Development Of Spontaneous Hypertension Research Articles

Abstract P168: Prevalence of Spontaneous Hypertension in African Green Monkeys is Age-related

Chlorocebus aethiops sabaeus , the African Green Monkey (AGM), is a novel translational model of hypertension and cardiovascular disease. The AGM is a diurnal, primarily bipedal nonhuman primate, in which ~ 1/3 of the population exhibits spontaneous hypertension (systolic blood pressure > 140mmHg). Since age and sex are related to the development of human hypertension, we hypothesized that age and sex may be crucial to the development of hypertension in this primate species. Hypertension prevalence was compared in animals with known ages or highly confident age estimates. Age estimates were performed by staff with over 50 years combined experience working with AGMs. Behavior, weight, incisor length, fur coarseness, tail stiffness, and troop hierarchy were used to reasonably estimate an animal’s age. Animals were binned into 1 of 4 age categories: juvenile, 0-4 years; young adult, 5-10 years; adult, 11-15 years; or mature adult, ≥ 16 years. Overall, hypertensive (HT) AGMs comprised 31.3±22.8 % (mean± 95%CI) of the juvenile group, n=16; 31.9±6.6% of the young adult group, n=244; 48.3±12.6% of the adult group, n=60; and 61±18.1% of the mature adult group, n=28. The prevalence of HT is greater in the adult and mature adult groups (Z = -2.3, p<0.05; Z = -2.9, p<0.05, respectively) compared to the young adult age group. No significant differences in prevalence were found between sexes within the same age (p>0.05). In males, HT animals comprised: 30±28.4% of the juvenile group, n=10; 28.9±8.1% of the young adult group, n=121; 50±13.6% of the adult group, n=52; and 61.5±18.7% of the mature adult group, n=26. In females, HT animals comprised: 33.3±38.1% of the juvenile group, n=6; 36.9±11.1% of the young adult group, n=73; 37.5±33.5% of the adult group, n=8; and 50±50% of the mature adult group, n=2. In males, the prevalence of HT is increased in the adult (Z = -2.6, p<0.05) and the mature adult age groups (Z = -3.1, p<0.05) compared to the young adult group. No differences were found in female age groups. Similar to humans, age is a strong contributor to the development of spontaneous hypertension in the AGM. Sex may contribute to the development of AGM spontaneous hypertension and future studies will assess the impact of age, sex hormones, and hypertension in female AGMs.

Sodium Alginate Oligosaccharides Attenuate Hypertension in Spontaneously Hypertensive Rats Fed a Low-Salt Diet

We investigated the effects of sodium alginate oligosaccharides (alginate) on the development of spontaneous hypertension in rats. Spontaneous hypertensive rats were treated with alginate for 7 weeks. Systolic blood pressure (SBP) and cardiovascular and kidney damage were assessed. Systolic blood pressure increased in SHRs and this elevation was attenuated with alginate treatment. The heart weight tended to decline. Alginate did not change plasma cholesterol levels or urinary sodium excretions. The slightly higher urinary protein excretion in SHRs was not changed with the treatment; however, morphologic glomerular damage was significantly attenuated. Sodium alginate oligosaccharide attenuates spontaneous hypertension in SHRs, and may help prevent early-stage kidney injury.

Genetic Low Nephron Number Hypertension is Associated with Altered Expression of Osteopontin and One of Its Receptors, CD44, but not Alpha(v)-Integrin during Nephrogenesis

Ziel: Low nephron number may represent a major determinant of human primary hypertension in adult life. This hypothesis is supported by a genetic rat model, the Munich-Wistar Frömter (MWF) rat, which demonstrates an inherited deficit in nephron number and the development of spontaneous hypertension.

