bluuebunny/crossref_metadata_2025 huggingface dataset:
LONG‐TERM THERAPEUTIC EFFECTS OF ACE INHIBITOR AND CALCIUM ANTAGONISTS ON HYPERTENSIVE VASCULAR LESIONS IN M‐SHRSP
Authors: Ohta Yoshio , Chikugo Taka‐aki , Suzuki Tsuneyuki
Published: June 2007

1. Our results indicate that the drugs used in this study are very effective in malignant hypertension therapy.

2. For M‐SHRSP treated with highly effective antihypertensive drugs, if blood pressure remains under 200 mmHg over the long‐term, the structures of the small arteries and/or arterioles stay as well preserved as they do in WKY.

3. For M‐SHRSP treated with drugs with a lower antihyper‐tensive effect, the occurrence of cerebrovascular lesions and angionecrosis in the various organs are suppressed significantly, even though blood pressure remains over 250 mmHg over the long‐term. Based upon effect alone, there is no difference between ACEI and a calcium antagonist. However, inhibition of the proliferation of vascular smooth muscle cells is more potent in the former than in the latter.

4. These results suggest that ACEI might have the potential to suppress smooth muscle cell proliferation independent of high blood pressure.
EFFECT OF FELODIPINE ON BLOOD PRESSURE, BODY SODIUM, PLASMA RENIN ACTIVITY AND PLASMA ALDOSTERONE IN HYPERTENSIVE AND NORMO‐TENSIVE RATS
Authors: Ledingham Janet M. , Hamada M. , Simpson F. O.
Published: June 2007

1. To explore its effect on blood pressure (BP) in relation to body sodium (Na), felodipine was given to New Zealand genetically hypertensive (GH) and normotensive (N) rats and to Japanese SHR and WKY rats, prepared for repeated measurements of body sodium (Na) by a whole body counting technique (22Na) using an Na‐free pelleted diet and 22Na‐NaCl fluid as the sole source of Na, with water also available. The drug was added to the food before pelleting pellets, 0.5 mg/g food.

2. Felodipine reduced BP in each strain; this effect was as great on normal Na intake as when on a zero Na intake. Felodipine caused an increase in plasma renin activity in each strain but the increase reached significant levels only in GH, SHR and WKY. Plasma aldosterone was decreased by treatment in GH and N and increased in SHR and WKY.

3. In rats on a zero Na intake (water sole drinking fluid), felodipine caused no fall in body Na (i.e. no natriuretic effect was detectable) except in WKY. When saline was freely available, felodipine tended to stimulate saline intake and was associated with an increase in body Na in all strains except SHR; body Na was high in SHR even in the absence of felodipine and did not increase further with felodipine treatment. Felodipine slightly speeded up the excretion of an Na load in rats on an ample NaCl intake (choice of 0.5%22Na‐NaCl and water) but this may have been due, in part, to the treated rats having taken, by choice, a greater intake of saline in the pre‐load period.

4. In this study, felodipine reduced BP and stimulated PRA and salt appetite. Its effects on Na handling varied to some extent between the strains; there was no consistent natriuretic effect, but rather some evidence of Na retention.
EFFECT OF FELODIPINE TREATMENT AND WITHDRAWAL ON BLOOD PRESSURE AND CARDIOVASCULAR STRUCTURE IN NEW ZEALAND GENETICALLY HYPERTENSIVE RATS
Authors: Ledingham J. M. , Phelan E. L. , Cross M. A. , Laverty R.
Published: June 2007

1. Four groups of New Zealand genetically hypertensive (GH) rats were treated with felodipine as follows: (A) from ages 4–12 weeks; (B) 4–20 weeks; (C) 4–12 weeks then withdrawn from felodipine till age 20 weeks; and (D) 12–20 weeks.

2. Effects on blood pressure (BP), left ventricular (LV) weight and the structure of myograph‐mounted mesenteric resistance arteries (MRA) were measured.

3. BP was about 170 mmHg in 4 week old GH rats and did not change substantially from this value in groups A and B but rose to over 230 mmHg in untreated controls. In rats of group D, started on felodipine at 12 weeks, BP fell rapidly and was 173 mmHg at 20 weeks. On withdrawal of felodipine at 12 weeks (group C) BP rose rapidly and exceeded control levels at 20 weeks.

4. LV mass was significantly lower (P < 0.001) in all groups (A, B and D) killed while on felodipine but rose to control levels in the rats taken off felodipine.

5. In the four treated groups there were no significant changes in MRA structure (lumen diameter, medial thickness, media/lumen ratio and volume of medial tissue) as measured on the myograph.

6. Felodipine induces substantial falls in BP in GH rats which are sufficient to prevent cardiac hypertrophy but do not alter MRA structure. Resistance artery structure in GH rats does not seem to relate to the level of hypertension, and may therefore not have a necessary role in the pathogenesis of this hypertensive strain.
PROTECTIVE EFFECT OF NICARDIPINE TREATMENT ON CEREBROVASCULAR MICRO ANATOMICAL CHANGES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Amenta Francesco , Fenante Fabio , Ricci Alberto , Sabbatini Maurizio
Published: June 2007

1. The effect of long‐term treatment with the dihydropyridine Ca2+ antagonist, nicardipine, on the morphology of different sized pial arteries was assessed in spontaneously hypertensive rats (SHR) using histological techniques associated with image analysis.

2. In control 20 week old SHR blood pressure values, the thickness of the tunica media, the media‐to‐lumen ratio and connective tissue content were significantly increased in comparison with reference normotensive Wistar‐Kyoto (WKY) rats.

3. Treatment for 8 weeks with a daily dose of 3 mg/kg of nicardipine decreased blood pressure values in SHR and significantly reduced the area occupied by the tunica media and the media‐to‐lumen ratio. This effect was observed primarily in small sized pial arteries and to a lesser extent in medium sized pial arteries. Nicardipine administration was without effect on connective tissue content in the wall of cerebral arteries.

