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.     

Genetic dissection of region around the Sa gene on rat chromosome 1: evidence for multiple loci affecting blood pressure

A region with a major effect on blood pressure (BP) is located on rat chromosome 1 in the vicinity of the Sa gene, a candidate gene for BP regulation. Previously, we observed a single linkage peak for BP in this region in second filial generation rats derived from a cross of the spontaneously hypertensive rat (SHR) with the Wistar-Kyoto rat (WKY), and we have reported the isolation of the region containing the BP effect in reciprocal congenic strains (WKY.SHR-Sa) and (SHR.WKY-Sa) derived from these animals. Here, we report the further genetic dissection of this region. Two congenic substrains each were derived from WKY.SHR-Sa (WISA1 and WISA2) and SHR.WKY-Sa (SISA1 and SISA2) by backcrossing to WKY and SHR, respectively. Although there was some overlap of the introgressed regions retained in the various substrains, the segments in WISA1 and SISA1 did not overlap. Furthermore, although the Sa allele in WISA1, WISA2, and SISA2 remained donor in origin, recombination in SISA1 reverted it back to the recipient (SHR) allele. Surprisingly, all 4 substrains demonstrated a highly significant BP difference compared with that of their respective parental strain, which was of a magnitude similar to those seen in the original congenic strains. The findings strongly indicate that there are at least 2 quantitative trait loci (QTLs) affecting BP in this region of rat chromosome 1. Furthermore, the BP effect seen in SISA1 indicates that at least a proportion of the BP effect of this region of rat chromosome 1 cannot be due to the Sa gene. SISA1 contains an introgressed segment of <3 cM, and this will facilitate the physical mapping of the BP QTL(s) located within it and the identification of the susceptibility-conferring genes. Our observations serve to illustrate the complexity of QTL dissection and the care needed to interpret findings from congenic studies.     

Castration Lowers and Testosterone Restores Blood Pressure in Several Rat Strains on High Sodium Diets

The objective of this study was to determine the effect of a high sodium diet and prepubertal castration (5-6 weeks) and androgen replacement therapy on blood pressure in male normotensive, borderline hypertensive and hypertensive rats on a high sodium diet between 9-22 weeks of age. The strains used were: Wistar Kyoto-(WKY), spontaneously hypertensive rat-(SHR), and borderline hypertensive rat-(BHR). Castration significantly reduced blood pressure (20-30mmHg) and testosterone replacement in castrated males restored blood pressure in all strains. Plasma norepinephrine (NE) increased with castration in the WKY and SHR strains but decreased in the BHR. However, there was a significant elevation in all strains between the midpoint and endpoint NE values. The high sodium diet did not prevent the blood pressure lowering effect of castration.     

Systematic polymorphism discovery after genome-wide identification of potential susceptibility loci in a hereditary rodent model of human hypertension

Genetic strategies such as linkage analysis and quantitative trait locus (QTL) mapping have identified a multitude of loci implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR). While several candidate genetic regions have been identified in the SHR and its control, the Wistar-Kyoto rat (WKY), systematic follow-up of candidate identification with polymorphism discovery has not been widespread. In the current report, we develop a data-mining strategy to identify candidate genes for hypertension in the SHR, and then sequence each gene in the SHR and WKY strains. We integrate blood pressure QTL data, microarray data and data-mining methods. First, we determined the set of genes differentially expressed in SHR and WKY adrenal glands. Next, the chromosomal position of all differentially expressed genes was compared with peak marker position of all reported SHR blood pressure QTLs. We also identified the set of differentially expressed genes with the most extreme fold-change. Finally, the QTL positional candidates and the genes with extreme differential expression were proposed as candidate genes if they had biologically plausible roles in hypertensive pathology. We identified seven candidate genes that merit resequencing (catechol-O-methyltransferase [Comt], chromogranin A [Chga], dopamine beta-hydroxylase [Dbh], electron transferring flavoprotein dehydrogenase [Etfdh], endothelin receptor type B [Ednrb], neuropeptide Y [Npy] and phenylethanolamine-N-methyltransferase [Pnmt]), and then discovered polymorphism in four of these seven candidate genes. Chga is proposed as the strongest candidate for additional functional investigation. Our method for candidate gene identification is portable and can be applied to microarray data from any tissue, in any disease model with a QTL database.     

