bluuebunny/crossref_metadata_2025 huggingface dataset:
MINERALOCORTICOID AND GLYCYRRHIZIC ACID BLOCK STRESS INDUCED HYPOTENSION IN RATS
Authors: Ruszymah B. H. I. , Nabishah B. M. , Aminuddin S. , Khalid B. A. K.
Published: June 2007

1. The aim of this study was to investigate the effect of repeated exposure to stress on tail blood pressure (TBP) of normal as well as GCA (glycyrrhizic acid) and steroid treated rats. Male Sprague‐Dawley rats (250 g) were exposed to ether vapour to achieve light anaesthesia prior to TBP recording. Rats were injected with either normal saline or naloxone prior to exposure to stress. Tail blood pressure was recorded daily for 2 weeks.

2. We found that ether stress caused a transient drop in TBP in control as well as in dexamethasone (DEX) treated rats. The stress‐induced fall in blood pressure was reduced by naloxone in control rats but not in DEX treated rats. However the transient drop in TBP following stress was not seen in either GCA or deoxycorticosterone (DOC) treated rats.

3. We conclude that first, the reduction in TBP was due to the release of endogenous opioids caused by stress. Second, DOC may block the release of such endogenous opioids, preventing the drop in TBP in response to stress, while DEX did not. Third, GCA caused a similar mineralocorticoid effect on reversing stress induced hypotension.
HISTORICAL PERSPECTIVE OF CARDIORENAL INTEGRATION
Authors: Henry James P.
Published: June 2007

1. Early research on blood volume as an independent parameter affecting kidney function took the approach that the sensors must be located in the most compliant, that is the reservoir portion, of the cardiovascular system. This encompasses the great veins and the cardiac atria.

2. Small changes in volume were shown not to affect the compliance of this reservoir and messages from the atrial receptor network were shown to travel in the vagus nerve and to control urine volume by antidiuretic hormone.

3. Although greatly affected by the water immersion stimulus, sodium excretion was not as dependent on vagus integrity. The ensuing search for the natriuretic arm of the blood volume mechanism persisted for the next 20 years.

4. Finally, one aspect of the elusive natriuretic factor was found exactly where theory had suggested, namely the most distensible part of the system, in specialized granules in the cardiac atria.
BRIEF REVIEW PAIN MECHANISMS AND MANAGEMENT: AN UPDATE
Authors: Siddall Philip J. , Cousins Michael J.
Published: June 2007

1. Recent findings have further helped to elucidate the mechanisms involved in the transmission and modulation of pain. It is now known that pain, inflammation and nervous system damage result in a number of changes in peripheral nerves, spinal cord and supraspinal structures. These changes themselves may be responsible for the development and maintenance of chronic pain syndromes.

2. In response to these findings, new agents and techniques have been applied in the clinical setting and new approaches have been developed to use existing agents more effectively. This review presents some of the findings from recent studies and the implications they have for the management of pain.
RENAL SYMPATHETIC AND HEART RATE BAROREFLEX FUNCTION IN CONSCIOUS AND ISOFLURANE ANAESTHETIZED NORMOTENSIVE AND CHRONICALLY HYPERTENSIVE RABBITS
Authors: Bell Leonard B. , Wilson Donald J. , Quandt Leslie M. , Kampine John P.
Published: June 2007

1. Baroreflex control of heart rate (HR) has been studied in normotensive (NT) and hypertensive (HT) awake and anaesthetized animals and man, but baroreflex control of sympathetic nerve activity has not been well studied. We investigated baroreflex control of HR and renal sympathetic nerve activity (RSNA) over a wide range of arterial pressure (AP) in conscious and isoflurane (ISO) anaesthetized NT and HT rabbits.

2. Animals were instrumented to record AP, HR and RSNA. Hypertension was accomplished by renal encapsulation. AP‐HR and AP‐RSNA baroreflex function curves were obtained while awake and after 1.0, 1.5, 2.0 and 2.5% ISO. All baroreflex curves were fit to sigmoid or exponential functions.