4. These results indicate that treatment with nicardipine reduces blood pressure elevation in SHR and exerts a protective effect on arteries controlling cerebrovascular resistance. The activity of the compound primarily on small sized pial arteries may protect the brain from generalized vasodilation which could cause cerebral hypoperfusion.
EFFECT OF BARNIDIPINE ON BLOOD FLOW TO MAJOR ORGANS AND RENAL FUNCTION IN ANAESTHETIZED DOGS AND SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Saitoh Minori , Kasai Chieko , Ishikawa Jun , Masaki Katsuhiro , Asano Masaharu
Published: June 2007

1. The effects of barnidipine on blood flow to major organs and on renal function were investigated in anaesthetized dogs and conscious spontaneously hypertensive rats (SHR), and the results were compared with those for nicardipine, nitrendipine, nisoldipine, manidipine and amlodipine.

2. In anaesthetized dogs, barnidipine (0.3–3 μg/kg i.v.) dose‐dependently decreased blood pressure and increased or preserved blood flow in the vertebral, coronary, femoral and renal arteries. The effect of barnidipine on blood flow was the most potent of the compounds tested. In conscious SHR, barnidipine (0.3–3 mg/kg p.o.) produced a dose‐dependent antihypertensive effect and decreased renal vascular resistance. Barnidipine also dose‐dependently increased urinary volume. The antihypertensive and diuretic effects of barnidipine were the most potent of the drugs tested.

3. In summary, barnidipine was shown to preserve or increase blood flow to major organs and to produce diuretic activity with a decrease in blood pressure. These findings suggest that barnidipine maintains or promotes renal function at antihypertensive doses.
EFFECT OF ANGIOTENSIN‐CONVERTING ENZYME INHIBITORS ON FRUCTOSE INDUCED HYPERTENSION AND HYPERINSULINAEMIA IN RATS
Authors: Erlich Y. , Rosenthal T.
Published: June 2007

1. The effect of angiotensin‐converting enzyme inhibitors (ACEI) enalapril, lisinopril and ramipril was studied on fructose‐induced hypertensive and hyperinsulinaemic rats.

2. 60 Sprague‐Dawley rats were fed a fructose‐enriched diet for 5 weeks, which produced hyperinsulinaemia, hypertri‐glyceridaemia and hypertension. Beginning with week 3 of the diet, lisinopril (10 and 20 mg per kg per day), ramipril (5 and 10 mg/kg per day) and enalapril (20 mg/kg per day) were given daily in drinking water for 2 weeks to 10 rats in each drug group. Ten rats fed only the fructose‐enriched diet served as control.

3. Systolic blood pressure was measured weekly by the indirect tail‐cuff method. Plasma insulin level was determined using RIA.

4. Data indicate that ACEI improve insulin resistance induced by high‐fructose intake in rats; that despite their equal hypotensive effect, ACEI differ in their ability to improve insulin resistance; and that improvement of insulin resistance by ACEI is dose‐dependent.
SUPPRESSION OF VASCULAR TRANSFORMING GROWTH FACTOR‐β1 AND EXTRACELLULAR MATRIX GENE EXPRESSIONS BY CILAZAPRIL AND NIFEDIPINE IN HYPERTENSIVE RATS
Authors: Kim Shokei , Ohta Kensuke , Hamaguchi Akinori , Miura Katsuyuki , Yukimura Tokihito , Iwao Hiroshi
Published: June 2007

1. We investigated the protective effects of an angiotensin‐converting enzyme inhibitor (ACEI) and a Ca antagonist on vascular injury in hypertension.

2. Thirteen week old stroke‐prone spontaneously hypertensive rats (SHRSP) were orally given cilazapril (ACEI 10 mg per kg day) or nifedipine (Ca antagonist 30 mg kg per day) for 12 weeks. After the treatment, the aorta and superior mesenteric artery were excised, and subjected to the extraction of RNA. mRNA levels for the transforming growth factor‐β1 (TGF‐β1) and extracellular matrix components such as fibronectin (FN), collagen type I (CoI), type III (CoIII) and type IV (CoIV) and laminin, were measured by northern blot analysis, using each specific cDNA probe.

3. In the mesenteric artery of SHRSP, TGF‐β1 mRNA levels were increased compared with Wistar‐Kyoto (WKY) rats, being accompanied by a significant increase in mRNA levels for FN, CoI, CoIII, CoIV and laminin. In the aorta, only TGF‐bland fibronectin mRNAs were increased in SHRSP, but collagen and laminin were not increased.

4. Both cilazapril and nifedipine, to similar extents, suppressed the above mentioned increased gene expressions in both mesenteric artery and aorta, being associated with the improvement of vascular hypertrophy.

5. These results suggest that TGF‐Blmay be responsible for smooth muscle cell hypertrophy and the increased deposition of extracellular matrix in hypertensive blood vessels. Both cilazapril and nifedipine may lessen hypertensive vascular thickening, by suppressing the gene expression of TGF‐Bland extracellular matrix.
DO KININS MEDIATE CARDIOPROTECTIVE AND RENOPROTECTIVE EFFECTS OF CILAZAPRIL IN SPONTANEOUSLY HYPERTENSIVE RATS WITH RENAL ABLATION?
Authors: Kohzuki Masahiro , Yasujima Minoru , Kanazawa Masayuki , Yoshida Kazunori , Sato Tokutato , Abe Keishi
Published: June 2007

1. We assessed the potential of the kallikrein–‐kinin system in mediating the cardioprotective and renoprotective effects of an angiotensin‐converting enzyme inhibitor (ACEI), cilazapril (CIL) in rats with renal ablation.