厄贝沙坦对自发性高血压大鼠瘦素、脂联素的影响

目的 探讨血管紧张素Ⅱ受体拮抗剂（ARB）厄贝沙坦对自发性高血压大鼠（SHR）瘦素、脂联素的影响及可能机制.方法 24只雄性SHR大鼠随机分为SHR模型组（SHR-C）、SHR氢氯噻嗪组（SHR-H）和SHR厄贝沙坦组（SHR-I）,每组8只;另设同源雄性Wistar Kyoto（WKY）大鼠8只为对照组.SHR-I组应用厄贝沙坦30 mg·kg-1·d-1灌胃,SHR-H组应用氢氯噻嚷10 mg·kg-1·d-1灌胃,SHR-C和WKY组均配以等量蒸馏水灌胃,连续8周后,测尾动脉收缩压（SBP）;颈动脉取血,检测血清血糖、胰岛素、瘦素和脂联素浓度;取大鼠附睾脂肪组织,通过反转录和聚合酶链反应（RT-PCR）,分析附睾脂肪瘦素mRNA和脂联素mRNA表达水平.结果 与WKY组比较,SHR-C组大鼠收缩压显著升高（P＜0.01）;与SHR-C组比较,SHR-I组和SHR-H组大鼠收缩压显著降低（P＜0.01）.与WKY组比较,SHR-C组大鼠胰岛素抵抗指数（HOMA-IR）显著升高（P＜0.01）;与SHR-H组和SHR-C组比较,SHR-I组大鼠HOMA-IR明显降低（P＜0.05）.与WKY组比较,SHR-C组大鼠血清瘦素浓度和脂肪瘦素mRNA表达水平显著增高（P＜0.01）;与SHR-C组比较,SHR-I组大鼠血清瘦素浓度显著降低（P＜0.01）,脂肪瘦素mRNA表达水平明显降低（P＜0.05）.与WKY组比较,SHR-C组大鼠血清脂联素浓度和脂肪脂联素mRNA表达水平显著降低（P＜0.01）;与SHR-C组比较,SHR-I组大鼠血清脂联索浓度和脂肪脂联索mRNA表达水平显著升高（P＜0.01）.结论 厄贝沙坦能改善自发性高血压大鼠胰岛索的敏感性,减少其脂肪组织瘦素的合成和分泌,增加脂联素的合成和分泌.     

Hypertension Produced by a High Sodium Diet in the Borderline Hypertensive Rat (BHR)

The effect of high dietary sodium (8%) on blood pressure in spontaneously hypertensive (SHR), borderline hypertensive (BHR), and normotensive Wistar-Kyoto (WKY) rats was determined weekly by tail cuff plethysmography for one week of baseline and four weeks of diet. After 4 weeks, significant elevations in systolic blood pressure were found in SHR and BHR groups, but not in WKY. BHR studied an additional 4 weeks showed a further progression of hypertension, reaching levels nearly equal to control SHR. Direct measurement of arterial pressure in conscious animals in their home cage confirmed the elevation in pressure in both SHR and BHR groups. Metabolic studies revealed that the high sodium diet reduced body weight in SHR and BHR strains, but not in WKY. Although both urinary volumes and sodium excretion values were significantly lower in SHR and BHR compared with WKY, this effect disappeared when adjustments for body weight were made.

Plasma norepinephrine determinations revealed a significant response to cold stress in all groups. Plasma epinephrine was elevated in all strains in response to cold stress; however, a consistent statistical elevation was seen only in WKY. The BHR is discussed as a model for determining the triggers responsible for environmentally-induced hypertension.     

