bluuebunny/crossref_metadata_2025 huggingface dataset:
NERVE GROWTH FACTOR, VESSEL INNERVATION AND HYPERTENSIVE PROGRESSION IN THE INBRED DAHL SS/Jr AND SR/Jr RATS
Authors: Tuttle Jeremy B. , Stewart Jeanine S. , Spitsbergen John M. , McCarty Richard M.
Published: June 2007

1. To test whether the inbred Dahl salt‐sensitive hypertensive rat strain shares disturbed vessel innervation with the spontaneously hypertensive rat (SHR) model, highly innervated and sparsely innervated tissues from the SR/Jr and SS/Jr strains at several ages were assayed for tissue norepinephrine (NE) content and nerve growth factor (NGF).

2. Only two significant differences were found: (i) 1 week old SS/Jr rat kidneys had more NGF than SR/Jr kidneys; and (ii) six week old mesenteric arteries from SS/Jr contained significantly more NE than those in the SR/Jr animals.

3. The differences are in the expected direction for vessel hyperinnervation as a consequence of high vessel NGF, but the data do not support the hypothesis of a central role for vessel NGF and innervation in the hypertensive progression of the Dahl strain, The vessels of young Dahl inbred rat strains do not display the same degree of vessel hyperinnervation associated with hypertension as found in the young SHR compared to WKY strains.

4. The Dahl strain may lack the disturbed NGF metabolism of the SHR. This might suggest that the Dahl inbred strains and the SHR represent two distinct genetic mechanisms that predispose to hypertension via essentially independent processes and that all forms will evidence at least mildly altered vessel innervation.
PHARMACOLOGICAL CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION OF DIHYDROPYRIDINE‐TYPE CALCIUM CHANNELS IN THE KIDNEY OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Amenta Francesco , Liu Aiping , Sabbatini Maurizio
Published: June 2007

1. The pharmacological profile and the microanatomical localization of Ca2+ channels of the L‐type were analysed in sections of the kidney of Wistar‐Kyoto (WKY) rats and of spontaneously hypertensive rats (SHR) of different ages.

2. [3H]‐Nicardipine was used as a ligand. It was bound to sections of rat kidney in a manner consistent with the labelling of Ca2+ channels of the L‐type. The density of [3H]‐nicardipine binding sites was similar in WKY rats of different ages and in SHR of 2 and 4 months, but was significantly increased in SHR of 6 months.

3. Light microscope autoradiography revealed the highest density of binding sites in the tubular portion of the nephron and to a lesser extent within smooth muscle of renal arteries and renal corpuscles. In SHR of 4 and 6 months the density of [3H]‐nicardipine binding sites was increased within the epithelium of proximal tubules and of the loop of Henle and decreased in renal corpuscles in comparison with WKY rats or 2 month old SHR.

4. These results show that the density of Ca2+ channels of the L‐type increases with the worsening of hypertension in SHR. The observation of a different sensitivity to hypertension of Ca2+ channels located in the various portions of the nephron indicates the usefulness of light microscope autoradiography for assessing hypertension‐related changes of Ca2+ channels in the kidney.
DIFFERENT CHOLESTEROL DEPOSITION IN AORTA OF DAHL SALT‐SENSITIVE RATS AND SPONTANEOUSLY HYPERTENSIVE RATS FED A HIGH‐CHOLESTEROL DIET
Authors: Yamaguchi Y. , Kitagawa S. , Kwon Y. , Shinozuka K. , Kunitomo M.
Published: June 2007

1. We compared the serum and aortic lipid levels in spontaneously hypertensive rats (SHR) and Dahl salt‐sensitive rats (DSR) fed a high‐cholesterol (HC) diet.

2. In SHR fed the HC diet, the serum cholesterol level significantly increased, but no aortic cholesterol deposition was observed.

3. The serum cholesterol level in DSR fed the HC diet markedly increased compared to that in DSR fed the basal diet, and this change was greater with the diet containing 8% NaCl than 0.4% NaCl. A significant increase in the content of aortic cholesterol, notably cholesteryl ester, was observed in only DSR fed the HC diet containing 8% NaCl.

4. These results suggest that the combination of hyper‐cholesterolaemia with salt‐induced hypertension acts as a greater risk factor for atherosclerosis than that with genetic hypertension.
PATHOGENESIS OF LACUNA‐LIKE CYST FORMATION AND DIFFUSE DEGENERATION OF THE WHITE MATTER IN THE BRAIN OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Hazama Fumitada , Chue Chin‐Hui , Kataoka Hideo , Sasahara Maskiyo , Amano Shigeru
Published: June 2007

1. In an attempt to clarify the developmental mechanisms of lacuna and diffuse degeneration of the white matter in the brain in chronic hypertension, we investigated histologically the cerebral changes and histochemically, as well as biochemically, the lysosomal enzymes in the brain of stroke‐prone spontaneously hypertensive rats (SHRSP).

2. The most prominent advanced lesions observed in SHRSP were cyst formation in the cortex and subcortical white matter, and diffuse degeneration of the white matter. On the other hand, the early cerebral changes were all related to blood‐brain barrier dysfunction. The localization of cystic lesions and degeneration of the white matter corresponded very well with the extent of brain oedema demonstrated by immunostaining for leaked fibrinogen. All lysosomal enzyme activities in the adult SHRSP, both in the cortex and white matter, were higher than those in the controls. Histochemical investigation showed that SHRSP had an increased number of cells, reactive astrocytes and microglial cells, with positive reaction to lysosomal enzymes in the oedematous portion.

3. These findings suggest that chronic oedema due to blood‐brain barrier dysfunction causes cystic changes as well as diffuse degeneration of the white matter, and that activated lysosomal enzymes in the reactive astrocytes and microglia play an important role in the development of such hypertensive lesions.
GENE EXPRESSION OF PROSTACYCLIN RECEPTOR IN THE HYPERTROPHIED HEART OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nakagawa O. , Sasaki Y. , Tanaka I. , Usui T. , Sando T. , Muro S. , Mori K. , Itoh H. , Yoshimasa T. , Narumiya S. , Nakao K.
Published: June 2007

1. Prostacyclin elicits potent vasodilation and inhibition of platelet aggregation through binding to its membrane receptor. The impairment of prostacyclin receptor activity is implicated in various human cardiovascular diseases. We recently succeeded in molecular cloning of cDNA for the mouse, rat, and human prostacyclin receptors.