Expression of Na+-K+-2Cl− Cotransporter 1 Is Epigenetically Regulated During Postnatal Development of Hypertension

The expression of Na(+)-K(+)-2Cl(-) cotransporter 1 (NKCC1) is upregulated in spontaneously hypertensive rat (SHR). We investigated whether expression of NKCC1 is epigenetically regulated during postnatal development of hypertension. The mesenteric arteries from 5-, 10-, and 18-week-old Wistar-Kyoto rats (WKY) and SHRs were subjected to vascular contraction. We determined expression levels of Nkcc1 mRNA and protein, methylation status, and histone modification of Nkcc1 promoter, and DNA methyltransferase (DNMT) activity. The inhibition of dose-response curves by bumetanide, an inhibitor of NKCC1, as well as the expression of Nkcc1 mRNA and protein was comparable between 5-week-old SHR and age-matched WKY, but greater in 18-week-old SHR than in age-matched WKY. Nkcc1 promoter in WKY was getting methylated with age whereas that in SHR mostly remained hypomethylated after development of hypertension. DNMT3B was highly associated with the promoter of WKY, whereas the CXXC finger protein 1 (Cfp1) was highly bound to the promoter of SHR. At the age of 18 weeks, the DNMT activity in aorta of WKY was about threefold higher than that of SHR. The transcription-activating histone code acetyl H3 was higher in SHR than in WKY, whereas suppressive histone code dimethyl H3K9 was greater in WKY than in SHR. It is concluded that expression of NKCC1 is epigenetically upregulated during postnatal development of hypertension. Our data indicate that maintenance of hypomethylation in Nkcc1 promoter of SHR resulting from low DNMT activity plays an important role in the upregulation of NKCC1 during development of spontaneous hypertension.

Comparison of the effects of indapamide and captopril on the development of spontaneous hypertension

The effects of indapamide, a thiazide-like diuretic, and captopril, an angiotensin-converting enzyme inhibitor, on spontaneous hypertension and the development of left ventricular hypertrophy (LVH), nitric oxide generation and oxidant status were investigated. Six-week-old male spontaneously hypertensive rats (SHR) were treated with indapamide (1 mg/kg per day) or captopril (10 mg/kg per day) or a combination of indapamide plus captopril. After the 6-week treatment, nitric oxide synthase (NOS) activity, the expression of NOS isoform proteins, conjugated dienes concentration and relaxation responses of the femoral artery were analyzed. Indapamide and captopril partly prevented a blood pressure increase in young SHR. Captopril in contrast to indapamide reduced LVH. The effect of the combined indapamide and captopril treatment on the prevention of hypertension was additive. Combined indapamide and captopril treatment increased NOS activity and endothelial NOS protein expression in the aorta and decreased conjugated dienes concentration in the kidney compared with the indapamide monotherapy group. Indapamide and indapamide and captopril treatment increased acetylcholine-induced relaxation of the femoral artery. Whereas captopril reduced LVH, indapamide enhanced NOS activity and decreased oxidative damage in the case of the combined treatment. It is concluded that the complex protective effects of the combined indapamide plus captopril treatment on hypertension may be exerted via its effects on blood pressure, hypertrophy and vasorelaxation.

A Twofold Genetic Increase of ACE Expression Has No Effect on the Development of Spontaneous Hypertension

To study the regulation of a naturally occurring genetic variant of high angiotensin-converting enzyme (ACE) gene (Ace in rat) expression, i.e., the Ace allele of the normotensive Wistar-Kyoto (WKY) rat, in the hypertensive background of stroke-prone spontaneously hypertensive (SHRSP) rats. We analyzed a congenic strain termed SHRSP.WKY-Ace derived from SHRSP in which a chromosomal fragment of rat chromosome 10 including Ace was replaced by the WKY locus. We compared blood pressures by radiotelemetry, measured plasma ACE activity, tissue ACE messenger RNA (mRNA) and enzyme activities in lung, kidney, and left ventricle (LV) of the heart in adult animals. Congenic animals demonstrated a twofold increase in plasma ACE activity in comparison to SHRSP (P < 0.05) and thus similar levels to WKY. The increased tissue expression of ACE mRNA and enzyme activities in lung, kidney, and LV observed in WKY were similarly found in congenic animals when compared to SHRSP (P < 0.05, respectively). Systolic and diastolic blood pressures were not different between congenic and SHRSP animals. Analysis of renin in plasma and angiotensin peptides in LV tissues indicated the induction of compensatory mechanisms by downregulation of renin and angiotensin I (Ang I) concentrations in congenic animals. We demonstrated that genetically determined high ACE expression linked to WKY Ace remains unchanged in the hypertensive background of SHRSP.WKY-Ace. Our data indicate that buffering mechanisms in the renin-angiotensin system contribute to the finding that the development of spontaneous hypertension is not affected, despite an average twofold higher expression of ACE in congenic animals.

