Hypertension in the spontaneously hypertensive rat is linked to the Y chromosome

The objective of our study was to determine the genetic influence on blood pressure in spontaneously hypertensive rats (SHR), and normotensive Wistar-Kyoto (WKY) rats using genetic crosses. Blood pressure was measured by tail sphygmomanometry from 8 to 20 weeks of age. Blood pressure was significantly higher from 12 to 20 weeks in the male offspring derived from WKY mothers x SHR fathers as compared with male offspring derived from SHR mothers X WKY fathers (180 +/- 4 versus 160 +/- 5 mm Hg, p less than 0.01). There was no significant difference between the blood pressure of the F1 females, further supporting Y chromosome linkage and not parental imprinting. The blood pressure data from F2 males derived from reciprocal crosses of parental strains were consistent with the presence of a Y-linked locus, but not with an X-linked locus controlling blood pressure. The data strongly suggest that hypertension in the SHR has two primary components of equal magnitude, one consisting of a small number of autosomal loci with a second Y-linked component.     

Identification of a candidate gene responsible for the high blood pressure of spontaneously hypertensive rats.

OBJECTIVE: We have recently isolated a gene, designated as the SA gene, which is more than 10 times more abundantly expressed in the kidneys of spontaneously hypertensive rats (SHR) than in those of Wistar-Kyoto (WKY) rats. To address the issue whether the SA gene is one of the genes responsible for the hypertension of SHR, a genetic cosegregation analysis of the blood pressure values with the genotypes in an F2 rat population was undertaken in this study. METHODS AND DESIGN: Male F2 rats were bred from SHR and WKY rats. The genotypes of the SA gene of the F2 rats were determined by utilizing the StuI restriction fragment length polymorphism of the SA gene between SHR and WKY rats. The blood pressure values were determined by the tail-cuff method. The effect of the genotype of the SA gene on the blood pressure of the F2 rats was analysed by one-way analysis of variance. RESULTS AND CONCLUSION: The blood pressure of the F2 rats inheriting two SHR alleles of the SA gene was significantly higher than that of the F2 rats inheriting two WKY alleles. This indicates that the SA gene, or a gene closely linked to it, has a capacity to influence the blood pressure values of the F2 rat population. Further studies to identify functions of the SA gene products will be necessary.     

Polymorphism in soluble epoxide hydrolase and blood pressure in spontaneously hypertensive rats

We measured soluble epoxide hydrolase (sEH) renal gene expression in prehypertensive (4 to 5 weeks old) spontaneously hypertensive rats of the Heidelberg SP substrain (SHR [Heid]) and when blood pressure levels entered the hypertensive plateau (17 to 18 weeks old) and compared expression with matched Wistar-Kyoto (WKY [Heid]) rats. Less expression of the gene encoding sEH (EPHX2) was observed in SHR (Heid) than in WKY (Heid). Analysis of sEH protein abundance showed a similar difference. However, no correlation between sEH abundance and blood pressure was observed in the F(2) progeny of a parental strain cross. Measurement of protein abundance in SHR and WKY obtained from Charles River confirmed a recent report that abundance of sEH was greater in SHR (CRiv) than WKY (CRiv) strains. Polymorphisms were detected in EPHX2. Resequencing revealed that 2 alleles of EPHX2 exist in these 4 rat strains, differing by 4 single nucleotide polymorphisms, of which 3 produce nonsynonymous amino acid substitutions. The ancestral allele was shared by SHR (Heid) and WKY (CRiv), and the variant allele was shared by WKY (Heid) and SHR (CRiv). Activity of sEH was greater in animals carrying the variant allele. However, inheritance of this allele was not correlated with blood pressure in the F(2) progeny of a cross between SHR (Heid) and WKY (Heid). These data indicate that sequence variation determining functional alterations in EPHX2 is not likely to contribute to blood pressure levels in SHR.     

Cosegregation of the Renin Gene With an Increase in Mean Arterial Blood Pressure in the F2 Rats of SHR-WKY Cross1

Using the restriction endonuclease, Bgl I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats (1). This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F₂rats produced from F₁ rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannuiation of the fomoral artery prior to sacrifice. The frequency of renin genotype showed a typical 1:2:1 Mendelian ratio in F₂ rats of SHR and WKY cross. The mean arterial blood pressure of F₂ rats homozygous with the SHR allele was significantly higher than F₂ rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in these F₂ rats. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F₂ rats of SHR and WKY cross.     