2. In the present study, we examined the mRNA expression of the prostacyclin receptor in various rat tissues, and further investigated its gene expression in the hypertrophied cardiac ventricles of stroke‐prone spontaneously hypertensive rats (SHRSP).

3. In rat tissues, a single RNA band of approximately 3.7 kb was detected by northern blotting analysis using rat prostacyclin receptor cDNA as a probe. In adult Wistar rats, abundant mRNA expression was observed in the aorta, lung and spleen. Substantial amounts of transcript were expressed in the heart, pancreas, thymus and stomach. In contrast, no mRNA expression was detected in the brain.

4. We further examined the mRNA expression of the prostacyclin receptor in the ventricles of 21 week old SHRSP. The ventricles of SHRSP showed remarkable hypertrophy, compared with those of age‐matched Wistar‐Kyoto (WKY) rats. The expression of prostacyclin receptor mRNA in the hypertrophied ventricles of SHRSP was almost equivalent to that in the ventricles of WKY.

5. The present study revealed the gene expression of the prostacyclin receptor in various rat tissues, and further demonstrated the receptor mRNA expression in hypertensive cardiac hypertrophy. The present study will give a clue to investigate the clinical implication of prostacyclin and its receptor.
EPIDEMIOLOGICAL INVESTIGATION OF INSULIN RESISTANCE SYNDROME (SYNDROME X) IN A CITY IN JAPAN
Authors: Imamura Minoru , Kishitani Yuzuru , Saika Toyohiko , Iio Kazuya , Ikami Hitoshi , Kagita Atushi , Nishimura Akiyoshi , Masuda Katuhiko , Ohno Yasuhiro , Aoki Norihiko
Published: June 2007

1. In order to study the prevalence of insulin resistance syndrome (syndrome X) in Japanese subjects, inhabitants aged above 40 years living in Osaka‐Sayama city from September 1992 through December 1993 were investigated. The population‐based study was performed on 2498 subjects (661 males and 1837 females) constituting 10.9% of the total population aged above 40 years.

2. The prevalence of glucose intolerance was 8.7% (n= 218) in 2498 subjects. The prevalence of hypertension was 36.9% (n= 923) and that of hypertriglyceridaemia was 19.0% (n= 475). The prevalence of syndrome X as characterized by an association of glucose intolerance, hypertension and hypertriglyceridaemia was 1.6% (n= 39) in all subjects examined and 17.4% in subjects showing glucose intolerance.

3. Fasting serum insulin levels were significantly higher in patients with syndrome X than in normal subjects. Furthermore, the levels were significantly correlated with blood levels of frucutosamine, fasting glucose and triglyceride, and with body mass index as well.

4. In conclusion, insulin resistance syndrome (syndrome X) is also found among the larger Japanese population, and fasting serum insulin levels can be a useful marker of this metabolic disorder.
ANTIHYPERTENSIVE EFFECTS, DETERMINED BY A TELEMETRY METHOD, OF TRICHLOROMETHIAZIDE AND 7–O‐ETHYLFANGCHINOLINE, A DERIVATIVE OF TETRANDRINE, IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kawashima K. , Negishi T. , Amano H. , Fujimoto K. , Suzuki T. , Fujii T.
Published: June 2007

1. The antihypertensive effects of 10 mg/kg trichloromethiazide (TCM), 10 mg/kg 7–O‐ethylfangchinoline (7–O‐EFC) and the combination of these drugs given orally once daily for 2 weeks were investigated by measuring the blood pressure (BP), heart rate (HR) and activity in conscious, freely moving spontaneously hypertensive rats (SHR) fitted with a telemetry device.

2. Clear diurnal rhythms of the HR and activity in synchrony with the light/dark cycle were observed during therapy, whereas the BP rhythm was obscure.

3. Alone, TCM and 7–O‐EFC produced slight and insignificant reductions of 24 h mean BP, whereas in combination they produced an additive and significant BP reduction, compared with the vehicle‐treated controls, from the third day of therapy. The BP reduction induced by the combination of these drugs during the dark phase was more marked than that during the light phase.

4. None of the drug therapies affected the HR and activity diurnal rhythms.

5. The results of the present study demonstrate that the telemetry method is useful for monitoring the antihypertensive effects of drugs in SHR under physiological conditions with minimal stress.
EFFECTS OF (‐)‐EPIGALLOCATECHIN‐3‐O‐GALLATE (GREEN TEA TANNIN) ON THE LIFE SPAN OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Uchida S. , Ozaki M. , Akashi T. , Yamashita K. , Niwa M. , Taniyama K.
Published: June 2007

1. Effect of (‐)‐epigallocatechin‐3‐O‐gallate (EGCG), a condensed tannin isolated from green tea leaves, on the life span and hypertensive lesions in the stroke‐prone spontaneously hypertensive rat (SHRSP) was compared with that of persimmon tannin.

2. Long‐term administration of either 0.5% EGCG or 0.5% persimmon tannin to SHRSP inhibited the incidence of stroke and prolonged the life span, but did not affect the blood pressure.

3. These results indicate that EGCG may prevent incidence of stroke due to the radical scavenging action and inhibition of lipid peroxidation, and may result in prolonging the life span of SHRSP, as in the case of persimmon tannin.
DIETARY DOCOSAHEXAENOIC ACID (22:6n‐3) PREVENTS THE DEVELOPMENT OF HYPERTENSION IN SHRSP
Authors: Kimura S. , Minami M. , Saito H. , Kobayashi T. , Okuyama H.
Published: June 2007

1. We previously reported that hypertension in stroke‐prone spontaneously hypertensive rats (SHRSP) caused renal membrane phospholipid degradation. Renal phospholipase A2 activity increased and membranous phospholipids decreased along with age in SHRSP. Membranous abnormalities induced by membrane fluidity and calcium permeability changes may contribute to the elevation of blood pressure in SHRSP. DHA, a major component of fish oil, constitutes a part of membrane phospholipid acylchains.