Contribution of captopril thiol group to the prevention of spontaneous hypertension

We aimed to compare the effect of angiotensin converting enzyme (ACE) inhibitors captopril (containing thiol group) and enalapril (without thiol group) on the development of spontaneous hypertension and to analyze mechanisms of their actions, particularly effects on oxidative stress and NO production. Six-week-old SHR were divided into three groups: control, group receiving captopril (50 mg/kg/day) or enalapril (50 mg/kg/day) for 6 weeks. At the end of experiment, systolic blood pressure (SBP) increased by 41 % in controls. Both captopril and enalapril prevented blood pressure increase, however, SBP in the captopril group (121+/-5 mmHg) was significantly lower than that in the enalapril group (140+/-5 mmHg). Concentration of conjugated dienes in the aorta was significantly lower in the captopril group compared to the enalapril group. Captopril and enalapril increased NO synthase activity in the heart and aorta to the similar level. Neither captopril nor enalapril was, however, able to increase the expression of eNOS. Both ACE inhibitors increased the level of cGMP. However, cGMP level was significantly higher in the aorta of captopril group. We conclude that captopril, beside inhibition of ACE, prevented hypertension by increasing NO synthase activity and by simultaneous decrease of oxidative stress which resulted in increase of cGMP concentration.

Genetic low nephron number hypertension is associated with dysregulation of the hepatic and renal insulin-like growth factor system during nephrogenesis

Low nephron number may represent a major determinant of human primary hypertension in adult life. This hypothesis is supported by a genetic rat model, namely the Munich-Wistar-Frömter (MWF) rat, which demonstrates an inherited deficit in nephron number and the development of spontaneous hypertension. Insulin-like growth factor (IGF) I and II exert endocrine and paracrine effects that are required for normal growth and nephron development. We tested the hypothesis that low nephron number is already present during fetal development, and the expression pattern of important molecules of the IGF system is altered in MWF rat during the critical period of kidney development. We compared MWF and normal Wistar rats during nephrogenesis at day 19 of fetal development (E19) and adult rats at postnatal day 100 (D100). Histomorphometric analysis was performed by stereological methods. Quantitative messenger RNA and protein expression was determined by real-time polymerase chain reaction and enzyme-linked immunosorbent assay. At E19, glomerular density (-32%) and hepatic mRNA (-48%) and protein (-18%) expression of IGF-I were decreased (P < 0.05, respectively), whereas renal mRNA expression of IGF-II receptor (+52%) and IGF binding protein 3 (+113%) were increased in MWF compared with Wistar rats (P < 0.05, respectively). Systolic blood pressure, urinary albumin excretion, and mean glomerular area were significantly elevated in MWF compared with Wistar rats at D100 (P < 0.05, respectively). The fetal expression of IGF system molecules in the MWF rat model points towards a link between the decreased availability of active IGF-I and IGF-II and the fetal development of low nephron number, with manifestation of genetic hypertension in adult life.

Effect of chronic N-acetylcysteine treatment on the development of spontaneous hypertension

The imbalance between NO (nitric oxide) and ROS (reactive oxygen species) is an important factor in the development of hypertension. The aim of the present study was to determine the preventive and therapeutic effects of NAC (N-acetylcysteine) in SHRs (spontaneously hypertensive rats). Young and adult SHRs and WKY (Wistar-Kyoto) rats were treated with NAC (20 g/l in the drinking water). After 8 weeks of treatment, BP (blood pressure) and NOS (NO synthase) activity, conjugated dienes and GSH (reduced glutathione) in the kidney and left ventricle were determined. Protein expression of eNOS (endothelial NOS), inducible NOS and NF-kappaB (nuclear factor kappaB) were also determined in the left ventricle and kidney. Chronic NAC treatment partially attenuated the rise in BP in young SHRs (179+/-6 compared with 210+/-8 mmHg in untreated animals), but it had no significant effect on BP in adult SHRs. The antioxidant action of NAC, measured as a decrease of the concentration of conjugated dienes or inhibition of NF-kappaB expression, was greater in young than in adult SHRs. Similarly, eNOS protein expression was attenuated more in young than in adult SHRs, although NAC treatment increased NOS activity to a similar extent in both young and adult rats. In conclusion, both decreased ROS production and increased NOS activity appear to participate in the BP changes after NAC treatment in young SHRs. In adult SHRs with established hypertension, however, the secondary alterations (such as pronounced structural remodelling of resistance vessels) might attenuate the therapeutic effect of NAC.