Cosegregation of the Renin Gene with an Increase in Mean Arterial Blood Pressure in the F2 Rats of SHR-Wky Cross

Using the restriction endonuclease, Bgl I, Samani et al. found a restriction fragment length polymorphism (RFLP) for the renin gene in spontaneously hypertensive rats (SHR) and its normotensive control Wistar-Kyoto (WKY) rats (1). This RFLP was confirmed in our laboratory in SHR and WKY rats using a rat renin cDNA probe. The correlation of blood pressure and the renin RFLP was examined in 106 F₂ rats produced from F₁ rats, the offspring of a cross between SHR males and WKY females. Systolic blood pressure was measured by the tail cuff method at 12 weeks of age. Mean arterial blood pressure of anesthetized rats was measured by cannulation of the femoral artery prior to sacrifice. The frequency of ranin genotype showed a typical 1:2:1 Mendelian ratio in F₂ rats of SHR and WKY cross. The mean arterial blood pressure of F₂ rats homozygous with the SHR allele was significantly higher than F₂ rats that were heterozygous or homozygous for the WKY allele. No significant difference in systolic blood pressure was observed in F₂ rats with different genotypes. Thus, the renin gene RFLP cosegregates with an increase in mean arterial blood pressure in the F₂ rats of SHR and WKY cross.     

Genetic analysis of blood pressure and sodium balance in spontaneously hypertensive rats

Blood pressure and parameters of sodium balance were measured during the first 16 weeks of life in male Okamoto spontaneously hypertensive rats (SHR, n = 22), Wistar-Kyoto rats (WKY, n = 25), and the F1 (n = 27) and F2 (n = 81) hybrids of the SHR and WKY. Genetic analysis revealed that blood pressure in SHR was controlled by approximately four independent genetic loci and the degree of genetic determination was 64.5%. No difference in blood pressure was discernible before 12 weeks of age between those F2 rats that at 16 weeks had blood pressures either higher or lower than one standard deviation from the mean. Exchangeable sodium was measured sequentially in individual rats of all populations by determining their whole-body radioactivity while receiving 37.5 mM 22Na/23NaCl drinking fluid of constant specific activity as their sole source of sodium. The SHR had consistently higher exchangeable sodium levels than WKY and showed evidence of relative sodium retention during the early developmental phase of hypertension. Sodium intake was higher in SHR than WKY from 4 to 16 weeks of age, although saline preference was the same in both strains. None of these parameters of sodium balance were found to correlate with blood pressure in the F2 population. It is concluded that the heritable abnormalities of sodium balance in SHR appear to represent coincidental inbred characteristics controlled by genetic loci that are unrelated to those loci responsible for the expression of hypertension in this model.     

Cosegregation Analysis of Salt Appetite and Blood Pressure in Genetically Hypertensive and Normotensive Rats

Enhanced sodium appetite is a robust behavioral characteristic of spontaneously hypertensive rats (SHR) which neither causes nor depends upon elevated blood pressure. However, the possibility remains that salt appetite and blood pressure are related by some unidentified common factor. The present study investigated the possible genetic co-determination of blood pressure and salt appetite in this animal model of hypertension.

Blood pressure of SHR, Wistar/Kyoto (WKY), and their F1 and F2 populations was measured prior to salt appetite testing by the tail cuff method. Sodium intake in these groups was measured daily for 5 days as the ad lib consumption of a 1.5% NaCl solution by subjects maintained on sodium deficient chow and demineralized water. Dynamic and stable components of salt appetite were identified in the parent strains and analyzed in the hybrid offspring.

The expected differences in blood pressure between SHR and WKY were observed, and the average blood pressure of the F1 and F2 groups fell roughly midway between SHR and WKY values. The SHR consumed substantially greater quantities of saline than WKY, but the F1 population consumed saline at a rate that was not different from WKY, rather than intermediate between SHR and WKY. There was no relationship in the F2 population between blood pressure and any measure of salt appetite. Thus, the high salt appetite and high blood pressure traits of SHR do not appear to share a common genetic basis. These results, considered with previously published work, suggest that approach and avoidance aspects of salt appetite may be separately inherited and also strongly suggest that neither is linked to hypertension.     