2. The purpose of this study was to clarify the effect of DHA on the relationship between the renal function and the development of hypertension in SHRSP.

3. Six week old male SHRSP were fed a semi‐purified diet supplemented with DHA (0,1 and 5%) for 14 weeks.

4. The systolic blood pressure of control SHRSP (DHA 0%) significantly increased from 120.2 mmHg to 202.9 mmHg. This increase in systolic blood pressure was significantly inhibited in a dose‐dependent manner by 1 and 5% DHA diet to 167.8 and to 149.8 rnmHg, respectively.

5. Serum creatinine concentration and blood urea nitrogen (BUN) were significantly lower in DHA (5%)‐treated SHRSP than in the control SHRSP.

6. These results indicate that DHA prevents the development of hypertension in SHRSP, which is associated with changes in renal function.
LIPID‐REGULATING ACTION OF GEMFIBROZIL IN THE STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Ogawa Hiroshi , Tasaka Masatsuna
Published: June 2007

1. Gemfibrozil (Lopid®) is extensively used as lipid‐regulating agent in the Western World, and its beneficial effect is demonstrated in human studies such as the Helsinki Heart Study. However, the mechanism of its hypolipidaemic action is not fully understood. In the present paper, to elucidate the hypolipidaemic mechanism, we examined the effects of gemfibrozil on lipid metabolism in the normocholesterolaemic and hypercholesterolaemic stroke‐prone spontaneously hypertensive rat (SHRSP).

2. Gemfibrozil effectively increased high density lipoprotein (HDL) subfraction rich in apoE (apoE‐HDL) and significantly decreased very low density lipoprotein (VLDL) in normocholesterolaemic SHRSP. In the liver of normocholesterolaemic SHRSP, gemfibrozil significantly reduced the activity of micro‐somal acyl‐CoA: cholesterol acyltransferase.

3. Gemfibrozil markedly reduced atherogenic & very low density lipoprotein (β‐VLDL) and low density lipoprotein (LDL) in hypercholesterolaemic SHRSP fed a high‐fat and high‐cholesterol diet (HFC diet). On the other hand, it significantly increased the contents of apoA‐I, A‐IV and E in the HDL fraction compared with the control group, suggesting that gemfibrozil effectively increases anti‐atherogenic HDL subfractions rich in apoA‐I, A‐IV or E. In the liver of hypercholesterolaemic SHRSP, gemfibrozil markedly prevented lipid accumulation.
INSULIN‐INDUCED RENAL DYSFUNCTION IN REGULAR SABRA RATS
Authors: Bursztyn Michael , Ben‐Ishay Drori , Mekler Judith , Raz Itamar
Published: June 2007

1. We tested the effects of chronic hyperinsulinaemia on renal function. Hyperinsulinaemia, in the range of 1.5–4 times the control levels, was achieved using a sustained‐release insulin implant. Sham‐treated rats served as controls.

2. Experiment 1. Acute saline loading: seven sham and seven hyperinsulinaemic rats received an acute saline load (4mL/100g). Two h post‐load urea and creatinine excretion rats were (μmol/min) 15 ± 5 and 9 ± 4, and 0.17 ± 0.05 and 0.10 ± 0.04, respectively;P < 0.05 for both.

3. Experiment 2. Chronic saline loading: 12 sham‐ and 24 insulin‐treated rats drank saline for 8 weeks plus 4% NaCl in the food for 2 more weeks. By week 10 plasma creatinine (μmol/L) was 62 ± 12 and 78 ± 13, and creatinine clearance (mL/min) was 1.9 ± 0.5 and 1.5 ± 0.4, respectively; P < 0.05 for both.

4. Experiment 3. Regular diet: 10 sham‐ and 14 insulin‐treated rats had, by week 8, plasma creatinine (μmol/L) of 75 ± 34 and 96 ± 37 and creatinine clearance (mL/min) of 1.260 ± 0.025 and 0.97 ± 0.22, respectively; P < 0.02 for both. Bodyweight, resting blood pressure and urinary Na+ and K+ excretion were comparable in sham‐ and insulin‐treated rats.

5. In three experimental settings long‐term hyperinsulinaemia was associated with a subtle but significant renal dysfunction. This finding may be related to the aetiology of renal complications of hypertension and diabetes mellitus, both of which are insulin‐resistant and hyperinsulinaemic states.
INFLUENCE OF LONG‐TERM TREATMENT WITH THE DIHYDROPYRIDINE‐TYPE CALCIUM ANTAGONIST NICARDIPINE ON RENAL MICROANATOMICAL CHANGES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Amenta Francesco , Abbate Francesco , Cavallotti Carlo , Ciriaco Emilia , Ferrante Fabio , Sabbatini Maurizio
Published: June 2007

1. The influence of hypertension and treatment with the dihydropyridine‐type Ca2+ antagonist, nicardipine, on the structure of the kidney was assessed in spontaneously hypertensive rats (SHR) of 12 weeks of age. Treatment went for 8 weeks with a daily oral dose of 1 mg/kg of nicardipine.

2. Control SHR exhibited hypertension and microanatomical vascular and glomerular changes. Vascular changes consisted of a thickening of the tunica media and decreased luminal area of medium‐ and small‐sized intrarenal artery branches. Glomerular changes included glomerulosclerosis and atrophy of varying degrees.

3. Administration of nicardipine significantly reduced blood pressure. The drug also decreased the thickening of tunica media and luminal narrowing of renal artery branches as well as the degree of glomerular injury in SHR.

4. These data indicate that nicardipine treatment is able to control elevated blood pressure in SHR, and to counter hypertension‐dependent microanatomical impairment of the kidney. This suggests that the compound exerts a protective effect on hypertensive kidney.
EFFECTS OF BENIDIPINE, A LONG‐ACTING CALCIUM ANTAGONIST, ON RENAL FUNCTIONS IN ANAESTHETIZED SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nomura H. , Kusaka H. , Karasawa A.
Published: June 2007

1. The effects of benidipine, a long‐acting calcium antagonist, on renal functions were determined in anaesthetized spontaneously hypertensive rats (SHR), as compared with those of amlodipine.