2. Eight week old spontaneously hypertensive rats (SHR) were subjected to 5/6 nephrectomy. One week after the operation, the rats were divided into 5 groups: (i) vehicle; (ii) CIL 1 mg/kg per day per os (p.o.); (iii) Hoe140 (HOE) 70 μg/kg per day given intraperitoneally (i.p.); (iv) CIL 1 mg/kg per day p.0. plus HOE 7 7μg/kg per day i.p.; (v) CIL 1 mg/kg per day p.o. plus HOE 70 μg/kg per day i.p. The treatment lasted for 4 weeks.

3. CIL alone significantly reduced systolic blood pressure, urinary protein excretion, heart weight and serum creatinine level. HOE alone did not induce any significant changes in these parameters. CIL in combination with HOE (7 or 70 μg/kg per day) did not induce any changes in these parameters, in addition to those associated with the effects of CIL alone.

4. These results indicate that the kallikrein‐kinin system might not play a major role in the cardioprotective and renoprotective effects of ACE inhibitors in the rat remnant kidney model of chronic renal failure.
PROTECTIVE EFFECT OF THROMBOXANE SYNTHETASE INHIBITOR ON HYPERTENSIVE RENAL DAMAGE IN DAHL SALT‐SENSITIVE RATS
Authors: Gomi T. , Ikeda T. , Sasaki Y. , Kosugi T. , Shibuya Y. , Sakurai J.
Published: June 2007

1. The effects of OKY‐046, a specific thromboxane (TX) synthetase inhibitor, on blood pressure, urinary excretion of TX and its release from blood platelets and renal papilla, and pathological change of glomeruli were evaluated in Dahl salt‐sensitive rats.

2. Average daily intakes of OKY‐046‐treated rats were 0.93 mg/kg (low dose), 9.8mg/kg (moderate dose), and 88 mg/kg (high dose).

3. Systolic blood pressure tended to decrease by 6.3, 11.4, and 10.9% in three OKY‐treated groups.

4. OKY‐046 suppressed the release of TX from platelets in a dose‐dependent fashion. Both TX in urine and released from renal papilla decreased in OKY‐treated groups with moderate and high dose. OKY‐046 resulted no change in urinary excretion or release from renal papilla of prostaglandin E2 or 6‐keto‐prostaglandin F1α.

5. Glomerular sclerosis score decreased significantly in both groups treated with moderate and high doses of OKY‐046.

6. An inhibition of renal TX synthesis by TX synthetase inhibitor has a protective effect on the development of hypertensive renal damage with minor antihypertensive effect in Dahl salt‐sensitive rats.
ELECTROENCEPHALOGRAPHIC EVALUATION OF THE THERAPEUTIC EFFICIENCY OF ANTIHYPERTENSIVE AGENTS ON M‐SHRSP
Authors: Ohta Yoshio , Chikugo Taka‐aki , Suzuki Tsuneyuki , Chichibu Shiko
Published: June 2007

1. In order to evaluate the therapeutic effects of antihypertensive agents on malignant hypertension in M‐SHRSP, EEG were performed as a non‐invasive, therapeutic index.

2. Under pentobarbital anaesthesia, the EEG pattern of rats with severe hypertension and/or cerebrovascular lesions showed alternate short‐active and long‐depressive phases with spike and sharp waves.

3. When M‐SHRSP were treated with an angiotensin converting enzyme inhibitor (SQ 29,852) or a calcium antagonist (manidipine), the depressive phases became shorter and active phases longer. These changes were more prominent in manidipine treated rats than in SQ 29,852 treated rats.

4. The EEG spike‐ and sharp‐wave complex seems to be a convenient index for evaluating cerebrovascular lesions and cerebral activity in M‐SHRSP.
IS THE M1‐MUSCARINIC RECEPTOR A CANDIDATE GENE FOR HYPERTENSION IN THE SPONTANEOUSLY HYPERTENSIVE RAT?
Authors: Klett Christoph P. R. , Printz Morton P.
Published: June 2007

1. Central nervous system muscarinic receptors have been implicated in genetic models of hypertension as well as in stress adaptive cardiovascular responses. To determine if the sequence of the M1‐muscarinic receptor is pathogenetic for hypertension, we analysed the differences between SHRLJ (spontaneously hypertensive rats) and WKYLJ (Wistar‐Kyoto) rats in the sequence of the M1‐receptor gene.

2. Specific primer sets were synthesized so as to cover the gene in 10 fragments (158–344 base pairs) with overlaps. Analysis was conducted by both polymerase chain reaction (PCR)‐acrylamide and by single‐stranded conformation polymorphism (SSCP).

3. No polymorphic locus was found by non‐denaturing PCR‐acrylamide nor by denaturing SSCP. Slight intrastrain variations in fragment 2 of the parental strains were examined by direct sequencing; however, no difference in sequence was found between SHRLJ and WKYLJ. TO identify the chromosomal location and possible linkage with a polymorphic locus, rat/mouse somatic hybrid cell lines were examined. The rat M1‐muscarinic receptor was assigned to chromosome 1.

4. Based on analysis of the coding sequence of the gene, our data do not support the hypothesis that the M1‐muscarinic receptor is a candidate gene for hypertension. We conclude that, pending analyses of the promoter and regulatory regions of the gene, differences in the M1‐muscarinic receptor in SHR either in receptor expression or in physiological response must be due to altered intracellular signalling or extracellular transynaptic events, but not due to a mutation of the gene sequence.
ELEVATED SPONTANEOUS ACTIVITY OF PHENYLEPHRINE‐EXCITED NEURONS IN THE CAUDAL VENTROLATERAL MEDULLA OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Wong T. M. , Yang Z. , Chan Y. S.
Published: June 2007

1. The caudal ventrolateral medulla (CVLM) of pentobarbital‐anaesthetized spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats was identified by the depressor response with microinjection of glutamate.