Resistance vessel structure and function in the etiology of hypertension studied in F2-generation hypertensive-normotensive rats

The role of certain resistance vessel characteristics in the etiology of hypertension has been investigated using F2-generation hypertensive/normotensive rats. The F2 populations were bred from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) as well as from stroke-prone SHR (SHRSP) and outbred Wistar-Kyoto rats (WKYO), and are denoted SHR/WKY and SHRSP/WKYO, respectively. Mesenteric resistance vessels (lumen diameter ca 200 micron) were taken from rats in the highest and lowest blood pressure quartiles of 14-week SHR/WKY and 18-week SHRSP/WKYO, as well as from 15-week pure SHR and WKY and from 18-week pure SHRSP and WKYO. The vessels were mounted on a myograph for determination of their structural and contractile characteristics. The structure of the vessels, as expressed for example by their media : lumen ratio, was greatest in the vessels from the SHR and the SHRSP compared to those from the WKY and WKYO. Increased structure was seen in the vessels from the rats in the high blood pressure quartiles of each group of F2 populations, compared to the vessels from the rats in the low blood pressure quartiles, although in the SHR/WKY the difference was smaller than expected if structure were a major determinant of blood pressure. Vascular sensitivity to calcium and the effect of cocaine on noradrenaline sensitivity were increased in the vessels from the SHR and SHRSP, but were the same in the high and low blood pressure quartiles of the F2 populations.(ABSTRACT TRUNCATED AT 250 WORDS)     

A high phosphate diet lowers blood pressure in spontaneously hypertensive rats

Plasma phosphate values are significantly lower in spontaneously hypertensive rats (SHR) than in normotensive Wistar-Kyoto rats (WKY). In this study, we increased plasma phosphate in SHR by a dietary phosphate intake and followed the effects on blood pressure. Fifteen male WKY and 15 male SHR were housed from 4 weeks of age up to 26 weeks. At 4 weeks of age all SHR manifested a hypophosphatemia compared with age-matched WKY (F = 62, p less than 0.0003). At 5 weeks of age, the rats were divided into three diet groups: a control group, a group receiving 1.41% (wt/vol) KCl in drinking water, and a group receiving 2% (wt/vol) K2HPO4 X KH2PO4 in drinking water. In the control (F = 16.2, p less than 0.02) and KCl groups, (F = 36.3, p less than 0.03), hypophosphatemia persisted throughout the study. The phosphate-supplemented diet normalized plasma phosphate level in SHR but did not change plasma phosphate level in WKY. As a consequence, no difference in plasma phosphate level between WKY and SHR was present in the group receiving additional phosphate from that time on (F = 1.2, p greater than 0.41). The phosphate-supplemented diet significantly decreased systolic blood pressure in both strains. In phosphate-supplemented SHR, a significant decline in systolic blood pressure was observed from 20 weeks of age on (at 20 weeks of age: 222 +/- 3 mm Hg for control SHR vs 198 +/- 5 mm Hg for phosphate-supplemented SHR; p less than 0.0003).(ABSTRACT TRUNCATED AT 250 WORDS)     

Role of chymase-dependent angiotensin II formation in regulating blood pressure in spontaneously hypertensive rats.

Vascular smooth muscle cells in spontaneously hypertensive rats (SHR) express angiotensin II-forming chymase (rat vascular chymase [RVCH]), which may contribute to blood pressure regulation. In this study, we studied whether chymase-dependent angiotensin II formation contributes to the regulation of blood pressure in SHR. The systolic blood pressure in 16-week-old Wistar-Kyoto (WKY) rats was 113 +/- 9 mmHg, compared to 172 +/- 3 mmHg in SHR. Using synthetic substrates for measuring angiotensin-converting enzyme (ACE) and chymase activities, it was found that both ACE and chymase activities in extracts from SHR aortas were significantly higher than in those from WKY rat aortas. Using angiotensin I as a substrate, angiotensin II formation in SHR was found to be significantly higher than that in WKY rats, and its formation was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. RVCH mRNA expression could not be detected in aorta extracts from either WKY rats or SHR. In carotid arteries isolated from WKY rats and SHR, angiotensin I-induced vasoconstriction was completely suppressed by an ACE inhibitor, but not by a chymase inhibitor. Angiotensin I-induced pressor responses in both WKY rats and SHR were also completely inhibited by an ACE inhibitor, but they were not affected by a chymase inhibitor. In SHR, an ACE inhibitor and an angiotensin II receptor blocker showed equipotent hypotensive effects, but a chymase inhibitor did not have a hypotensive effect. These results indicated that chymase-dependent angiotensin II did not regulate blood pressure in SHR in the present study.     