Expression of nitric oxide synthase isoforms in hypothalamo–pituitary–adrenal axis during the development of spontaneous hypertension in rats

This study was performed to investigate the expression of the major isoforms of nitric oxide synthase mRNA and protein in the hypothalamo–pituitary–adrenal axis (HPA axis) of spontaneously hypertensive rats (SHR) at two different postnatal ages corresponding to the development of genetic hypertension. Using RT-PCR and Western blot techniques, the mRNA and protein levels of neuronal (nNOS), endothelial (eNOS) and inducible (iNOS) isoforms were measured in 3- to 4-week-old (prehypertensive phase) and 12- to 13-week-old (established hypertension phase) SHR and age-matched normotensive Wistar–Kyoto (WKY) rats. nNOS but not eNOS mRNA levels were increased at prehypertensive and hypertensive phases in SHR HPA axis. Compared to age-matched WKY rats, significantly higher levels of nNOS protein were found in the hypothalamus, lower levels in the adrenal glands and no changes were observed in the pituitary gland. At both ages tested, there was no significant change in eNOS protein expression in SHR HPA axis. The expression of iNOS mRNA and protein was under detection limit. In the HPA axis, the expression of nNOS isoform appears to be differentially controlled at the transcriptional and translational levels in SHR. Increased mRNA levels and differential nNOS protein expression from birth in SHR HPA axis may contribute in the pathogenesis of genetic hypertension.

Changes and significance of hydrogen sulfide/cystathionine gamma-lyase system in hypertension: an experimental study with rats

To explore the significance of hydrogen sulfide/cystathionine gamma-lyase (H(2)S/CSE) system in the development of hypertension and the effects of H(2)S/CSE system on the modulation of aortic remodeling process of hypertension. Eight 4-week-old male WKY rats were used as WKY control group, and another sixteen SHR rats at the age of 4 weeks were randomly divided into SHR control group (n = 8) and SHR + NaHS (H(2)S donor) group (n = 8). The rats of SHR control and WKY control were injected with normal saline and the rats of the SHR + NaHS group were injected with NaHS each day. Five weeks later, the blood pressure and the left-to-whole heart weight ratio were determined. The transcriptional level of CSE in aorta and the H(2)S level in plasma were detected. The morphometric parameters of the thoracic aorta including the outer radius, medium area and ratio of wall thickness to lumen radius were detected too. At the age of 9 weeks the systolic blood pressure and the left-to-whole heart weight ratio of the SHR control rats were both higher than those of the WKY control rats [(184 +/- 12) mm Hg vs (108 +/- 23) mm Hg, 1 mm Hg = 0.133 kPa, and (0.853 +/- 0.021) vs (0.826 +/- 0.024)]. The transcriptional level of CSE in aorta and the H(2)S level in serum of the rats in the SHR control group were both lower than those of the rats in the WKY control group (9.3 +/- 0.7) x 10(-8) fmol vs (16.1 +/- 1.0) x 10(-8) fmol, and (20 +/- 9) micro mol/L vs (48 +/- 13) micro mol/L, while the morphometric parameters of the thoracic aorta including the outer radius, the medium area and ratio of lumen radius and wall thickness of the SHR control rats were all higher compared with those of the WKY control rats [outer radius: (1999 +/- 45) micro m vs (1790 +/- 96) micro m], medium area: (0.60 +/- 0.06) mm(2) vs (0.48 +/- 0.03) mm(2), and ratio of wall thickness to lumen radius: (0.066 +/- 0.006) vs (0.060 +/- 0.004). The exogenous administration of NaHS made the systolic blood pressure of rats in the SHR + NaHS group much lower than that of the rats in SHR control group [(158 +/- 13) mm Hg vs (184 +/- 12) mm Hg], however, the transcriptional level of CSE in aorta and the H(2)S level in serum of the rats in SHR + NaHS group were much higher than those of the rats in SHR control group [(12.4 +/- 1.0) x 10(-8) fmol vs (9.3 +/- 0.7) x 10(-8) fmol] vs [(96 +/- 32) micro mol/L vs (20 +/- 9) micro mol/L]. The morphometric parameters of SHR + NaHS group were lower than those of the SHR control group. Down regulation of H(2)S/CSE system is a major factor in the development of spontaneous hypertension and the accompanying structural remodeling of aorta. Exogenous administration of H(2)S may attenuate the process of hypertension.