3. In conscious rabbits, HT for 3–5 weeks, AP was significantly higher (75.6 ± 0.8 vs 102.3 ± 8.9 mmHg); HR significantly lower (218.0 ± 5.5 vs 189.5 ± 5.5 beats/min); and RSNA not different than NT rabbits (14.9 ± 2.2 vs 9.9 ± 3.2% max RSNA).

4. ISO shifted AP‐HR and AP‐RSNA baroreflex curves to the left in NT and HT animals, and significantly attenuated baroreflex range and slope. At low ISO concentrations, baroreflex compensation for decreases in AP is limited to small increases in HR and sympathetic nerve activity. At higher ISO concentrations, baroreflex responses to decreases in AP are lost. RSNA responses to increases in AP are preserved with increasing ISO concentrations while HR responses are progressively attenuated. The sole effect of chronic hypertension was to shift the AP‐HR and AP‐RSNA barocurves to the right along the pressure axis in both conscious and ISO anaesthetized animals with no additional change in range or slope.

5. At this stage of hypertension development, ISO anaesthesia affects baroreflex function equally in normotensive and hypertensive rabbits.
FORCE AND INTRACELLULAR Ca2+ DURING NANC‐MEDIATED RELAXATION OF RAT ANOCOCCYGEUS MUSCLE AND THE EFFECTS OF CYCLOPIAZONIC ACID
Authors: Raymond G. L. , Wendt I. R. , Kotsanas G.
Published: June 2007

1. Simultaneous recordings of tension and [Ca2+]i during NANC‐mediated relaxation were made in the rat anococcygeus muscle under various conditions.

2. In muscles precontracted with guanethidine, nitrergic stimulations at 2 Hz produced a rapid decrease in both the tension and [Ca2+]i.

3. The nitric oxide synthase inhibitor, NG‐nitro‐L‐Arginine (NOLA, 100 μmol/L) completely abolished the decreases in the [Ca2+]i and force response of the NANC‐mediated relaxation.

4. Noradrenergic‐mediated contractions elicited by electrical field stimulation were potentiated by the addition of NOLA. In the absence of NOLA, the motor responses were larger in magnitude at 10 Hz stimulation than at 2 Hz. After NOLA, both the force response and the associated rise in [Ca2+]i were substantially increased in comparison to the control stimulations. Proportionately the potentiation of the 2 Hz response was of a far greater magnitude than that of the 10 Hz response.

5. The guanylate cyclase inhibitor methylene blue (10 μmol/ L), partially inhibited the force and [Ca2+]i response of the NANC relaxation.

6. Following exposure of the muscles to the sarcoplasmic reticulum Ca2+‐ATPase inhibitor, cyclopiazonic acid, (10 μmol/ L) the responses to NANC stimulation were inhibited. The attenuated relaxation response displayed a bi‐phasic timecourse and the Ca2+ change in comparison to that of the control was markedly smaller. In some cases, a relaxation was observed with no detectable change in the [Ca2+]i.

7. The results suggest that part of the relaxation response observed with NANC‐mediated relaxation in the rat anococcygeus is dependent on Ca2+ sequestration into the sarcoplasmic reticulum. However, other Ca2+ lowering mechanisms and possible Ca2+ independent mechanisms may also contribute to the NANC relaxation response.
IMPACT OF CYCLO‐OXYGENASE BLOCKADE ON JUXTAMEDULLARY MICROVASCULAR RESPONSES TO ANGIOTENSIN II IN RAT KIDNEY
Authors: Harrison‐Bernard Lisa M. , Carmines Pamela K.
Published: June 2007

1. Experiments were designed to evaluate the hypothesis that cyclo‐oxygenase products modulate the influence of angiotensin II (AII) on the renal juxtamedullary microvasculature of enalaprilat‐treated rats.

2. The in vitro blood‐perfused juxtamedullary nephron technique was utilized to provide access to afferent arterioles, efferent arterioles and descending vasa recta located in the outer stripe of the outer medulla.

