the renal parenchyma. Previous investigations of the existence of ANF mRNA in the renal parenchyma have yielded conflicting results. The investigations reported here were designed to detect and measure ANF mRNA in normal rats and in rats subjected to a deoxycorticosterone acetate (DOCA)-salt treatment schedule known to strongly activate cardiac ANF gene expression. The expression of the renal ANF gene was measured using a newly developed quantitative competitive reverse transcription-polymerase chain reaction (QC-RT-PCR). This method uses an internal competitor thatserves as an internal standard and makes the procedure independent of measurement relative to housekeeping genes. It was found that renal ANF mRNA levels were 107times lower than those found in left or right atria, but immunoreactive (ir) renal ANF concentration by specific radioimmunoassay was 104times lower than that of atrial irANF levels. Reverse-phase high-performance liquid chromatography analysis revealed that more than 99% of renal irANF is processed ANF99-126. This finding suggests that most of the irANF measured in kidney extracts likely originates from atrial sources. Left atrial ANF mRNA levels after 1 week of DOCA-salt treatment was significantly higher than that of control rats ([21.06 +/- 2.99] x 10 (-15) mol/micro gram total RNA versus [8.59 +/- 1.26] x 10-15mol/micro gram total RNA, P < .05). However, renal ANF mRNA levels in DOCA-salt rats were significantly decreased compared with those of control rats ([1.64 +/- 0.34] x 10-22mol/micro gram total RNA versus [3.96 +/- 0.61] x 10-22mol/micro gram total RNA, P < .05). These results indicate that (1) renal ANF mRNA can be consistently and specifically demonstrated after reverse transcription and PCR amplification; (2) renal and cardiac ANF synthesis are regulated in a tissue-specific, opposite manner during DOCA-salt treatment; and (3) the finding that renal ANF mRNA is downregulated by DOCA-salt treatment together with previous findings suggest the need for further investigation into the role of renal ANF mRNA downregulation in the pathogenetic mechanism that leads to volume expansion and hypertension after chronic DOCA-salt treatment. (Hypertension. 1997;30:1342-1347.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The upregulation of left ventricular (LV) atrial natriuretic peptide (ANP) mRNA is a highly conserved marker of cardiac hypertrophy. The aim of this study was to further examine the pathway leading to ANP induction during pressure overload of the heart. Systolic wall stress was imposed acutely on isovolumetrically beating rat hearts in a Langendorff apparatus (sigma = 300 x 103 dyne/cm2). Northern and Western blots revealed that elevated wall stress induced LV c-fos and c-jun mRNAs (3.5- and 3-fold, P < .05 after 60 minutes), c-Fos and c-Jun proteins (3.9- and 4.3-fold, P < .05 after 120 minutes), as well as ANP mRNA (2.2-fold, P < .05 after 120 minutes). ANP upregulation was prevented by inhibition of protein synthesis (cycloheximide). Electrophoresis mobility shift assays were performed to link c-Fos and c-Jun (ie, components of the heterodimeric transcription factor AP-1) and ANP induction. A putative AP-1 binding site within the rat ANP promoter (nucleotides -512 to -473) bound specifically to nuclear proteins of wall stress-stimulated hearts. Antibodies directed against c-Fos protein resulted in a shift of this DNA/protein complex, suggesting physical interaction between AP-1 and the ANP promoter. Myocardial transfection of promoter constructs revealed that after acute imposition of wall stress, this AP-1 site enhanced a reporter gene (8- to 10-fold compared with a minimal promoter, P < .05). Interestingly, nuclear extracts of stimulated hearts as well as pure AP-1 protein bound to a putative CRE site (nucleotides -613 to -584) as well. Like the AP-1 site, this cAMP-responsible element (CRE) site was found to enhance the transfected ANP promoter/reporter gene significantly (17.5-fold, P <.05). Mutation of either AP-1 or CRE sites did not decrease reporter gene activity, whereas mutation of both resulted in loss of inducibility. These experiments suggest that LV ANP regulation after acute wall stress includes the activation of AP-1 and/or CRE cis acting elements. However, the transient nature of c-fos and c-jun upregulation also suggests that AP-1 is not the only mediator of ANP induction in LV hypertrophy. (Hypertension. 1997;30:1348-1355.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The alpha1-adrenoceptor-G protein-phosphoinositide-specific phospholipase C (PLC) signal transduction pathway is assumed to play an important role in the regulation of contractile force and in the pathophysiology of myocardial hypertrophy. In the present study, the components of this pathway were investigated in left ventricles of hearts from hypertensive transgenic rats overexpressing the mouse renin gene [TG(mREN2)27] in comparison to age- and weight-matched Sprague-Dawley control rats. Contractile force was assessed in isolated electrically driven left ventricular papillary muscle strips. Alpha1-adrenoceptor density was measured by radioligand binding using [(3) H]prazosin, steady state levels of alpha q/11, and G protein beta-subunits by Western blotting. PLC activity was determined by a cell-free assay using exogenous phospholipid vesicles containing [(3) H]phosphatidylinositol (4,5)-bisphosphate as a substrate. Alpha1-Adrenoceptor density was significantly increased (by 80%) in transgenic rats compared with control rats, while the positive inotropic response to the alpha1-adrenoceptor agonist phenylephrine was significantly reduced, suggesting a postreceptor defect in TG(mREN2)27. The expression of alpha q and alpha11 was verified by reverse transcription-polymerase chain reaction, and alpha q/11 steady state protein levels were shown to be similar in transgenic and control rats. Western blotting using a beta-common antibody revealed two bands at approximately 35 and 36 kD. The quantities of both were similar in TG(mREN2)27 compared with those in control rats. In contrast, PLC activity was significantly reduced (by 32%) in transgenic rats. In conclusion, our findings are consistent with a desensitization of the alpha1-adrenergic signal transduction pathway at the level of the effector. (Hypertension. 1997;30:1356-1361.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID

摘要:

The spontaneously hypertensive rat (SHR) exhibits a transition from stable compensated left ventricular (LV) hypertrophy to heart failure (HF) at a mean age of 21 months that is characterized by a decrease in alpha-myosin heavy chain (alpha-MHC) gene expression and increases in the expression of the atrial natriuretic factor (ANF), pro-alpha1(III) collagen, and transforming growth factor beta1(TGF-beta1) genes. We tested the hypotheses that angiotensin-converting enzyme inhibition (ACEI) in SHR would prevent and reverse HF-associated changes in gene expression when administered prior to and after the onset of HF, respectively. We also investigated the effect of ACEI on circulating and cardiac components of the renin-angiotensin system. ACEI (captopril 2 g/L in the drinking water) was initiated at 12, 18, and 21 months of age in SHR without HF and in SHR with HF. Results were compared with those of age-matched normortensive Wistar-Kyoto (WKY) rats, and to untreated SHR with and without evidence of HF. ACEI initiated prior to failure prevented the changes in alpha-MHC, ANF, pro-alpha1(III) collagen, and TGF-beta (1) gene expression that are associated with the transition to HF. ACEI initiated after the onset of HF lowered levels of TGF-beta1mRNA by 50% (P < .05) and elevated levels of alpha-MHC mRNA two- to threefold (P < .05). Circulating levels of renin and angiotensin I were elevated four- to sixfold by ACEI, but surprisingly, plasma levels of angiotensin II were not reduced. ACEI increased LV renin mRNA levels in WKY and SHR by two- to threefold but did not influence LV levels of angiotensinogen mRNA. The results suggest that the anti-HF benefits of ACEI in SHR may be mediated, at least in part, by effects on the expression of specific genes, including those encoding alpha-MHC, ANF, TGF-beta1, pro-alpha1(III) collagen, and renin-angiotensin system components. (Hypertension. 1997;30:1362-1368.)

ISSN:0194-911X    

出版商:OVID    

年代:1997

数据来源: OVID