Defining the blood pressure QTL on Chromosome 7 in Dahl rats by a 177-kb congenic segment containing Cyp11b1

Previously we reported that there is a blood pressure quantitative trait locus (QTL) on rat Chromosome (Chr) 7 seen when comparing Dahl salt-sensitive (S) rats and Dahl salt-resistant (R) rats. Evidence was also presented that this QTL was due to genetic variants in the adrenal steroidogenic enzyme 11beta-hydroxylase ( Cyp11b1). A series of congenic strains supported this contention. In the present work we have constructed a final congenic substrain that retains a blood pressure effect and that has an introgressed congenic segment which includes Cyp11b1 and is < 177 kb in size. None of the other genes in the congenic region (eight known genes) have known biological functions for influencing blood pressure. We believe that we have reached the limit of resolution for congenic analysis of a QTL in a rodent animal model, and we conclude that Cyp11b1 causes the observed QTL on rat Chr 7 in Dahl rats.     

Congenic mapping of a blood pressure QTL on Chromosome 16 of Dahl rats

A Chromosome (Chr) 16 segment of the Dahl salt-sensitive (S) rat was shown by linkage to contain a blood pressure (BP) quantitative trait locus (QTL). To verify and further narrow down the region harboring the QTL, we made two congenic strains by replacing two segments of the S rats with the homologous segments of the Lewis (LEW) rats. The construction of these congenic strains was facilitated by a genome-wide marker screening. The two congenic strains contained a segment in common, and BPs of both were significantly lower than that of the S strain. Consequently, a BP QTL could be localized to the overlapping region of about 49.4 centiRay (cR) including the telomere on a radiation hybrid map. Heart weights, left and right ventricular weights, kidney weights, and aortic weights over length were all significantly decreased in the congenic strains compared with the S strain. Thus, there appeared to exist an association between the effects of the QTL on BP and on cardiac, renal, and vascular hypertrophy.     

High-resolution mapping of the blood pressure QTL on chromosome 7 using Dahl rat congenic strains

It was previously shown using Dahl salt-sensitive (S) and salt-resistant (R) rats that a blood pressure quantitative trait locus (QTL) was present on rat chromosome 7. In the present work, this QTL was localized to a region less than 0.54 cM in size on the linkage map using a series of congenic strains. This region was contained in a single yeast artificial chromosome that was 220 kb long. This small segment still contained the primary candidate locus Cyp11b1 (11beta-hydroxylase), but the adjacent candidate genes Cyp11b2 (aldosterone synthase) and Cyp11b3 were ruled out. It is concluded that 11beta-hydroxylase, through its known genetic variants altering the production of 18-hydroxy-11-deoxy corticosterone, is very likely to account for the blood pressure QTL on chromosome 7 in the Dahl rat model of hypertension. This QTL accounts for about 23 mm Hg under the condition of 2% NaCl diet for 24 days.     

Linkage map and congenic strains to localize blood pressure QTL on rat Chromosome 10

Our purposes were to develop a linkage map for rat Chromosome (Chr) 10, using chromosome-sorted DNA, and to construct congenic strains to localize blood pressure quantitative trait loci (QTL) on Chr 10 with the map. The linkage mapping panel consisted of three F₂ populations totaling 418 rats. Thirty-two new and 29 known microsatellite markers were placed on the map, which spanned 88.9 centiMorgans (cM). The average distance between markers was 1.46 cM. No markers were separated by more than 6.8 cM. Four congenic strains were constructed by introgressing various segments of Chr 10 from the Milan normotensive strain (MNS) onto the background of the Dahl salt-sensitive (S) strain. A blood pressure QTL with a strong effect on blood pressure (35–42 mm Hg) when expressed on the S background was localized to a 31-cM region between D10Mco6 and D10Mcol. The region does not include the locus for inducible nitric oxide synthase (Nos2), which had been considered to be a candidate locus for the QTL. Received: 25 September 1996 / Accepted: 9 November 1996     

