bluuebunny/crossref_metadata_2025 huggingface dataset:
PARALLEL ORGANIZATION OF SOMATOSENSORY CORTICAL AREAS I AND II FOR TACTILE PROCESSING
Authors: Rowe MJ , Turman AB , Murray GM , Zhang HQ
Published: June 2007

1. The two principal tactile processing areas in the cerebral cortex, somatosensory areas I and II, receive direct projections from the thalamus and, as well, are linked through intracortical reciprocal connections. Tactile information may therefore be conveyed to SII, for example, over either a direct path from the thalamus or an indirect, or serial, path from the thalamus via SI.

2. Reports in recent years that tactile responsiveness within the hand area of SII was abolished by surgical ablation of the hand area of the postcentral, or SI, area of cortex in the macaque and marmoset monkeys indicated that a serial processing scheme may operate, at least in primates.

However, as the surgical ablation is clearly irreversible and precludes examination of individual SII neurons in both the control and test circumstances, that is, when SI is intact and when it is inactivated, we have examined in the cat, the rabbit and the marmoset monkey the behaviour of SII neurons before, during and after the selective, rapidly‐reversible inactivation of SI by means of localized cooling.

3. The results demonstrate that in the cat and rabbit, SII responsiveness is never abolished and infrequently affected by SI inactivation and that tactile inputs to SII therefore traverse a direct path from thalamus, organized in parallel with that to SI. In the marmoset (Callithrix jacchus), in contrast to earlier studies based on ablation of SI we found that with reversible inactivation of SI, SII responsiveness was unaffected in 25% of neurons and, although reduced in the remainder, was rarely abolished (<10% of SII neurons).

4. The results indicate that there is substantial direct thalamic input to SII, even in this simian primate, and therefore necessitate revision of the hypothesis that tactile processing at the thalamocortical level in simian primates is based on a strict serial scheme in which tactile information is conveyed from the thalamus to SI and thence to SII.
INSIGHTS INTO MOTOR PERFORMANCE AND MUSCLE FATIGUE BASED ON TRANSCRANIAL STIMULATION OF THE HUMAN MOTOR CORTEX
Authors: Gandevia SC
Published: June 2007

1. Direct cortical stimulation of motor and sensory areas of the cortex in experimental animals and some neurosurgical patients has provided much useful physiological information. Some of the benefits of this approach can be provided in awake volunteer subjects using new techniques which activate the motor cortex thorough the skull (i.e. transcranial electrical or magnetic stimulation).

2. Both electrical and magnetic transcranial stimulation produce complex descending corticospinal volleys which usually contain a direct component (via corticofugal axons) and an indirect trans‐synaptic component. Changes in cortical ‘excitability’ can affect the evoked corticofugal volleys and the electromyographic responses which they involve.

3. Apart from its diagnostic applications to patients with neurological disorders, transcranial stimulation has been applied to the study of a range of aspects of human motor control ranging from apparent cortical ‘plasticity’ to the changes in cortical behaviour produced by exercise.
THE HIPPOCAMPUS, LONG‐TERM POTENTIATION AND MEMORY
Authors: Redman Stephen
Published: June 2007

1. The induction of long‐term potentiation (LTP) at excitatory synapses on CA1 pyramidal neurons occurs partly through an increase in the quantal AMPA current. It is also accompanied by an increase in the number of active sites. Any presynaptic modification, requiring the presence of a retrograde messenger, remains uncertain.

2. There are no definitive data that establish a causal link between LTP and the formation of memories. Pharmacological blockage of NMDA and m GLU receptors and genetic mutants with proteins deleted that are thought to be involved in LTP induction or maintenance or in the formation of memories have all linked deficits in LTP with impairments to behavioural learning, but these links are not necessarily causal. The development of tissue‐ and time‐specific lesions of gene expression for multiple gene products may overcome the present limitations of gene deletion experiments and provide more revealing insights into the relationship between LTP and memory.
PHOSPHODIESTERASE INHIBITORS AND ENDOTHELIN AS MODULATORS OF RESPIRATORY NEUROTRANSMISSION
Authors: Fernandes LB
Published: June 2007

1. Airway smooth muscle receives cholinergic, adrenergic and non‐adrenergic, non‐cholinergic (NANC) neural input. In guinea‐pig airways cholinergic and NANC nerves provide contractile innervation, while adrenergic and NANC nerves provide nerves provide relaxant pathways. In contrast, the major relaxant innervation in human airways is NANC in nature.

2. The present review describes the effects of selective phosphodiesterase (PDE) inhibitors on NANC relaxant and contractle responses in guinea‐pig trachea as well as on NANC relaxations in human bronchus.

3. The effects of endothelin‐1 on cholinergic contractile responses obtained in a variety of species are also assessed.
ILLUMINATION OF THERAPEUTICS BY TOXICOLOGY: A PERSONAL VIEW*
Authors: Pond Susan M.
Published: June 2007

1. My specialties are therapeutics and toxicology. When we think in classical terms about drugs, therapeutics refers to curative healing, toxicology to the capacity to produce harm. However, they are not opposite disciplines, but rather reflect a continuum along the dose‐response curve of a drug or toxin. Since antiquity, the study of toxicology has underpinned and illuminated therapeutics. Even the most potent toxins, such as botulinum and ricin, are used for therapeutic purposes.

2. In the case of one of my favourite research topics, the herbicide paraquat, I illustrate how investigating methods to treat patients poisoned by it has led to important advances in knowledge in medicine and therapeutics. Studying paraquat has launched my own research group on a path towards elucidating the mechanisms of the chronic neurological side effects of the antipsychotic drug, haloperidol, which is used widely to treat schizophrenia. In tracing these tortuous paths, the roles that serendipity and creativity play in research and their implications for education and funding policies are highlighted.
POTASSIUM CHANNELS AND THE CEREBRAL CIRCULATION
Authors: Faraci Frank M. , Sobey Christopher G.
Published: June 2007

1. Hyperpolarization of vascular muscle in response to activation of potassium channels is a major mechanism of vasodilatation.