3. Baseline afferent arteriolar diameter was 20.8 ± 1.9 μm in kidneys subjected to cyclo‐oxygenase blockade (1μmol/L piroxicam), a value significantly lower than that observed in untreated kidneys (26.1 ± 1.0 μm). Baseline diameters of efferent arterioles and outer medullary descending vasa recta did not differ between untreated and piroxicam‐treated groups.

4. Topical application of 1 nmol/L AII reduced blood flow through outer medullary descending vasa recta by 22 ± 6% in untreated kidneys and by 24 ± 7% in piroxicam‐treated kidneys.

5. In untreated kidneys, AII (0.01–100nmol/L) produced concentration‐dependent afferent and efferent arteriolar constrictor responses of similar magnitudes. Neither afferent nor efferent arteriolar AII responsiveness was significantly altered in piroxicam‐treated kidneys, although afferent responses exceeded efferent responses at AII concentrations ≥ 10 nmol/L.

6. We conclude that endogenous cyclo‐oxygenase products exert a vasodilator influence on juxtamedullary afferent arterioles under baseline conditions. Although cyclo‐oxygenase inhibition had little effect on juxtamedullary microvascular responses to AII, the response to high AII concentrations may be modulated by cyclo‐oxygenase products in a manner which delicately alters the relative influence of the peptide on pre‐ vs postglomerular resistances.
EFFECTS OF A SELECTIVE ENDOTHELIN A‐RECEPTOR ANTAGONIST, BQ‐123, IN SALT‐LOADED STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Okada Megumu , Kobayashi Masahiko , Maruyama Hiromi , Takahashi Risa , Ikemoto Fumihiko , Yano Mitsuo , Nishikibe Masaru
Published: June 2007

1. We examined the effects of a selective endothelin A (ETA)‐receptor antagonist, BQ‐123, on the development of hypertension and organ damage in stroke‐prone spontaneously hypertensive rats (SHRSP) given 1% NaCl for 6 weeks.

2. BQ‐123 at doses of 0.7, 2.1 and 7.1 mg/day was continuously administered for 6 weeks to 8 week old salt‐loaded SHRSP, who were given water containing 1% NaCl for the following 6 weeks, via a subcutaneous osmotic minipump.

3. Development of high blood pressure was accelerated in salt‐loaded SHRSP compared with that in non‐salt‐loaded SHRSP. After 6 weeks of salt‐loading, incidence of cerebral infarction, renal sclerosis and renal fibrosis were greater in salt‐loaded than non‐salt‐loaded SHRSP.

4. BQ‐123 attenuated the age‐related rise in blood pressure in a dose‐dependent manner. The effect coincided with reduction in the incidence of cerebral infarction and prevention of renal sclerosis and fibrosis. Kidney function was improved as observed by an increase in glomerular filtration rate and decreases in urinary protein excretion, blood urea nitrogen and fractional sodium excretion. Furthermore, BQ‐123 prevented increases in the heart weight/bodyweight ratio and aortic wall thickness in salt‐loaded SHRSP.

5. These results suggest that endogenous endothelin‐1 (ET‐1) and ETA‐receptors may be, at least in part, involved in the pathogenesis of hypertension and organ damage in salt‐loaded SHRSP.
THE PHYSIOLOGY OF PRE‐ECLAMPSIA
Authors: Brown Mark A.
Published: June 2007

1. Pre‐eclampsia is a multisystem disorder of human pregnancy with a genetic predisposition. It occurs more commonly in first pregnancies and primarily affects maternal renal, cerebral, hepatic and clotting functions while elevating blood pressure. The foetus is affected through placental insufficiency arising from abnormal ‘placentation’, that is, failure of adequate trophoblast invasion of maternal vasculature, and possibly from abnormal autacoid production.

2. Pre‐eclampsia is caused by the placenta; delivery of the placenta is the only known cure. Its manifestations are considered secondary to organ hypoperfusion which arises as a result of vasoconstriction, intravascular coagulation and reduced maternal blood volume.

3. Current hypotheses propose that pre‐eclampsia is due to widespread maternal endothelial cell damage, perhaps secondary to a cytotoxic factor released by the placenta. This hypothesis has gained wide acceptance, but scientific evidence is lacking.