Differential regulation of cardiac adrenomedullin and natriuretic peptide gene expression by AT1 receptor antagonism and ACE inhibition in normotensive and hypertensive rats

OBJECTIVE: To study the effects of long-term treatment with the type 1 angiotensin (AT1) receptor antagonist losartan and the angiotensin-converting enzyme (ACE) inhibitor enalapril, on cardiac adrenomedullin (ADM), atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) gene expression. METHODS: Spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were given losartan (15 mg/kg per day) or enalapril (4 mg/kg per day) orally for 10 weeks. The effects of drugs on systolic blood pressure, cardiac hypertrophy, ANP, BNP and ADM mRNA and immunoreactive-ANP (IR)-ANP, IR-BNP and IR-ADM levels in the left ventricle and atria were compared. RESULTS: Losartan and enalapril treatments completely inhibited the increase of systolic blood pressure occurring with ageing in SHR. The ratio of heart to body weight was reduced in both losartan- and enalapril-treated SHR and WKY rats. Treatment with losartan or enalapril reduced left ventricular ANP mRNA and IR-ANP in both strains, and ventricular BNP mRNA levels in SHR rats. Inhibition of ACE, AT1 receptor antagonism, changes in blood pressure or cardiac mass had no effect on left ventricular ADM gene expression in SHR and WKY rats. In addition, atrial IR-ANP and IR-ADM levels increased in SHR whereas IR-BNP levels decreased in WKY and SHR rats in response to drug treatments. CONCLUSIONS: Our results show that ventricular ADM synthesis is an insensitive marker of changes in haemodynamic load or cardiac hypertrophy. Furthermore, the expression of ADM, ANP and BNP genes is differently regulated both in the left ventricle and atria in response to AT1 receptor antagonism and ACE inhibition.     

Dissociation of hypertension and genetically enhanced cell growth capacity in skin fibroblasts of F2 hybrid spontaneously hypertensive rats/Wistar-Kyoto rats.

Skin fibroblasts from newborn spontaneously hypertensive rats (SHR) grow faster in culture than Wistar-Kyoto rat (WKY) cells. Similar results have been described for vascular smooth muscle cells from prehypertensive and adult SHR. This suggests the existence of an intrinsic abnormality in vascular and nonvascular cells of mesodermal origin affecting cell growth control in those rats. In an attempt to determine the relation between high blood pressure and this trait, we cultured skin fibroblasts from adult SHR, WKY, F1, and F2 hybrid SHR/WKY populations by explant technique. Their growth capacity was determined by culture well DNA doubling time and by [3H]thymidine incorporation. Adult SHR fibroblasts grew more quickly (doubling time [DT] = 37.2 +/- 2.3 h, n = 8) than WKY ones (DT = 53.9 +/- 3.6 h, n = 6). Female SHR were crossed with male WKY to produce an F1 and an F2 hybrid generation presenting a Mendelian distribution of blood pressure. Skin fibroblasts were cultured from 21 rats belonging to the highest and the lowest blood pressure groups. No difference was observed between the two groups in either growth (DT = 47.5 +/- 4.1 h, n = 11 v DT = 44.6 +/- 3.2 h, n = 10) or epidermal growth factor-induced [3H]thymidine incorporation. These observations suggest that the increased growth capacity observed in SHR is not a determinant of high blood pressure initiation but may be involved in early cardiovascular enlargement.     

自发性高血压大鼠心脏重构与ACE2 mRNA的表达

目的:观察不同月龄的自发性高血压大鼠(SHR)的心脏血管紧张素转换酶2(ACE2)mRNA表达水平,探讨心脏重构与ACE2的内在联系。方法:将12周龄雄性SHR 18只和12周龄WKY Wistar-Kyoto rats大鼠18只随机分为两组,从WKY大鼠组和SHR组中各抽取9只处死,剩余的9只再喂养12周后处死。测量大鼠心脏的质量(HW)与体质量(BW)并计算HW/BW的比值。以实时定量RT-PCR法检测ACE2 mRNA的表达。结果:①与同周龄WKY大鼠组比较,SHR组HW/BW的比值显著增加(P0.01);与12周龄SHR组比较,24周龄SHR组的HW/BW显著增加(P0.05)。②与同周龄的WKY大鼠组比较,SHR组ACE2 mRNA的表达显著降低(P0.01);与12周龄的SHR组比较,24周龄的SHR组ACE2 mRNA的表达显著降低(P0.01)。结论:自发性高血压大鼠心脏重构伴随着心脏中ACE2 mRNA的表达下调。     

Identification of quantitative trait loci for cardiac hypertrophy in two different strains of the spontaneously hypertensive rat.