2. In cerebral blood vessels, two potassium channels have received considerable study recently: ATP‐sensitive and calcium‐dependent potassium channels. Activation of these potassium channels appears to play a major role in the relaxation of cerebral arteries and arterioles in response to diverse stimuli, including receptor‐mediated agonists, intracellular second messengers, reactive oxygen species and hypoxia.

3. The functional influence of ATP‐sensitive and calcium‐dependent potassium channels may be altered in disease states, including hypertension, diabetes and subarachnoid haemorrhage.
EXPERIMENTAL BASIS FOR REALISTIC LARGE‐SCALE COMPUTER SIMULATION OF THE ENTERIC NERVOUS SYSTEM
Authors: Furness JB , Bornstein JC , Kunze WAA , Bertrand PP , Kelly H. , Thomas EA
Published: June 2007

1. The enteric nervous system is perhaps the most accessible part of the mammalian nervous system in which it is feasible to attempt large scale computer simulation that is based closely on experimentally determined data. Here we summarize the data obtained for simulation of motility reflexes in the guineapig small intestine.

2. The chemistry, morphology and connectivity of each type of neuron involved in intrinsic reflexes have been investigated and most classes of neurons are physiologically well characterized. This includes primary sensory neurons, ascending and descending interneurons and motor neurons to circular and longitudinal muscle.

3. The responses of primary sensory neurons and the physiology of synaptic transmission from sensory neurons to interneurons and motor neurons, from interneurons to interneurons and from interneurons to motor neurons have been recorded during reflexes and in some cases the pharmacology of transmission has also been investigated.

4. Computer simulation, in which the activities of up to 30000 neurons are modelled, produces patterns of activity that closely mimic those recorded in physiological experiments.
CYCLOSPORINE A IMMUNOSUPPRESSION IN SHEEP WITH RESPONSE ENHANCEMENT BY CONCOMITANT KETOCONAZOLE
Authors: O'Donoghue HL , Penhale WJ , Manning LS , Reynoldson JA , Turner JH
Published: June 2007

1. The pharmacokinetics of a single dose of Cyclosporine A (CsA) administered to sheep by intravenous (i.v.) route were examined.

2. Concomitant administration of ketoconazole was found to increase the area under the blood CsA concentration‐time curve (AUC) and was effective when adminstered by the oral or intraperitoneal route.

3. The effects of CsA and ketoconazole on the immune system of sheep were also assessed.

4. A single dose of CsA 5mg/kg resulted in abrogation of in vitro lymphocyte function manifest at 24h after injection of CsA. Normal responsiveness recovered in 48‐72h. Numbers of T lymphocytes in peripheral blood were elevated transiently at 48h although no other significant alteration in lymphocyte subsets was observed with this treatment.

5. Concomitant ketoconazole administration enhanced the CsA‐induced suppression of in vitro lymphocyte responses. Blood levels of CsA (AUC values to 24h) were significantly elevated with concomitant ketoconazole administration and depression of lymphocyte responses to mitogens were also significantly enhanced. An increase in the proportion of T4 positive cells in the blood was observed at 48h and at 7 days after administration of CsA with ketoconazole.

6. These findings indicate that CsA effectively abrogates immunocompetence in the sheep and this immunosuppressive effect is enhanced by concomitant administration of ketoconazole.
RENAL KALLIKREIN IN CHRONIC HYPOXIC RATS
Authors: Chen Chau‐Fong , Chen Li‐Wen , Chien Chiang‐Ting , Wu Ming‐Shieu , Tsai Tun‐Jun
Published: June 2007

1. We have studied the role of kallikrein (KK) in the maintenance of renal function in chronic hypoxic rats (high altitude; HA), compared with control rats kept at sea level (SL). Hypoxia was induced by placing female Wistar rats (198‐290 g) in an altitude chamber (5500m) 15 h/day for 4 weeks. Experiments were also conducted to study the interaction of KK with renal nerve activity and endothelin (ET), two parameters previously shown to be altered in this model.

2. It was found that renal cortex tissue KK activity (TKA) was not significantly different in 10 SL and 10 HA rats. However, the urinary KK activity (UKA) was reduced nearly to half (from 35.2±4.6 to 18.5±1.7 pkat/min) in HA rats after 4 weeks of chronic hypoxia.

3. Acute renal denervated diuresis was accompanied by a significant increase in UKA (from 9±2 to 14±2 pkat/min in HA and denervated HA rats, respectively; P < 0.05) in HA rats. Intrarenal arterial pretreatment of aprotinin reduced the denervated diuresis.

4. Endothelin (600 ng/kg per h) reduced urine flow, sodium and potassium excretion in the ipsilateral kidney in another 10 SL and 10 HA rats. The extent of the drop of these parameters was significantly less in HA rats. Urinary KK activity was correlated significantly with the measured renal functional parameters (r ranging from 0.472 to 0.612) in SL rats, but was insignificant in HA rats (r ranging from 0.032 to 0.192).

5. We have demonstrated that chronic exposure to hypoxia decreases urinary KK excretion and that KK is involved in acute renal denervated diuresis generated in these animals. The present study suggests that KK plays a partial role in the maintenance of renal function in chronic hypoxic rats.
MAGNOLOL REDUCES INFARCT SIZE AND SUPPRESSES VENTRICULAR ARRHYTHMIA IN RATS SUBJECTED TO CORONARY LIGATION
Authors: Hong CY , Huang SS , Tsai SK
Published: June 2007

1. Magnolol is an active component of Magnolia officinalis. It is 1000‐times more potent than α‐tocopherol in inhibiting lipid peroxidation in rat heart mitochondira. In the present study, the in vivo antiarrhythmic and anti‐ischaemic effects of magnolol in coronary ligated rats were investigated.