4. Defining the abnormal balance of vasoactive factors in pre‐eclampsia has proved a difficult task. There is enhanced pressor reactivity to infused angiotensin 11 (AII) despite reduced plasma concentrations of AII, renin and aldosterone. Prostacylclin production appears reduced, and the balance of thromboxane/prostacyclin favours vasoconstriction and platelet aggregation. There is no convincing evidence for enhanced endothelin or reduced nitric oxide production. Plasma concentrations of atrial natriuretic peptide are paradoxically elevated in the face of plasma volume contraction. An intriguing observation, which remains unexplained, is why some vascular beds are affected predominantly in one patient (eg. hepatic ischaemia) while another has a similar degree of hypertension but involvement of a different organ system (eg. renal insufficiency yet normal liver function).

5. Volume homeostasis is disturbed with redistribution of intravascular volume to the interstitial fluid space due to increased capillary permeability and in some cases reduced plasma oncotic pressure. This redistribution is not always clinically apparent as peripheral oedema. Whether this change in volume is compensated for by venoconstriction and maintenance of adequate cardiac output is undetermined.

6. Improved understanding of the pathophysiology of pre‐eclampsia is necessary to allow better clinical management of this serious disorder.
PEPTIDES AS NEUROTRANSMITTERS IN VASCULAR AUTONOMIC NEURONS
Authors: Morris J. L.
Published: June 2007

1. Neuropeptides are present in the majority of autonomic neurons projecting to blood vessels, where they are co‐localized with non‐peptide transmitters and sometimes with other peptides.

2. Neuropeptides are released from vasoconstrictor and vasodilator nerve terminals after high frequency stimulation (>2–5 Hz) with trains of impulses.

3. Neuropeptides can have potent post‐synaptic effects on vascular tone, but often these effects are restricted to selected regions of the vasculature.

4. Post‐synaptic effects of neuropeptides tend to be more slowly‐developing and more long‐lasting than those of non‐peptide transmitters.

5. Autonomic vasoconstrictor and vasodilator responses often have multiple phases, with the faster phases being mediated by non‐peptide transmitters and the slower phases mediated predominantly by one or more neuropeptides.

6. Some neuropeptides do not seem to have post‐synaptic effects in a particular vascular bed, but can have presynaptic actions on neurotransmitter release.

7. Neuropeptides form an important component of the repertoire of neurotransmitters used by vascular autonomic neurons to regulate regional blood flow in response to a range of physiological stimuli.
CHANGE IN OPIOID PEPTIDE LEVEL IN THE HEART AND BLOOD PLASMA DURING ACUTE MYOCARDIAL ISCHAEMIA COMPLICATED BY VENTRICULAR FIBRILLATION
Authors: Maslov L. N. , Lishmanov Y. B.
Published: June 2007

1. The influence of acute myocardial ischaemia (AMI) complicated by ventricular fibrillation (VF) on opioid peptide level in myocardium and blood plasma of rats has been studied.

2. Leu‐enkephalin level in myocardium of rats with AMI and VF has been found to be significantly lower than in animals with AMI but without VF.

3. Met‐enkephali level has been found to be significantly increased in both animals with VF and without it. We have not found a significant difference in met‐enkephalin level in myocardium of animals with VF and without it.

4. AMI was induced to increase the enkephalin and β‐endorphin level in blood plasma of all the animals, whether VF had occurred or not.

5. Preliminary administration of D‐Ala2, Leu5, Arg6‐enkephalin, a synthetic analogue of leu‐enkephalin, has prevented a decrease of ventricular fibrillation threshold in experimental coronary occlusion.

6. The obtained results allow us to conclude that enkephalins of myocardium but not opioid peptides of blood plasma play an important role in VF occurrence.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: PHARMACOKINETIC/CYTOKINETIC PRINCIPLES IN THE CHEMOTHERAPY OF SOLID TUMOURS
Authors: Baguley Bruce C. , Finlay Graeme J.
Published: June 2007

1. The solid tumour has various properties which tend to minimize the effects of a cytotoxic agent; the low vascular density of tumours, in particular, limits the diffusion of many anti‐tumour drugs.