2. The mean firing rate of the spontaneously active phenyl‐ephrine‐excited CVLM neurons was significantly greater in SHR than in WKY. The pattern of neuronal firing in terms of coefficient of variation and skewness of the interspike interval histogram was similar in both types of rats.

3. Administration to CVLM of kainic acid, an excitotoxic agent, led to a biphasic blood pressure response—a transient reduction followed by a gradual and sustained elevation. The elevation in blood pressure was significantly greater in SHR than in WKY.

4. These findings suggest that the barosensitive CVLM neurons are more active and the tonic inhibitory influence from CVLM to rostral ventrolateral medulla (RVLM) is greater in SHR than in WKY. It is therefore not likely that the elevated spontaneous activity of the RVLM cardiovascular neurons in SHR is due to a smaller inhibitory influence from CVLM.
HYPOTHALAMIC AND MEDULLARY GABAA AND GABAb‐ERGIC SYSTEMS DIFFERENTLY REGULATE SYMPATHETIC AND CARDIOVASCULAR SYSTEMS
Authors: Takenaka K. , Sasaki S. , Nakamura K. , Uchida A. , Fujita H. , Itoh H. , Nakata T. , Takeda K. , Nakagawa M.
Published: June 2007

1. To determine whether hypothalamic and medullary GABA (gamma‐aminobutyric acid)B stimulation would affect the sympathetic and cardiovascular activities, and to determine whether these effects would be altered in hypertension, baclofen (a GABAb agonist) was injected into a hypothalamic pressor area (ventromedial hypothalamus, VMH), a depressor area (anterior hypothalamus, AH), or a nucleus tractus solitarius (NTS) in normotensive and spontaneously hypertensive rats (SHR).

2. Intracetebroventricular (ICV) injections of a GABAa agonist (muscimol, 1 μg) decreased blood pressure (BP) and heart rate (HR). ICV injections of baclofen (2μg) elicited biphasic depressor and pressor effects, and these effects were abolished by a pretreatment with saclofen (GABAb antagonist, 100 μg, icv).

3. Muscimol (400 ng) and baclofen (800 ng) injected into VMH decreased sympathetic nerve activity (SNA), BP and HR to almost similar levels, while saclofen injected into VMH increased HR without affecting BP levels.

4. The same dose of baclofen injected into AH increased BP, but muscimol (AH) did not alter BP.

5. Both muscimol and baclofen injected into NTS increased BP, but its magnitude was larger in baclofen injections.

6. Depressor and sympathoinhibitory effects of baclofen (VMH) in SHR were larger than those in normotensive Wistar‐Kyoto (WKY) rats, while pressor responses elicited by baclofen (AH) did not differ between SHR and WKY.

7. In summary, GABA reduces SNA, BP and HR through both GABAa and GABAb receptors in VMH. In addition, the GABAb system acts on AH and NTS to further regulate the cardiovascular activities. In SHR, GABAB‐ergic dysfunction in VMH but not in AH might contribute to the development of hypertension.
FUNCTIONAL ALTERATION OF THE GABAB RECEPTOR IN THE BRAIN OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ichida Tatsuya , Sasaki Susumu , Takeda Kazuo , Kuriyama Kinya , Nakagawa Masao
Published: June 2007

1. We studied the ontogenetic development of GABAB receptors and their coupling to cyclic AMP formation in spontaneously hypertensive (SHR) and normotensive Wistar‐Kyoto (WKY) rat brains. GABAB receptor binding to various brain regions was compared in age‐matched SHR and WKY rats.

2. The specific [3H]‐GABA binding to the posterior hypothalamus (PH) was significantly lower in not only 4 week old (normotensive) but also 11 week old (hypertensive) SHR, when compared with age‐matched WKY.

3. Moreover, GABAB receptor agonists (baclofen and DN‐2327)‐induced suppression of adenylate cyclase activity also showed a decrease in 4 week old and 11 week old SHR PH.

4. We concluded that the number and the functional responsiveness of GABAB receptors in rat brains decrease in SHR, preceding blood pressure elevation. The activity of GABABergic mechanisms may be different in the brains of SHR and WKY rats.
BARORECEPTORS IN THE CAROTID SINUS CONTRIBUTE TO ARTERIAL BARORECEPTOR REFLEXES IN NORMOTENSIVE RATS
Authors: Ohta H. , Talman W. T.
Published: June 2007

1. Baroreceptor reflex influences on renal sympathetic nerve activity (RSNA) were estimated with non‐linear regression analysis (sigmoidal curve fitting) before and after transection of carotid sinus nerves (CSN) and aortic depressor nerves (ADN) in rats.

2. Transection of ADN reduced the gain of the reflex to 42% of basal levels with increases in arterial pressure (MAP) and RSNA. Subsequent transection of CSN eliminated the remaining sigmoidal correlation between MAP and RSNA without further changes in resting MAP and RSNA.

3. By comparison, the transection of CSN reduced the gain of the reflex to 53% of basal levels without affecting other variables. Additional transection of both ADN eliminated the remaining sigmoidal correlation between MAP and RSNA with further increases in resting MAP and RSNA.

4. These results indicate that carotid sinus baroreceptors exist in rats. They contribute to baroreceptor‐mediated reflex changes in RSNA as do aortic baroreceptors, although the working range of MAP may increase with transection of the latter.
α‐ADDUCIN MAY CONTROL BLOOD PRESSURE BOTH IN RATS AND HUMANS
Authors: Bianchi Giuseppe , Tripodi Maria G. , Casari Giorgio , Torielli Lucia , Cusi Daniele , Barlassina Cristina , Stella Paola , Zagato Laura , Barber Barry R.
Published: June 2007

1. Previous studies on the pathogenetic mechanisms of hypertension in the Milan hypertensive strain of rat (MHS) showed that a polymorphism within the α‐adducin gene is responsible for up to 50% of the blood pressure difference between MHS and their MNS normotensive control strain. A case‐control study has shown also in humans an association between α‐adducin locus and hypertension using 4 multiallelic markers surrounding the α‐adducin locus.