2. Male Sprague‐Dawley rats were anaesthetized with urethane. Magnolol, at dosages of 10−7, 10−8 and 10−9 g/kg, was adminstered intravenously 15 min before ligation of the coronary artery.

3. The incidence and duration of ventricular tachycardia and ventricular fibrillation during 30 min coronary ligation were significantly reduced by magnolol. Ventricular arrhythmias during 10 min reperfusion after the relief of coronary ligation were also reduced.

4. In rats subjected to 4h coronary ligation, 10−7 and 10−8 g/kg magnolol significantly reduced infarct size.

5. We conclude that magnolol may protect the myocardium against ischaemic injury and suppress ventricular arrhythmia during ischaemia and reperfusion.
LOSS OF NITRIC OXIDE PRODUCTION IN THE CORONARY CIRCULATION AFTER THE DEVELOPMENT OF DILATED CARDIOMYOPATHY: A SPECIFIC DEFECT IN THE NEURAL REGULATION OF CORONARY BLOOD FLOW
Authors: Zhao Gong , Shen Weiqun , Zhang Xiaoping , Smith Carolyn J. , Hintze Thomas H.
Published: June 2007

1. The aims of our study were to determine the role of nitric oxide (NO) in cholinergic reflex dilation of the coronary circulation in normal healthy conscious dogs and after the development of pacing‐induced dilated cardiac myopathy and overt congestive heart failure.

2. Dogs were instrumented using sterile surgical techniques under general anaesthesia and allowed to fully recover. The Bezold‐Jarisch reflex was stimulated by the intra‐atrial injection of veratrine or the intravenous injection of PGI2, while the carotid chemoreflex was stimulated by the intracarotid injection of nicotine. Experiments were performed before and after the development of overt congestive heart failure (HF) caused by rapid left ventricular pacing for 4 weeks.

3. The release of NO, or NO‐mediated vascular relaxation following administration of acetylcholine (ACh) may have little physiological significance since as ACh is released from nerve endings in vivo. Stimulation of the Bezold‐Jarisch or carotid chemoreflex resulted in typical vagal cholinergic reflex coronary vasodilation, an increase in coronary blood flow and a decrease in coronary vascular resistance, which was substantially reduced following NO synthesis inhibition with nitro‐L‐arginine.

4. After the development of severe congestive HF, the production of NO by sieved coronary microvessels from the heart was markedly reduced accompanied by a 60‐80% reduction in both the mRNA (northern blot) and protein (western blot) for endothelial NO synthase in the aorta.

5. After the development of severe pacing‐induced HF, activation of the Bezold‐Jarisch or carotid chemoreflex no longer resulted in coronary vasodilation due to the disappearance of NO production from the coronary circulation.

6. Therefore, cholinergic reflex coronary vasodilation is mediated by NO. Because coronary blood vessels lose the ability to produce NO after the development of HF, reflex cholinergic coronary vasodilation is markedly altered, uncovering a previously undiscovered specific defect in the integrated control of the coronary circulation in the failing heart.
PROBING EXCITATION‐CONTRACTION COUPLING IN TRACHEALIS SMOOTH MUSCLE WITH THE MYCOTOXIN CYCLOPIAZONIC ACID
Authors: Amoako Daniel , Qian Yun , Kwan Chiu‐Yin , Bourreau Jean‐Pierre
Published: June 2007

1. Muscarinic stimulation‐induced tonic contraction of airway smooth muscle is independent of membrane potential. This contraction is not sensitive to inhibition by voltage‐operated Ca2+ channel blockers or by K+ channel openers.

2. Cyclopiazonic acid (CPA) inhibits Ca2+ loading of internal stores but does not affect maximal tonic contraction induced by acetylcholine (ACh) in steady state conditions.

3. After depletion of internal Ca2+ stores with CPA, AChinduced tonic contraction becomes dependent upon values of membrane potential. The contraction is then sensitive to voltage‐operated Ca2+ channel blockers and to K+ channel openers.

4. Treatment of trachealis muscle with CPA potentiates the M2‐mediated component of ACh stimulation, but this potentiation is not entirely responsible for the switch in excitation‐contraction (E‐C) coupling.

5. It is proposed that depletion of internal Ca2+ stores with CPA and promotion of M2‐stimulation can lead to a switch in E‐C coupling in trachealis smooth muscle from pharmaco‐ to electromechanical mode, perhaps by targeting a plasma membrane K+ channel.
SLOW PRESSOR EFFECT OF ANGIOTENSIN II IN NORMOTENSIVE RATS WITH RENAL ARTERY STENOSIS
Authors: Melaragno Matthew G. , Fink Gregory D.
Published: June 2007

1. We have shown previously that renal artery stenosis in rats causes enhanced responsiveness to the slow pressor effect of angiotensin II (AngII) and suggested that two‐kidney, one clip (2K1C) hypertension may depend, in part, on changes in responsiveness to the peptide.

2. The present experiment was performed in order to investigate whether a degree of renal artery stenosis that was insufficient to raise blood pressure was able to enhance responsiveness to the slow pressor effect of AngII.

3. Two to four weeks after placement of a 0.2 mm clip over the left renal artery (2K1C) or a sham operation, some 2K1C rats were normotensive. These rats and the sham rats then received an intravenous infusion of AngII (4 ng/min) for 10 days.

4. AngII caused the 2K1C rats to attain significantly higher mean arterial pressure than the sham rats (152 ± 7 vs 133 ± 7 mmHg) and did not result in water or electrolyte retention in the 2K1C rats.

5. These results indicate that normotensive 2K1C rats exhibit enhanced responsiveness to the slow pressor effect of AngII and that the arterial pressure response to renal ischaemia may depend on both AngII formation and responsiveness to the chronic actions of the peptide.
HIGH POTASSIUM DIETS REDUCE ENDOTHELIAL PERMEABILITY IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ishimitsu Toshihiko , Tobian Louis
Published: June 2007

1. High potassium (K) diets are known to prevent hypertensive arterial lesions and reduce stroke incidence without affecting blood pressure.