Role of female sex hormones in the development and reversal of dahl hypertension.

Female sex hormones protect against the development of Dahl hypertension mediated by increases in dietary sodium. The role of female sex hormones in the reversal of Dahl hypertension mediated by decreases in dietary sodium is unknown. The goal of this study was to identify sex differences in the reversal of Dahl hypertension and the associated changes in water and electrolyte homeostasis. Male (M, n=8), female (F, n=8), and ovariectomized female (OVX, n=9) Dahl salt-sensitive rats were instrumented with an abdominal radiotelemetry device for 24-hour monitoring of blood pressure (BP) and heart rate. Daily measurements of food intake, water intake, and urine output were recorded as diet was changed from a low-sodium diet (0.15% NaCl) to a diet containing 8% NaCl. The diet was then changed back to 0.15% NaCl. The responses to changes in the salt diet were compared with responses observed in rats (M, n=4; F, n=4; OVX, n=4) that were maintained on 0.15% NaCl during the experiment. Sex differences in BP were observed when M, F, and OVX rats were fed 8% NaCl diet for 2 weeks (152+/-4, 141+/-3, and 154+/-5 mm Hg, respectively). BP was significantly greater (P<0.05) in M and OVX rats than in F rats. Fluid balance (water intake minus urine volume) and sodium balance (sodium intake minus sodium excretion) were similar in all groups on the 8% NaCl diet. BP in time-control M, F, and OVX rats was 121+/-3, 130+/-4, and 162+/-11 mm Hg, respectively. Compared with time-control groups, differences in BP while rats were eating the 8% NaCl diet were observed in M and F rats but not OVX rats. Reinstatement of an NaCl-deficient diet reversed the hypertension in M and F but not OVX rats (124+/-4, 124+/-2, and 145+/-5 mm Hg, respectively). The changes in dietary sodium caused similar changes in renal handling of sodium and water in all groups of rats; therefore, the effect on blood pressure was independent of renal excretory function. The inability to reverse the hypertension by decreasing sodium intake in OVX rats and the development of spontaneous hypertension in OVX females maintained on a low-sodium diet indicates that removal of the female sex hormones predisposes the animal to the development of hypertension that is sodium independent. We conclude that female sex hormones protect Dahl S rats against the development of sodium-dependent and -independent hypertension.

Genetic basis of salt-susceptibility in the Sabra rat model of hypertension

The Sabra salt-sensitive SBH/y and salt-resistant SBN/y rats constitute a unique experimental model of hypertension in which salt-susceptibility is genetically determined and expressed only after salt-loading, without the development of spontaneous hypertension. To determine the genetic basis of salt-susceptibility in the Sabra rats, the candidate gene and total genome screen approaches were adopted. The likely candidate genes in this model incorporate salt-related physiological mechanisms such as the nitric oxide system, the arginine vasopressin axis and the epithelial sodium channel. In the random genome search scheme for culprit genes, SBH/y and SBN/y were cross-bred. A highly unusual and composite mode of transmission of salt-susceptibility was found in this cross, emphasizing the complexity of the genetic basis of salt-susceptibility. Linkage analysis of the entire rat genome with a large number of widely distributed microsatellite markers identified three putative gene loci on chromosomes 1 and 17 that contribute importantly to salt-sensitivity and/or resistance, and uncovered sex specificity in the role that salt-susceptibility genes fulfill in the development of hypertension.