2. With a multiple regression approach we provide an estimate of the contribution of the genotype for each marker to the blood pressure variability in comparison to that provided by sex, body mass index and age.

3. While sex, body mass index and age contributed by about 40–45% to the overall blood pressure variability, the inclusion of the genotype for the marker closer to the α‐adducin locus provided a further increase of the variability explained of about 5%.

4. The contribution independently provided by the other markers decreased exponentially with the increase of distance from α‐adducin locus.
ROLE OF CEREBRAL ATP‐SENSITIVE K+ CHANNELS IN ARTERIAL PRESSURE REGULATION DURING ACUTE CEREBRAL ISCHAEMIA IN SHR AND WKY RATS
Authors: Nishimura M. , Nanbu A. , Sakamoto M. , Nakanishi T. , Takahashi H. , Yoshimura M.
Published: June 2007

1. ATP‐sensitive K+ channels (KATP) are activated either by decreased intracellular ATP content or ATP/ADP ratio during ischaemia. We examined the role of a cerebral KATP in arterial pressure regulation during acute cerebral ischaemia using SHR and WKY rats. Thirteen week old male SHR or WKY rats were anaesthetized with urethane, and arterial pressure and heart rate were recorded under an artificial ventilation.

2. Intracerebroventricular (i.c.v.) injections of glibenclamide, a specific inhibitor of KATP, elicited dose‐dependent vasopressor responses in WKY with bilateral ligation of carotid arteries, whereas it caused smaller vasopressor responses in SHR than WKY.

3. Systemic administration of AVP V1 receptor antagonist, OPC‐21268, abolished the vasopressor responses of i.c.v. injections of glibenclamide in WKY but not in SHR.

4. Intracerebroventricular injections of glibenclamide caused both the increase in plasma concentration of AVP and the decrease in pituitary AVP content in WKY with bilateral ligation of carotid arteries, whereas it elicited no significant change in plasma and pituitary concentration of AVP in SHR with bilateral ligation of carotid arteries.

5. Cerebral KATP may play a role in the protection of excess hypertension by inhibiting AVP release from the pituitary glands during acute ischaemia in WKY, but this mechanism might not work in SHR during acute cerebral ischaemia.
MECHANISMS FOR PRESERVED CEREBROVASCULAR AUTOREGULATION DURING HYPERTENSION IN RATS AFTER SINOAORTIC DENERVATION
Authors: Talman W. T. , Dragon D. Nitschke
Published: June 2007

1. Cerebral blood flow (CBF) and cerebrovascular resistance (CVR) autoregulate to higher levels of arterial pressure (AP) in rats after sinoaortic denervation (SAD) than in intact rats.

2. Potential mechanisms for this phenomenon were studied by monitoring CBF by laser flowmetry while increasing AP in rats after: (i) SAD; (ii) SAD plus bilateral removal of the superior cervical ganglia; (iii) SAD plus interruption of all renal vessels and nerves (renal isolation); (iv) SAD plus sympathectomy and renal isolation; and (v) intravenous treatment with the nitric oxide synthase inhibitor L‐nitroarginine (LNA).

3. Compared to intact control rats autoregulation persisted to higher absolute levels of AP in SAD rats with isolation of the kidneys and resistance did not fall significantly below that in rats with SAD alone.

4. Effects of SAD on autoregulation were not altered by combining renal isolation with an interruption of sympathetics.

5. LNA did not affect the baroreflex but blocked a breakthrough of autoregulation even at a maximal mean AP (MAP) of 189 ± 2mmHg.

6. Breakthrough occurred in animals pretreated with LNA plus L‐arginine but not in animals given LNA plus D‐arginine.

7. These data are consistent with a role of the baroreflex in the expression of breakthrough and suggest that breakthrough may result from release of nitric oxide or a nitric oxide donor.
MONITORING NOREPINEPHRINE LEVELS BY MICRODIALYSIS IN THE WHITE ADIPOSE TISSUE OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Cabassi A. , Bergamaschi E. , Mutti A. , Franchini I. , Borghetti A.
Published: June 2007

1. To investigate whether microdialysis is suitable to monitor catecholamine in white adipose tissue of conscious rat and to assess eventual differences in norepinephrine (NE) interstitial levels, two groups of 12 male spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats, 14–16 weeks old, were compared.

2. A flexible microdialysis probe was implanted subcutaneously in the parascapular region, and perfused with Ringer solution (flow rate: 2.0 μL/min). After a 20min equilibration period, NE levels were monitored over a 120 min period; then, tyramine hydrochloride (0.1 nmol/min) was perfused for 80 min. Dialysates from each 20 min collection period were analysed by HPLC with electrochemical detection for NE.

3. Basal levels of NE (adjusted for the recovery) were higher in SHR compared to WKY (1210.0 ± 140.5 pg/mL dialysate vs 573.3 ± 75.8 pg/mL dialysate; P < 0.001, ANOVA). In both strains tyramine perfusion increased NE concentration in dialysates; the net (i.e. baseline subtracted) NE output was lower (76.3 pg/h, s.e.m. 22.3) in SHR compared with that shown by WKY rats (201.0 pg/h, s.e.m 18.4, P < 0.01).

4. The increased basal levels of NE observed in SHR are associated with a blunted response to tyramine challenge. Since tyramine is known to cause NE release from the cytosol but not from vesicle stores, such a blunted response is consistent with an increased turnover rate of NE or with an accelerated uptake in pre‐synaptic vesicles which, together with the higher basal levels, would suggest increased noradrenergic activity.
CYCLOSPORINE A‐INDUCED HYPERTENSION IN SHR AND WKY: ROLE OF THE SYMPATHO‐ADRENAL SYSTEM
Authors: Grobecker H. F. , Riebel K. , Wellenhofer T.
Published: June 2007

1. Cyclosporine A induced a highly significant additional increase in blood pressure in spontaneously hypertensive rats (SHR) and elevated clearly the blood pressure in the genetically related normotensive controls, Wistar‐Kyoto (WKY) rats, after both single (i.v.) and long‐term administration (oral).