Interval mapping and congenic strains for a blood pressure QTL on rat Chromosome 13

The renin locus (Ren) on rat Chromosome (Chr) 13 had previously been shown to cosegregate with blood pressure in crosses involving Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. In the present work, interval mapping of blood pressure on Chr 13 with a large F₂ (S × R), n = 233, population yielded a maximum LOD = 4.2 for linkage to blood pressure, but the quantitative trait locus (QTL) was only poorly localized to a large 35-centiMorgan (cM) segment of Chr 13. In the linkage analysis, the S-rat QTL allele (S) was associated with higher, and the R-rat QTL allele (R) with lower blood pressure, the difference between homozygotes being about 20 mm Hg. A congenic strain was made by introgressing the R-rat Ren allele into the recipient S strain. This congenic strain showed a 24 mm Hg reduction (P = 0.004) in blood pressure compared with S rats for rats fed 2% NaCl diet for 24 days; this difference was confirmed by two other independent tests. Two congenic substrains were derived from the first congenic strain with shorter R Chr 13 segments on the S background. Comparisons among these congenic strains showed that a blood pressure QTL was in the 24-cM chromosomal segment between Syt2 and D13M1Mit108. This segment does not include the renin locus, which is thus excluded from being the gene on rat Chr 13 responsible for genetic differences in blood pressure detected by linkage analysis. Received: 20 December 1996 / Accepted: 7 April 1997     

Blood pressure and survival of a Chromosome 7 congenic strain bred from Dahl rats

11β-hydroxylase (Cyp11b1) mutations were previously linked to altered steroid biosynthesis and blood pressure in Dahl salt-resistant (R) and Dahl salt-sensitive (S) rats. In the present work, interval mapping identified a putative blood pressure quantitative trait locus (QTL) near Cyp11b1 in an F₁(S×R)×S population (LOD = 2.0). Congenic rats (designated S.R-Cyp11b) were constructed by introgressing the R-rat Cyp11b1 allele into the S strain. S.R-Cyp11b rats had significantly lower blood pressure and heart weight compared with S rats, proving the existence of a blood pressure QTL on Chromosome (Chr) 7 despite the fact that QTL linkage analysis of blood pressure never achieved stringent statistical criteria for significance. To test the effects of the introgressed region on blood pressure and survival, S.R.-Cyp11b and S rats were maintained on a 4% NaCl diet until they died or became moribund. Analysis of variance (ANOVA) indicated significant strain differences in blood pressure and days survived (P < 0.0001 for both) as well as gender differences in days survived (P = 0.0003). Kaplan-Meier survival analysis also found significant strain (P < 0.0001) and gender (P = 0.007) differences in days survived. However, when the effects of blood pressure were removed, significant strain differences in survival essentially disappeared. This suggests that the increased survival of S.R-Cyp11b rats was largely due to their decreased blood pressure and thus strongly corroborates the existence of a blood pressure QTL on Chr 7 near or at Cyp11b1. Received: 7 April 1997 / Accepted: 10 August 1997     

Two blood pressure/cardiac mass quantitative trait loci on Chromosome 3 in Dahl rats

Interval mapping was used to identify putative quantitative trait loci (QTL) for blood pressure and cardiac mass on Chromosome (Chr) 3 in F₁(S × R) × S population of 150 rats raised on an 8% NaCl diet. Two genetic markers 95.7 cM apart, D3Wox3 and D3Mco5 (tightly linked to Edn3), showed ``suggestive' linkage to blood pressure (LOD = 2.0 and 1.8 respectively). In addition, D3Wox3 showed ``suggestive' linkage to heart weight (LOD = 2.5), and D3Mco5 showed ``suggestive' linkage to body weight–adjusted heart weight (LOD = 2.1). Congenic rats (designated S.R-Edn3) were constructed by introgressing the R-rat Edn3 allele (and flanking loci) into the S strain. On a 2% NaCl diet, S.R-Edn3 rats had lower blood pressure (21.4 mm Hg, P= 0.0005) and heart weight (59 mg, P= 0.0038) compared with S rats, confirming the existence of a blood pressure QTL on Chr 3 near Edn3 even though QTL linkage analysis of blood pressure did not achieve stringent statistical criteria for significance. The results of the congenic experiment and the large distance between the two putative QTL suggest the presence of at least two independent blood pressure/cardiac mass QTL detectable on Chr 3 in the Dahl rat model of genetic hypertension. Received: 24 April 1998 / Accepted: 29 September 1998     