Pulse pressure, aortic reactivity, and endothelium dysfunction in old hypertensive rats

The reactivity of old hypertensive rat aortas has not been investigated in relation to each phenotype of the blood pressure curve, mean arterial pressure (MAP), and pulse pressure (PP). Aortic reactivities from 3- to 78-week-old Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) were studied with the use of organ chambers and invasive blood pressure, carotid diameter, and histomorphometry. MAP and PP were elevated in SHR, but at 78 weeks, a selective increase of PP without further MAP increase was observed for the same carotid diameter as WKY. Aortic relaxation in response to carbamylcholine decreased similarly with age in both strains. With (+) or without (-) endothelium (E), maximal developed tension (MDT) under KCl increased linearly with age in SHR, proportionally to wall thickness and MAP increase. Under norepinephrine (NE), MDT of E(-) aortas from SHR and controls increased with age and reached plateaus at 12 weeks, whereas MDT of E(+) aortas from SHR increased linearly with age. Because the NE-induced MDT was higher for E(-) than E(+), the difference estimated endothelial function. This difference reached plateaus from 12 to 78 weeks in WKY but was abolished beyond 12 weeks in SHR, a finding also observed under NO-synthase inhibition. In old hypertensive rats, (1) increased KCl reactivity is endothelium independent but influenced by the MAP-dependent aortic hypertrophy with resulting increased vascular smooth muscle reactivity, whereas (2) increased NE reactivity is endothelium dependent in association with increased PP, altered endothelial function, and extracellular matrix, with resulting enhanced intrinsic arterial stiffness.     

Body weight of the spontaneously hypertensive rat during the suckling and weanling periods

The body weight of the spontaneously hypertensive rat (SHR) during the suckling, birth to 3 weeks of age, and weanling period, through 6 weeks of age, is compared to that of its normotensive controls, the Wistar Kyoto (WKY) and Wistar (WR) rats. Litters were normalized to 6 pups per dam just after birth. The WR is larger than the SHR and WKY at all time points examined. The WKY is similar in weight to the SHR at birth but larger than the SHR at the other time points studied. These findings suggest the WR is inherently a larger rat than the SHR and WKY during the suckling and weanling periods while the development of a weight difference between the SHR and WKY after birth suggest an extrauterine influence.     

Cosegregation analysis in genetic crosses suggests a protective role for atrial natriuretic factor against ventricular hypertrophy.

In most rat models studied to date, increased ventricular mass is associated with high ventricular expression of the atrial natriuretic factor (ANF) gene. However, it is unknown whether ANF plays a beneficial or detrimental role in the course of left ventricular hypertrophy or whether ANF gene expression could be genetically linked to cardiac mass. To address such questions, we performed a cosegregation analysis in genetic crosses of inbred strains of rats. To select strains with the appropriate phenotypic characteristics, we first compared the ventricular abundance of ANF mRNA to ventricular mass (corrected for body weight) in 2 recombinant inbred strains derived from Wistar-Kyoto (WKY)/spontaneously hypertensive rat (SHR) hybrid crosses, ie, WKY-derived hyperactive (WKHA) and WKY-derived hypertensive (WKHT) rats, as well as in their parental inbred strains. In the 2 such strains that were normotensive, we observed that ventricular mass was higher in WKHA than in WKY rats, yet ventricular ANF mRNA was less abundant in WKHA than in WKY rats. Within a segregating population of F2 animals generated from a cross between WKY and WKHA genitors, the abundance of ventricular ANF mRNA and peptide correlated inversely with left ventricular mass, in contrast to the positive correlation observed with beta-myosin heavy chain mRNA. Finally, in the equally hypertensive SHR and WKHT strains, we found that ventricular mass was higher in SHR than in WKHT, yet ventricular ANF mRNA was less abundant in SHR than in WKHT. These results demonstrate for the first time that low ventricular ANF gene expression can be linked genetically to high cardiac mass independently of blood pressure and are consistent with a protective role for ANF against left ventricular hypertrophy.     

