Blood-brain barrier disruption in the hypothalamus of young adult spontaneously hypertensive rats

Vascular permeability and endothelial glycocalyx were examined in young adult spontaneously hypertensive rats (SHR), stroke-prone SHR (SHRSP), and Wistar Kyoto rats (WKY) as a control, in order to determine earlier changes in the blood-brain barrier (BBB) in the hypothalamus in chronic hypertension. These rats were injected with horseradish peroxidase (HRP) as an indicator of vascular permeability. Brain slices were developed with a chromogen and further examined with cationized ferritin, a marker for evaluating glycocalyx. Staining for HRP was seen around vessels in the hypothalamus of SHR and SHRSP, but was scarce in WKY. The reaction product of HRP appeared in the abluminal pits of endothelial cells and within the basal lamina of arterioles, showing increased vascular permeability in the hypothalamus of SHR and SHRSP, whereas there were no leaky vessels in the frontal cortex of SHR and SHRSP, or in both areas of WKY. The number of cationized ferritin particles binding to the capillary endothelial cells was decreased in the hypothalamus of SHR and SHRSP, while the number decreased in the frontal cortex of SHRSP, compared with those in WKY. Cationized ferritin binding was preserved in some leaky arterioles, while it was scarce or disappeared in other leaky vessels. These findings suggest that BBB disruption occurs in the hypothalamus of 3-month-old SHR and SHRSP, and that endothelial glycocalyx is markedly damaged there without a close relationship to the early changes in the BBB.     

The free fatty acid pattern in blood serum in young spontaneously hypertensive rats

An investigation on the free fatty acid (FFA) profile in blood serum, using liquid gas chromatography, has been carried out on young (8-9 week-old) spontaneously hypertensive rats (SHR). A significative increase in the level of unsaturated FFA was found in SHR in comparison to their controls. The deviations in the composition of the FFA spectrum found were elevation of the polyunsaturated fatty acids: hexadecanoic acid (C16:2), linoleic acid (C18:2), linolenic acid (C18:3), eicosadienoic acid (C20:2), eicosatrienoic acid (C20:3), eicosapentaenoic acid (C20:5). The differences between FFA profile in SHR and control group can reflect genetically controlled variables.     

Sexual dimorphism in the renin-angiotensin system in aging spontaneously hypertensive rats

In young adult spontaneously hypertensive rats (SHR), mean arterial pressure (MAP) is higher in males than in females and inhibition of the renin-angiotensin system (RAS) eliminates this sex difference. After cessation of estrous cycling in female SHR, MAP is similar to that in male SHR. The purpose of this study was to determine the role of the RAS in maintenance of hypertension in aging male and female SHR. At 16 mo of age, MAP was similar in male and female SHR (183+/-5 vs. 193+/-8 mmHg), and chronic losartan (40 mg.kg-1.day-1 po for 3 wk) reduced MAP by 52% (to 90+/-8 mmHg, P<0.05 vs. control) in males and 37% (to 123+/-11 mmHg, P<0.05 vs. control) in females (P<0.05, females vs. males). The effect of losartan on angiotensin type 1 (AT1) receptor blockade was similar: MAP responses to acute doses of ANG II (62.5-250 ng/kg) were blocked to a similar extent in losartan-treated males and females. F2-isoprostane excretion was reduced with losartan more in males than in females. There were no sex differences in plasma renin activity, plasma angiotensinogen or ANG II, or renal expression of AT1 receptors, angiotensin-converting enzyme, or renin. However, renal angiotensinogen mRNA and protein expression was higher in old males than females, whereas renal ANG II was higher in old females than males. The data show that, in aging SHR, when blood pressures are similar, there remains a sexual dimorphism in the response to AT1 receptor antagonism, and the differences may involve sex differences in mechanisms responsible for oxidative stress with aging.     