2. Acceleration of rise in blood pressure by cyclosporine is caused by sympatho‐adrenal activation. Evidence for this mechanism of action came from the following pharmacological interventions: After chemical sympathectomy with 6‐hydroxydopamine increase in blood pressure by cyclosporine was significantly reduced. Depletion of catecholamine stores by reserpine also diminished significantly the cyclosporine induced hypertension. Selective cyladrenergic receptor blockade by prazosin blunted acute hypertension induced by cyclosporine.

3. Norepinephrine concentrations in the spleen of both WKY and SHR were reduced by long‐term administration of cyclosporine. In the kidneys of WKY rats the level of norepinephrine was decreased but increased in the kidneys of SHR after long‐term administration of cyclosporine.

4. Also the immunosuppressive agent FK506 with a macrolide‐like structure induced acute hypertension in normotensive rats. The hypertensive effect was blunted by the vasoselective calcium channel blocker felodipine.

5. It is concluded that immunosuppressive agents like cyclosporine or FK506 activate the sympatho‐adrenal system in normotensive and genetically hypertensive rats, thereby inducing hypertension. The mechanism of action may contribute to the hypertension seen in patients treated with cyclosporine after transplantation of heart, kidney or liver.
CURRENT STATUS OF PUTATIVE IMIDAZOLINE (I1) RECEPTORS AND RENAL MECHANISMS IN RELATION TO THEIR ANTIHYPERTENSIVE THERAPEUTIC POTENTIAL
Authors: Evans Roger G.
Published: June 2007

1. A ‘second generation’ of centrally acting antihypertensive agents has recently been developed. Unlike the ‘first generation’ of these agents (e.g. α‐methylodopa, clonidine, guanabenz), which act predominantly by an agonist action at α‐adrenoceptors, these agents (e.g. rilmenidine, moxonidine) are believed to exert their antihypertensive effects chiefly by an interaction at putative imidazoline (I) receptors of the I1‐type, and so have a reduced profile of α‐adrenoceptor‐mediated side effects. There is also evidence from studies in experimental animals that activation of I1‐receptors mediates a natriuretic effect. This review evaluates the evidence that they mediate renal effects different from those of α‐adrenoceptors that could contribute to their long‐term efficacy.

2. Data from binding studies suggest that I1‐binding sites are heterogeneous. There is conflicting evidence concerning whether any of there binding sites are truly receptors. Indeed, the best evidence for the existence of I1‐receptors comes from in vivo experiments receptive sites in the central nervous system to reduce sympathetic drive and blood pressure.

3. There are a wide range of potential sites and mechanisms through which centrally acting antihypetensive agents can affect renal function, including actions mediated within the central nervous system, heart, systemic circulation and within the kidneys themselves. ‘First generation’ centrally acting anti‐hypertensive agents cause diuresis and natriuresis in rats, while in dogs and humans a diuresis is often seen with variable effects on sodium excretion.

4. Evidence from studies in anaesthetized rats indicates that rilmenidine and moxonidine can promote sodium excretion by interacting with both central nervous system and renal putative I1‐receptors. This does not appear to necessarily be the case in other species. At this time there are few or no published data from clinical studies to suggest that ‘second generation’ centrally acting antihypertensive agents affect salt and water balance differently from ‘first generation’ agents.
BAROREFLEX CONTROL OF CORONARY BLOOD FLOW VARIES REGIONALLY IN AWAKE DOGS
Authors: Quail Anthony W. , Cottee David BF , White Saxon W. , Proges William L. , Hennessy Edmund J.
Published: June 2007

1. Baroreflex responses to changes in aortic pressure were measured simulataneously in three main coronary regions of awake dogs.

2. Pulsed Doppler flow probes were mounted at prior surgery on the right, circumflex and anterior descending coronary arteries; the animals were placed in complete heart block and the left ventricle was placed. After 2‐4 weeks recovery, baroreflexes were evoked by inflating a balloon catheter placed in the mid‐thoracic aorta via the femoral arteriotomy. Flow and pressure data were collected at rest, and during acute (8 s) and steady‐state (25 s) baroreflex challenge.

3. Changing ventricular rate alone caused a fall in aortic pressure at low rates; however, over the range 60 to 180 b.p.m., circumflex and anterior descending coronary flow and conductance changed directly with ventricular rate, but right coronary flow and conductance remained unchanged.

4. Acute aortic pressure elevation increased flow at 8 s in all beds at all rates. Conductance effects at 60 b.p.m. were negligible in all three beds, but rose at 100 and 180 b.p.m. in the right and circumflex beds.

5. Sustained aortic pressure elevation (25 s) caused flow to return towards control in all beds at all ventricular rates, but in the right coronary at 60 b.p.m. flow fell below control. Conductance at this time was unchanged at all rates in the anterior descending bed, fell modestly in the circumflex, and decreased to below resting in the right coronary bed.

6. Baroreflex control of coronary flow and conductance thus varies between territories, and within territories, depending on ventricular rate. The right coronary bed appears to be regulated by a bidirectional, baroreflex‐linked mechanism, which is functionally opposite in action to that found in most vascular beds.
PHENYTOIN‐INDUCED HYPERGLYCAEMIA MAY CONFOUND RAT CEREBROPROTECTION MODELS
Authors: Qi Hui , Newman George C.
Published: June 2007

1. The anticonvulsant phenytoin (PHT) has been used with variable success in animal models of cerebral ischaemia. Although PHT has been reported to alter glucose regulation in man, this potential effect has been largely ignored in animals. Because hyperglycaemia strongly influences the outcome of cerebral ischaemia, we sought to systematically delineate the effects of PHT on serum glucose in several rat strains.

