ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Linkage analyses in the spontaneously hypertensive rat (SHR) suggest that a gene involved in blood pressure regulation may be located on rat chromosome 1, in the Sa region. To confirm this possibility, we replaced a region of chromosome 1 in the Wistar-Kyoto rat (WKY) defined by the markers D1Mit3 and MTPA with the corresponding chromosome segment from SHR. Genotyping using 65 polymorphic microsatellite markers throughout the entire genome confirmed the congenic status of this new strain designated WKY.SHR-D1Mit3/Rat57. In male WKY.SHR-D1Mit3/Rat57, mean blood pressures in the daytime and in the nighttime assessed by radiotelemetry were significantly higher than those in male progenitor WKY. Moreover, salt loading significantly increased the mean blood pressure in male WKY.SHR-D1Mit3/Rat57 but not in male progenitor WKY. The present study confirmed the existence of a gene that contributes to high blood pressure and salt sensitivity in this chromosomal segment. This congenic strain represents a new animal model for fine mapping and characterization of the gene in this region involved in salt-sensitive hypertension. (Hypertension. 1998;32:636-638.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Linkage analyses in experimental crosses of hypertensive and normotensive rats have strongly suggested the presence of a quantitative trait locus (QTL) influencing blood pressure on rat chromosome 1, at or near the Sa gene. To confirm the presence of such a locus and move toward identification of the causative gene, we have developed, through targeted breeding over 10 generations using an Sa gene polymorphism to select breeders at each generation, 2 congenic strains, 1 containing a segment of spontaneously hypertensive rat (SHR) chromosome 1 in a Wistar-Kyoto rat (WKY) genetic background (WKY.SHR-Sa), and the other a segment of WKY chromosome 1 in an SHR background (SHR.WKY-Sa). WKY.SHR-Sa contains at least [almost equal to]26 cM of SHR chromosome 1, between markers mD7mit206 and D1Mit2 (and including the SHR allele of the Sa gene), and SHR.WKY-Sa carries at least [almost equal to]15 cM of WKY chromosome 1, between mD7mit206 and D1Wox34 (and including the WKY allele of the Sa gene). Blood pressure of WKY.SHR-Sa rats measured at 16, 20, and 25 weeks of age was significantly higher than that of WKY, whereas blood pressure of SHR.WKY-Sa rats was significantly lower than that of SHR. At 25 weeks, the mean differences in systolic and diastolic blood pressure between WKY.SHR-Sa and WKY were +11.5 mm Hg (P=0.001) and +11.6 mm Hg mm Hg (P<0.001), respectively. The corresponding differences between SHR.WKy-Sa and SHR were -11.3 mm Hg (P=0.002) and -9.1 mm Hg (P=0.005), respectively. The differences represent about one fifth of the blood pressure difference between SHR and WKY. Renal Sa mRNA levels in the congenic strains reflected their Sa allele with a high level in WKY.SHR-Sa and a low level in SHR.WKY-Sa, consistent with previous data suggesting that the level of Sa expression is primarily determined by cis-acting elements in or near the Sa gene. Our results show that we have successfully isolated a major rat chromosome 1 blood pressure QTL located in the vicinity of the Sa gene in reciprocal congenic strains derived from SHR and WKY. The strains can now be used to further define the region containing the QTL and also to characterize intermediary mechanisms through which the QTL influences blood pressure. In addition, comparison of the regions introgressed in our congenic strains with the location of the peak LOD score for chromosome 1 blood pressure QTL in second filial generation progeny derived from our SHR x WKY cross suggests that there may be at least 1 further QTL influencing blood pressure on this rat chromosome. (Hypertension. 1998;32:639-646.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