Time-Dependent Changes in Catecholamine Turnover in Spontaneously Hypertensive Rats Exposed to Hypoxia

In three separate experiments, 4 to 5-week-old spontaneously hypertensive rats (SHR) and normotensive controls (Wistar-Kyoto [WKy]) were exposed to hypobaric hypoxia (simulated altitude = 3658 m) for 3 hr, 3 days, or 3 weeks. Comparable groups were maintained in ambient laboratory conditions (normoxia). Hypoxia prevented the increase in blood pressure noted in 8-week-old normoxic SHR. Right ventricular hypertrophy first occurred after 3 days of hypoxia, and was found in both SHR and WKy. Catecholamine turnover was measured using the tyrosine hydroxylase inhibitor, alpha-methyl-p-tyrosine. In myocardium, both strains evidenced hypoxia-induced changes in norepinephrine (NE) turnover, which was increased at 3 hr, normalized at 3 days, and increased again at 3 weeks. Reduced basal NE concentration at 3 days indicated a temporary deficit in synthetic capacity, which would allow maintenance of a heightened neuronal output. Catecholamine turnover in right and left ventricles differed little in response to hypoxia, in spite of differential hemodynamic demands on SHR versus WKy or on right versus left ventricle. In contrast to findings in myocardium, significant interactive effects between strain and altitude exposure were noted for adrenal catecholamine turnover. Specifically, hypoxia exerted a suppressive influence in SHR that was not evident in WKy, and this may represent an important component of hypoxia-induced protection against the development of spontaneous hypertension.

Immunoregulatory Failure in the Pathophysiology of Hypertension

Positive correlation has been found between serum immunoglobulin G levels and blood pressure in untreated hypertensive patients. In the Okamoto spontaneously hypertensive rat, several functional indexes of the immune system are depressed. Selective interventions with the immune system result in antihypertensive effects or delay development of spontaneous hypertension.

Chronic Central GABAergic Stimulation Attenuates Hypothalamic Hyperactivity and Development of Spontaneous Hypertension in Rats

To determine whether chronic central gamma-aminobutyric acid (GABA) stimulation would attenuate development of hypertension, tail-cuff systolic pressures were measured in male spontaneously hypertensive rats (SHR) treated with either an inhibitor of GABA breakdown (valproate, VPA), or a GABA-receptor agonist (muscimol). When VPA was injected intraperitoneally (i.p.) daily for 4 weeks, tail-cuff systolic pressures were decreased during the last 2 weeks. On the other hand, continuous infusion of muscimol into the lateral cerebral ventricle for 14 days using an osmotic minipump decreased systolic pressures throughout the 10-day observation period. During terminal experiments under urethane anesthesia, pressor and sympathetic nerve responses to electrical stimulation of the ventromedial hypothalamus were reduced in VPA- or muscimol-treated SHR. Pressor responses to intravenously (i.v.) injected norepinephrine (NE) were unaltered by either treatment, indicating that diminished pressor responsiveness to hypothalamic stimulation was not due to diminished cardiovascular reactivity. Regardless of either VPA acid or muscimol treatment, basal blood pressure (BP), heart rate (HR), and responses to hypothalamic stimulation were lower in normotensive Wistar-Kyoto controls (WKY) than in SHR. In addition, chronic treatment with either drug had weaker hypotensive and hypothalamic depressant effects in WKY than in SHR. Our results suggest that in SHR the central GABAergic system is impaired and that chronic treatment with GABAergic stimulants can attenuate development of spontaneous hypertension by reducing hypothalamic overactivity.

Reduced intracellular pH in lymphocytes from the spontaneously hypertensive rat.

