Strain, age, but not gender, influence ulcer severity induced by water-restraint stress

Two ulcerogenic procedures, supine restraint (SR) and water restraint (WR) were compared. In Experiment 1, Fischer-344 (F344), Sprague-Dawley (S-D), Wistar, Long-Evans (L-E), Spontaneously Hypertensive rats (SHR) and Wistar Kyoto normotensive (WKY) rats were exposed to SR and WR. WR produced more ulcers than SR. There was no difference in ulcer scores between WKY, F344 and L-E but these rats had significantly more ulcers as compared to SHR, Wistar and S-D rats. In Experiment 2, 4- and 16-month-old SHR, WKY and F344 rats were exposed to SR and WR. The older WKY rats had more ulcers than all other treatment groups. Experiment 3 revealed no significant differences between male and female rats exposed to either SR or WR. Body temperature (BT) scores obtained after restraint and after 2-hr postrestraint rest were only marginally related to ulcer severity. Rats exposed to WR had lower BT scores but the strain and age ulcer differences did not have corresponding BT differences. These studies revealed the following: the ulcer susceptibility of WKY rats; the WR technique is a useful ulcerogenic procedure; and hypothermia is a weak covariant to restraint-induced stress ulcer.     

"Behavioral despair" test predicts stress ulcer in WKY rats

Spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) and Wistar rats were exposed to Porsolt's forced-swimming test of "behavioral despair." In addition to floating time, which was the measure of despair, headshakes, bobbing, diving and struggling time were also recorded. Rats were subsequently exposed to the activity stress (A-S) ulcer procedure. Wistar rats had the highest struggling time scores and the fewest A-S ulcers. WKY rats were judged as more depressed and their ulcer severity scores were significantly greater as compared to SHR and Wistar rats. In addition, a within strains analysis revealed that WKY rats with high despair scores also had the most severe stress-ulcer scores. These data suggested that stress-ulcer disease may be more prevalent in animals which are prone to depression as defined by the Porsolt test. The value of WKY rats as an animal model to study the relationship between depression and stress ulcer is discussed.     

Stress ulcer in normotensive and spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) and their normotensive progenitors, the Wistar-Kyoto (WKY) rats, were tested in the open-field arena and subsequently exposed to either cold-restraint stress or activity-stress. SHR rats were more active and judged less fearful in the open-field test. Changes in core body temperature, and adrenal and thymus weights did not differentiate between SHR and WKY rats in the cold-restraint procedure. A significant adrenal hypertrophy was observed for SHR rats in the activity-stress procedure. WKY rats were more susceptible to stress ulcer in both the cold-restraint and the activity-stress procedures. While running-wheel activity had been considered an important etiological variable for activity-stress ulcer, the lower activity demonstrated by the ulcer-prone WKY rats suggested that genetic variables might be more relevant to stress ulcer disease.     

Age, sex and strain differences in activity and habituation in SHR and WKY rats

The highly inbred strain of Wistar-Kyoto spontaneously hypertensive rat (SHR) and its normotensive, genetic control (WKY) were examined with respect to strain differences in spontaneous activity scores in a novel environment (small activity cage) and in ability to habituate to that environment. These behaviors were examined in experimentally naive rats, 197 SHR and WKY, males and females, at varying ages from 4 to 56 weeks, in order to determine whether there are sex and age differences in addition to the well-known strain differences in these behaviors. Total activity scores, determined in a 15 min test in the activity cage, were higher in SHR than WKY rats; females were significantly more active than males in either strain, and activity scores varied significantly with age both within strains and between strains. Ability to habituate to the test cage was determined by repeating the 15 min activity test at hourly intervals for three additional trials on the same day. The results indicate that the SHR, males and females and at all ages tested, habituate poorly if at all to the test cage as compared with WKY rats. Moreover, despite the variability of baseline activity scores (first trial) observed across ages, sexes and strains, the habituation patterns of either strain remained relatively fixed throughout the first year of life.     