2. To elucidate the mechanism of this beneficial effect, we studied the effect of K supplementation on the extravasation of plasma albumin in high NaCl‐fed stroke‐prone spontaneously hypertensive rats (SHRSP). Increased permeability of the endo‐thelium to macromolecules is assumed to be an early manifestation of vascular injury.

3. The disappearance of intravenously injected [125I]‐albumin was examined in SHRSP rats fed high NaCl diets containing either 0.5% normal K or 2.1% high K for 5 weeks.

4. The bodyweight, blood pressure, plasma volume and urinary protein excretion were not significantly different between the two SHRSP groups.

5. The high K SHRSP showed a slower plasma albumin disappearance rate than the normal K SHRSP (10.3 vs 14.7%/h, P<0.004). The albumin radioactivity remaining in the aortic wall and in the brain after removing blood after perfusion was lower in the high K SHRSP than in the normal K SHRSP (aorta, ‐ 20%, P<0.02; brain, ‐ 26%, P<0.04).

6. These results suggest that the high K diet reduced the endothelial permeability to albumin in high NaCl‐fed SHRSP rats. High K diets may have a protective effect against endothelial dysfunction and thereby contribute to the reduction of vascular lesion formation and stroke incidence.
GENDER‐RELATED DIFFERENCES IN THE DEVELOPMENT OF ATHEROSCLEROSIS: STUDIES AT THE CELLULAR LEVEL
Authors: Fitzpatrick Lorraine A.
Published: June 2007

1. Calcified arteriosclerotic lesions have been recognized early in life as abnormalities in coronary arteries.

2. We examined coronary arterial plaques as an undecalcified tissue and revealed widespread mineralization within the plaque. Non‐collagenous proteins that regulate calcification, such as osteopontin, have been identified within the atherosclerotic plaque. In vitro, smooth muscle cells derived from porcine coronary arteries express non‐collagenous proteins and type I collagen.

3. We have demonstrated that oestrogen regulates the proliferation of smooth muscle cells obtained from the coronary arteries of sexually mature pigs. The inhibition of proliferation by β‐estradiol occurred in coronary smooth muscle cells (VSMC) obtained from female animals and no proliferation was noted in VSMC isolated from intact male animals after exposure to β‐estradiol.

4. The dynamic changes in matrix composition and cellular proliferation in atherosclerotic vessels may be responsible for the calcification associated with the atherosclerotic plaque.
ENHANCED TISSUE POLYAMINE CONTENT IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Ibrahim Jamila , Hughes Alun D , Schachter Michael , Sever Peter S
Published: June 2007

1. Endogenous polyamines play a key role in mediating cellular growth and differentiation. Hypertension is associated with structural modifications of the circulatory system, a process that may be facilitated by polyamines. In this study, we examined whether there are elevated polyamine concentrations in the cardiovascular tissues of spontaneously hypertensive rats (SHR) relative to Wistar‐Kyoto (WKY) rats. We also determined the chronic effect of 2% difluoromethylornithine (DFMO; a polyamine biosynthesis inhibitor) on tissue polyamines and hypertension.

2. SHR and WKY rats were treated with either 2% DFMO or drug‐free drinking water; blood pressure was measured on alternate days and tissue polyamines were analysed at the end of the study.

3. We found that spermidine and spermine concentrations were markedly raised in the ventricles, resistance vessels and liver of the SHR, in comparison with corresponding tissues of WKY rats. DFMO did not affect SHR resistance vessel and liver polyamines, although spermidine in the ventricles was reduced. The blood pressure of neither SHR nor WKY rats was affected by DFMO.

4. In conclusion, this study shows for the first time a raised concentration of polyamines in the resistance vasculature of the SHR, in relation to their normotensive counterparts. The inability of DFMO to significantly reduce tissue polyamines in this study is in contrast to the effectiveness of 2% DFMO in other hypertension models, suggesting that polyamine homeostasis in this model may be stringently regulated.
ANGIOTENSIN II ACTIVATES PRESSOR AND DEPRESSOR SITES OF THE PONTOMEDULLA THAT REACT TO GLUTAMATE
Authors: Chai CY , Chen SY , Lin AMY , Tseng CJ
Published: June 2007

1. In cats anaesthetized with a mixture of α‐chloralose (40 mg/kg) and urethane (400 mg/kg) and in rats anaesthetized with a mixture of α‐chloralose (60 mg/kg) and urethane (800 mg/kg), changes in systemic arterial pressure (SAP), heart rate (HR) and sympathetic activities of vertebral (VNA) and renal (RNA) nerves were determined following the micro‐injection of angiotensin II (AngII; 0.16 mmol/L; 50 nL) into the pressor and depressor sites of the pontomedulla previously reacted to a microinjection of monosodium l‐glutamate (Glu; O.1 mol/L; 50 nL). Pressor sites included gigantocellular tegmental field (FTG) and dorsal medulla (DM) and rostral ventrolateral medulla (VLM). The depressor site was the caudal VLM (CVLM). The effects of losartan (1 mmol/L; 50 nL), a specific AT1 receptor non‐peptide antagonist for AngII, on responses induced by AngII in the VLM, DM and CVLM were also determined.

2. In 30% of pressor sites in the FTG, 55% in the VLM and 67% in the DM and in 76% of depressor sites in the CVLM previously exposed to Glu, microinjection of AngII to the same site produced pressor or depressor responses similar to that of Glu, but smaller in magnitude, particularly in the pressor VLM. Changes in both VNA and RNA induced by AngII were also smaller than those induced by Glu, particularly RNA from DM activation.

3. In the dorsal motor nucleus of the vagus, AngII, as Glu, produced marked bradycardia, but again this was smaller in magnitude than the bradycardia produced by Glu.