2. Benidipine at 3 and 10 μg/kg (i.v.) significantly increased urine volume, sodium (Na) and potassium (K) excretions with no change in creatinine clearance (C‐CRE). The increase in K excretion was relatively slight. Benidipine increased p‐amino‐hippuric acid clearance (C‐PAH) without any change in C‐CRE and, thus, decreased filtration fraction (FF).

3. On the other hand, amlodipine at 300 μg/kg (i.v.) significantly increased Na and K excretions, but did not change FF.

4. Thus benidipine, but not amlodipine, can dilate glomerular efferent arteriole as well as afferent arteriole in SHR. It is, therefore, expected that benidipine would not induce intraglomerular hypertension, which could result in the progression of glomerular injury.

5. Benidipine at 3 μg/kg (i.v.) increased lithium clearance, while it decreased CRE concentration and increased Na concentration in the stop‐flow urine from the distal tubule.

6. These results suggest that benidipine produces diuresis by the inhibition of water and Na reabsorption at both the proximal and the distal tubules.
PROTECTIVE EFFECTS OF MANIDIPINE ON SPERMATOGENESIS IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Akagashi Keigo , Itoh Naoki , Kumamoto Yoshiaki , Tsukamoto Taiji , Suzuki Tsuneyuki , Ohta Yoshio
Published: June 2007

1. We evaluated the protective effects of manidipine on spermatogenic damage induced by the hypertensive vascular changes in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. Blood pressure reached more than 250 mmHg in SHRSP at 15 weeks of age, and thereafter the hypertensive changes in testicular arterioles developed. Manidipine reduced both the blood pressure and the hypertensive vascular changes.

3. Although immature and mature spermatids greatly diminished in SHRSP at 23 weeks of age, manidipine could preserve almost normal spermatogenesis even at 23 weeks of age. Transferrin concentration in testicular cytosol, which was considered to be indicative of the Sertoli cell function, in SHRSP with manidipine administration was significantly higher than that in SHRSP with no treatment at 23 weeks of age.

4. In conclusion, manidipine could prevent the development of the hypertensive changes in intratesticular arterioles and maintain normal Sertoli cell function. As a result, manidipine protected spermatogenic damage in SHRSP.
LONG‐TERM EFFECTS OF TREATMENT WITH ENALAPRIL ON THE STRUCTURE OF MESENTERIC RESISTANCE ARTERIES IN NEW ZEALAND GENETICALLY HYPERTENSIVE RATS
Authors: Ledingham Janet M. , Laverty R.
Published: June 2007

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril (20mg/kg per day in drinking fluids) from age 4–10 weeks; one group (GHex‐enal) was then taken off enalapril and followed for 6 more weeks to see if the drug‐induced changes in blood pressure (BP) and structure of mesenteric resistance arteries (MRA) were long lasting once the enalapril was withdrawn. Control groups consisted of untreated GH and their normotensive (N) control strain.

2. Tail‐cuff BP in GH treated rats fell significantly to N BP levels during treatment. On cessation of treatment BP rose rapidly. At age 16 weeks BP, although at a hypertensive level (mean ± s.e.m., GHex‐enal, 210.8 ± 4.7 mmHg), was still significantly below the GH controls (230 ± 6.9, P < 0.05), but above the N control group (137 ± 3, P < 0.0001).

3. Left ventricular (LV) mass in GH rats was reduced by enalapril to that in N rats; at the end of the subsequent period without treatment it was still significantly lower than the GH control group, but also significantly above the N group (GHexenal, 255 ± 6; GH 306 ± 11; N 179 ± 3, mg/100 g bodyweight).

4. The large changes in media, lumen and media/lumen ratio seen after 6 weeks of treatment were not sustained over the subsequent non‐treatment period. However, values in the GHex‐enal group at 16 weeks were closer to those in the N16 control group.

5. The persisting effects on smooth muscle (SM) cell density and SM fraction of the media contributed to an increase in SM cell volume which was significantly greater than the N16 group (P < 0.01). The number of layers of SM in the media was less than in the GH16 control group and not different from the N16 controls.

6. In GH rats the effect of ACEI on BP, LV mass and MRA structure is relatively longlasting once treatment is withdrawn.
ENALAPRIL IMPROVES GLUCOSE TOLERANCE IN TWO RAT MODELS: A NEW HYPERTENSIVE DIABETIC STRAIN AND A FRUCTOSE‐INDUCED HYPERINSULINAEMIC RAT
Authors: Rosenthal T. , Erlich Y. , Rosenmann E. , Grossman E. , Cohen A.
Published: June 2007

1. The present study was undertaken to examine the effect of the angiotensin converting enzyme (ACE) inhibitor, enalapril, on blood pressure and spontaneous blood glucose levels in two rat models: our new diabetic hypertensive rat in which genetic hypertension and diabetes develop following cross‐breeding of Cohen diabetic rat (CDR) and spontaneous hypertensive rats (SHR); and a rat in which hypertension, hyperinsulinaemia and hyperlipidaemia were induced by fructose diet.

2. The new strain of animal was fed the usual copper‐poor sucrose diet, and for 4 weeks received enalapril. The fructose‐induced hyperinsulinaemic animals were fed a fructose‐enriched diet for 3 weeks, and enalapril 20 mg per kg per day was added to the drinking water for 2 more weeks.

3. The new strain of diabetic‐hypertensive rats that received enalapril showed a significant decrease in blood pressure level. The fructose‐fed animals showed a fall in insulin and blood pressure following the introduction of enalapril to their diet.