Chronic hydralazine treatment alters the acute pressure-natriuresis curve in young spontaneously hypertensive rats

The pressure-natriuresis relationship was studied in anesthetized, 7- to 9-week-old control spontaneously hypertensive rats (SHR) and in SHR that had been treated with hydralazine (20 mg.kg-1.day-1 in drinking water) starting at 4-5 weeks of age. To minimize reflex changes in kidney function during changes in renal artery pressure, neural and hormonal influences on the kidney were fixed by surgical renal denervation, adrenalectomy, and infusion of a hormone cocktail (330 microL.kg-1.mikn-1) containing high levels of aldosterone, arginine vasopressin, hydrocortisone, and norepinephrine dissolved in 0.9% NaCl containing 1% albumin. Changes in renal function were measured using standard clearance techniques, while renal artery pressure was varied between 136 +/- 1 and 186 +/- 2 mmHg (1 mmHg = 133.32 Pa) in control SHR (n = 10) and between 113 +/- 1 and 162 +/- 2 mmHg in treated SHR (n = 11). Mean arterial pressure (+/- SE) under Inactin anesthesia was 172 +/- 3 mmHg in control SHR and 146 +/- 3 mmHg in treated SHR (p less than 0.05). Where renal artery pressure overlapped between groups, there were no significant differences in glomerular filtration rate. Renal blood flow was also similar in both groups, although at 160 mmHg blood flow was slightly but significantly reduced in treated SHR. Urine flow and total and fractional sodium excretion increased similarly with increases in renal artery pressure in both groups, but the pressure-natriuresis curve in hydralazine-treated SHR was displaced to the left along the pressure axis. The data indicate that chronic administration of hydralazine in young SHR enhances fractional sodium excretion, suggesting that tubular reabsorption of sodium is decreased by hydralazine.     

Calpastatin level in spontaneously hypertensive rats

We studied calpastatin activity in erythrocytes of Milan hypertensive and prehypertensive rats, in their normotensive controls, in F1 and F2 hybrids, and in two inbred strains derived from F2, one hypertensive and the other normotensive. Our results show that the decrease in calpastatin activity observed in Milan hypertensive rats was not caused by hypertension, it was transmitted in a recessive way in heterozygous, and it was not correlated to hypertension.     

Interval bisection in spontaneously hypertensive rats

An interval bisection procedure was used to study time discrimination in spontaneously hypertensive rats (SHR), which have been proposed as an animal model for the attention deficit hyperactivity disorder (ADHD); Wistar Kyoto and Wistar rats were used as comparison groups. In this procedure, after subjects learn to make one response (S) following a short duration stimulus, and another (L) following a long duration stimulus, stimuli of intermediate durations are presented, and the percentage of L is calculated for each duration. A logistic function is fitted to these data, and different parameters that describe the time discrimination process are obtained. Four conditions, with different short and long durations (1-4, 2-8, 3-12, 4-16s) were used. The results indicate that time discrimination is not altered in SHR, given that no difference in any of the parameters obtained were significant. Given that temporal processing has been proposed as a fundamental factor in the development of the main symptoms of ADHD, and that deficits in time discrimination have been found in individuals with that disorder, the present results suggest the necessity of exploring time perception in SHR with other procedures and sensory modalities, in order to assess its validity as an animal model of ADHD.     

Tissue catecholamine concentrations in spontaneously hypertensive rats

Tissue concentrations of noradrenaline (NA), dopamine (DA) and adrenaline (A) were compared in spontaneously hypertensive (SHR) and normotensive (NCR) rats, aged 1, 3, 8, 14 and 24 weeks The organs analyzed included the brain, subdivided into prosencephalon and rhombencephalon, heart, adrenal glands and kidney. Brain catecholamines were significantly lower in SHR than in NCR, and the difference appeared already at the age of 3 weeks. Concomitant increase was found in the adrenal NA and A concentrations of the SHR. Concentration of NA in the heart decreased in the SHR following onset of hypertension. It is concluded that the diminished NA, DA and A concentrations in the brain as well as the augmented adrenal NA and A levels in the SHR may be causally related to the development of hypertension, while the heart NA level reflects the secondary, hypertension -- related changes.     