自发性高血压大鼠脑底动脉含神经肽Y、含降钙素基因相关肽、含P物质神经的变化

用免疫组织化学（ＡＢＣ）方法，观察了含ＮＰＹ、含ＣＧＲＰ和含ＳＰ神经在自发性高血压大鼠脑底动脉的变化．结果表明，和对照用的京都Ｗｉｓｔａｒ大鼠相比，含ＮＰＹ神经在脑底动脉环吻侧的密度略低，而尾侧略高；自发性高血压大鼠大脑前动脉和大脑后动脉含ＮＰＹ神经纵行纤维密度比对照大鼠低，而环行纤维密度比对照大鼠高．自发性高血压大鼠脑底动脉含ＳＰ和含ＣＧＲＰ神经的密度均比对照大鼠低．本文对上述变化的意义进行了讨论．关键词     

The SHR Y-Chromosome Increases Testosterone and Aggression, but Decreases Serotonin as Compared to the WKY Y-Chromosome in the Rat Model

The Spontaneously Hypertensive Rat (SHR) model was used to test the hypothesis that a locus on the SHR Y-chromosome is responsible for increased aggression resulting from increased serum testosterone and decreased amygdala serotonin content compared to the WKY Y-chromosome. To examine the Y-chromosome in SHR and WKY males, consomic Y-chromosome strains were used (WKY.SHR-Y and SHR.WKY-Y). Novel resident intruder tests and intra-colony scarring behavioral paradigms were used to measure aggression in a colony environment. Both resident intruder test attack number and wounding, along with intra-colony scarring scores showed the colony males with the SHR Y-chromosome (SHR and WKY.SHR-Y strains) were more aggressive than the colony males with the WKY Y-chromosome (WKY and SHR.WKY-Y strains). The SHR Y-chromosome colony male animals also had significantly higher serum testosterone, as well as overall lower amygdala serotonin content than the WKY Y-chromosome colony male animals. The results suggest that these behavioral and physiological differences between the SHR and WKY strains are a result of a mutation in the non-pseudoautosomal region unique to the Y-chromosome.     

Differences between natriuretic peptide receptors in the olfactory bulb and hypothalamus from spontaneously hypertensive and normotensive rat brain

Natriuretic peptide receptor-A (NPR-A) functional characteristics in the hypothalamus and olfactory bulb (OB) have been investigated in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY). Autoradiographic studies demonstrate a decreased number of atrial natriuretic peptide (ANP) binding sites in the olfactory bulb and hypothalamus in SHR compared to WKY rats. We found that NPR-A showed a lower maximal binding capacity (B(max)) and higher affinity in SHR than in WKY rats both in the olfactory bulb and hypothalamus. However, despite the lower B(max) in SHR, both ANP(1-28) and ANP(5-25) stimulated similar or greater cGMP production than in WKY rats. These differences were found even before the development of hypertension. NPR-A in the olfactory bulb and hypothalamus from 3-week-old SHR showed a lower B(max) and K(d) and a higher cGMP production rate than in WKY rats, suggesting that these characteristics are intrinsic of NPR-A in SHR, instead of being a result of hypertension itself. The present study provides evidences for altered NPR-A receptor properties and function in the olfactory bulb and hypothalamus from SHR, which might be involved in the pathogenesis of hypertension.     

Sodium appetite as well as 24-h variations of fluid balance, mean arterial pressure and heart rate in spontaneously hypertensive (SHR) and normotensive (WKY) rats, when on various sodium diets