This study was designed to determine the cytoplasmic pH (pHi) profile of lymphocytes from a rat model of genetic hypertension that is well suited for study before and after the development of spontaneous hypertension. For this purpose, pHi was measured in thymic lymphocytes obtained from spontaneously hypertensive rats (SHR) and from age-matched Wistar-Kyoto (WKY) control rats using 2',7'-bis carboxyethyl-5,6-carboxyfluorescein (BCECF), a pH-sensitive fluorescence probe. At the age of 16-20 weeks, pHi of lymphocytes suspended in a HCO3-free HEPES-buffered solution, was markedly lower in the SHR than in the WKY rats (7.07 +/- 0.02, n = 16 and 7.22 +/- 0.01, n = 15, respectively, p less than 0.001), whereas systolic blood pressure was higher in SHR than in WKY rats (175 +/- 5.0 and 105 +/- 3.0 mm Hg, respectively, p less than 0.001). In rats less than 5 weeks of age, pHi was also lower in SHR than in WKY rat lymphocytes (7.12 +/- 0.04, n = 11 and 7.23 +/- 0.04, n = 11, respectively, p less than 0.05), although at this age systolic blood pressure was not different between the two groups (87 +/- 4.0 and 85 +/- 3.0 mm Hg, respectively). In lymphocytes suspended in a more physiological HCO3/CO2-buffered solution, pHi was again lower in the adult SHR than in the WKY rat (7.18 +/- 0.02, n = 16 and 7.31 +/- 0.02, n = 16, respectively, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Metabolic alterations in discrete regions of the rat brain during development of spontaneous hypertension

Hexokinase histochemistry was used to identify brain regions that undergo metabolic changes during the development of hypertension in the spontaneously hypertensive rat (SHR). Photodensitometric measurements of reaction product were made in the commissural subdivision of the nucleus of the tractus solitarius, medial subdivision of the rostral nucleus of the tractus solitarius, subfornical organ, supraoptic nucleus, magnocellular division of the paraventricular nucleus, parvocellular division of the paraventricular nucleus, anterior hypothalamic area, and posterior hypothalamus of prehypertensive SHR (4 weeks) and SHR with developing hypertension (8 weeks). These values were compared with those obtained from age-matched Sprague-Dawley and Wistar-Kyoto rats. At 4 weeks, significantly lower levels of hexokinase were observed in the commissural subdivision of the nucleus of the tractus solitarius and the magnecellular division of the paraventricular nucleus of SHR; a higher level was seen in the posterior hypothalamus. At 8 weeks, significantly higher levels of hexokinase were observed in the anterior hypothalamic area and the posterior hypothalamus. These results can be compared to those from adult SHR 11 where lower levels of activity were found in the parvo- and magnocellular divisions of the paraventricular nucleus. Together these results suggest that, while the role of the magnocellular division of the paraventricular nucleus remains nuclear, the commissural subdivision of the nucleus of the tractus solitarius and posterior hypothalamus may participate in the initial events leading to hypertension whereas the parvocellular division of the paraventricular nucleus does not.

Rat Brain Regional Preproenkephalin A Messenger RNA Levels Are Altered in Genetic Hypertension

Considerable neuroanatomical and pharmacological evidence suggests that preproenkephalin A-derived peptides, particularly methionine-enkephalin, are involved in regulation of the cardiovascular system in both physiological and pathological states. In this study, we used a rat preproenkephalin A complementary DNA to determine whether proenkephalin A-derived peptides participate in the pathogenesis of hypertension as reflected by brain regional messenger RNA levels. Complementary DNA clones of the rat preproenkephalin A mRNA and rat small myelin basic protein mRNA were hybridized to total RNA extracted from hypothalamus, pons-medulla, thoracic cord, midbrain, and cerebellum of 3 1/2-week-old and 12-week-old Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats. In 3 1/2-week and 12-week animals there were no differences in the levels of myelin basic protein messenger RNA between the two groups in any brain region. At 3 1/2 weeks, preproenkephalin A mRNA levels did not differ between normotensive and hypertensive strains. In contrast, at 12 weeks preproenkephalin A mRNA levels were increased in hypothalamus, midbrain, thoracic cord, and cerebellum of SHR relative to WKY. Preproenkephalin A mRNA was significantly reduced in the pons-medulla of SHR relative to WKY. Our findings provide evidence that alterations in brain regional preproenkephalin A mRNA levels are associated with the development of spontaneous hypertension in the rat.

Maternal effects on the development of spontaneous hypertension.

Cross-fostering spontaneously hypertensive rat (SHR) pups to Wistar-Kyoto (WKY) normotensive mothers influenced physical development, resting mean arterial pressure and heart rate, open-field behavior, and sympathetic-adrenal medullary responses to stressors. In contrast, cross-fostering WKY pups to SHR mothers at birth did not affect these developmental processes.