Intact hindquarter vascular responses of young spontaneously hypertensive rats to norepinephrine and tyramine

Intact hindquarter vascular responses to abdominal aortic injections of subpressor doses of norepinephrine (0.01, 0.02, 0.03 μg) or tyramine (5, 10, 15 μg) were examined in young ($\text{2}\text{1}\text{2}\text{–3}\text{months}$) spontaneously hypertensive rats (SHR) and age-matched Wistar-Kyoto (WKY) normotensives to ascertain whether altered vascular response to catecholamines in SHR could be detected in the presence of relatively constant systemic arterial perfusion pressure. Increases in vascular resistance (Δ mmHg. min/ml) and total decreases in blood flow volume (Δ ml) were determined by using electromagnetic flowmetry and blood flow integration techniques. Under a resting condition the abdominal aortic flow rate (ml/min) was similar between the SHR (8.7 ± 0.5) and WKY control (9.1 ± 0.5), whereas hindquarter vascular resistance was greater (73.8%) in SHR than in WKY normotensives (P < 0.05). The increase in vascular resistance in response to a low dose of norepinephrine (0.1 μg) was greater (85%) in SHR than in WKY rats (P < 0.05) and at higher doses of norepinephrine (0.02, 0.03 μg) there was a tendency of greater increase in resistance (20–30%) in SHR (0.05 < P < 0.1). Tyramine at all doses tested produced greater increases (50–66%) in resistance in SHR compared to WKY normotensives (P < 0.05). On the other hand, the decreases in the integrated total blood flow volume passing to the hindquarters after norepinephrine or tyramine administration at all doses were less (27–46%) in SHR than in WKY control (P < 0.05). The data demonstrate increased catecholamine vasoconstrictor responses in the intact hindquarters of SHR with attenuated blood flow volume decreases due to the higher resting vascular resistance, supporting the contention that the elevated vascular resistance in SHR may be attributed to vasoconstrictor hyperresponsiveness of catecholamines.     

Angiotensin stimulates respiration in spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) have an activated brain angiotensin system. We hypothesized 1) that ventilation (V) would be greater in conscious SHR than in control Wistar-Kyoto (WKY) rats and 2) that intravenous infusion of the ANG II-receptor blocker saralasin would depress respiration in SHR, but not in WKY. Respiration and oxygen consumption (VO(2)) were measured in conscious aged-matched groups (n = 16) of adult female SHR and WKY. For protocol 1, rats were habituated to a plethysmograph and measurements obtained over 60-75 min. After installation of chronic intravenous catheters, protocol 2 consisted of 30 min of saline infusion ( approximately 14 microliter. kg(-1). min(-1)) followed by 40 min of saralasin (1.3 microgram. kg(-1). min(-1)). V, tidal volume (VT), inspiratory flow [VT/inspiratory time (TI)], breath expiratory time, and VO(2) were higher, and breath TI was lower in "continuously quiet" SHR. In SHR, but not in WKY rats, ANG II-receptor block decreased V, VT, and VT/TI and increased breath TI. During ANG II-receptor block, an average decrease in VO(2) in SHR was not significant. About one-half of the higher V in SHR appears to be accounted for by an ANG II mechanism acting either via peripheral arterial receptors or circumventricular organs.     