Altered expression of BK channel beta1 subunit in vascular tissues from spontaneously hypertensive rats

Correlation of blood pressure (BP) with expression levels of large-conductance, voltage- and Ca2+-activated K+ (BK) channel beta1 subunit in vascular tissues from spontaneously hypertensive rats (SHR), Wistar-Kyoto rats (WKY), and Sprague-Dawley rats (SD) at different ages was investigated. Systolic BP and BK beta1 expression in mesenteric arteries at either mRNA or protein levels were not different among 4-week-old SHR, WKY, and SD. With hypertension developed at 7 weeks and reached plateau at 12 weeks, expression levels of BK beta1 mRNA in mesenteric arteries and aortae from SHR during this period of time were significantly higher than in age-matched normotensive WKY. The BK beta1 protein expression was significantly higher in mesenteric arteries from 12-week-old but not 7-week-old SHR when compared with age-matched WKY and SD. The BK beta1 protein levels in aortae were not different among 7-week-old SHR, WKY, and SD but were significantly lower in 12-week-old WKY than in age-matched SHR and SD. Captopril treatment normalized BP of 12-week-old SHR. This treatment downregulated BK beta1 protein in mesenteric arteries but upregulated it in aortae. No significant difference in BK alpha subunit expression was detected in mesenteric arteries from three strains of rats as well as the captopril-treated SHR. It appears that expression patterns of BK beta1 in vascular tissues vary depending on tissue types, animal age, and animal strains. Expression of BK beta1 in mesenteric arteries is closely correlated with BP in SHR. Increased BK beta1 expression in mesenteric arteries may represent a compensatory reaction to limit the development of hypertension.     

Diverse effects of chronic treatment with losartan, fosinopril, and amlodipine on apoptosis, angiotensin II in the left ventricle of hypertensive rats.

This study was designed to investigate diverse effects of angiotensin II (AngII) type I receptor antagonists, losartan, angiotensin converting enzyme (ACE) inhibitors, fosinopril, and calcium channel blockade, amlodipine on cardiomyocyte apoptosis and AngII in the left ventricle of spontaneously hypertensive rats (SHR). The SHRs were randomized to four groups: SHR-L (treated with losartan, 30 mg x kg(-1) x d(-1)), SHR-F (with fosinopril, 10 mg x kg(-1) x d(-1)), SHR-A (with amlodipine, 10 mg x kg(-1) x d(-1)) and SHR-C (with placebo). The cardiomyocyte apoptosis was examined by in situ TDT-mediated dUTP nick end labeling, AngII concentrations of plasma and myocardium were measured by radio immunoassay at 8 and 16 weeks of the study respectively. The results showed that: (1) compared with SHR-C at 8 and 16 weeks respectively; the systolic blood pressure was decreased similarly in the three treatment groups. Left ventricular weight and mass indexes were reduced in the three treatment groups. The latter parameter at 16 weeks was lower in SHR-F than that in the other two treatment groups. (2) Compared with SHR-C, the cardiomyocyte apoptotic index (APOI) was reduced significantly at 8 weeks only in SHR-F, and at 16 weeks in all three treatment groups. The APOI of SHR-F was lowest among the three treatment groups examined at latter endpoint. (3) Compared with SHR-C at both endpoints of this study, plasma and myocardium AngII levels were increased in SHR-L. However, plasma AngII concentrations were not altered in SHR-F and SHR-A, myocardium AngII concentrations were reduced significantly at 8 weeks only in SHR-F, and at 16 weeks in SHR-F and SHR-A. Meanwhile, myocardium AngII in SHR-F at 16 weeks was lower than that in SHR-A. The results of this study indicate that losartan, fosinopril, and amlodipine each effectively reverses heart hypertrophy and inhibits cardiomyocyte apoptosis, and fosinopril may be most effective in these cardioprotective effects. These findings suggest that the effects of the three blockers on myocardiocyte apoptosis and left ventricular hypertrophy were related to inhibition of the myocardium rennin-angiotensin-aldsterone system.     