4. The present study confirms the advantage of the ACE inhibitor enalapril in improving the metabolic parameters of hypertensive diabetic rats, including insulin sensitivity.
EFFECT OF AN ANGIOTENSIN II RECEPTOR ANTAGONIST, TCV‐116, ON NEOINTIMAL FORMATION FOLLOWING BALLOON INJURY IN THE SHR CAROTID ARTERY
Authors: Kino Hirofumi , Hama Junkichi , Takenaka Toshihiko , Sugimura Keiichi , Kamoi Kouji , Shimada Seijiro , Yamamoto Yoshihiro , Nagata Shuzo , Kai Tatsuya , Horiuchi Masatsugu , Katori Ryo
Published: June 2007

1. In the present study, we examined the effect of a novel angiotensin II type I receptor antagonist, TCV‐116, on carotid neointimal formation after balloon injury in SHR and WKY rats.

2. Oral administration of TCV‐116 at a dose of 10mg/kg per day reduced not only systolic blood pressure but also neointimal formation after carotid balloon injury. TCV‐116 also suppressed cardiac hypertrophy. An angiotensin‐converting enzyme inhibitor, lisinopril (20mg/kg per day), had a similar effect to that of TCV‐116.

3. In the WKY experiment, both TCV‐116 and lisinopril suppressed neointimal formation as well as systolic blood pressure, but did not suppress cardiac hypertrophy.

4. Although SHR showed markedly enhanced neointimal formation after balloon injury compared with age‐matched WKY rat, both TCV‐116 and lisinopril showed similar sup‐pressive effects on neointimal formation in both SHR and WKY rats.

5. These results confirm the important role of angiotensin II in neointimal formation following balloon injury. Further studies are needed to clarify the mechanism of the difference between SHR and WKY rats in the response of vascular smooth muscle cells.
CARDIOVASCULAR AND RENAL PROTECTIVE EFFECTS OF LOSARTAN IN SPONTANEOUSLY HYPERTENSIVE RATS WITH DIABETES MELLITUS
Authors: Kohzuki Masahiro , Yasujima Minoru , Liu Ping Fu , Obara Katsuya , Kanazawa Masayuki , Yoshida Kazunori , Saito Takao , Sato Tokutaro , Abe Keishi
Published: June 2007

1. Cardiovascular and renal benefits of a specific angiotensin II (AII) receptor antagonist, losartan (LOS), were assessed in diabetic rats with renal impairment.

2. Uninephrectomized SHR made diabetic by streptozotocin administration were given LOS (5 mg/kg per day, i.p.) alone, captopril (CAP) (50 mg/kg per day, i.p.) alone, or a combination of CAP and LOS via osmotic minipumps for 8 weeks.

3. Both CAP alone and LOS alone completely blocked the development of hypertension in diabetic SHR in the same manner. CAP + LOS did not enhance the antihypertensive effects of LOS alone or CAP alone.

4. CAP+LOS, LOS alone and CAP alone significantly decreased urinary protein excretion and serum creatinine to the same extent.

5. These results indicate that both LOS and CAP exert antihypertensive and renoprotective effects in this model: these actions are mainly through inhibition of AII production.
RENIN‐ANGIOTENSIN SYSTEM IN THE ANTIHYPERTENSIVE EFFECT OF ISOTEOLINE IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Markov M. , Higashino H. , Suzuki A.
Published: June 2007

1. The aim of the present study was to examine the effects of isoteoline (IST), a new tetrahydroaporphine derivative, on the blood pressure and some of the components of renin‐angiotensin‐aldosterone system (RAAS) in spontaneously hypertensive rats (SHR).

2. After long‐term treatment (14 days, 3 times daily) in a dose of 1 mg/kg orally and intraperitoneally, IST induced a significant decrease of the systolic blood pressure (SBP) in SHR (from 192 ± 2 to 155 ± 5 mgHg).

3. At the same time, IST induced a significant decrease of the levels of plasma renin activity (PRA) and aldosterone (ALD) and manifested a trend to increase the sodium plasma level.

4. These results indicate that IST after chronic long‐term treatment induced a marked antihypertensive effect and inhibited the components of RAAS in SHR. Apparently, the long‐lasting antihypertensive effect of IST in SHR was mediated and realized in part by inhibition of the components of RAAS.
EVOLUTION OF DOSE‐RELATED CARDIOVASCULAR RESPONSES TO L‐GLUTAMATE MICROINJECTED INTO THE NUCLEUS TRACTUS SOLITARII AFTER REMOVAL OF THE NODOSE GANGLION IN RAT
Authors: Talman W. T. , Colombari E.
Published: June 2007

1. In this study, we sought to determine if sensitivity to dose‐related changes in arterial pressure (AP) and heart rate (HR) elicited by microinjection of L‐glutamate (L‐GLU) into the nucleus tractus solitarii (NTS) evolves after deafferentation in adult male Sprague‐Dawley rats.

2. Twelve rats served as unoperated controls; and eight were studied 5 days, eleven 10 days and nine 15 days after ganglionectomy. Each rat was anaesthetized (halothane 1.5–2.096) and cannulated for recording AP and HR. Vehicle or L‐GLU (3, 30, 75, 150, 300 and 1500 pmole/50 nL) was microinjected into the right and left NTS. Injection sites were confirmed histologically.

3. In control animals and in animals 5 days and 15 days after ganglionectomy, the lowest dose of L‐GLU that produced a significant fall of AP was 30 pmole. The threshold dose with injections on the lesioned side 10 days after ganglionectomy was 3 pmole. In rats studied at 10 days, but not in control, 5 or 15 day rats, dose‐related responses for injections made on the left were shifted significantly to the left of those made on the right (P < 0.05).

4. In control, 5 and 15 day rats there were no significant differences between dose‐related responses elicited from right and left NTS. Responses of HR did not differ between groups of animals or sides of injection.

5. These results suggest that supersensitivity to L‐GLU evolves after nodose ganglionectomy and support a role for L‐GLU as a transmitter of cardiovascular afferents in the NTS.
ACETYLCHOLINE RELEASE IN THE ROSTRAL VENTROLATERAL MEDULLA OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kubo Takao , Ishizuka Takanobu , Asari Tetsuya , Fukumori Ryuji
Published: June 2007

1. Central acetylcholine (ACh) has been implicated in the pathogenesis of experimental hypertension and the rostral ventrolateral medulla (RVLM) is an important area for cardiovascular regulation. The purpose of this study was to determine whether cholinergic neurotransmission in the RVLM is altered in spontaneously hypertensive rats (SHR).