To test the novel hypothesis that neonatal degeneration of capsaicin-sensitive sensory nerves causes the rat to respond to a salt load with a significant and sustained rise in blood pressure, newborn Wistar rats were given 50 mg/kg capsaicin subcutaneously on the 1st and 2nd day of life. Control rats were treated with vehicle. Immediately after the weanling period, male rats were divided into 4 groups and fed different sodium diets for 2 weeks: capsaicin pretreatment plus high sodium diet (4%, CAP-HS), capsaicin plus normal sodium diet (0.5%, CAP-NS), control plus high sodium diet (CON-HS), and control plus normal sodium diet (CON-NS). Both tail-cuff systolic blood pressure and mean arterial pressure with anesthesia were significantly higher in CAP-HS than in CAP-NS, CON-HS, and CON-NS (P<0.05), but they were not different among the latter 3 groups. Radioimmunoassay revealed that levels of calcitonin gene-related peptide in dorsal root ganglia were markedly decreased by capsaicin treatment (P<0.05). Twenty-four-hour urine volume and urine sodium excretion were significantly lower in CAP-HS than in CON-HS but were higher in CAP-HS and CON-HS compared with CAP-NS and CON-NS (P<0.05). Urine potassium excretion was not different among the 4 groups. Thus, this study provides the first evidence that neonatal degeneration of capsaicin-sensitive sensory nerves renders the rat salt-sensitive in terms of blood pressure regulation. Furthermore, our data suggest that neonatal capsaicin treatment may impair renal sodium and water excretion responses to high sodium intake. This model will provide a novel experimental paradigm for exploring underlying molecular mechanisms linked with salt-sensitive hypertension and sensory nerve function. (Hypertension. 1998;32:649-653.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

The dose and time dependence of angiotensin II (Ang II)-induced hypertension and structural vascular changes and the effect of dietary sodium supplementation on these relationships were investigated. Male Sprague-Dawley rats were treated with 50, 100, or 200 ng [middle dot] kg-1[middle dot] min-1Ang II subcutaneously for 4 or 12 weeks on normal sodium diet (0.7% NaCl) or with 50 ng [middle dot] kg (-1) [middle dot] min-1Ang II SC for 12 weeks on high sodium diet (2% NaCl). Additional rats were sham-operated and fed normal sodium (control rats) or high sodium diet. Plasma Ang II level of rats receiving 100 ng [middle dot] kg-1[middle dot] min-1Ang II for 4 weeks was 26 +/- 5 pg/mL (mean +/- SEM, n = 7) compared with 11 +/- 2 pg/mL (n = 15) in control rats (P<0.03). Lumen and external diameters of small (50 to 100 [micro sign]m OD) and intermediate-size (100 to 150 [micro sign]m OD) resistance arteries were measured in maximally dilated, pump-perfused (55 to 60 mm Hg), in situ fixed mesenteric vascular beds of rats, and wall-to-lumen ratios (W/L) were calculated. Large mesenteric arteries of rats treated with 100 ng [middle dot] kg-1[middle dot] min-1Ang II for 12 weeks were examined to distinguish hypertrophy from hyperplasia of vascular muscle. Tail systolic blood pressure (BP) and W/L of resistance arteries of Ang II-treated rats increased in a dose-dependent manner. Treatment with 50 ng [middle dot] kg-1[middle dot] min-1Ang II for 12 weeks had no significant effect on BP but produced the same increase in W/L (+ 10%, n=8, P<0.06) as 100 ng [middle dot] kg-1[middle dot] min-1Ang II for 4 weeks (+ 9%, n = 18, P<0.05) (time dependence). A 2% NaCl diet for 12 weeks had no significant effect on either BP or W/L, but in combination with 50 ng [middle dot] kg-1[middle dot] min-1Ang II, it increased systolic BP by 31 mm Hg (P<0.01) and W/L of small resistance arteries by 28% (P<0.01) (synergism). In rats treated with 100 ng [middle dot] kg-1[middle dot] min-1Ang II for 12 weeks, arterial smooth muscle cell thickness was increased without a change in the number of cell layers (hypertrophy). There was a dissociation between the average BP load (the area under the weekly systolic BP curve) of Ang II-treated rats and the W/L of their mesenteric resistance arteries. Ang II-induced hypertension and structural vascular changes are dose- and time-dependent and synergistically enhanced by dietary sodium supplementation. Dissociation between BP and vascular structure in Ang II-treated rats suggests that a direct trophic effect of Ang II may contribute to the development of structural vascular changes. (Hypertension. 1998;32:654-660.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Mitogen-activated protein (MAP) kinase cascades are major signaling systems by which cells transduce extracellular cues into intracellular responses. In general, MAP kinases are activated by phosphorylation on tyrosine and threonine residues and inactivated by dephosphorylation. Therefore, MAP kinase phosphatase-1 (MKP-1), a dual-specificity protein tyrosine phosphatase that exhibits catalytic activity toward both regulatory sites on MAP kinases, is suggested to be responsible for the downregulation of extracellular signal-regulated kinase (ERK), stress-activated protein kinase (SAPK), and p38 MAP kinase. In the present study, we examined the role of these MAP kinases in the induction of MKP-1 in vascular smooth muscle cells (VSMCs). Extracellular stimuli such as platelet-derived growth factor (PDGF), 12-O-tetradecanoylphorbol 13-acetate (TPA), and angiotensin II, which activated ERK but not SAPK/p38 MAP kinase, induced a transient induction of MKP-1 mRNA and its intracellular protein. In addition, PD 098059, an antagonist of MEK (MAP kinase/ERK kinase), the upstream kinase of ERK, significantly reduced the PDGF-induced activation of ERK and potently inhibited the expression of MKP-1 after stimulation with PDGF, thereby demonstrating the induction of MKP-1 in response to activation of the ERK signaling cascade. Furthermore, anisomycin, a potent stimulus of SAPK and p38 MAP kinase, also induced MKP-1 mRNA expression. This effect of anisomycin was significantly inhibited in the presence of the p38 MAP kinase antagonist SB 203580. These data suggest the induction of MKP-1, not only after stimulation of the cell growth-promoting ERK pathway but also in response to activation of stress-responsive MAP kinase signaling cascades. We suggest that this pattern of MKP-1 induction may be a negative feedback mechanism in the control of MAP kinase activity in VSMCs. (Hypertension. 1998;32:661-667.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