2. We have studied the PHT dose‐response curve for serum PHT and glucose concentrations and several physiological variables. Phenytoin induces a significant, concentration‐dependent hyperglycaemia, even in the ranges commonly used for humans and in animal models.

3. Hypothermia of several degrees was observed during PHT administration, but no hypotension or bradycardia was found.

4. Both hyperglycaemia and hypothermia must be considered when PHT is studied as a neuroprotective agent in animal models.
FUNCTIONAL IMAGING STUDIES OF HUMAN VISUAL CORTEX
Authors: Watson John DG
Published: June 2007

1. The past decade has seen a burgeoning of functional imaging studies of cerebral activity in normal humans. Much of this work has been performed on the visual system, which is an important and often conveniently studied part of the brain.

2. Previously, what we believed about the functional anatomy of the human visual system was almost entirely obtained by studying individual patients with cerebral lesions and from experiments in animals. Early functional imaging experiments were often quite simple, descriptive exercises.

3. Techniques such as positron emission tomography have become quite mature; with this and increasing experience on the part of the investigators, the experiments performed have become more novel. Functional imaging methods have become part of the mainstream of investigations to be used for research on vision. They already have led to novel hypotheses about how aspects of this system work.
INJURY‐ AND USE‐RELATED PLASTICITY IN THE PRIMARY SENSORY CORTEX OF ADULT MAMMALS: POSSIBLE RELATIONSHIP TO PERCEPTUAL LEARNING
Authors: Irvine DRF , Rajan R.
Published: June 2007

1. Restricted cochlear lesions in adult animals result in a reorganization of auditory cortex such that the cortical region deprived of its normal input by the lesion is occupied by expanded representations of adjacent cochlear loci (and thus of the frequencies represented at those loci). Analogous injury‐induced reorganization is seen in somatosensory, visual and motor cortices of adult animals after restricted peripheral lesions.

2. Rather than constituting a central compensation for the peripheral loss, such reorganization appears to be an extreme form of changes in cortical organization that occur as a consequence of altered patterns of input such as arise from differential use of restricted regions of receptor surfaces (‘userelated’ reorganization). Thus, the frequency organization of auditory cortex is modified in animals trained to perform a frequency discrimination task and analogous changes in the frequency selectivity of cortical neurons are produced by classical conditioning procedures.

3. Recent evidence from the visual system suggests that changes similar to those involved in injury‐ and use‐related cortical reorganization may underlie some forms of what has been called ‘perceptual learning', the improvement in sensory/ perceptual discriminative performance with practice. Some forms of such learning are highly specific to the particular stimuli used in training (i.e. do not generalize to other stimuli), suggesting that the improved performance reflects a change in neural circuitry at a relatively early level of sensory processing. The limited available evidence supports the occurrence of such learning in the auditory system.

4. Recent studies using functional imaging and related techniques indicate that injury‐ and use‐related reorganization occurs in human sensory and motor cortex.
RENAL TRANSPORT OF DRUGS: SPECIFICITY AND MOLECULAR MECHANISMS
Authors: Somogyi Andrew
Published: June 2007

1. The kidney is principally an excretory organ for drugs and their metabolites and has developed high capacity transport systems to rapidly eliminate the large quantities of foreign compounds delivered to it.

2. There are specific and selective transporters for organic cations and organic anions at the contraluminal and luminal membranes of the epithelial cells lining the proximal tubule.

3. For organic anions, the transporter (termed PAH‐transporter) is located at the contraluminal cell membrane and uptake is a tertiary active transport process. Important physicochemical properties for interaction with this transporter are hydrophobicity, ionic charge strength and electron‐attracting side groups.

4. For organic cations, there is evidence for one common transport system at the contraluminal membrane and substrate requirements are the degree of hydrophobicity, ionic charge strength and hydrogen bond formation. At the luminal membrane, an electroneutral H+/organic cation exchanger in which the degree of substrate hydrophobicity is critical for interaction and a choline transport system have been described.

5. P‐Glycoprotein present in renal brush border membranes transports organic cationic drugs but is dissimilar to the luminal electroneutral H+/organic cation exchanger.

6. Clinically, several drugs have been implicated in causing interactions via these transport systems. For organic anions, probenecid blocks the tubular secretion of other organic anions and this has been used to prolong the duration of action of penicillin‐like compounds. For organic cations, cimetidine and trimethoprim are potent inhibitors of the secretion of a number of organic cations, particularly procainamide, which can result in significant clinical toxicity.

7. An understanding of the mechanisms of renal tubular secretion of drugs and their metabolites will allow for the prediction of drug interactions involving renal excretory mechanisms.
IMIDAZOLINE BINDING SITES AND SIGNAL TRANSDUCTION PATHWAYS
Authors: Musgrave IF , Krautwurst D. , Schultz G.
Published: June 2007

1. Discrete, non‐adrenergic binding sites for imidazolines have been characterized in the brain and periphery. The 11 clonidine‐preferring site is mainly distributed in the brain and brain stem, while the 12 idazoxan‐preferring site is more widely distributed.

2. The 11 site appears to be associated with modulation of blood pressure. Imidazolines act within the rostral ventrolat ral medulla to produce hypotension. The underlying signal transduction mechanism is poorly understood.

3. The imidazolines clonidine and cirazoline inhibited nicotine‐stimulated calcium entry into rat phaeochromocytoma (PC‐12) cells by a non‐adrenergic mechanism. This effect was not attributable to the stimulation of protein kinases.

4. Similarly, clonidine and cirazoline inhibited nicotinestimulated inward currents into PC‐12 cells. This inhibitory action was not altered by inhibitors of signal transducing G‐proteins.