Localization of a blood pressure QTL to a 2.4-cM interval on rat chromosome 9 using congenic strains

A blood pressure (BP) quantitative trait locus (QTL) was previously found on rat chromosome 9 using Dahl salt-sensitive (S) and Dahl salt-resistant (R) rats. A congenic strain, S.R(chr9), constructed by introgressing an R chromosomal segment into the S background, previously proved the existence of a BP QTL in a large 34.2-cM segment of chromosome 9. In the current work congenic substrains were constructed from the progenitor congenic strain, S.R(chr9). BP and heart weight comparisons between these congenic substrains and their S control localized the BP QTL to a 4.6-cM interval. Two solute carrier (Na(+)/H(+) exchanger) genes, Nhe2 and Nhe4, were excluded as candidates based on their map locations. A second iteration of congenic substrains was used to localize the QTL further to a 2.4-cM interval. Another solute carrier (Cl(-)/HCO3- exchanger) gene, Ae3, is in this reduced interval and was sequenced for both S and R strains, but no coding sequence variations were found. Ae3 mRNA was not differentially expressed in the kidney of congenic compared to S rats. Although the identity of the QTL remains unknown its map location has been reduced from an interval of 34.2 to 2.4 cM.     

Rosiglitazone reduces blood pressure in female Dahl salt-sensitive rats

Postmenopausal women (PMW) are at greater risk for salt-sensitive hypertension and insulin resistance than premenopausal women. Peroxisome-proliferator-activated receptor-gamma (PPARγ) agonists reduce blood pressure (BP) and insulin resistance in humans. As in PMW, ovariectomy (OVX) increases salt sensitivity of BP and body weight in Dahl salt-sensitive (DS) rats. This study addressed whether rosiglitazone (ROSI), a PPARγ agonist, attenuates salt-sensitive hypertension in intact (INT) and OVX DS rats, and if so, whether insulin resistance, nitric oxide (NO), oxidative stress, and/or renal inflammation were contributing mediators. Telemetric BP was similar in OVX and INT on low salt diet (0.3% NaCl), but was higher in OVX than INT on high salt (8% NaCl). ROSI reduced BP in OVX and INT on both low and high salt diet, but only attenuated salt sensitivity of BP in OVX. Nitrate/nitrite excretion (NO_x; index of NO) was similar in INT and OVX on low salt diet, and ROSI increased NO_x in both groups. High salt diet increased NO_x in all groups but ROSI only increased NO_x in OVX rats. OVX females exhibited insulin resistance, increases in body weight, plasma leptin, cholesterol, numbers of renal cortical macrophages, and renal MCP-1 and osteopontin mRNA expression compared to INT. ROSI reduced cholesterol and macrophage infiltration in OVX, but not INT. In summary, PPARγ activation reduces BP in INT and OVX females, but attenuates the salt sensitivity of BP in OVX only, likely due to increases in NO and in part to reductions in renal resident macrophages and inflammation.     