Cardiac hypertrophy and left ventricular hypertrophy are known to be substantially controlled by genetic factors. As an experimental model, we undertook genome-wide screens for cardiac mass in F2 populations bred from the stroke-prone spontaneously hypertensive rats (SHRSP) and normal spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) of a Japanese colony. Two F2 cohorts were independently produced: F2(SHRSP x WKY) (110 male and 110 female rats) and F2(SHR x WKY) (151 male rats). The ratio of heart weight to body weight (Hw/Bw) was evaluated at 12 months of age in F2(SHRSP x WKY) after salt-loading for 7 months, and at around 15 weeks of age in F2(SHR x WKY) who had been fed a normal rat chow diet. Subsequent to an initial screen with 251 markers in F2(SHRSP x WKY) male progeny, 170 and 161 markers were selected and characterized in F2(SHRSP x WKY) female progeny and F2(SHR x WKY) male progeny, respectively. Markers from four chromosomal regions showed suggestive or significant linkage to Hw/Bw. The strongest and the most consistent linkage was found in the vicinity of D3Mgh16 on rat chromosome (RNO) 3 (a maximal log of the odds score reached 4.0 to 6.6 across the F2 populations studied). In the other three regions on RNO6, RNO10 and RNO13, the degree of linkage was more prominent in either males or females. These data provide solid evidence for a "principal" RNO3 quantitative trait loci regulating Hw/Bw in SHRSP and SHR, and also suggest the possible presence of sexual dimorphism in regard to genetic susceptibility for cardiac hypertrophy.     

Kynureninase is a novel candidate gene for hypertension in spontaneously hypertensive rats.

The rostral ventrolateral medulla (RVLM) plays a critical role in the tonic and reflexive regulation of arterial blood pressure. Recent studies have demonstrated that injection of kynurenic acid (KYN) into the RVLM of spontaneously hypertensive rats (SHR) decreases arterial blood pressure. We hypothesized that a relative increase in the excitatory amino acid-mediated drive of RVLM vasomotor neurons in SHR may be due to derangement of one of the enzymes that affect the KYN level in the brain. We selected kynureninase, kynureninase hydroxylase, kynurenine aminotransferase type I, and kynurenine aminotransferase type II as candidates that may affect the KYN level in the brainstem. We conducted association studies between polymorphisms of these genes and blood pressure in an F2 population derived from SHR and Wistar-Kyoto rats (WKY). The cosegregation analysis indicated that only the kynureninase gene (KYNU) polymorphism influenced systolic blood pressure (SBP) and residuals of systolic blood pressure after adjusting for heart rate and body weight (RSBP). KYNU was found to be located on rat chromosome 3, and quantitative trait loci analysis at this locus indicated that the logarithms of the odds scores for KYNU in terms of SBP and RSBP were 2.0 and 3.3, respectively. This association with blood pressure decreased in proportion to the distance from KYNU. The expression level of KYNU mRNA in the brainstem was about 3.1 and 2.9 times higher in 10-week-old and 16-week-old SHR than in age-matched WKY, respectively. The increased expression of KYNU in SHR is thought to decrease the KYN level. KYNU seems to be one of the genes that contributes to hypertension in SHR.     

Partitioning of erythrocytes from spontaneously hypertensive and Wistar-Kyoto rats

The charge-associated and non-charge-associated (probably lipid-related) surface properties of erythrocytes from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), from which SHR were originally derived, were studied by cell partitioning in dextran-polyethylene glycol aqueous phase systems. A major difference was found in the surface charge-associated and lipid-related properties of red blood cells from SHR and WKY: the cells from WKY had the higher partition ratio in both charge-sensitive and non-charge-sensitive phases. No difference in partitioning could be found between any two SHR nor between any two WKY. The SHR and WKY erythrocytes showed the same difference when compared with one another even when rats had the same blood pressure. When red blood cells from SHR with different blood pressure were compared, there still was no difference in their surface properties. These results suggest that the differences in both charge-associated and lipid-related surface properties of erythrocytes from SHR and WKY are strain-specific (i.e., genetic) but that there is no correlation, reflected by partitioning, between red blood cell surface properties and the degree of the rats' hypertension.     