4. In rats, in the DM near or around the nucleus of the solitary tract where Glu increased SAP, microinjection of AngII (0.8 mmol/L; 60 nL) produced a depressor response, while the microinjection of 1.6 mmol/L (60 nL) AngII produced a pressor response.

5. Losartan blocked the increases in SAP induced by AngII in the VLM and DM. Decreases in SAP induced by AngII in the CVLM, however, were only slightly decreased by losartan.

6. Our data suggest that a significant portion of pressor and depressor sites of the pontomedulla contain neurons responsive to both AngII and Glu. In neurons in the VLM and DM, AngII produced pressor responses that were primarily mediated through AT1 receptors, while the depressor actions of AngII in the CVLM were not mediated by AT1 receptors.
A STUDY OF ANGIOTENSIN II RECEPTORS AFTER CHRONIC INHIBITION OF NITRIC OXIDE SYNTHASE IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Yang Y. , Macdonald GJ , Duggan KA
Published: June 2007

1. Nitric oxide (NO) synthase inhibition, induces a sustained increase in blood pressure and amplifies the pressor response to infused angiotensin II (AngII). This study was designed to investigate the contribution of AngII receptors to the elevated blood pressure and enhanced pressor response to AngII in the spontaneously hypertensive rat (SHR) chronically treated with NG‐nitro‐l‐arginine‐methyl ester (l‐NAME).

2. Two groups of 13 week old female SHR were housed four to a box. Group I rats received l‐NAME for 7 days (2.5 mg/kg per day) in their drinking water. Group II rats received water only. Blood pressure was monitored daily by tail‐cuff plethysmography. Plasma AngII was measured by radioimmunoassay. Aortic and uterine receptor binding was determined by saturation analysis using [125I]‐Sar8, Ile1)AngII. Data was analysed using the computer program ligand.

3. Mean systolic blood pressure was significantly elevated in rats treated with l‐NAME compared with the control group. Plasma AngII concentration was slightly decreased in rats treated with l‐NAME compared with control. Densities of both aortic and uterine AngII receptors increased significantly following NO synthase inhibition. Receptor affinity in the aorta decreased in the l‐NAME group compared with control. However, uterine AngII receptor affinity was unchanged.

4. We conclude that the increased blood pressure and enhanced pressor responsiveness that occurs with chronic inhibition of NO synthesis may result partly from increased vascular AngII receptor expression.
BRAIN ANGIOTENSIN AND CIRCULATORY CONTROL
Authors: Muratani Hiromi , Teruya Hiroshi , Sesoko Shogo , Takishita Shuichi , Fukiyama Koshiro
Published: June 2007

1. Components of the renin‐angiotensin system (RAS) are found in the brain; both outside and inside the blood‐brain barrier.

2. Almost all of the classical actions of the brain RAS are attributable to angiotensin (Ang) II and mediated by AT1 receptors.

3. Circumventricular organs (CVO), which lack the blood‐brain barrier, are rich in AngII receptors and monitor circulating AngII levels. In vivo binding studies suggest that the CVO are also accessible to cerebrospinal fluid‐derived AngII.

4. The median preoptic nucleus, paraventricular hypothalamic nucleus, supraoptic nucleus, nucleus tractus solitarius and ventrolateral medulla are inside the blood‐brain barrier and are sites of action of brain AngII. In these nuclei, AngII seems to act as an excitatory neurotransmitter or neuromodulator.

5. Actions of AngII in the brain, both inside and outside the blood‐brain barrier, are implicated in the central regulation of blood pressure and sympathetic outflow, release of hypothalamic and pituitary hormones and renal sodium handling.

6. Alterations in the activity of brain AngII may be involved in the mechanisms of some types of hypertension.
IBUDILAST PROTECTS AGAINST NEURONAL DAMAGE INDUCED BY GLUTAMATE IN CULTURED HIPPOCAMPAL NEURONS
Authors: Tominaga Yasuhiro , Nakamura Yoichi , Tsuji Koji , Shibata Taiho , Kataoka Kiyoshi
Published: June 2007

1. The effect of ibudilast, a drug that has been clinically used for asthma and the improvement of cerebrovascular disorders, was examined on glutamate neurotoxicity in cultured neurons from rat hippocampus.

2. The extent of neuronal damage induced by exposure of the neurons to glutamate for 5 min was estimated by the activity of lactate dehydrogenase (LDH) released from degenerated neurons into the medium during a 24 h postexposure period. When ibudilast was added into all pre‐incubation, exposure and postexposure media, the extent of neuronal damage decreased to approximately half that of control at an ibudilast concentration of 43 μmol/L.

3. The neuroprotective effects of ibudilast were dose‐dependent. Sufficient protection was detected even when ibudilast was added only into the postexposure medium.

4. The extent of 45Ca2+ influx during glutamate exposure was slightly reduced by the addition of ibudilast. Intracellular cAMP, as measured by radioimmunoassay, was increased by neuronal exposure to glutamate and then decreased after the removal of glutamate; however in the presence of ibudilast, AMP was maintained at the high level.

5. These results suggest that protection against glutamate neurotoxicity by ibudilast is not only attributable to the inhibition of phenomena that occur during glutamate exposure, such as Ca2+ influx, but also to some beneficial metabolic changes that are induced by a sustained high level of intracellular cAMP.
EXAMINATION OF THE ROLE OF NITRIC OXIDE SYNTHASE AND RENAL KALLIKREIN AS CANDIDATE GENES FOR ESSENTIAL HYPERTENSION
Authors: Friend LR , Morris BJ , Gaffney PT , Griffiths LR
Published: June 2007

1. Nitric oxide synthase and renal kallikrein are both involved in blood pressure regulation. Genes for these enzymes may, therefore, be considered candidates for hypertension pathogenesis.

2. In the present study, genotypes for nitric oxide synthase and renal kallikrein microsatellite markers were determined in a cross‐sectional association analysis of hypertensive patients and normotensive control subjects.