G-proteins in kidneys of spontaneously hypertensive rats

G(s alpha)-, total G(i alpha)- and G(q/11alpha)-protein concentrations were investigated by quantitative immunoblotting in membranes of total kidney, renal cortex and medulla as well as in cortical tubules and glomeruli of Spontaneously Hypertensive Rats (SHR) and normotensive Wistar Kyoto rats (WKY), aged 5 weeks, 3 or 8 months. We found that total kidney of 5 week old SHR possess less G(s alpha)-, G(i alpha)- and G(q/11alpha)-proteins than controls. For G(s alpha)-proteins, differences found in total kidney were mirrored both in cortex (tubules and glomeruli) and in medulla. Decreased G(i alpha)-concentrations were accompanied by lower tubular but higher glomerular levels, while medullar levels were also increased. Decreased G(q/11alpha)-concentrations were reflected in decreased glomerular and medullary concentrations. Kidneys of 3 month old SHR and WKY possessed similar concentrations of all G(alpha)-species. In 8 month old SHR similar G(i alpha)-, but decreased G(s alpha)-and G(q/11alpha)-concentrations were observed. The G(s alpha)-decrease was reflected in cortex and medulla, the G(q/11alpha)-decrease in the medulla. We conclude that the main strain-related differences in G(alpha)-concentrations are seen in prehypertensive SHR.     

Impaired angiotensin-induced drinking in spontaneously hypertensive rats

The drinking response during the 30 minutes following intracerebroventricular injection of angiotensin II (AII) (1 to 200 ng) was compared in male spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto control rats (WK). SHR drank significantly less than WK at the 10, 50 and 100 ng doses. In contrast, responses to intracerebroventricular carbachol and intraperitoneal hypertonic saline were not different between SHR and WK. These agents are believed to induce drinking by mechanisms independent of angiotensin. Binding of I¹²⁵-labelled AII to particles prepared from the hypothalamus, thalamus, septum and midbrain (HTSM) region was measured in one month old male and two month old female SHR and their respective age matched WK controls. No differences were found in binding between SHR and WK of either sex. These data demonstrate an impairment of drinking responses in the SHR which seem to be specific for angiotensin. This finding supports the hypothesis that the CNS angiotensin system might be abnormal in these animals.     

Renal microvasculature in spontaneously hypertensive rats.

The renal microvasculature was studied in normotensive rats and in rats with spontaneous hypertension. The microvascular pattern was normal in both groups of animals, suggesting normal renin secretion. This may or may not indicate a role for renin in the cause of spontaneous hypertension.     

Decrease in urinary excretion of active kallikrein in conscious young and adult spontaneously hypertensive rats

Urinary excretion of active kallikrein was determined every day (amidolytic assay) in 6 male Okamoto-Aoki spontaneously hypertensive rats (SHR) and 6 male normotensive Wistar-Kyoto rats (WKY) from ages 4 to 7 weeks and from 12 to 15 weeks. The rats were housed in individual metabolic cages and were allowed free access to food having normal sodium content and to tap water. Urinary kallikrein excretion was lower in 4-week-old SHR than in age-matched WKY (7.8 +/- 1.4 vs. 15.5 +/- 2.3 nkat/24 h respectively, P less than 0.01) at a moment when systolic blood pressure (BP) in SHR was already higher than in WKY. The slope of the increase in active kallikrein excretion from week 4 to 7 was not different for SHR and WKY (6.34 +/- 1.05 vs. 7.50 +/- 1.02 nkat/24 h-1 . wk-1 respectively). In contrast, from week 12 to 15, this slope was not significant for SHR (1.67 +/- 2.55 nkat/24 h-1 . wk-1) while it remained positive in WKY (7.36 +/- 3,44 nkat/24 h-1 . wk-1). In both SHR and WKY, urinary kallikrein excretion was directly related to BP from week 4 to 7 but the slope of the regression line was less for SHR than for WKY (0.19 +/- 0.05 vs. 0.48 +/- 0.12 nkat/24 h-1 . mm Hg respectively). From ages 12 to 15 weeks, kallikrein excretion was still related to pressure in WKY (y = 1.92 x - 180.8; r = 0.93) but not in SHR (y = 0.71 x - 81.48; r = 0.52).(ABSTRACT TRUNCATED AT 250 WORDS)     

Breathing pattern of spontaneously hypertensive rats

The trachea of rats anaesthetized with sodium pentobarbitone was cannulated and the air flow velocity and the pressure of the oesophagus were measured. In the spontaneously hypertensive rats the breathing frequency was higher, the tidal volume and the effective lung resistance were smaller than that of the normotensive Wistar rats. It seems that the neurohumoral control of respiration in SHR animals differs from that of normotensive rats.     