Cosegregation of Genes on Chromosome 5 with Heart Weight and Blood Pressure in Genetic Hypertension

Genetic factors may be involved in both essential hypertension and cardiac hypertrophy. To identify genes contributing to elevated for blood pressure and cardiac hypertrophy in the spontaneously hypertensive rat (SHR), we performed a cosegregation analysis between blood pressure and heart weight and microsatellite markers for the candidate gene ANF on chromosome 5 in F2 animals obtained by mating SHR with Wistar-Kyoto (WKY) rats. We found evidence for a quantitative trait locus (QTL) determining mean blood pressure on chromosome 5 between atrial natriuretic factor (ANF) and MITR-3893 loci. No evidence for a QTL influencing heart weight was found. We propose that in SHR, blood pressure and heart weight may be independently controlled by different genetic mechanisms and that a gene close to ANF locus on chromosome 5 contributes towards hypertension in these animals.     

Functional and metabolic responses to ischemia in the perfused heart isolated from normotensive and spontaneously hypertensive rats

The difference between normotensive rats (WKY) and spontaneously hypertensive rats (SHR) in functional and metabolic responses to ischemia was studied. Systolic arterial blood pressure of SHR (171.2 +/- 2.9 mmHg) was significantly higher than that of WKY (135.3 +/- 1.2 mmHg), and the left ventricular mass of SHR was larger than that of WKY. Hearts isolated from either WKY or SHR were perfused by the working heart technique. Ischemia was induced by lowering the afterload pressure of the working heart. Ischemia produced cardiac arrest, and decreased the tissue levels of adenosine triphosphate and creatine phosphate in both WKY and SHR. Recovery of mechanical function of the heart during reperfusion following ischemia in SHR was better than that in WKY, while recovery of the high-energy phosphates level in SHR was less prominent than in WKY. It is postulated that hypertension has a deleterious effect on myocardial energy metabolism in ischemic heart, even when cardiac mechanical function is maintained.     

Role of oxidative stress in the sex differences in blood pressure in spontaneously hypertensive rats

OBJECTIVE: The hypothesis was tested that differences in oxidative stress play a role in the sex differences in the development and maintenance of hypertension in spontaneously hypertensive rats (SHR). DESIGN AND METHODS: Male and female SHR [and Wistar-Kyoto (WKY) rats in the long-term study] (n = 6-12 per group) received tempol (30 mg/kg per day) or tap water for 6 weeks from 9 to 15 weeks of age or from birth until 15 weeks of age. Blood pressure [mean arterial pressure (MAP)] and kidney tissue F2-isoprostane (IsoP) were measured at 15 weeks of age. RESULTS: In SHR given tempol for 6 weeks, blood pressure and IsoP were reduced in males, but not in females. In SHR given tempol from birth, MAP was higher in SHR than WKY rats (SHR males, 181 +/- 2 mmHg; SHR females, 172 +/- 3 mmHg; WKY males, 100 +/- 2 mmHg; WKY females, 101 +/- 2 mmHg, P < 0.01), and tempol reduced MAP by 14% (156 +/- 3) and 26% (127 +/- 4) in male and female SHR, respectively, but had no effect on WKY rats. IsoP was higher in SHR than WKY rats and higher in male SHR than female SHR (SHR males, 5.18 +/- 0.23 ng/mg; SHR females, 3.71 +/- 0.19 ng/mg, P < 0.01; WKY males, 1.72 +/- 0.45 ng/mg; WKY females, 2.21 +/- 0.08 ng/mg, P < 0.05, compared with SHR). Tempol reduced IsoP in SHR to levels found in WKY rats, but had no effect on IsoP in WKY rats. CONCLUSIONS: Development of hypertension in SHR is mediated in part by oxidative stress independent of sex. Also, tempol is effective in reducing blood pressure in females only when given prior to the onset of hypertension.     

Angiotensin Converting Enzyme Activity in Strains of Normo- and Hypertensive Rats

The concentration of angiotensin converting enzyme (ACE) in the lung, kidney and plasma of the following strains of rats were investigated: Sprague Dawley (SD), Wistar Kyoto (WKY), spontaneously hypertensive (SHR), stroke prone SHR (SP-SHR) and low blood pressure SHR (LBP-SHR) i.e. SHR whose blood pressures were below 150 mm Hg. The enzyme concentrations in the lung of the hypertensive rats were significantly higher than those of the normotensive rats but the reverse was true for plasma ACE concentrations. The kidney ACE concentrations in the hypertensive rats were also lower than those of the normotensive rats, but the differences were not significant. There were no significant differences in enzyme concentrations between the normotensive SD and WKY. Similar results were obtained with the three sub-strains of hypertensive rats despite the fact that their mean blood pressure (MBP) varied significantly from each other.