2. Experiments were performed on male SHR (12–16 weeks) and age‐matched Wistar‐Kyoto rats (WKY). The rats anaesthetized with pentobarbital were placed in a stereotaxic apparatus. For determining the release of ACh in the RVLM, a dialysis probe was introduced into the RVLM.

3. An RVLM microinjection of cholinergic agents elicited an increase in blood pressure. The pressor response to physostigmine was greater in SHR than that of WKY whereas there was no difference in the pressor response to ACh or carbachol between SHR and WKY.

4. The release of ACh in the RVLM was greater in SHR than that of WKY. Physostigmine (0.5 mg/kg, i.p.) produced increases in medulla ACh contents. The increase in ACh content of the rostroventral medulla including the RVLM was greater in SHR than that of WKY whereas there was no difference in ACh contents of the other three parts of the medulla oblongata between SHR and WKY.

5. Depressor responses to scopolamine injected bilaterally into the RVLM were greater in SHR than those of WKY.

6. These results suggest that ACh release is enhanced specifically in the RVLM of SHR. It appears that this enhanced release of ACh in the RVLM of SHR contributes to the maintenance of hypertension in SHR.
ALTERED BASAL RELEASE AND PRESSOR EFFECT OF L‐DOPA IN THE ROSTRAL VENTROLATERAL MEDULLA OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Yue Jin‐Liang , Miyamae Takeaki , Ueda Hiroshi , Misu Yoshimi
Published: June 2007

1. Transmitter‐like L‐DOPA functions as a tonic to produce postsynaptic cardiopressor responses in the rostral ventrolateral medulla (RVLM) of rats. We attempted to clarify whether a transmitter‐like L‐DOPA system is altered in the RVLM of spontaneously hypertensive rats (SHR) to maintain the hypertension.

2. By microdialysis of left RVLM area, the basal L‐DOPA release was higher in SHR than in Wistar‐Kyoto (WKY) rats. This release was partially inhibited by tetrodotoxin (TTX, 1 μmol/L) to a similar degree in both strains. TTX‐sensitive L‐DOPA release was higher in SHR than in WKY.

3. L‐DOPA (10–600 ng) and L‐glutamate (10–300 ng) microinjected into left RVLM produced dose‐dependent hypertension and tachycardia. Pressor but not tachycardiac responses to L‐DOPA at lower doses were slightly greater in SHR than in WKY, whereas no difference to L‐glutamate was observed in either strain.

4. In RVLM regions, there was no difference of tyrosine hydroxylase activity in SHR or WKY; however, L‐aromatic amino acid decarboxylase activity was lower in SHR than in WKY.

5. Enhanced presynaptic neuronal L‐DOPA release, including a decrease in decarboxylation and sensitization of postsynaptic pressor sites to L‐DOPA in RVLM, may be involved in the maintenance of hypertension in SHR.
SYNERGISTIC EFFECTS OF BAY K 8644 AND BRADYKININ ON NOREPINEPHRINE RELEASE IN THE HYPOTHALAMUS OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Tsuda Kazushi , Tsuda Seiko , Nishio Ichiro , Masuyama Yoshiaki , Goldstein Menek
Published: June 2007

1. In the present study, we examined the effects of Bay K 8644, a dihydropyridine (DHP)‐sensitive Ca2+ channel agonist, and bradykinin on norepinephrine release in the hypothalamus of spontaneously hypertensive rats (SHR).

2. In the preliminary studies using Sprague‐Dawley rats, Bay K 8644 by itself had no significant effects on the stimulation‐evoked [3H]‐norepinephrine release from hypothalamic slices. Bradykinin increased the stimulation‐evoked [3H]‐nor‐epinephrine release in a dose‐related fashion. The facilitatory effects of bradykinin on norepinephrine release were potentiated by Bay K 8644.

3. In SHR, Bay K 8644 significantly increased the stimulation‐evoked norepinephrine release from hypothalamic slices. However, exposure of slices to Bay K 8644 caused no significant effects on norepinephrine release in Wistar‐Kyoto (WKY) rats. The effects of Bay K 8644 in combination with bradykinin on the stimulation‐evoked norepinephrine release were also greater in SHR than in WKY rats.

4. These results demonstrate that Bay K 8644 significantly potentiated the facilitatory effects of bradykinin on norepinephrine release in rat hypothalamus. The finding indicates a possible interaction of bradykinin with DHP‐sensitive Ca2+ channels in the central nervous system. Furthermore, the pronounced effects of Bay K 8644 and bradykinin in SHR suggest that bradykinin‐related Ca2+ channels might have a role in the regulation of norepinephrine release in the hypothalamus of SHR.
ALTERATION OF BARORECEPTOR AND CHEMORECEPTOR REFLEXES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ohta H. , Talman W. T.
Published: June 2007

1. Electrical stimulation of the aortic depressor nerve elicited depressor and bradycardiac responses in both spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKY) rats, but in spontaneously breathing animals responses were weaker in SHR than in WKY.

2. Responses did not significantly differ in artificially ventilated animals except that high stimulation intensity elicited significantly greater bradycardiac responses in WKY. A decrease in ventilatory rate occurred in both strains.

3. Electrical stimulation of the carotid sinus nerve (CSN) elicited an initial pressor response followed by a depressor response with a minimal change in heart rate in either strain. The pressor response in SHR was greater than in WKY. Depressor responses in SHR were weaker than those in WKY with or without artificial ventilation. CSN stimulation increased ventilatory rate in both strains but the frequency‐related responses differed at higher stimulation intensity.