3. Results from this study did not indicate an association of either of the candidate gene polymorphisms with essential hypertension. Hence, findings for this study do not support a role for these genes in human hypertension.
NO DIFFERENCE IN THE PROPORTION OF INSULIN RECEPTOR EXON 11 +/‐ ISOFORM mRNA IN THE LIVER OF RATS AFTER DEVELOPMENT OF HYPERTENSION
Authors: Lou Yi‐kun , Zee Robert YL , Li Ming , Morris Brian J
Published: June 2007

1. There are two functionally different isoforms of the insulin receptor in humans and rats. We hypothesized that a change in their relative proportion could be of relevance to insulin resistance in hypertension.

2. A reverse‐transcriptase polymerase chain reaction technique was established for the detection of mRNA for the exon 11+ and exon 11—isoforms and the proportion of each was determined in 3, 6, 9 and 12 week old spontaneously hypertensive rats and Wistar‐Kyoto rats, as well as adrenocorticotrophin (ACTH)‐induced hypertensive rats and controls.

3. The proportion of the exon 11+ form (∼95%) and exon 11—form (∼5%) was similar in the liver of all rats studied.

4. We conclude that there is no change in insulin receptor isoform expression in the liver in the models of hypertension studied.
FULL EXPRESSION OF THE EXAGGERATED SALT APPETITE OF THE SPONTANEOUSLY HYPERTENSIVE RAT REQUIRES A PRENATAL FACTOR
Authors: Erkadius E. , Morgan TO , Di Nicolantonio R.
Published: June 2007

1. The spontaneously hypertensive rat (SHR) exhibits a lower bodyweight in utero and an exaggerated salt appetite post partum. To determine whether salt appetite is affected by the perinatal environment, we measured the salt appetite of embryo‐cross‐transferred SHR and Wistar Kyoto (WKY) rats at maturity.

2. One‐cell embryos were collected from the oviducts of donor rats and transferred into the oviducts of recipients through the infundibulum. The salt appetite of the resultant female offspring for 0.10 and 0.15mol/L saline was measured at 20–30 weeks of age.

3. Salt intake of SHR gestated in WKY rats was significantly lower than that of SHR gestated in SHR, while that of WKY rats gestated in SHR was higher than that of WKY rats gestated in WKY rats.

4. Therefore, some maternal factor plays a role in the development of the exaggerated salt appetite of the SHR. This factor is also able to affect the later salt appetite of WKY rat offspring born to SHR surrogates.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: MOLECULAR MECHANISMS OF ANGIOTENSIN II (AT1a) RECEPTOR ENDOCYTOSIS
Authors: Thomas Walter G , Thekkumkara Thomas J , Baker Kenneth M
Published: June 2007

Angiotensin II (AngII) initiates a variety of cellular responses through activation of type 1 (AT1; with subtypes AT1a and AT1b) and type 2 (AT2) cell surface angiotensin receptors. Both AT1 and AT2 receptors couple to heterotrimeric guanyl nucleotide binding proteins (G‐proteins) and generate intracellular signals following recognition of extracellular AngII, but only AT1 is targeted for the rapid ligand‐stimulated endocytosis (internalization) typical of many plasma membrane receptors.

AT1 endocytosis proceeds through clathrin‐coated pits and is independent of G‐protein coupling which predicts that the AngII‐AT1 receptor complex attains a conformation necessary for interaction with the endocytotic machinery, but separate from receptor signalling activation.

The function of AT1 endocytosis and the reason for the disparity between AT1 and AT2 endocytosis is not fully appreciated, but the latter probably reflects differences in the primary amino acid sequence of these two receptor types.

For many receptors that undergo internalization, it has been established that internalization motifs (2–6 amino acids, often incorporating crucial tyrosine and hydrophobic amino acids) within the cytoplasmic regions of the receptor mediate the selective recruitment of activated receptors into clathrin‐coated pits and vesicles.

Mutagenesis studies on the AT1a receptor, aimed at identifying such motifs, reveal that sites within the third cytoplasmic loop and the cytoplasmic carboxyl terminal region are important for AngII‐stimulated AT1a receptor endocytosis.
AT1 RECEPTOR ANTAGONIST, TCV 116, DOES NOT PREVENT CARDIAC HYPERTROPHY IN SALT‐LOADED DAHL SALT‐SENSITIVE RATS
Authors: Sugimoto Koh‐ichi , Gotoh Eiji , Takasaki Izumi , Ebina Toshiaki , Iwamoto Tamio , Takizawa Toshikazu , Shionoiri Hiroshi , Ishii Masao
Published: June 2007

1. We investigated the effects of direct blockade of angiotensin II (AngII) by a potent, non‐peptide angiotensin II type 1 (AT1) receptor antagonist, TCV 116, on the development of cardiac hypertrophy in salt‐loaded Dahl salt‐sensitive rats.

2. Six week old male Dahl salt‐sensitive rats (n= 44) were fed a 4% salt diet and were simultaneously given various doses of TCV 116 orally for 7 weeks. Each control group received vehicle alone.

3. Dietary high salt intake elevated blood pressure continuously and caused left ventricular hypertrophy in rats treated with vehicle. TCV 116 had a minor effect on the rise in blood pressure. Left ventricular mass (left ventricular weight/body‐weight) decreased slightly but not significantly, in rats treated with 3mg/kg per day of TCV 116 (n= 8). Higher doses of TCV 116 (6 and 10 mg/kg per day; n= 8 each) did not show a decrease in left ventricular mass compared with the vehicle control.

