Inhibition of the cysteamine-induced gastric ulcer by the sympathoadrenal medullary system in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY)]

We previously reported that cysteamine induces severe gastric ulcers in WKY, but very mild in SHR. The aim of this study is to elucidate the role on the sympathoadrenal medullary system in the pathogenesis of the cysteamine-induced gastric ulcer. Catecholamine (CA) contents in the stomach and adrenal gland were significantly higher in the non-treated SHR than in the non-treated WKY, suggesting that the sympathetic nervous system is more facilitated in SHR. Cysteamine decreased the noradrenaline and adrenaline contents in these tissues in both strains, however the values of CA was still higher in the treated SHR than the non-treated WKY. Histologically the adrenal medulla was severely damaged by cysteamine administration in WKY than in SHR. In contrast an immunohistological study revealed that chromogranin reactivity of the adrenal medulla was significantly stronger in the treated SHR than in the treated WKY. The celiac plexus was well preserved morphologically even in the cysteamine treatment in both strains. These results suggest that the capacity of the sympathetic nervous system in both the adrenal medulla and the stomach plays an important role in preventing the cysteamine-induced gastric ulcer in SHR.     

The concentration of neuropeptide Y immunoreactivity falls with age selectively in microdissected regions of the ventrolateral medulla of spontaneously hypertensive and normotensive Wistar-Kyoto rats

The concentrations of neuropeptide Y immunoreactivity were measured in microdissected regions enriched in noradrenergic (A1, A2, A6) and adrenergic (C1, C2, C3) nuclei of the brainstem, and in the nucleus of the spinal tract of the trigeminal nerve (Sp5C) of spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at 8, 18 and 31 weeks of age. The aim of this study was to compare the manner in which changes in neuropeptide Y immunoreactivity levels related to increases in blood pressure with ageing in each rat strain. The concentration of neuropeptide Y immunoreactivity in the A1 nucleus progressively fell with increasing age in both SHR and WKY. In contrast, the levels of neuropeptide Y immunoreactivity in the C1 region fell at 18 weeks of age but did not fall further by 31 weeks. No significant age-related changes occurred in the concentrations of neuropeptide Y immunoreactivity in the A2, C2, A6 and Sp5C nucleus. The levels of neuropeptide Y immunoreactivity in the C3 region were below assay sensitivity. The neurochemical changes that occur in the A1 nucleus are consistent with the increase in blood pressure observed with ageing in both rat strains. However, this observation alone does not account for the elevated blood pressure measured in the SHR strain.     

Effects of haemorrhagic hypotension on brain and liver metabolism in normotensive (WKY) and spontaneously hypertensive rats (SHR)

Hypertensive disease is known to increase the risks in connection with acute changes in blood pressure due to the presence of pronounced structural as well as functional changes in the cardiovascular system. In the present study the metabolic consequences of fixed haemorrhagic hypotension [mean arterial pressure (MAP) 70 and 45 mmHg] were studied in spontaneously hypertensive (SHR) and in normotensive rats (WKY). Blood gases and acid-base balance, blood glucose, liver (ATP, glucose, lactate) and brain (ATP, ADP, AMP, CP, glucose, lactate) metabolites were determined in unbled animals and after 35 min hypotension in bled animals. In the liver haemorrhage to MAP 70 mmHg resulted in a 70% reduction of the ATP content in SHR while that in WKY remained unchanged. At MAP 45 mmHg reduced liver ATP levels (35% reduction) were observed in WKY as well. In the brain metabolic changes indicative of tissue ischaemia (reduced CP, increased AMP and lactate, decreased energy charge potential) were present only in SHR at MAP 45 mmHg. The more pronounced metabolic disturbances in SHR than in WKY indicate that blood loss is more deleterious for the hypertensive individual.     