Young SHR and WKY rats were compared, first, concerning sodium (Na) appetite during 'rest', mild social stress and ACTH injections, second, concerning the diurnal patterns of water intake, urine output, mean arterial pressure (MAP) and heart rate (HR) while on various Na diets: 0.5 mmol Na(LNa), 5 or 12-13 mmol Na (CNa), 50 (HNa) or 120 mmol Na (vHNa) per 100 g food. Sodium appetite and water intake were about 50% higher in SHR than in WKY (4-4.5 vs 2.5-3 mmol Na per 100 g body wt day-1). It was modestly increased by both social stress and ACTH, and more so in WKY, thereby approaching that in SHR. Concerning the various Na diets and their influences, daytime resting MAP was modestly lowered in LNaSHR and slightly increased in vHNaSHR compared with CNaSHR but largely equal in all WKY groups. Food-water consumption was concentrated to the active night period, but even high Na-water intakes caused no signs of sustained hypervolaemia, because each intake bout was in both SHR and WKY eliminated by urine within 30-40 min. However, particularly the vHNa diet in SHR also increased the frequency of drinking, and each bout caused transient, evidently neurogenic MAP and HR increases which occurred too rapidly to be consequences of blood volume expansion. As a result, the diurnal MAP-HR patterns in SHR varied markedly with the Na diets, in vHNa group resulting in considerably raised average diurnal MAP levels even though resting daytime MAP was here nearly the same as in CNaSHR. These findings illustrate how largely continuous diurnal recordings are needed to judge correctly the relationships between, for example, Na intake, volume equilibrium and MAP. Finally, the relevance of these results in rats for also judging the control of Na balance in man is discussed.     

Morphometrical and biochemical differences of endocrine pancreata between spontaneously hypertensive and normotensive rats with or without neonatal streptozotocin-induced diabetes

We studied the morphometrical and biochemical changes of endocrine pancreata in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY) with or without noninsulin-dependent diabetes mellitus induced by neonatal streptozotocin (STZ) treatment at 4 months of age. Female (2-day-old) neonates were intraperitoneally injected with 62.5 or 75.0 mg/kg of STZ for SHR, 87.5 or 100.0 mg/kg of STZ for WKY, and vehicle for control. In STZ-treated groups, overt hyperglycemia developed in SHR with significantly decreased serum immunoreactive insulin (IRI), whereas in WKY, hyperglycemia was very mild and serum IRI was not lowered. The number and mean size of pancreatic islets did not differ between SHR and WKY, although mean islet size was reduced by half in both compared with that in the corresponding control, respectively. Percentage distribution of insulin-positive B cells in the islet was significantly reduced more in SHR than in WKY (34% of control versus 64% of control, p less than 0.05). Furthermore, pancreatic IRI content was far more reduced in SHR than in WKY (3% of control versus 43% of control, p less than 0.001). In vehicle-treated groups, the glycemic levels and the morphometrical islets did not differ between SHR and WKY. However, serum IRI was significantly lower but pancreatic IRI content was higher in SHR than in WKY. The mechanisms of strain differences between SHR and WKY seen in the present study were discussed.     

Lithium chloride stabilizes systolic blood pressure and increases adrenal catecholamines in the spontaneously hypertensive rat

The effects of daily, intraperitoneal injections of LiCl (3 mEq/kg) on systolic blood pressure (SBP) and adrenal catecholamine levels were measured in spontaneously hypertensive rats (SHR) and in normotensive Wistar-Kyoto rats (WKY). Control animals from each strain were injected with equivalent volumes (0.1 ml/100 g b.wt.) of 0.9% saline (0.15 mEq/kg). SBP in LiCl-treated SHR was significantly lower (p less than 0.05) than that of saline-treated SHR (177 +/- 7 vs. 196 +/- 4 mm Hg, respectively) after one week. After two weeks SBP was lower in LiCl SHR than in saline controls, but this difference was not significant. While SBP of both LiCl and saline treated WKY was not significantly different (146 +/- 4 vs. 147 +/- 8 mm Hg, respectively), SBP in both WKY groups remained lower than the SBP for either group of SHR. LiCl induced a significant weight loss in the SHR, but not in the WKY. Adrenal norepinephrine and epinephrine were significantly (p less than 0.05) higher in LiCl-treated rats of both strains; dopamine was also higher in LiCl-treated rats of both strains, but significant only between SHR-LiCl and SHR controls. It appears that LiCl's effect in slowing the development of hypertension is independent of its action on adrenal catecholamines. The SHR's increased sensitivity to LiCl, relative to weight loss and SBP, may reflect differences in genetic or physiological status of the animal compared to WKY. These differences may be associated with alterations in membrane ion transport systems.     