Normalization of active urinary kallikrein excretion by young spontaneously hypertensive rats by chronic inhibition of conversion enzyme

This study was designed to investigate the decreased urinary kallikrein excretion (Ukall.V) in Okamoto-Aoki spontaneously hypertensive rats (SHR) and the effect of long-term converting enzyme inhibition. From ages 4 to 7 weeks, Ukall.V was determined (amidolytic assay: nanokatals/wk) in 4 groups of 6 male rats housed into individual metabolic cages and fed a normal sodium diet: SHR and normotensive Wistar-Kyoto rats (WKY); SHR-C and WKY-C which were given captopril: 30 mg/kg BW every 12 hours by gavage. Ukall.V was each time lower in SHR than in age-matched WKY, even at 4 wks of age (54.6 +/- 9.1 vs 108.5 +/- 16.1 nkat/wk; p less than .01) when systolic blood pressure (s.BP) was already higher. In SHR-C, s.BP was identical or slightly lower to that in WKY. Ukall.V was still lower at wk 4 when captopril was first administered (60.9 +/- 8.4 nkat/wk; p less than .01), but identical to that in WKY at each subsequent age (105.7 +/- 25.9 vs 114.1 +/- 5.6 nkat/wk at wk 5; 219.8 +/- 44.5 vs 253.4 +/- 22.4 nkat/wk at wk 7). Excretion of active kallikrein was highly correlated to s.BP in WKY (r = .87), SHR (r = 0.91) and SHR-C (r = 0.95). The slope of the regression line relating Ukall.V with s.BP was significantly less in SHR than WKY (1.33 +/- 0.35 vs 3.36 +/- 0.84 nkat/wk/mmHg; p less than .01); the slope in SHR-C (3.35 +/- 0.77 nkat/wk/mmHg) was significantly steeper than in SHR (p less than .01) and identical to that in WKY.(ABSTRACT TRUNCATED AT 250 WORDS)     

Resistance artery phosphoinositide metabolism in genetic hypertension

Precapillary resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were found to contain three inositol lipids and to produce five inositol phosphate peaks. These were assessed by a highly sensitive procedure which involved the separation of radiolabelled inositol-containing components by anion-exchange high-performance liquid chromatography. Basal levels of radiolabelled inositol lipids were found to be significantly increased in SHR at 5 weeks of age, and also increased at 12 weeks, although this was only statistically significant for glycerophosphoinositol. At 5 weeks of age, exposure to a maximal concentration of noradrenaline brought about a significant increase in lipid radioactivity in WKY and in glycerophosphoinositol and glycerophosphoinositol 4-phosphate in SHR. The levels of these lipids remained significantly raised in the SHR at this time. At 12 weeks of age, exposure to noradrenaline produced reductions in radioactivity associated with inositol lipids. These new levels were elevated in SHR and significant for glycerophosphoinositol 4-phosphate. Basal levels of four inositol phosphates were not different between the two rat strains at 5 weeks of age. Inositol 1,3,4-trisphosphate was only present at minute levels and could not be measured. At 12 weeks of age, basal radiolabelling of inositol phosphates was not different between the two strains. The application of noradrenaline caused age-dependent changes in arterial inositol-containing compounds in both strains, which resulted in increased levels of inositol 1,4,5-trisphosphate in young SHR and also in adult rats in which the blood pressure level had become established.(ABSTRACT TRUNCATED AT 250 WORDS)     

Differential regulation of IGF-I, its receptor and GH receptor mRNAs in the right ventricle and caval vein in volume-loaded genetically hypertensive and normotensive rats.