2. This applies particularly to two general classes of anti‐cancer drugs which already play an important role in chemotherapy: mitotic poisons and topoisomerase poisons. Such compounds bind strongly to proteins and/or DNA, and their diffusion from the bloodstream into solid tumours is slow, as is their clearance from tumour tissue.

3. The specific question posed here is whether anti‐cancer compounds of these types are more cytotoxic when administered at a low concentration for a long time (mimicking conditions in solid tumours) than at a correspondingly high concentration for a short time (mimicking conditions in host tissue). Two possible principles may be involved, the first baaed on cytokinetic considerations and the second on self‐inhibition of drug cytotoxicity.

4. Using cultured human cancer cells we have shown that taxol, which acts on mitotic cells and camptothecin, which acts on S‐phase cells, are examples of the first principle. Exposures to high drug concentrations for short times are much less cytotoxic than exposure to correspondingly lower drug concentrations for a longer time (with the same concentration × time of exposure). We also show that the drug DACA (N‐[2‐(dimethylamino)ethyl]acridine‐4‐carboxamide), developed in this laboratory and currently undergoing clinical trial, achieves the same result through the principle of self‐inhibition of cytotoxicity.

5. Matching of the cytokinetic or self‐inhibitory profile of a drug's action with the pharmacokinetics of drug in tumours may provide new drugs with increased anti‐tumour effects.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NEW DRUGS IN THE TREATMENT OF HEART FAILURE
Authors: Brown Lindsay
Published: June 2007

1. Current therapy of heart failure relies on diuretics, positive inotropic compounds and vasodilators. The short‐term haemo‐dynamic benefits, especially of the cAMP generators, may be compromised by long‐term limitations leading to an increased mortality. In contrast, some vasodilators, especially angiotensin converting enzyme inhibitors, improve survival even in severe heart failure.

2. Modulation of Na+‐ or K+‐channels and calcium sensitization are positive inotropic mechanisms whose promise in treatment of heart failure needs to be fully explored.

3. The introduction of vasodilator therapy has been a significant advance. Newer compounds act to inhibit the endogenous vasoconstrictors angiotensin II and endothelin, or to potentiate the endogenous vasodilators atrial natriuretic factor and nitric oxide. The full potential of these compounds is yet to be realised.
OPIOIDS: A PHARMACOLOGIST'S DELIGHT!
Authors: Mather Laurence E.
Published: June 2007

1. Opioids, in one form or another, have been used for their pain‐relieving properties from prehistoric times: they are still the first line medication for the treatment of severe nociceptive pain and are likely to remain so for the foreseeable future.

2. The therapeutic index of opioids used for pain management is low: opioid side effects are essentially extensions of therapeutic effects and no available agent has a marked advantage over the others. When used for opioid ‘anaesthesia’, differences in therapeutic index are more obvious due to differences in non‐opioid effects.

3. Opioid receptors in brain and spinal cord periphery are the main ‘therapeutic targets’ and clinical dosage strategies have been derived using a variety of systemic (indirect or blood‐borne) methods as well as intraspinal and intracerebro‐ventricular (direct) methods: no method, however, is without potential side effects. Peripheral opioid effects are now being exploited with intra‐articular injection.

4. Opioid pharmacokinetics and pharmacodynamics are characterized by high inter‐subject variability: accordingly, patient‐controlled dosage strategies are found to be more successful for pain control than deterministic recipes.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: A NEW VIEW OF THE ROLE OF DOPAMINE RECEPTORS IN THE REGULATION OF MUSCLE TONE
Authors: Crocker A. D.
Published: June 2007

1. Clinical and exptrimental studies support the view that nigrostriatal dopaminergic neurons are involved in the maintenance of muscle tone.

2. The effects of inactivating dopamine receptors in the rat substantia nigra on muscle tone, assessed as tonic electro‐myographic (EMG) activity, was investigated.