Role of Ca-dependent K channels in the membrane potential and contractility of uterus from spontaneously hypertensive rats

Membrane potentials and the contractile responses to prostaglandin F₂, oxytocin, bradykinin, 5-hydroxytryptamine and acetylcholine were determined in uteri from spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), both in the absence and in the presence of the Ca²⁺-dependent K⁺ channel blocker apamin. Compared to WKY, the uterine smooth muscle from SHR was more reactive to all the agonists tested. In the presence of apamin, the contractile responses of WKY uteri were enhanced, whereas the responses of SHR uteri were either unaltered or decreased, so that the WKY responses became similar or even greater than those of SHR. Smooth muscle cell membrane potentials were lower in SHR than in WKY. Treatment with apamin did not affect the membrane potential of SHR cells, but caused depolarization of WKY cells. It is concluded that a reduced activity of Ca²⁺-dependent K⁺ channels in SHR uteri contributes to their lower membrane potentials and higher responsiveness to contractile stimuli by agonists, It is possible that uterine quiescence, essential for the normal fetal development, is impaired in SHR, resulting in lower uterine blood fluxes with consequent lower fetal and litter size and weight observed in this strain.     

WKY大鼠与自发性高血压模型大鼠(SHR)大脑中动脉拉伸力学特性的对比分析

对比分析WKY大鼠和SHR大鼠大脑中动脉的拉伸力学特性,为预防高血压提供生物力学基础。取5月龄正常WKY雄性大鼠大脑中动脉20个,5月龄SHR雄性大鼠大脑中动脉20个,试样以0.5mm/Min的实验速度进行纵向拉伸实验。WKY雄性大鼠大脑中动脉组拉伸最大应力、最大应变、弹性限度应变大于SHR雄性大鼠大脑中动脉组(P0.05),SHR雄性大鼠大脑中动脉的弹性模量值大于WKY雄性大鼠大脑中动脉(P0.05)。WKY大鼠大脑中动脉和自发性高血压模型大鼠(SHR)大脑中动脉具有不同的拉伸力学特性,自发性高血压模型大鼠(SHR)大脑中动脉拉伸力学特性发生了改变。     

Sympatho-adrenal hyperreactivity to footshock stress but not to cold exposure in spontaneously hypertensive rats

No significant differences in plasma levels of catecholamines were found in blood obtained via an indwelling tail artery catheter from awake, undisturbed spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) or NIH Sprague-Dawley rats. Although the blood pressures of SHR rats increased between 4 and 10 months of age, there were no changes in basal plasma catecholamine levels. Exposure to cold for 20 or 240 min resulted in significant increments in plasma catecholamine levels which were similar in SHR and WKY rats. In contrast, exposure to 5 min of inescapable footshock (2.5 mA, 0.4 sec duration, every 5 sec) produced striking increments in plasma catecholamines that were greater in SHR rats than in normotensive WKY or NIH Sprague-Dawley rats. SHR rats also exhibited greater levels of plasma corticosterone than WKY rats at 15 min after termination of footshock. Our results demonstrate that SHR rats are hyperadrenergic in their responses to some but not all forms of stressful stimulation.     

Cardiovascular effects of central 6-OHDA treatment: a comparison of indirect and direct measurements

The effect of intracerebro-ventricular treatment with 6-hydroxydopamine on blood pressure and heart rate was studied in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto controls (WKY). When measured with the indirect tail-cuff method, the development of hypertension was found to be markedly inhibited in 6-OHDA treated SHR, while blood pressure was slightly lower in treated WKY. Heart rate was lower in both strains, although the greatest effect was found in SHR. In contrast, direct measurement via an arterial cannula indicated significantly lower blood pressure in 6-OHDA treated SHR only. Heart rate was by this method found to be not different between the SHR groups, but was increased in treated WKY. These results indicate that the mild stress of indirect blood pressure determinations has a marked influence on the results found.     

Age-related reduction in pituitary corticotropin-releasing hormone receptors in two rat strains.