Distinct quantitative trait loci for kidney, cardiac, and aortic mass dissociated from and associated with blood pressure in Dahl congenic rats

Blood pressure (BP) is largely determined by quantitative trait loci (QTLs) in Dahl salt-sensitive (DSS) rats. Little is known about QTLs controlling kidney (K), cardiac (C), and aortic (A) mass (i.e. Km, Cm, and Am, respectively) of DSS rats independent of BP. Their identification can facilitate our understanding of end organ damage. In this work, 36 congenic strains were employed to define QTLs for Km, Cm, and Am either independent of or associated with BP. Five new QTLs, i.e., KmQTLs, that influence Km independent of Cm, Am, and BP were defined. Four new CakmQTLs were defined for Cm, Am, and Km independent of BP. Among them, the CakmC10QTL1 interval contained 13 genes and undefined loci, and none was known to influence the phenotypes in question, paving the way for a novel gene discovery. Among 17 individual QTLs for BP, 14 also affected Cm, Km, and Am, i.e., they are BpcakmQTLs. In contrast, one BpQTL had no effect on Cm, Am, and Kam. Therefore, BP and Cm, Am, and Km have distinct and shared genetic determinants. The discovery of individual Km and Cakm QTLs will likely facilitate the identification of mechanisms underlying renal, cardiac, and/or aortic hypertrophy independent of hypertension. Electronic Supplementary Material Electronic Supplementary material is available for this article at and accessible for authorised users. Chenda Duong and Sophie Charron contributed equally to this work.     

Congenic mapping of a blood pressure QTL region on rat chromosome 10 using the Dahl salt-sensitive rat with introgressed alleles from the Milan normotensive strain

Multiple blood pressure (BP) quantitative trait loci (QTLs) are reported on rat chromosome 10 (RNO10). Of these, QTLs detected by contrasting the genome of the hypertensive Dahl salt-sensitive (S) rat with two different relatively normotensive strains, Lewis (LEW) and the Milan normotensive strain (MNS), are reported. Because the deduced QTL regions of both S vs. LEW and S vs. MNS comparisons are within large genomic segments encompassing more than 2 cM, there was a need to further localize these QTLs and determine whether the QTLs are unique to specific strain comparisons. Previously, the S.MNS QTL1 was mapped to less than 2.6 cM as a differential segment between two congenic strains. In this study, multiple congenic strains spanning the projected interval were studied. The BP effect of each strain was interpreted as the net effect of alleles introgressed within that congenic strain. The results suggest that the MNS alleles within the previously proposed differential segment (D10Rat27-D10Rat24) do not independently lower BP of the S rat. However, another congenic strain, S.MNS(10) × 9, containing introgressed MNS alleles that are outside of the previously proposed differential segment is of interest because (1) it demonstrated a BP-lowering effect, (2) it is contained within a single congenic strain and is not based on the observed effect of a differential segment, and, more importantly, (3) it overlaps with the previously identified S.LEW BP QTL region. Identification of the same QTL affecting BP in multiple rat strains will provide further support for the QTL’s involvement and importance in human essential hypertension.     

Effect of 3beta-hydroxysteroid dehydrogenase inhibition by trilostane on blood pressure in the Dahl salt-sensitive rat

The brains of rats and humans express the enzymes required for the synthesis of aldosterone from cholesterol, including the 3beta-steroid dehydrogenase that catalyzes the conversion of pregnenolone to progesterone in the pathway of adrenal steroid synthesis. Salt-induced hypertension in the Dahl inbred salt-sensitive (SS/jr) rat is associated with normal to low levels of circulating aldosterone, yet it is abrogated by the central infusion of mineralocorticoid receptor antagonists. To test the hypothesis that de novo synthesis of aldosterone in the brain has a pathophysiological role in the salt-induced hypertension of the SS rat, the 3beta-steroid dehydrogenase antagonist trilostane was infused continuously intracerebroventricularly or subcutaneously in two different cohorts of Dahl SS/jr rats, one female, the other male, during and after the development of salt-induced hypertension. The doses of trilostane used had no effect on blood pressure when infused subcutaneously. Animals receiving vehicle intracerebroventricularly experienced a 30- to 45-mmHg increase in systolic blood pressure measured by tail cuff. The intracerebroventricular, but not subcutaneous, infusion of 0.3 microg/h trilostane effectively blocked the increase in systolic blood pressure and reversed the hypertension produced by drinking 0.9% saline. Trilostane was equally effective in female and male rats. Weight gain, serum aldosterone and corticosterone concentrations, and behavior assessed subjectively and by elevated plus maze were unchanged by the trilostane treatment. These studies suggest that the synthesis in the brain of a mineralocorticoid receptor agonist, probably aldosterone, is responsible in part for the salt-induced hypertension of the inbred Dahl SS/jr rat.     