4. These results suggest that there are alterations in the function of central or afferent components of chemoreceptor and baroreceptor reflexes in SHR in addition to previously described structural changes at the level of peripheral sensory receptors.
BARORECEPTOR FUNCTION IS RESTORED BY ANTIHYPERTENSIVE THERAPY THROUGH LOWERING OF BLOOD PRESSURE IN ADULT SHR
Authors: Ichikawa Masashi , Suzuki Hiromichi , Kumagai Kazuhiro , Ryuzaki Munekazu , Kumagai Hiroo , Nishizawa Masahiko , Saruta Takao
Published: June 2007

1. We investigated the effects of antihypertensive treatment (8 weeks) with four different agents (trichlormethiazide, atenolol, nicardipine and enalapril) on baroreceptor function in 28 week old spontaneously hypertensive rats (SHR) to measure aortic depressor nerve (ADN) activity.

2. Threshold pressure (P th) of ADN activity was elevated and the gain sensitivity of the pressure–‐activity curve, as determined by the maximum gain (Gmax) of a logistic function curve, was depressed in untreated SHR compared to those in untreated Wistar‐Kyoto (WKY) rats.

3. Treatment with the four agents similarly reduced blood pressure in SHR. Each of the four agents induced a decrease in Pth and an increase in Gmax to a similar extent in SHR.

4. These findings suggest that antihypertensive therapy in chronic hypertension augments baroreceptor function through the lowering of blood pressure but not through specific pharmacological actions.
ROLE OF AN ENDOGENOUS MONOAMINE OXIDASE INHIBITOR, ISATIN, IN SHRSP BRAIN
Authors: Hamaue N. , Endo T. , Hirafuji M. , Yamazaki N. , Togashi H. , Saito H. , Minami M.
Published: June 2007

1. The acute effects of isatin, an endogenous monoamine oxidase (MAO) inhibitor, on norepinephrine (NE) and serotonin (5‐HT) concentrations in the brain of stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto rats (WKY) were determined in order to elucidate its pathophysiological role.

2. Isatin was identified in purified extracts of SHRSP brain.

3. A single dose of isatin significantly increased NE concentration in the cerebral cortex of WKY. Isatin also significantly increased 5‐HT concentration in WKY brains.

4. After isatin administration NE and 5‐HT levels in the SHRSP brain did not differ from those in WKY.

5. These data suggest that isatin, an endogenous MAO inhibitor, presents in the SHRSP brain and maintains high blood pressure.
EFFECT OF METHOXAMINE ON NORADRENALINE RELEASE IN THE CAUDAL ARTERY OF HYPERTENSIVE RATS
Authors: Shinozuka Kazumasa , Kunitomo Masaru , Bjur Richard A. , Westfall David P. , Hattori Keisuke
Published: June 2007

1. The effect of methoxamine, an α1‐adrenoceptor agonist, on the overflow of endogenous noradrenaline (NA) was examined in the electrically field stimulated (EFS) caudal artery obtained from Wistar rats, Wistar‐Kyoto rats (WKY) and age‐matched spontaneously hypertensive rats (SHR).

2. Methoxamine inhibited the EFS‐evoked release of endogenous NA in the arteries from Wistar rats and WKY, but not in the arteries of SHR. 2‐chloroadenosine, a purinoceptor agonist, also inhibited the NA release in the arteries from normotensive rats but not in the arteries of SHR.

3. The inhibitory effect of methoxamine was blocked by adenosine deaminase and potentiated by adenosine uptake inhibitor, dipyridamole.

4. Methoxamine caused the release of adenine nucleotides and adenosine from the caudal arteries of WKY and SHR.

5. These suggest that the inhibitory effect of methoxamine on NA release is mediated by endogenous adenyl purines and that the failure of methoxamine to inhibit NA release in the caudal artery of SHR is due to a dysfunction of the pre‐junctional purinoceptors on sympathetic nerve terminals.
α1‐ADRENOCEPTOR SUBTYPES MEDIATING THE CONTRACTION OF ARTERIES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Fujimoto S. , Sumi‐Fujimoto K.
Published: June 2007

1. This study was undertaken to determine which (α1‐adrenoceptor (AR) subtypes were involved in the activation of the femoral artery and the aorta by norepinephrine (NE) in spontaneously hypertensive rats (SHR).

2. Negative log EC50 values and maximum responses of NE‐induced contraction of the SHR femoral artery were unchanged and increased, respectively, compared with those of Wistar‐Kyoto (WKY) rats.

3. Contractile responses of the SHR aortas to NE were similar to those of the normotensive tissues.

4. Schild plot data for cut‐AR antagonists indicated that α1‐AR in the aorta were predominantly α1H subtype. In the femoral artery, because Schild plots for bunazosin had slopes of less than 1.0, there were α1H (or α1C) and α1L subtypes.

5. The α1‐AR subtype in the aorta was essentially identical to the α1H subtype in the femoral artery. α1‐AR subtypes mediating contraction in the SHR blood vessels were identical to those in the WKY tissues.
DOPAMINE‐INDUCED RELAXATION IN ISOLATED INTRARENAL ARTERIES FROM ADULT STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Gao Y. J. , Nishimura Y. , Suzuki A.
Published: June 2007

1. The relaxant effects of dopamine (DA) on the intrarenal arteries obtained from 6 month old stroke‐prone spontaneously hypertensive rats (SHRSP) and age‐matched Wistar‐Kyoto (WKY) rats were pharmacologically investigated in vitro.

2. DA (10−7−3 × 10−5 mol/L) produced endothelium‐independent relaxation on the arterial rings which had been incubated with phenoxybenzamine (2 × 10−6 mol/L) and precontracted with KCI.

3. DA‐induced relaxation was greater in the arterial rings from SHRSP than in those from WKY. SKF 38393 (10−8−10−6 mol/L) partially mimicked DA‐produced relaxation in both groups. SCH 23390 dose‐dependently inhibited DA‐induced relaxation with pD′2 value of 9.33 for SHRSP and of 9.26 for WKY.

4. There were no significant differences between SHRSP and WKY in the relaxation caused by forskolin, dibutyryl cyclic AMP, or 3‐isobutyl‐1‐methylxanthine.