Open field behavior and age-related changes in anterior pituitary corticotropin-releasing hormone (CRH) receptors, as well as plasma ACTH levels, were measured in two inbred rat strains. The strains utilized were Wistar Kyoto (WKY) and Brown-Norway (BN), the former characterized by shorter life-span and hyper-reactivity to stressors as compared to the latter. Behaviorally, WKY rats showed hyper-responsivity to a novel environment as indicated by their delay in entering the open field, increased grooming, reduced rearing, and reduced locomotion. These strain-dependent behavioral differences were not affected by aging. The binding capacity of CRH receptors was similar in both strains and Bmax values were decreased (25-27%) with aging, with no changes in Kd values. In contrast, plasma ACTH levels were 67% higher in WKY than in BN rats but did not change with aging. Thus, despite pituitary CRH receptor down regulation, plasma ACTH levels following decapitation were sustained during aging. This suggests the presence of some compensatory factors in the hypothalamic-pituitary axis regulation which sustain ACTH response during aging. Furthermore, the findings indicate that higher plasma ACTH levels and hyper-reactivity to a novel environment are inversely correlated with longevity in the rat.     

Effects of exercise training on pathological cardiac hypertrophy related gene expression and apoptosis

This study determined whether exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial and apoptosis-associated genes. We used spontaneously hypertensive rats (n=15, non-exercise SHR), exercise-trained SHR (n=15, treadmill exercise for 12 weeks), and sedentary Wistar-Kyoto (WKY) rats (n=15). Exercise-trained SHR expressed adaptive changes such as reduced body weight, heart rate, blood pressures, left ventricle wall thickness, lipid profiles, and homocysteine level. The mRNA expression of angiotensin converting enzyme, endothelin-1, and brain natriuretic peptides in the heart was lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR, whereas mRNA expression of caveolin-3 and eNOS in the heart was higher. Bcl-2 protein was higher in the exercise-trained SHR than in the WKY and the non-exercise SHR. In contrast, Bax protein levels were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. Furthermore, the levels of the active forms of caspase-3 (20 kDa) were lower in the exercise-trained SHR and in the WKY than in the non-exercise SHR. These findings suggest that exercise training prevents pathological hypertrophy in the left ventricle by modulation of myocardial genes and that it interferes with a signal transduction pathway of apoptosis secondary to the pathological cardiac hypertrophy.     

自发性高血压大鼠血浆一氧化氮浓度的变化

目的　观察自发性高血压大鼠 (SHR)血浆NO浓度的变化 ,探讨NO与高血压发生发展的关系。方法　颈总动脉插管测定大鼠血压 ,硝酸银还原法测定SHR血浆中NO的含量。结果　 (1)血压变化 :各时期WKY大鼠血压无显著性差异 ;高血压组大鼠血压随着月龄增加逐渐升高 ,均明显高于WKY大鼠 (P <0 0 1)。 (2 )血浆NO浓度的变化 :WKY大鼠血浆NO浓度各时期无显著性差异 ;高血压组大鼠血浆NO浓度在 3m、6m时间点明显高于WKY大鼠 ,但在 12m时间点却较WKY大鼠明显降低 (P<0 0 1) ,同组内与 3m、6m时间点比较亦显著减少 (P <0 0 1)。相关分析显示 ,在 3m、6m时间点高血压大鼠血浆NO浓度与血压之间呈正相关 (P <0 0 1) ,在 12m时间点与血压呈负相关 (P <0 0 1)。结论　随着高血压发生和发展 ,血浆NO升高 ,而在高血压后期 ,NO的变化不明显 ,这种变化可能与高血压的发生发展有关。     

Activities of hypothalamic angiotensin II-sensitive neurons are greately enhanced even in prehypertensive spontaneously hypertensive rats