Effect of dietary sodium on estrogen regulation of blood pressure in Dahl salt-sensitive rats

The effects of high-sodium (HS) and normal-sodium (NS) diets on ovarian hormone modulation of mean arterial pressure (MAP) were examined in Dahl salt-resistant (DR) and salt-sensitive (DS) rats. Ovariectomy increased MAP (OVX-Sham) to a greater extent in DS rats maintained for 2 wk on a HS (22 mmHg) compared with a NS (6 mmHg) diet. Ovariectomy had no effect on MAP in DR rats on NS but did increase MAP in rats on HS (10 mmHg) diets. On HS diets, glomerular filtration rate (GFR) was 36% less in the DS-Sham than DR-Sham animals; ovariectomy increased GFR in both strains by 1.4-1.5-fold; glomerular angiotensin II type 1 receptor (AT(1)R) densities were 1.6-fold higher in the DS-Sham than in the DR-Sham group; ovariectomy increased glomerular AT(1)R densities by 1.3-fold in DR rats but had no effect in DS rats; 17beta-estradiol (E(2)) downregulated adrenal AT(1)R densities in both strains on either diet; ovariectomy reduced estrogen receptor-alpha (ER-alpha) protein expression in the renal cortex by 40-50% although renal ER-alpha expression was 34% lower in DS than in DR rats. These observed effects of gonadectomy were prevented by E(2) treatment, suggesting that E(2) deficiency mediates the effects of ovariectomy on MAP, GFR, AT(1)R densities, and renal ER-alpha protein expression. In conclusion, ovariectomy-induced increases in MAP are augmented by HS diet in both strains, and this effect is not mediated by a reduction in GFR. Aberrant renal AT(1)R regulation and reduced renal ER-alpha expression are potential contributors to the hypertensive effects of E(2) deficiency in DS rats. These findings have implications for women with salt-sensitive hypertension and women who are E(2) deficient, such as postmenopausal women.     

Examination of OLETF-derived non-insulin-dependent diabetes mellitus QTL by construction of a series of congenic rats

The Otuska Long-Evans Tokushima Fatty (OLETF) rat is one of the well-characterized animal models for the study of type 2 diabetes. Our previous QTL mapping identified 11 loci responsible for non-insulin-dependent diabetes mellitus (NIDDM) susceptibility in the OLETF rat. Here we generated a series of congenic animals by individually introgressing all 11 OLETF-derived NIDDM loci into a normoglycemic F344 background. Subsequent oral glucose tolerance test revealed that the congenic strains for Nidd1/of, Nidd2/of, Nidd3/of Nidd4/of, Nidd7/of, and Nidd10/of showed significantly higher levels of blood glucose in comparison with parental host strain F344. Furthermore, simultaneously made heterozygote animals for Nidd1/of and Nidd2/of did not increase blood glucose levels, indicating that these loci are recessively inherited as predicted by the QTL analysis. Congenic strains for the other five loci—Nidd5/of, Nidd6/of, Nidd8/of, Nidd9/of, and Nidd11/of—were apparently normoglycemic, presumably owing to heterosis or because the effect of these loci may not be detected unless interactions with other OLETF genes exist. We believe that these congenic strains should provide useful agents for decomposing complex diabetic traits and for positional cloning.     