An examination of the arterial media in transplanted arteries of spontaneously hypertensive (SHR) and normotensive Wistar Kyoto rats (WKY)

The hypothesis that arterial medial hypertrophy occurs in the SHR due to genetic factors inherent to the arterial wall, was examined in jejunal arteries cross transplanted between four-week-old SHR and WKY rats as a shunt between the femoral artery and vein. Four weeks after transplant, the arteries were removed and processed for embedding in resin and measurement of wall parameters by light microscopy. It was determined that irrespective of the origin of the transplanted artery, the wall thickness of transplants was higher in SHR hosts than in WKY hosts. Taken with results from other studies, this suggests that genetic factors inherent to the arterial wall are not the cause of arterial hypertrophy in the SHR.     

Effect of lisinopril on tissue levels of neuropeptide Y in normotensive and spontaneously hypertensive rats

Angiotensin-converting enzyme (ACE) inhibitors reduce systemic and coronary vasoconstriction by modulating sympathetic neuroeffector function and by decreasing sympathetic activation. Here, blood pressure, and tissue concentrations of noradrenaline and neuropeptide Y (NPY) were studied in normotensive and spontaneously hypertensive rats (SHR) after 2 weeks treatment with lisinopril (0.3 mg/day; osmotic mini-pump). MAP was reduced in both normotensive rats and SHR after lisinopril by 32 mm Hg and 66 mm Hg respectively (P < 0.001 compared to corresponding control rats). NPY levels were significantly higher in extracts of atria, kidney, spleen and adrenal of normotensive rats compared to SHR. Lisinopril treatment increased NPY levels in atria and skeletal muscle extracts of SHR by 15% and 70% respectively (P < 0.05). Lisinopril also significantly increased noradrenaline content of the atria by 16% in SHR (P < 0. 05). The decrease in MAP and increase in tissue levels of sympathetic neurotransmitters provide further evidence that inhibition of ACE decreases sympathetic neurotransmission leading to accumulation of stored neurotransmitters. Journal of Human Hypertension (2000) 14, 381-384     

Enhanced neuropeptide Y immunoreactivity and vasoconstriction in mesenteric small arteries from spontaneously hypertensive rats

Enhanced sympathetic nerve activity is thought to play a role in the pathogenesis of hypertension. The purpose of the present study was to investigate the mechanisms underlying the enhanced vasocontractile response to perivascular stimulation of mesenteric arteries isolated from female spontaneously hypertensive rats (SHR). Innervation of mesenteric small arteries was evaluated by immunohistochemistry and confocal microscopy while functional studies were conducted in a microvascular myograph. The distribution of nerve terminals immunoreactive for tyrosine hydroxylase (TH) and neuropeptide Y (NPY) was similar in mesenteric small arteries from Wistar-Kyoto (WKY) and SHR rats. However, immunointensity of TH or NPY immunoreactivities were much higher in small arteries from SHR compared to WKY. Expressed as percentage of contractions elicited by 124 mM K(+), concentration-response curves for noradrenaline (NA) and NPY were shifted leftward in SHR compared with WKY rats. The combination of noradrenaline (1 microM) and NPY (10 nM) contracted mesenteric arteries from WKY and SHR to higher levels than compared to either contractile agent added alone. The NPY Y(1) receptor antagonist, BIBP 3226, inhibited these contractions with 87 +/- 0.7 and 80 +/- 1.3% (p < 0.05, n = 6) in arteries from WKY and SHR rats, respectively. In arteries incubated with the alpha(1)-adrenoceptor antagonist, prazosin, and preactivated with vasopressin, electrical field stimulation evoked contractions which were more pronounced in mesenteric arteries from SHR compared to WKY rats. BIBP 3226 partially inhibited these contractions. In vasopressin-activated arteries BIBP 3226 caused rightward shifts of the concentration-response curves for NPY in mesenteric arteries from SHR rats, but in addition it also abolished the maximal NPY contraction in arteries from WKY rats. In the presence of BIBP 3226, low concentrations (1 pM to 10 nM) of NPY caused relaxations in arteries from WKY, but not in segments from SHR rats. Mechanical removal of the endothelium abolished NPY relaxation in arteries from WKY. In arteries activated with vasopressin and exposed to either forskolin or sodium nitroprusside, the addition of NPY evoked contractions which were more pronounced in arteries from SHR compared to WKY arteries. The present study suggests that enhanced NPY content and vasoconstriction to NPY in arteries from hypertensive rats can contribute to the enhanced sympathetic nerve activity and vascular resistance in female hypertensive rats. Endothelial cell dysfunction as well as alterations in smooth muscle response to NPY seem to contribute to the enhanced vasoconstriction in arteries from hypertensive animals.     