4. These results suggest that AngII blockade has only minor effects on hypertension and on cardiac hypertrophy in salt‐loaded Dahl salt‐sensitive rats and that the renin‐angiotensin system may not contribute to the development of cardiac hypertrophy in Dahl salt‐sensitive rats on a moderately high‐salt diet.
DISTRIBUTION AND ANTI‐INFLAMMATORY EFFECT OF MESALAZINE ON CARRAGEENAN‐INDUCED COLITIS IN THE RABBIT
Authors: Kitano A. , Matsumoto T. , Oshitani N. , Nakagawa M. , Yasuda K. , Watanabe Y. , Tomobuchi M. , Obayashi M. , Tabata A. , Fukushima R. , Okabe H. , Nakamura S. , Obata A. , Okawa K. , Kobayashi K.
Published: June 2007

1. A controlled‐release preparation of mesalazine microgranules (PentasaR; Ferring AS, Vanlose, Denmark) releases the active ingredient over a wide area from the small intestine to the rectum and is consequently expected to bring about therapeutic benefits to patients with ulcerative colitis and Crohn's disease.

2. Mesalazine microgranules (50 or 150 mg/kg per day) were administered orally to each rabbit with carrageenan‐induced colitis for six weeks. Its inhibitory effect on colonic mucosal damage was assessed in terms of the microscopic damage scores, leukotriene B4 concentrations and concentrations of mesalazine derivatives.

3. At the end of the experiment, the mesalazine 150 mg group had gained a significantly greater bodyweight than the control group. Microscopic damage was significantly lower in the 150 mg group than in the untreated control group. Tissue concentrations of 5‐aminosalicylic acid and acetyl‐5‐aminosalicylic acid in the small and large intestine were higher in the 150 mg group than in the 50 mg group. Mucosal leukotriene B4 levels tended to be lower in rabbits receiving the larger dose of mesalazine.

4. The present study indicates that slow release 5‐aminosalicylic acid at the larger dose reaches the large bowel in sufficiently high concentrations following oral administration and significantly reduces carrageenan‐induced colitis in the rabbit.
SYMPOSIUM Experimental Biology 1995 Endothelin Receptors: Role in Renal Function and Dysfunction ENDOTHELINS: RENAL TUBULE SYNTHESIS AND ACTIONS
Authors: Kohan Donald E
Published: June 2007

1. Renal tubules and, in particular, the inner medullary collecting duct, produce endothelin and express cognate receptors.

2. Endothelins inhibit vasopressin‐stimulated cAMP accumulation and water reabsorption in the collecting duct; endothelins may also inhibit sodium reabsorption in the proximal tubule and collecting duct.

3. Autocrine inhibition of sodium and water reabsorption in the inner medullary collecting duct by endothelin may play a role in maintaining extracellular fluid volume homeostasis.

4. Derangements in autocrine inhibition of sodium and water reabsorption in the inner medullary collecting duct by endothelin may be involved in the pathogenesis of the hypertensive state.

5. Nephron‐derived endothelins may function in a paracrine manner to regulate interstitial, juxtaglomerular and vascular smooth muscle cell function.
EFFECTS OF ENDURANCE TRAINING ON SUPEROXIDE DISMUTASE ACTIVITY, CONTENT AND mRNA EXPRESSION IN RAT MUSCLE#
Authors: Oh‐ishi S. , Kizaki T. , Nagasawa J. , Izawa T. , Komabayashi T. , Nagata N. , Suzuki K. , Taniguchi N. , Ohno H.
Published: June 2007

1. The purpose of the present study was to investigate the changes in superoxide dismutase (SOD) isoenzyme (Mn2+‐SOD and Cu2+, Zn2+‐SOD) activities, contents and mRNA expressions in rat skeletal muscle during endurance training and a single bout of exercise.

2. Thirty‐eight male Wistar rats were divided into untrained (U) and trained (T) groups. The T group rats were treadmill‐trained for 9 weeks. The activity, content and mRNA expression of Mn2+‐SOD and Cu2+, Zn2+‐SOD were determined in the soleus muscle of each rat.

3. Mn2+‐SOD activity and content in the T group were significantly higher than in the U group, both at rest (22 and 21%, respectively) and after exercise (24 and 46%, respectively), while a single bout of exercise affected neither the activity nor content of Mn2+‐SOD in either group.

4. The content of Cu2+, Zn2+‐SOD in both groups was not different at rest and after exercise, although its activity at rest was significantly higher in the T group than in the U group (by 29%).

5. After exercise, the expression of Mn2+‐SOD mRNA was markedly attenuated only in the U group (49%); the expression of Cu2+, Zn2+‐SOD mRNA was not influenced by exercise.

6. Our results suggest that adequate endurance training increases both the activity and content of Mn2+‐SOD and that untrained rats are rather susceptible to oxidative stress during physical exercise. It thus appears that Mn2+‐SOD provides a reliable index of physical training.

7. The results obtained in the present study also suggest that muscle has the capacity of responding to training in such a manner as to reduce the potential harm arising from the accumulation of oxygen free radicals resulting from enhanced metabolic activity.
ACUTE EFFECTS OF ORAL GLIBENCLAMIDE ON BLOOD PRESSURE AND FOREARM VASCULAR RESISTANCE IN DIABETICS
Authors: Sundaresan Purnima , Lykos Denise , Daher AH , Morris Richard , Diamond Terence , Howes Laurence G.
Published: June 2007

1. To determine the effects of an acute oral dose of glibencla‐mide on blood pressure (BP), basal forearm vascular resistance (FVR) and FVR responses to the K+ATP channel activating vasodilator diazoxide, a placebo‐controlled, double‐blind cross‐over study was performed in eight male volunteers with non‐insulin‐dependent diabetes mellitus.

2. Changes in vascular responses to progressively increasing concentrations of diazoxide (3.75–30 mg/kg per min) and noradrenaline (25–100 ng/kg per min) were measured by venous occlusion plethysmography.

3. Glibenclamide significantly lowered plasma glucose levels compared with placebo (P < 0.02) and attenuated the decrease in FVR (P < 0.05) and the decrease in systolic BP (P < 0.05) that followed a meal. However, vasodilator responses to diazoxide were potentiated by the administration of oral glibenclamide (P < 0.01).