Plasma concentrations of endothelin-1 in spontaneously hypertensive rats and DOCA-salt hypertensive rats

To investigate the possible involvement of endothelin-1 (ET-1), an endothelium-derived potent vasoconstrictor peptide, in the pathophysiology of hypertension, plasma ET-1 levels in 15-week-old spontaneously hypertensive rats (SHR) and DOCA-salt hypertensive rats were measured with a sandwich-type enzyme immunoassay. The vasocontractile effect of ET-1 in aortic helical preparations was significantly more sensitive in DOCA-salt hypertensive rats than in control sham-operated rats, but plasma levels of ET-1 did not differ between them. Plasma ET-1 levels in genetically hypertensive rats (SHR and stroke-prone SHR) were significantly lower than those in age-matched normotensive Wistar-Kyoto (WKY) rats. The plasma concentrations of big ET-1, a precursor of ET-1, in both SHR and SHR-SP were significantly lower than those of WKY, suggesting that the production of ET-1 is decreased in rats of genetic hypertension. Although the vascular reactivity to ET-1 increased in both DOCA-salt hypertensive and genetically hypertensive rats, present findings of the plasma ET-1 levels suggest that the role of ET-1 in the vascular control system may be different in DOCA-salt hypertensive rats and genetically hypertensive rats.     

自发性高血压大鼠多组织炎症状态

高血压是一种慢性血管性疾病,易累及肾、肝、心、脑等组织,引起脑卒中和心、肾损害等并发症.本研究对高血压时肾、肝、心、脑等组织的炎症状态进行了观察.实验采用自发性高血压大鼠(spontaneously hypertensive rat,SHR)和正常血压的Wistar-Kyoto(WKY)大鼠,用RT-PCR和Western blot法观察肾、肝、心、脑等组织炎症相关因子IL-1p、TNFα、ICAM-1、iNOS、C/EBPδ和PPARγ的基因表达;紫外分光光度法观察蛋白质羰基化水平和FRAP法检测组织总抗氧化能力.结果显示(1)SHR组织炎症相关因子表达较对照WKY增强,除IL-1βmRNA在肝和脑的增加不明显外,其余均有显著性差异(P＜0.05);(2)SHR和WKY大鼠肾、心、脑蛋白质羰基化水平(nmol/mg蛋白)分别为8.93±1.08和2.27±0.43、2.23±0.23和0.17±0.02、13.42±1.10和5.72±1.01,SHR明显增加(P＜0.05);而肝脏蛋白质羰基化水平无明显变化;(3)SHR肾、肝、心、脑总抗氧化能力水平显著低于WKY大鼠(P＜0.05).以上结果表明,SHR多个组织(肾、肝、心和脑)均存在炎症因子被诱导和氧化应激反应等明显的炎症状态,提示炎症可能在高血压及其并发症的病理改变中起重要作用.     

Pressor responsiveness to vasopressin in spontaneously hypertensive rats

The present study was designed to find out whether pressor responsiveness to vasopressin (AVP) is altered in spontaneously hypertensive rats (SHR) in comparison with their normotensive controls (WKY). Blood pressure and heart rate changes after injection of graded doses of 2.5, 5.0 and 10.0 ng of AVP (Calbiochem) i.v. were compared in 9 conscious, unrestrained spontaneously hypertensive (SHR) and 11 normotensive Wistar Kyoto (WKY) rats, chronically instrumented with venous and arterial catheters. The threshold dose necessary to elicit a significant increase in blood pressure and reduction of heart rate was lower in WKY than in SHR. At each dose level the blood pressure elevation persisted for a longer period in WKY than in SHR. Bradycardia was greater in WKY than in SHR both in absolute terms and in relation to the blood pressure increase. Thus, the results reveal diminished pressor responsiveness to moderate doses of AVP in SHR in spite of suppressed reflex bradycardia. It is suggested that the peripheral action of AVP on the vascular system is attenuated in SHR.