It has been suggested, mainly by in vitro findings, that cardiovascular tissue in the spontaneously hypertensive rat (SHR) should be more prone to proliferate/hypertrophy than that of the Wistar-Kyoto rat (WKY). The present study tests the hypothesis that the tissue of the low-pressure compartment in SHR, being structurally similar to that of the WKY, shows an increased growth response due to activation of the GH-IGF-I system. An aortocaval fistula (ACF) was induced in 64 SHR and WKY male rats and 44 rats served as controls. They were all followed for 1, 2, 4 and 7 days after surgery. In separate groups of SHR (n=4) and WKY (n=3), central venous pressure was measured by telemetry recordings prior to opening of the fistula and for up to 16 h post-surgery. Systolic blood pressure was measured during the week post-surgery. The right ventricular (RV) and the caval vein IGF-I mRNA and RV IGF-I receptor and GH receptor mRNAs were quantitated by means of solution hybridisation assay. In rats with ACF the systolic blood pressure decreased, approximately 29% in SHR and 16% in WKY between 1 and 7 days post-surgery (P<0.05, n=5-6 in each group). SHR with ACF showed a transient elevation in central venous pressure vs WKY. Within the week following fistula induction both strains showed a similar, pronounced increase in RV hypertrophy. SHR with ACF showed a smaller, or even blunted, overall response with respect to activation of the GH-IGF-I system compared with WKY, the latter showing clear-cut elevation of gene expressions. Two days after shunt opening in SHR, RV and caval vein IGF-I mRNA increased by 57% and 108% (P<0.05 for both, n=5-6 in each group) respectively, and these expressions were then turned off, whereas RV GH receptor and IGF-I receptor mRNA expression remained unaffected compared with WKY rats. WKY rats showed on average a later and a greater response of GH-IGF-I system mRNA expression vs SHR. The present in vivo study suggests that the SHR requires less activation of the GH-IGF-I system for creating a given adaptive structural growth response.     

Differential effects of angiotensin II type-1 receptor antisense oligonucleotides on renal function in spontaneously hypertensive rats

The effect of selectively decreasing renal angiotensin II type 1 (AT1) receptor expression on renal function and blood pressure has not been determined. Therefore, we studied the consequences of selective renal inhibition of AT1 receptor expression in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in vivo. Vehicle, AT1 receptor antisense oligodeoxynucleotides (AS-ODN), or scrambled oligodeoxynucleotides were infused chronically into the cortex of the remaining kidney of conscious, uninephrectomized WKY and SHR on a 4% NaCl intake. Basal renal cortical membrane AT1 receptor protein was greater in SHR than in WKY. In WKY and SHR, AS-ODN decreased renal but not cardiac AT1 receptors. AT1 receptor AS-ODN treatment increased plasma renin activity to a greater extent in WKY than in SHR. However, plasma angiotensin II and aldosterone were increased by AS-ODN to a similar degree in both rat strains. In SHR, sodium excretion was increased and sodium balance was decreased by AS-ODN but had only a transient ameliorating effect on blood pressure. Urinary protein and glomerular sclerosis were markedly reduced by AS-ODN-treated SHR. In WKY, AS-ODN had no effect on sodium excretion, blood pressure, or renal histology but also modestly decreased proteinuria. The major consequence of decreasing renal AT1 receptor protein in the SHR is a decrease in proteinuria, probably as a result of the amelioration in glomerular pathology but independent of systemic blood pressure and circulating angiotensin II levels.     

Effects of sinoaortic baroreceptor denervation on blood pressure and PNMT activity in medulla oblongata and spinal cord of normotensive and genetically hypertensive rats

The effects of sinoaortic denervation on arterial blood pressure and central activity of phenylethanolamine-N-methyl transferase (PNMT, the last enzyme in adrenaline biosynthesis), were compared in normotensive Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHR-SP). Denervation of the arterial baroreceptors caused immediate increases in mean arterial blood pressure (MAP) in all three strains which were maximal at 90 min (32 mmHg in WKY, 51 mmHg in SHR and 80 mmHg in SHR-SP). Spinal cord PNMT activity increased above sham-operated levels in WKY at 90 min, but PNMT levels in SHR and SHR-SP, already significantly higher than in WKY, were not altered acutely after sinoaortic denervation. Over a seven day period after baroreceptor denervation, MAP rose by 15 mmHg in WKY and PNMT activity was about 100% greater in spinal cord and ventral medulla. In the two genetically hypertensive strains sinoaortic denervation failed to produce a further sustained rise in pressure or and PNMT activity in the ventral medulla or spinal cord. We suggest that increased activity of bulbospinal adrenaline neurons contribute to the sustained elevation in pressure seen in intact SHR and SHR-SP, as well as in WKY after denervation of arterial baroreceptors.     

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.