4. Acute administration of oral glibenclamide attenuates the normal decrease in FVR and systolic BP that follows a meal and potentiates rather than inhibits forearm vasodilator responses to intra‐arterial diazoxide, probably via indirect humoral effects. These results suggest that glibenclamide has direct or indirect vasoconstrictor effects that antagonize the normal increase in forearm blood flow that follows a meal and that the inhibition of vascular K+ATP channels following acute oral glibenclamide administration is clinically insignificant compared with other indirect vascular effects of the drug.
CONCENTRATION‐EFFECT RELATIONSHIPS OF MORPHINE AND MORPHINE‐6β‐GLUCURONIDE IN THE RAT
Authors: van Crugten Jacoba T. , Somogyi Andrew A. , Nation Roger L. , Reynolds Geoffrey
Published: June 2007

1. The aims of the present study were to determine the relationship between the antinociceptive effect and concentrations of morphine and morphine‐6β‐glucuronide (M6G) in plasma and in the brain.

2. Morphine (14.0 and 28.0 μ‐mol/kg) or M6G (8.67 and 17.3 μmol/kg) were administered s.c. to male Hooded‐Wistar rats. The antinociceptive effect was measured by the thermal tail‐flick method at various times up to 2 h and concentrations of morphine, morphine‐3β‐glucuronide (M3G) and M6G in plasma and in the brain were determined.

3. With a two‐fold increment in morphine dose, the areas under the antinociceptive effect‐, plasma morphine concentration‐ and brain morphine concentration‐time curves increased by 1.9‐, 2.3‐ and 2.3‐fold, respectively. The area under the plasma M3G concentration‐time curve increased 2.7‐fold. Morphine‐6β‐glucuronide was not detected in any sample. For M6G, doubling of the dose led to a 1.7‐fold increase in the area under the curve for plasma‐time M6G concentrations but an 8.7‐fold increase in the area under the curve for the antinociception‐time effect. Concentrations of M6G in the brain were below the limit of quantification. The relationship between antinociceptive effect and plasma morphine or M6G were characterized by counterclockwise hysteresis loops, probably reflecting a delay in crossing the blood‐brain barrier.

4. Morphine‐6β‐glucuronide was approximately equipotent to morphine on the basis of dose, but substantially more potent on the basis of brain concentration.
NITRIC OXIDE SYNTHASE INHIBITION WITH Nω‐NITRO‐L‐ ARGININE METHYL ESTER AFFECTS BLOOD PRESSURE AND CARDIOVASCULAR STRUCTURE IN THE GENETICALLY HYPERTENSIVE RAT STRAIN
Authors: Ledingham Janet M. , Laverty R.
Published: June 2007

1. Inhibition of nitric oxide (NO) synthesis with the nitric oxide synthase (NOS) inhibitor Nω‐nitro‐L‐arginine methyl ester (L‐NAME) was used as a tool to investigate further a possible endothelial defect in the New Zealand genetically hypertensive (GH) rat strain compared with its normotensive (N) control strain.

2. Nω‐nitro‐L‐arginine methyl ester was given to GH and N groups in their drinking water from age 7–10 weeks (10 mg/kg per day for weeks 1 and 2 and then 5 mg/kg per day for week 3). Tail‐cuff blood pressure (BP) was measured weekly and at the end of the experiment the mesentery was fixed by perfusion, second order branches of the mesenteric artery were embedded in Technovit and stained sections were used to quantify the structure of the mesenteric resistance arteries (MRA). The heart was removed and weighed for determination of left ventricular (LV) mass.

3. In GH rats, BP and LV mass were significantly raised by L‐NAME, while in N rats L‐NAME treatment significantly elevated BP, but had no effect on LV mass.

4. In GH rats, the media width was significantly increased by L‐NAME treatment (P < 0.01) lumen diameter remained unchanged. Thus, the ratio of media width/lumen diameter (M/L) was significantly increased by exacerbation of the hypertrophic outward remodelling characteristic of the GH strain. There were no significant changes in the M/L ratio in L ‐NAME‐treated N rats.

5. Thus, in the GH strain, cardiovascular structure is more sensitive to NOS inhibition than either its N control strain or (on evidence from the literature) the spontaneously hypertensive rat strain.
ACUTE BUT NOT CHRONIC ANGIOTENSIN‐CONVERTING ENZYME INHIBITION INDUCES ENZYME SYNTHESIS IN THE GLOMERULUS OF THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Hodge G. , Makarious MM , Charlesworth JA , Duggan KA
Published: June 2007

1. Treatment with angiotensin‐converting enzyme (ACE) inhibitors slows the rate of progression of nephropathy in the spontaneously hypertensive rat (SHR) with streptozotocin‐induced diabetes. Paradoxically, however, chronic ACE inhibitor therapy has been reported to be associated with induction of ACE in the plasma. We sought to determine whether induction also occurred in the glomerulus.

2. Seven days after induction of diabetes rats were randomized to receive perindopril (4mg/kg per day) in the drinking water or water alone. Blood glucoses were maintained 6–10 mmol/L by daily ultralente insulin. Rats were killed after 1 and 12 weeks of ACE inhibitor therapy and the kidneys were harvested. Angiotensin‐converting enzyme activity was determined in isolated glomeruli before and after removal of perindopril and reconstitution with zinc sulphate.

3. After 1 week of ACE inhibitor therapy, glomerular ACE was significantly greater after removal of perindopril than either before its removal (P < 0.025) or in the untreated controls (P < 0.025). After 12 weeks of therapy, ACE activity was significantly lower in the perindopril‐treated group than in the untreated controls (P < 0.025). There was no increase in ACE activity following removal of perindopril.

4. These studies suggest that short‐term ACE inhibition is associated with induction of ACE in the glomerulus. However, there was no increase in ACE activity after removal of perindopril, suggesting that induction of synthesis of this enzyme in the glomerulus does not occur during chronic ACE inhibition.