Platelet neuropeptide Y in spontaneously hypertensive rats.

OBJECTIVE: To investigate the pathological role of platelet neuropeptide Y (NPY) in genetically hypertensive rats, we measured the platelet content and plasma concentration of immunoreactive (ir)-NPY in hypertensive and normotensive rats and examined the aggregating ability of rat platelets and the NPY releasing reaction in each of these rat types. In addition, we purified platelet NPY and determined its amino acid sequence. DESIGN AND METHODS: To characterize immunoreactive NPY in rat platelets, rat platelet NPY was purified to homogeneity and the purified peptide was analysed by gas-phase sequencer. Platelet content and plasma concentration of NPY was measured by a sensitive radioimmunoassay for NPY. Aggregating ability was examined by a turbidimetric method; aggregation was recorded for 5 min and the maximum aggregation was read. RESULTS: Rat platelet NPY was purified and the amino acid sequence was determined to be YPSKPDNPGEDAPAEDMARYYSALRHYINLITRQRY. The platelet content of ir-NPY in 5-, 10-, and 15-week-old spontaneously hypertensive rats (SHR) was higher than that in Wistar-Kyoto (WKY) rats of the same age. The platelet content of ir-NPY in 10-week-old stroke prone-SHR was also higher than that in 10-week-old WKY rats. No differences were observed between any of the pairs in any WKY rats, SHR or stroke-prone SHR group with regard to the plasma concentration of ir-NPY. Ir-NPY was not released from rat platelets when adenosine diphosphate was used for aggregation. However, NPY was released from the platelets when they were aggregated by collagen and, furthermore, in this case the amount of NPY released from platelets was greater in SHR than in WKY rats. CONCLUSION: That the platelet content of NPY in SHR (and stroke-prone SHR) was higher than that in WKY rats seems to be an important genetic characteristic of SHR. As NPY is a potent vasoconstrictor, it may be involved in the progression of vascular lesions.     

Immediate and prolonged hemodynamic effects of TA-3090 on spontaneously hypertensive [SHR] and normal Wistar-Kyoto [WKY] rats

Summary Systemic and regional hemodynamic effects of the new effects of the new calcium antagonist TA-3090, a benzothiazepine derivative that is similar to diltiazem, were studied both acutely (0.3 and 0.6 mg/kg IV) and chronically (30 mg/kg by once-daily gastric gavage for 3 weeks) in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats. All hemodynamic data were obtained in the conscious state using the reference sample radio-microsphere method. Mean arterial pressure was reduced significantly by both immediate and long-term treatment in both rat strains. Stroke index remained unchanged in each study group, but the heart rate of the SHR and WKY decreased and increased, respectively, with the higher dose in the intravenous aspect of this study. As a result, total peripheral resistance decreased significantly in all groups, normotensive or hypertensive, although this fall was not distributed uniformly throughout the body. Intrarenal hemodynamics revealed significant differences between SHR and WKY by prolonged treatment with TA-3090. Efferent as well as afferent glomerular arteriolar resistances decreased and therefore calculated glomerular capillary hydrostatic pressure decreased in SHR; however, efferent glomerular arteriolar resistance and glomerular pressure remained unchanged in WKY. By contrast, in the acute study, no such differences were obtained. Further, 3 weeks' treatment did not alter cardiac mass in either rat strain. Thus, TA-3090 decreased arterial pressure through a fall in total peripheral resistance without major cardiac effects in both rats strains. In contrast, the agent reduced vascular resistances only in the SHR; and this was achieved with dilation of both the afferent and efferent glomerular arterioles. These latter changes may be beneficial in the hypertensive state since glomerular hyperfiltration may be reduced, thereby providing a beneficial protective effect on the glomeruli.     