In cardiac fibroblasts, angiotensin II (Ang II) induced a rapid increase in extracellular signal-regulated kinase (ERK) activity in a pertussis toxin-insensitive manner. This ERK activation was abolished by the Gq-associatedphospholipase C inhibitor U73122 but was insensitive to protein kinase C (PKC) inhibitors or PKC downregulation by phorbol ester. Intracellular Ca2+chelation by BAPTA-AM or TMB-8 abolished Ang II-induced ERK activation, whereas treatment with EGTA or nifedipine did not affect it. Ca2+ionophore A23187 also induced a rapid increase in ERK activity to an extent similar to that of Ang II stimulation. Calmodulin inhibitors (W7 and calmidazolium) and tyrosine kinase inhibitors (genistein and ST638) completely blocked ERK activation by Ang II and A23187. Both Ang II and A23187 caused a rapid increase in the binding of GTP to p21Ras, which was nearly abolished by genistein and calmidazolium. Transfection with the dominant negative mutant of Ras and the Ras inhibitor manumycin completely inhibited Ang II-induced ERK activation. It was also found for the first time that cardiac fibroblasts abundantly expressed Ca2+-sensitivetyrosine kinase Pyk2/CAK beta/RAFTK and that Ang II markedly induced its activation in a Ca2+/calmodulin-sensitivemanner. Overexpression of the dominant negative mutant of Pyk2 significantly attenuated Ang II- or A23187-induced ERK activities (36% and 38% inhibition compared with that in mock-transfected cells, respectively) and ERK tyrosine phosphorylation levels, as well as an increase in the binding of GTP to p21Ras. These findings demonstrate that in cardiac fibroblasts, Ang II-induced Ras/ERK activation is dominantly regulated by Gq-coupledCa2+/calmodulinsignaling and that Pyk2 plays an important role in the signal transmission for efficient activation of the Ang II-induced Ras/ERK pathway. (Hypertension. 1998;32:668-675.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Despite advances in the understanding of monogenic hypertensive disorders, the genetic contribution to essential hypertension has yet to be elucidated. The position of tyrosine hydroxylase (TH) as the rate-limiting enzyme in catecholamine biosynthesis renders it a candidate gene for the etiology of hypertension. The TH gene contains an internal, informative microsatellite marker (TCAT)9. We undertook (1) an association study in a group of well-characterized hypertensive subjects (HT) and control subjects (NT) and (2) an affected sibling pair (ASP) study using sibships from our local family practices. Two hundred twenty-seven hypertensive patients (pretreatment systolic/diastolic blood pressure [BP] range, 139/94 to 237/133 mm Hg; age range [SD], 30 to 71 [8.5] years) were age- and gender-matched with 206 control subjects (BP range, 96/62 to 153/86 mm Hg; age range, 40 to 70 [7.6] years). One hundred thirty-six affected sibling pairs were recruited for our linkage study; 73 young borderline hypertensive subjects (YHT) (pretreatment BP range, 123/76 to 197/107 mm Hg; age range, 20 to 51 [9.4] years) were also recruited in whom recent pretreatment norepinephrine and epinephrine levels were available. All subjects were white. The TH short tandem repeat (STR) was amplified using specific polymerase chain reaction cycling conditions in all subjects, and products were run on an ABI 373A sequencer. TH alleles were assigned using Genescan and Genotyper software. Five TH alleles were present and designated A through E. Allele frequencies in the NT population (A, B, C, D, and E: 0.24, 0.17, 0.13, 0.20, and 0.26, respectively) were significantly different from the HT cohort (A, B, C, D, and E: 0.24, 0.19, 0.11, 0.11, and 0.35, respectively), P<0.0005 (Pearson's test chi squared=19.94; 4 df). The E allele appears overrepresented in the HT group, whereas the D allele appears to be overrepresented in the NT group. TH genotype frequencies were also significantly different between cases and controls (P<0.001; chi squared=36.57; 14 df). Both groups were in Hardy-Weinberg proportion. There was a trend (NS) for the D allele to be associated with a lower BP when BP was analyzed as a quantitative trait. ASP linkage data was analyzed using Splink, a nonparametric program. Expected values for sharing 0, 1, and 2 alleles (Z0, Z1, and Z20.05). There was a trend for lower pretreatment plasma norepinephrine levels with the D allele in this YHT cohort. A common and potentially functional variant at codon 81Val[right arrow]Met within exon 2 of the TH gene (which we show to be in linkage disequilibrium with TH-STR) was also typed in our YHT but did not associate with catecholamine levels and is therefore unlikely to account for our findings with D and E TH-STR. In conclusion, the TH locus strongly associates with essential hypertension in a case-control model using well-characterized hypertensive and control groups. An ASP linkage model was negative, presumably because of lack of power. This study suggests that the TH gene, or a nearby gene, may be involved in the etiology of essential hypertension. (Hypertension. 1998;32:676-682.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID

摘要:

Pregnancy induces uterine spiral arteries to remodel into dilated uteroplacental vessels by an unknown mechanism called "physiological change." In women who develop preeclampsia, however, many spiral arteries remain unchanged or develop medial hyperplasia and atherosis. We recently demonstrated that angiotensinogen is expressed by remodeling spiral arteries in first-trimester decidua. We hypothesize that a local spiral artery renin-angiotensin system mediates pregnancy-induced remodeling of these vessels. In this study we tested for expression of renin, angiotensin-converting enzyme, and angiotensin II type 1 receptor genes in the first-trimester uterus using reverse-transcription polymerase chain reaction. Expression was localized by in situ hybridization and immunohistochemistry. Renin, angiotensin-converting enzyme, and the angiotensin II type 1 receptor are all expressed in and around remodeling spiral arteries. These observations suggest that a local spiral artery renin-angiotensin system may play a role in pregnancy-induced remodeling of these vessels. Elevated angiotensinogen expression in women homozygous for the A(-6) variant in the angiotensinogen promoter may promote abnormal remodeling, whereas relatively lower levels in women homozygous for G(-6) may permit enough normal remodeling to protect these women from preeclampsia. (Hypertension. 1998;32:683-687.)

ISSN:0194-911X    

出版商:OVID    

年代:1998

数据来源: OVID