Utilization of marker-assisted congenics to map two blood pressure quantitative trait loci in Dahl rats

A broad Chromosome (Chr) 10 region of the Dahl salt-sensitive (S) rat was shown by linkage and the use of congenic strains to contain a blood pressure (BP) quantitative trait locus (QTL). To further narrow down the region harboring the QTL, four congenic strains carrying smaller segments were made by replacing various segments of the S rats with the homologous segments of the Lewis (LEW) rats. The construction of these congenic strains was facilitated by a genome-wide marker screening. One congenic strain, assigned as S.L4, showed a BP-lowering effect, and the region harboring a BP QTL, designated QTL1, is localized to a segment of about 15 cM. Two other strains, assigned as S.L2 and S.L5, contained an overlapping segment, and both showed a BP-lowering effect. In contrast, the fourth congenic strain, assigned as S.L1, contained a smaller and shared fragment with S.L2 and S.L5, but it did not have a BP-lowering effect. Deducing from the segment in common in S.L2 and S.L5, and not shared between S.L1 and both congenic strains S.L2 and S.L5, the region harboring a QTL, designated as QTL2, was narrowed to about 12 cM. The current work showed the general applicability of the `speed congenic' approach to map and fine-map BP QTL. Received: 1 February 2001 / Accepted: 29 March 2001     

A novel mouse Chromosome 2 congenic strain with obesity phenotypes

Linkage studies have identified many chromosomal regions containing obesity genes in mice. However, only a few of these quantitative trait loci (QTLs) have been used to guide the production of congenic mouse strains that retain obesity phenotypes. We seek to identify chromosomal regions containing obesity genes in the BSB model of spontaneous obesity because the BSB model is a multigenic obesity model. Previous studies identified QTLs on Chromosomes (Chrs) 2, 6, 7,12, and 15. BSB mice are made by backcross of lean C57BL/6J × Mus spretus. F₁s were backcrossed to C57BL/6J mice to produce BSB progeny. We have constructed a new BSB cross and produced congenic mice with obesity phenotypes by marker-directed selection called B6.S–D2Mit194–D2Mit311. We found a highly significant QTL for percentage body lipid on Chr 2 just proximal to the Agouti locus. Chr 2 congenics were constructed to determine whether the main effects would be detectable. We observed highly significant linkage of the Chr 2 congenic containing Agouti and containing markers distal to D2Mit311 and proximal to D2Mit194. Thus, this congenic contains approximately 14.6 cM or 30 Mb (about 1.1% of the spretus mouse genome) and several hundred genes. The obesity phenotype of the QTL is retained in the congenic. The congenic can now be used to model the genetic and physiological basis for a relatively simple, perhaps monogenic, obesity.     

Triple VPI CGS 35601 reduces high blood pressure in low-renin, high-salt Dahl salt-sensitive rats

We previously reported that CGS 35601, a potent triple inhibitor of angiotensin-converting enzyme, neutral endopeptidase, and endothelin-converting enzyme 1, completely normalized mean arterial blood pressure (MABP) in 36-week-old spontaneously hypertensive rats, a normal renin model. The aim of the present study was to determine the effects of this triple vasopeptidase inhibitor (VPI) on the hemodynamic profile of instrumented, conscious, and unrestrained Dahl salt-sensitive (DSS) rats, a gene-prone, high-salt diet-induced low-renin hypertension model. Male DSS rats (mean weight [+/-SEM], 385 +/- 10 g) were fed a normal diet (Group 1) or a high-salt diet (Groups 2 and 3; 8% NaCl in food) for 6 weeks and then instrumented with a carotid catheter and placed individually in metabolic cages for 30 days. The hemodynamic, hematological, and biochemical profiles were assessed daily. Dose-dependent treatment started after a 7-day stabilization period in Groups 1 and 2 (vehicle dosage, 250 microl/hr) and Group 3 (CGS 35601 dosages of 0.1, 1, and 5 mg/kg/day for 6 days per dose by means of constant intra-arterial infusion), followed by a 5-day washout period. Two additional groups included normotensive Wistar rats (Group 4) and DSS rats that received a double high-salt solid (8% NaCl) and liquid (1% NaCl) diet (Group 5).The MABP in rats receiving CGS 35601 decreased in a dose-dependent fashion toward the baseline level observed in DSS rats receiving a normal diet. The heart rate was unaffected. The hemodynamic profile returned to normal during the washout period. This novel triple VPI is a potent and effective antihypertensive agent with a safe short-term profile that may be of interest for treating hypertension and other cardiovascular diseases. Other hypertensive rat models are being tested.     