Regional brain concentrations of calcitonin gene-related peptide in spontaneously hypertensive and normotensive Wistar-Kyoto rats

The regional brain and spinal cord concentrations of calcitonin gene-related peptide (CGRP) were measured in age-matched (22-23-week-old) spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The highest concentration of CGRP in the WKY rats was in the spinal cord (172 +/- 9 pmol/g), followed by the medulla oblongata/pons (88 +/- 5 pmol/g). The relative order of distribution in the remaining regions was: hypothalamus (12.6 +/- 0.8 pmol/g) = striatum greater than thalamus greater than midbrain = hippocampus greater than cortex (2.1 +/- 0.3 pmol/g). The concentration of CGRP in the cerebellum was at the level of the assay's sensitivity (0.5 pmol/g). The relative order of distribution in the SHR strain was essentially the same. However, in comparison with the WKY rats, the SHR had significantly lower levels of CGRP in the hippocampus (-47%), striatum (-49%) and medulla oblongata/pons (-24%), and in the spinal cord (-24%). In younger age-matched (16-17-week-old) rats, the spinal cord and medulla oblongata/pons concentrations of CGRP were also lower in SHR than in WKY rats. CGRP is a putative neurotransmitter which, when administered centrally or peripherally, has potent cardiovascular effects. The reduced levels of this peptide may be an important factor in the cardiovascular and/or behavioural abnormalities of the SHR strain.     

Dexamethasone suppression of cushingoid degenerative changes in obese spontaneously hypertensive rats (SHR)

Male and female, young (2 months old) and mature (10 months old), obese and nonobese, spontaneously hypertensive rats (SHR) were treated with dexamethasone, 5 micrograms/rat and 10 micrograms/rat, respectively, subcutaneously (SC) 2 times daily for 5 months. Steroid treatment stilled the voracious appetite of the obese SHR, and the massively obese, mature animals were reduced to almost normal size. The young, steroid-treated, obese SHR did not develop their genetically programmed corpulency. The untreated, young and mature, obese SHR ate voraciously, became massively obese, and developed their characteristic Cushing's disease-like spectrum of degenerative changes, eg, hypertension, hyperlipidemia, hyperglycemia, muscle wasting, kidney stones, thin skin, and accelerated aging. The blood pressure of the steroid-treated animals was lowered concomitant with reduced levels of circulating ACTH, beta endorphin, insulin, triglycerides, and cholesterol. Dexamethasone caused hyperlipidemia, hyperglycemia, and increased BUN levels in young obese and nonobese SHR only. The mature obese SHR had giant-sized thymus glands that were further enlarged with steroid treatment; dexamethasone was thymolytic in young, obese and nonobese SHR. Dexamethasone caused severe reduction of pituitary and adrenal gland size, simulating the condition of hypophysectomy. These findings demonstrate that dexamethasone suppression of the pituitary-adrenal axis palliates and prevents the spontaneous development of Cushingoid degenerative changes in these genetically obese and hypertensive rats.     