5. Clonidine and cirazoline displaced the ion channel ligand [3H]‐phencyclidine from nicotinic acetylcholine receptors, suggesting that these drugs act by direct blockade of the intrinsic ion channel of the nicotinic acetylcholine receptor.

6. This ion channel‐blocking activity represents a novel action of these imidazolines and may underlie some of the proposed physiological actions of 11 sites.
TRINUCLEOTIDE‐REPEAT EXPANSIONS AND NEURODEGENERATIVE DISEASE: A MECHANISM OF PATHOGENESIS*
Authors: Hannan Anthony J.
Published: June 2007

1. Studies of a number of hereditary neurodegenerative diseases, the most common of which is Huntington's disease, have identified the expansion of trinucleotide repeats as a common causative mutation.

2. The diseases are caused by expansions of CAG repeats, encoding polyglutamine tracts, within the coding regions of a variety of unrelated genes. The mechanism whereby this specific genetic instability leads to selective neurodegeneration is currently unknown.

3. Our current understanding of these polyglutamine expansion neurodenerative diseases is outlined. A potential mechanism is discussed whereby subtle alterations in glutamine, and consequently glutamate levels, may induce chronic excitotoxicity and slow cell death in neuronal populations possessing specific glutamate receptors. The potential role of glutamate receptor‐mediated changes to intracellular calcium levels and energy metabolism in the neurodegenerative pathway is also addressed.
CARDIORESPIRATORY AND RENAL RESPONSES TO ARTERIAL CHEMORECEPTOR STIMULATION BY HYPOXIA OR ALMITRINE IN MEN
Authors: Brauer H. , Gens A. , Ledderhos C. , Sanchez R. , Schuster R. , Quies W. , Honig A.
Published: June 2007

1. The cardiorespiratory and renal responses to 3h of normobaric whole‐body hypoxic hypoxia (F1O2= 0.12) as well as to arterial chemoreceptor stimulation by the oral administration of 100 mg almitrine bismesylate during normoxia were measured in 12 normotensive young men undergoing water diuresis. A third series of responses obtained under comparable conditions in the same subjects served as time controls.

2. No significant changes could be detected over time in the parameters measured in control experiments. The subjects reacted to both whole‐body hypoxic hypoxia and to pharmacological chemoreceptor stimulation with significant increases in heart rate, tidal volume, minute ventilation and filtration fraction. Overall renal vascular resistance rose significantly in hypoxia; increases in renal vascular resistance in almitrine experiments were not significant.

3. Renal fractional lithium excretion decreased significantly in response to whole‐body hypoxic hypoxia and increased slightly in response to almitrine. Fractional urine and sodium excretion showed negligible changes.

4. The data indicate that, in humans, both almitrine and whole‐body hypoxic hypoxia affect not only alveolar ventilation but also renal haemodynamics.

5. The renal electrolyte excretion pattern suggests that under certain circumstances (e.g. dilated renal vascular bed) acute, but well‐tolerated, whole‐body hypoxic hypixia can simultaneously stimulate renal proximal tubular sodium reabsorption and inhibit distal tubular sodium reabsorption. The renal tubular responses also indicate that almitrine may influence renal tubular lithium reabsorption by, thus far, unknown mechanisms.
COSEGREGATION OF THE NEW REGION ON CHROMOSOME 3 WITH SALT‐INDUCED HYPERTENSION IN FEMALE F2 PROGENY FROM STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE AND WISTAR‐KYOTO RATS
Authors: Matsumoto Chiho , Nara Yasuo , Ikeda Katsumi , Tamada Tomoko , Mashimo Tomoji , Nabika Toru , Sawamura Makoto , Yamori Yukio
Published: June 2007

1. We investigated candidate loci for salt‐sensitive high blood pressure (BP) in F2 progeny from crossing Wistar‐Kyoto and stroke‐prone spontaneously hypertensive rats.

2. In female F2 progeny, systolic and diastolic BP on the 12th day and the seventh month after salt loading was strongly liked with the D3Mgh12 and D3Mgh6 loci on chromosome 3, respectively.

3. These loci were linked with BP only in female F2 progeny, not in males.

4. These results indicate that hormonal factors may influence salt sensitivity, particularly with respect to gender differences.
GAP JUNCTION CHANNELS GATING AND PERMSELECTIVITY: THERE ROLES IN CO‐ORDINATED TISSUE FUNCTION
Authors: Brink Peter R.
Published: June 2007

1. The gating and permselective properties of gap junction channels are important parameters to determine in delineating their role in co‐ordinated tissue function. This is of particular relevance in non‐excitable tissues.

2. In the present study gating characteristics of rCx43 are demonstrated. The mean open times are of the order of 0.45‐1.1 s. These values are extraordinarily large.

3. The permselectivity of a variety of gap junction channels is also illustrated to show the poor selectivity properties of gap junctions and, hence, their potential to allow the permeation of second messenger molecules.

4. Gating and permselectivity, along with diffusion modelling, produce a picture for gap junction channels that is consistent with physiologically relevant modulation or regulation of gap junction channel patency.
GAP JUNCTION INVOLVEMENT IN SECRETION: THE PANCREAS EXPERIENCE
Authors: Meda Paolo
Published: June 2007

1. Gap junctions and junction‐mediated cell‐to‐cell communications are obligatory features of gland cells, whatever their secretory product is.

2. Studies on pancreatic islets and acinar cells indicate that cell‐to‐cell communication via gap junction channels is required for proper biosynthesis, storage and release of both insulin and amylase.

3. However, the endocrine and exocrine portions of the pancreas show opposite connexin (Cx) and coupling changes in relation to the activation and inhibition of their secretory functions.

4. These differences may be accounted for by the expression of Cx43 in pancreatic islets and of Cx26 and Cx32 in pancreatic acini. This alternative expression of connexin isoforms is also found in several other endocrine and exocrine glands.

5. These observations indicate that connexin‐made channels play a central role in the control of secretory events.