5. These results suggested that DA1 receptor‐mediated relaxation was increased in the intrarenal arteries from SHRSP, and this increase might not be associated with altered vasodilation mediated by cyclic AMP.
ENHANCED CONTRACTILE RESPONSES MEDIATED BY DIFFERENT 5‐HT RECEPTOR SUBTYPES IN BASILAR ARTERIES, SUPERIOR MESENTERIC ARTERIES AND THORACIC AORTAS FROM STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nishimura Y. , Suzuki A.
Published: June 2007

1. The contractile effects of 5‐hydroxytryptamine (5‐HT) in isolated ring preparations of basilar arteries (BA), thoracic aortas (TA) and superior mesenteric arteries (SMA) from stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats were investigated pharmacologically.

2. The pD2 values (expressed as a negative logarithm of of EC50) for 5‐HT in BA of SHRSP were greater than those of WKY. Increased pD2 values for 5‐HT were also found in SMA and TA of SHRSP when compared to WKY.

3. Ketanserin (a 5‐HT2 antagonist) produced a biphasic displacement of the concentration‐response curves for 5‐HT in BA of WKY and SHRSP but elicited a parallel rightward shift of the 5‐HT curve in SMA and TA of the two groups.

4. 5‐CT (a 5‐HT1 agonist)‐induced contractions and their pD2 values in the presence of ketanserin were larger in BA of SHRSP than in those of WKY, while 5‐CT did not contract SMA or TA in either group.

5. No significant difference was found in the contractile response induced by α‐methyl‐5‐HT (a 5‐HT2 agonist) in BA from SHRSP and WKY, while the pD2 values for α‐methyl‐5‐HT were increased in SMA and TA from SHRSP when compared to WKY.

6. These results suggest that the hyperresponsiveness to 5‐HT found in SHRSP arteries may be mediated by different 5‐HT receptor subtypes, that is, by 5‐HT1 in BA and by 5‐HT2 in SMA and TA.
AN EXPERIMENTAL MODEL OF MIGRAINE WITH AURA: CORTICAL HYPOPERFUSION FOLLOWING SPREADING DEPRESSION IN THE AWAKE AND FREELY MOVING RAT
Authors: Shimazawa Masamitsu , Hara Hideaki
Published: June 2007

1. Cortical spreading depression (CSD) was induced by direct current stimulation of the lateral frontal cortex in awake and freely moving rats.

2. Regional cerebral blood flow (rCBF) was continuously measured by a laser Doppler flowmeter using an acrylic cup which was chronically fixed on the surface of the cerebral cortex. Under the resting condition rCBF remained constant throughout the observation period and showed a high reproducibility.

3. rCBF increased to approximately 190% of control values during 1‐3 min after CSD, and decreased to approximately 80% of control values, before returning to normal values 60 min after CSD.

4. These results are consistent with those found in anesthetized animals. This is the first study which has continuously monitored cortical hypoperfusion after CSD in awake and freely moving rats. The model is a useful system for studying migraine with aura.
BASIC INFORMATION PROCESSING AND HIGHER COGNITION: DOES THE MAMMALIAN CEREBRAL CORTEX DEAL WITH THEM AT DIFFERENT HIERARCHICAL LEVELS?
Authors: Vidyasagar TR
Published: June 2007

1. The primary visual cortex has been generally considered as a feature processing area where the neurons code for basic stimulus attributes, such as orientation, colour and direction of movement. Higher cognitive functions, such as attention and memory, were believed to be mediated by extrastriate regions at higher levels in a hierarchy of visual areas. However, the experiments reported here suggest that the function of the primary visual cortex is more than basic information processing in at least two respects.

2. First, significant modulation of visual responses occur in the primary visual cortex (V1) of the monkey depending upon attentional factors. There appears to be a feedback to V1 from extrastriate regions that facilitates neuronal responses in areas of attention and suppresses responses in other regions of the visual field.

3. Second, one would expect a region that is concerned with coding basic stimulus features to be rather resistant to plastic changes, as cells need to be reliable feature detectors for meaningful behaviour by the organism. However, the experiments on anaesthetized cats reported here show that a subset of neurons in visual area 17 of the cat have a potential for synaptic plasticity. Their response properties can undergo longterm changes under certain circumstances. To induce these changes, specific visual stimuli were combined with iontophoretic administration of NMDA and the GABA antagonist, bicuculline, which are believed to provide the molecular milieu for long‐term potentiation and long‐term depression.
LIMITS OF PARALLEL PROCESSING: EXCITATORY CONVERGENCE OF DIFFERENT INFORMATION CHANNELS ON SINGLE NEURONS IN STRIATE AND EXTRASTRIATE VISUAL CORTICES
Authors: Dreher B. , Wang C. , Burke W.
Published: June 2007

1. It has been postulated that the distinct parallel retinogeniculo‐cortical information channels characterizing visual pathways of virtually all mammals are selectively linked to parallel motion, colour and/or form information processing ‘streams’ distinguishable within the primary visual cortices, extrastriate cortical areas of occipital lobes and the temporal and parietal visual cortices.

2. Using selective pressure‐blocking of the large‐fibre channel (the so‐called Y‐channel) in the optic nerve of the cat, we have experimentally examined the ‘selective excitatory parallel links’ hypothesis. We conclude that the majority of neurons in the primary visual cortices (areas 17, 18) as well as in the two ‘higher order’ visual areas, area 21a and posteromedial lateral suprasylvian (PMLS) area, constituting, respectively, part of the ‘form’ and part of the ‘motion’ processing streams, receive their excitatory inputs from both Y‐ and non‐Y‐information channels. In areas 17, 18 and 21a (but not in PMLS area), there are, however, subpopulations of cells that apparently receive excitatory inputs from only one information channel.

3. Review of the relevant work on the macaque monkey suggests that the situation is similar in the primate: that is, there is a substantial degree of excitatory convergence of different retino‐geniculo‐cortical information channels on single neurons in the primary visual cortices and the extrastriate cortices constituting parts of the form/colour or the motion processing streams.

4. Despite this high degree of excitatory convergence of different information channels, the large‐fibre channels (the Y‐channel in the cat and the magnocellular or Y‐like channel in macaque), are in both carnivores and primates the principal contributors to the motion processing cortical streams.