Tunica media changes in the spontaneously hypertensive rat (SHR)

The histological, ultrastructural, morphometrical and histochemical aspects of the arterial media were studied in young and aged SHR, and compared to normotensive Wistar Kyoto rats. The diffuse thickening was the most characteristic feature of the hypertensive media. It seems due to three processes: Early generalized hypertrophy of smooth muscle cells (smc); connective matrix neogenesis and smc proliferation, more evident in peripheral vasculature. The present paper discusses the following hypertensive tunica media changes in relation to the atherosclerotic process: the decrease in lipolytic esterase and cholinesterase activities; the activation of some lysosomal enzymes; the increase in collagen, glycosaminoglycan and elastin content; the increased media thickness; the modified smc behavior (migration, secretion, proliferation). These alterations might positively influence arterial susceptibility to atherosclerosis through reduced smc lipolytic activity; slowed transmural diffusion; perturbed efflux and aggravated media hypoxia.     

Pathogenesis of myocardial fibrosis in spontaneously hypertensive rats (SHR)

The pathomechanisms of myocardial fibrosis are incompletelyunderstood. Coronary microvessels (MV), interstitial reactionsand focal myocardial lesions characterized by morphologicalsigns of ischaemia were found in 39 spontaneous hypertensiverats (SHR) and 33 control rats aged 3, 13, 27, 52 and 78 weeks,using new morphological preparations and measuring methods.In the developing phase of spontaneous hypertension (SH) thenumerical and area densities (developed for up to 13 weeks)of MV were lower than at 3 weeks and lower than control. Thesame was true for the fibrotic tissue density. However, allvalues were increased in the manifest phase of SH (27–78weeks). The increase in interstitial tissue is topologicallyand causally related to pathological MV reactions that representmorphologically chronically increased contractions. Small MVthat mostly elude detection with conventional staining methodsare of particular importance. The first phase of manifest SH(27th–52nd week) is characterized by a generalized developmentof myocardial fibrosi the late phase (52nd–78th week)by a reinforced localized fibrosis that is attributable to theenhanced progression of focal ischaemic myocardial lesions.The septal region is not included in this phase. Thus, in thetwo phases of manifest SH, the pathomechanisms responsible forthe development of myocardial fibrosis must be different.     

Effects of high-calorie diet on blood pressure and sodium retention in spontaneously hypertensive rats and normotensive Wistar-Kyoto rats

Previous reports from our laboratory have documented that spontaneously hypertensive rats (SHR) have insulin resistance and that insulin resistance is enhanced by high-caloric diet (HCD) feeding. The aim of this study was to elucidate the effect of HCD on blood pressure and sodium retention in both SHR and normotensive Wistar-Kyoto rats (WKY). SHR and WKY were divided into two groups. One group of rats was fed normal diet (ND). The other rats were fed HCD. After the 8-week feeding period, insulin suppression tests were performed. The animals were individually housed in metabolic cages for the last 2 days of the experiment. Food consumption was recorded for 24 h, and a 24-h urine was collected to calculate the sodium excretory ratio. In both strains, body weight was significantly increased by HCD feeding. Blood pressure was significantly elevated in SHR by HCD feeding, whereas that of WKY was not affected by HCD feeding. In both strains, steady-state plasma glucose (SSPG) during the insulin suppression test was higher in the HCD group than in the ND group. SSPG was consistently higher in SHR than in WKY treated with HCD. Urinary sodium excretion ratio was significantly decreased in SHR by HCD, and plasma potassium concentrations were significantly lower in SHR with HCD than in SHR with ND, whereas those of WKY were not affected by HCD feeding. SHR are more sensitive to the induction of insulin resistance than WKY, resulting in sodium retention and elevation of blood pressure.     

环孢素A调控肾性高血压大鼠血浆神经肽Y的作用机制

目的:探讨一肾一夹肾性高血压大鼠模型中,血浆神经肽Y（NPY）含量变化调控机制。方法:健康雄性Wistar大鼠,随机分为3组。①假手术组;②高血压组:通过一肾一夹法复制肾性高血压大鼠;③环孢素A组:环孢素A（CsA）5mg·kg-1·d-1皮下注射;全部大鼠均在实验14d后,测量尾动脉压,取心脏测量左心室质量/体质量（LVW/BW）,用放免方法测定血浆NPY、血管紧张素Ⅱ（AⅡ）、醛固酮（Ald）含量。结果:高血压组较假手术组BP、LVW/BW升高,NPY下降,Ald增加;CsA组较高血压组LVW/BW降低,NPY增加,Ald无显著变化。结论:Ald对血浆NPY水平的负性调控,是通过CaN信号转导通路介导而发生的。     

Lipid metabolism in spontaneously hypertensive rats (SHR).