Narrowing a region on rat chromosome 13 that protects against hypertension in Dahl SS-13BN congenic strains

Transfer of chromosome 13 from the Brown Norway (BN) rat onto the Dahl salt-sensitive (SS) genetic background attenuates the development of hypertension, but the genes involved remain to be identified. The purpose of the present study was to confirm by telemetry that a congenic strain [SS.BN-(D13Hmgc37-D13Got22)/Mcwi, line 5], carrying a 13.4-Mb segment of BN chromosome 13 from position 32.4 to 45.8 Mb, is protected from the development of hypertension and then to narrow the region of interest by creating and phenotyping 11 additional subcongenic strains. Mean arterial pressure (MAP) rose from 118 ± 1 to 186 ± 5 mmHg in SS rats fed a high-salt diet (8.0% NaCl) for 3 wk. Protein excretion increased from 56 ± 11 to 365 ± 37 mg/day. In contrast, MAP only increased to 152 ± 9 mmHg in the line 5 congenic strain. Six subcongenic strains carrying segments of BN chromosome 13 from 32.4 and 38.2 Mb and from 39.9 to 45.8 Mb were not protected from the development of hypertension. In contrast, MAP was reduced by ～30 mmHg in five strains, carrying a 1.9-Mb common segment of BN chromosome 13 from 38.5 to 40.4 Mb. Proteinuria was reduced by ～50% in these strains. Sequencing studies did not identify any nonsynonymous single nucleotide polymorphisms in the coding region of the genes in this region. RT-PCR studies indicated that 4 of the 13 genes in this region were differentially expressed in the kidney of two subcongenic strains that were partially protected from hypertension vs. those that were not. These results narrow the region of interest on chromosome 13 from 13.4 Mb (159 genes) to a 1.9-Mb segment containing only 13 genes, of which 4 are differentially expressed in strains partially protected from the development of hypertension.     

Sympathetic hyperreactivity to air-jet stress in the chromosome 1 blood pressure quantitative trait locus congenic rats

A chromosome 1 blood pressure quantitative trait locus (QTL) was introgressed from the stroke-prone spontaneously hypertensive rats (SHRSP) to Wistar-Kyoto (WKY) rats. This congenic strain (WKYpch1.0) showed an exaggerated pressor response to both restraint and cold stress. In this study, we evaluated cardiovascular and sympathetic response to an air-jet stress and also examined the role of the brain renin-angiotensin system (RAS) in the stress response of WKYpch1.0. We measured mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nerve activity (RSNA) responses to air-jet stress in WKYpch1.0, WKY, and SHRSP. We also examined effects of intracerebroventricular administration of candesartan, an ANG II type 1 receptor blocker, on MAP and HR responses to air-jet stress. Baseline MAP in the WKYpch1.0 and WKY rats were comparable, while it was lower than that in SHRSP rats. Baseline HR did not differ among the strains. In WKYpch1.0, air-jet stress caused greater increase in MAP and RSNA than in WKY. The increase in RSNA was as large as that in SHRSP, whereas the increase in MAP was smaller than in SHRSP. Intracerebroventricular injection of a nondepressor dose of candesartan inhibited the stress-induced pressor response to a greater extent in WKYpch1.0 than in WKY. Intravenous injection of phenylephrine caused a presser effect comparable between WKYpch1.0 and WKY. These results suggest that the chromosome 1 blood pressure QTL congenic rat has a sympathetic hyperreactivity to an air-jet stress, which causes exaggerated pressor responses. The exaggerated response is at least partly mediated by the brain RAS.