We have previously demonstrated that some neurons in the anterior hypothalamic area (AHA) of rats are tonically activated by endogenous angiotensins and that reactivities of these neurons to angiotensin II are enhanced in 15- to 16-week-old spontaneously hypertensive rats (SHR). To investigate whether the enhanced reactivity of SHR AHA neurons to angiotensin II is secondary to raised blood pressure, we examined whether the enhanced reactivity to angiotensin II also occurs in prehypertensive SHR. We also examined whether reactivities of AHA angiotensin II-sensitive neurons to intracerebroventricular hypertonic saline are enhanced in prehypertensive SHR, since intracerebroventricular injection of hypertonic saline increases the firing rate of AHA neurons via release of angiotensins at AHA neuron levels. Male 4-week-old SHR and age-matched Wistar Kyoto rats (WKY) were used in this study. There was no difference in systolic blood pressure between both rats. They were anesthetized and artificially ventilated. Extracellular potentials were recorded from single neurons in the AHA. Pressure application of angiotensin II onto some AHA neurons increased their firing rate. The basal firing rate of angiotensin II-sensitive neurons was increased in SHR as compared with WKY. The increase of unit firing by angiotenisn II was enhanced in SHR as compared with WKY. Intracerebroventricular injection of hypertonic saline increased the firing rate of AHA angiotensin II-sensitive neurons. The average threshold sodium concentration for the saline-induced increase of neural firing was lower in SHR than in WKY. These findings demonstrate that basal activities and responsiveness to angiotensin II in AHA angiotensin II-sensitive neurons are enhanced in prehypertensive SHR as compared with age-matched WKY. In addition, these findings indicate that central saline-induced activation of AHA angiotensin II-sensitive neurons is also enhanced in SHR. It appears that the enhanced reactivity of SHR AHA neurons to angiotensin II occurs primarily in nature but not secondarily to raised blood pressure in SHR.     

Influence of circadian time, ageing, and hypertension on the urinary excretion of nitric oxide metabolites in rats

Urinary excretion of NO metabolites (NOx) was measured in male spontaneously hypertensive rats (SHR) and their normotensive Wistar-Kyoto controls (WKY) in two age groups: young (11 weeks) and old (58 weeks). Urine was collected every 6 h throughout 24 h with and without injection interperitoneally of N(G)-nitro-L-arginine-methyl-ester (L-NAME), 30 mg/kg, at 7:00 or 19:00 h. In addition, blood pressure changes by L-NAME were evaluated using radiotelemetry. In both strains of rats, injection of L-NAME abolished almost completely the urinary excretion of NOx, indicating that urinary NOx indeed reflect the endogenous rate of NO synthesis. Time-dependent variation in urinary NOx excretion was observed in WKY rats of both ages (analysis of variance, P<0.05), with higher excretion in the dark period. In SHR rats, time-dependent variation in NOx excretion was lost, and the overall amount of NOx excreted within 24 h was significantly lower in young SHR than in age-matched WKY rats. Moreover, blood pressure increases by L-NAME were significantly smaller in SHR than in WKY rats. In old rats of both strains, NOx excretion was reduced, and the difference between the strains disappeared. Our findings demonstrate that ageing is accompanied by a loss in NOx excretion, and suggest that hypertension in SHR leads to a reduction in NO synthesis already at young age.     

The spontaneously hypertensive rat's preference for salted foods

Sprague-Dawley rats drink mild salt (NaCl) solutions in preference to plain water. In contrast, rats of this strain are less likely to show preferences when salt is tested in food. Others have established that rats of the spontaneously hypertensive strain (SHR) have greater preferences for salt water than do their normotensive counterparts (WKY). The question addressed in the present research was whether SHR rats would show an enhanced salted food preference when compared with WKY rats. SHR and WKY rats were given choices between a variety of salted and unsalted foods. When tested with potato chips, no major strain differences in salt preferences were observed; depending on concentrations, rats ate either equal amounts of salted and unsalted chips or avoided salted chips. However, when tested with liquid milk products (heavy cream and half & half), SHR rats showed both higher salt preferences and consumed more salt. The SHR actually preferred these products salted, whereas the WKY rats, like Sprague-Dawley rats, never ate more salted milk than plain milk. When tested with skim milk, SHR and WKY did not differ; both preferred the milk salted. In order to test the effect of physical state (or texture) upon salt preference, the skim milk was gelled. Salt preferences of the SHR rats fell to 50% whereas the salt preferences of the WKY rats remained unchanged.