Plasma cholesterol was lower in spontaneously hypertensive rats (SHR), while plasma triglyceride and free fatty acid were increased in comparison with control normotensive Wistar-Kyoto (WK) rats. Correspondingly, [1-14C]-acetate incorporation into liver cholesterol was clearly decreased in SHR as compared with WK. As for lipogenic enzyme activities, glucose-6-phosphate dehydrogenase, malic enzyme and acetyl-CoA carboxylase in SHR were respectively decreased, increased and not significantly different, in comparison with WK rats. Liver cholesterol was rather low and cardiac triglyceride was slightly increased in SHR. Aortic cholesterol and triglyceride levels were not significantly different between SHR AND WK rats. Thus, SHR have an abnormality in lipid metabolism, especially in cholesterol synthesis, but the pathological implication of this in hypertension and related vascular lesions is not yet clear.     

Age-related changes in cholesterol and bile-acid metabolism in spontaneously hypertensive rats

Age-related changes in serum and liver cholesterol, phospholipid and triglyceride levels, serum lipoproteins, biliary secretion of cholesterol, phospholipids and bile acids, fecal excretion of sterols and bile acids, and the pool size of bile acids were examined in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKR). SHR showed distinct age- and sex-related changes when young and marked aged-rat hypercholesterolemia after 1 yr of age. (1) Cholesterol shifted from blood to the liver between 10 and 20 wk only in male SHR and not at all in WKR. (2) Serum lipoprotein percentages changes; α-lipoprotein decreased, pre-β-lipoprotein increased, but β-lipoprotein did not change. These changes appeared only in male SHR and after 13 to 15 wk of age. (3) Liver enlargement in SHR, although not detected at 5 to 6 wk, progressed more rapidly than in WKR, giving values almost double those in WKR after 13 to 15 wk. Liver enlargement in female SHR was much less than in the male. (4) Bile flow, biliary secretion, and the pool size of bile acids increased. However, when expressed on the basis of liver weight, these values were similar to those in WKR, suggesting that the increases were caused by the hepatomegaly. (5) Differences appeared in the bile acid composition. A large amount of β-muricholic acid was present in SHR of both sexes and the cholic acid percentage was low in male SHR. (6) Changes were observed in fecal bile acid excretion. Since the daily amounts in male SHR were similar to those in WKR, the hepatic synthesis activity (mg per day per 10 g liver) in male SHR was almost half that in WKR at all ages.     

Alloxan-induced diabetes in young vs old spontaneously hypertensive rats (SHR)

Young and old, male and female, spontaneously hypertensive rats (SHR), were subjected to severe alloxan diabetes. Young and old diabetic SHR became emaciated with reduced heart weights and blood pressure. SHR developed progressively worsening hyperlipidemia and hyperglycemia with age. Diabetic old SHR were unable to mobilize glucose or lipid, i.e., trigycerides, free fatty acids, or total cholesterol, as effectively as their younger counterparts. BUN levels were lower in older SHR and even lower in diabetic old SHR. Older SHR secreted supranormal quantities of corticosterone; young SHR secreted subnormal quantities. Old, diabetic SHR developed extensive myocardial fibrosis, cerebral edema, gonadal atrophy and extensive intimal hyalin fibrosis of the gonadal arteries, and calcification of the medium-sized testicular arteries. The genetic programming of hypertension in SHR may affect the variety of degenerative changes which develop in young vs old SHR during severe diabetes.