3. Dopamine receptors were inactivated by injections of the irreversible dopamine receptor antagonist, N‐ethoxycarbonyl‐2‐ethoxy‐l,2‐dihydroquinoline (EEDQ) into the pars reticulata of the substantia nigra.

4. Significant increases in EMG activity were observed from 2 to 24 h after EEDQ injection and were associated with a loss of nigral dopamine receptors.

5. Increases in EMG activity were found only when both D1 and D2 receptors were inactivated.

6. Inactivation of α‐adrenoceptors, 5HT2c and muscarinic receptors had no effect on EMG activity.

7. Injections of apomorphine did not reduce the increased EMG activity associated with nigral dopamine receptor loss.

8. The results are consistent with the hypothesis that dopamine receptors in the substantia nigra of the rat play an important role in the regulation of muscle tone.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: THE ALLOMETRIC APPROACH FOR INTERSPECIES SCALING OF PHARMACOKINETICS AND TOXICITY OF ANTI‐CANCER DRUGS
Authors: Paxton James W.
Published: June 2007

1. The rationale for extrapolation or ‘scaling’ across animal species is based on their underlying anatomical, physiological and biochemical similarities.

2. Research carried out in the 19th and early 20th century resulted in Benedict's famous ‘mouse‐to‐elephant’ graph which showed that the log of the basal metabolic rate plotted against the log of body weight (W) produced a straight line with a slope of 0.76. Since then it has become apparent that a number of other physiological variables (Y) exhibit a similar relationship which can be represented by the general allometric equation, Y =αWβ; where β is the slope of the log‐log plot and α is the intercept on the y axis.

3. The major pharmacokinetic parameters such as clearance and volume of distribution of many drugs are also related to W in a similar manner.

4. This empirical approach does not require a strong mathematical background and offers a relatively simple method of predicting the kinetics of anti‐cancer drugs in patients from pre‐clinical animal data.

5. The occurrence of major qualitative and quantitative differences in the metabolism of drugs between species is probably the single greatest complicating factor in the use of animals as predictors of drug toxicity and kinetics in patients.

6. Despite this, the allometric approach is useful for allowing the estimation of a more appropriate starting dose for some drugs in a Phase I trial, which might result in potential savings in escalation steps and maximize the chance that the dose which an individual receives has the potential for therapeutic value.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOXIA‐ACTIVATED PRODRUGS AS ANTITUMOUR AGENTS: STRATEGIES FOR MAXIMIZING TUMOUR CELL KILLING
Authors: Wilson William R. , Pruijn Frederik B.
Published: June 2007

1. Hypoxia arises in solid tumour because of inefficient blood supply. While hypoxic cells are resistant to radiotherapy and probably to many chemotherapeutic drugs they can, in principle, be turned to advantage through the development of hypoxia‐activated cytotoxic drugs (bioreductive drugs).

2. Three general approaches to exploiting tumour hypoxia are discussed. The first relies on fluctuating blood flow in tumours and the consequent cycling of cells through the hypoxic compartment. The second incorporates a prodrug approach in which drug activation gives rise to cytotoxic metabolites which diffuse out of hypoxic zones. The third utilizes selective inhibitors of tumour blood flow to induce additional hypoxia and thus enhance bioreductive drug activation.

3. The latter two approaches are illustrated by recent studies with the dinitrobenzamide nitrogen mustard class of bioreductive drugs and their combination with the tumour blood flow inhibitor 5,6‐dimethylxanthenone‐4‐acetie acid.
RELATIVE CONTRIBUTIONS OF VOLUNTARY APNOEA, EXPOSURE TO COLD AND FACE IMMERSION IN WATER TO DIVING BRADYCARDIA IN HUMANS
Authors: Marsh Neville , Askew Debra , Beer Kelli , Gerke Michelle , Muller Diane , Reichman Coral
Published: June 2007

1. Diving or face immersion bradycardia is a well recognized but incompletely understood reflex which occurs in man and other mammals.

2. In order to investigate the contributions made by voluntary apnoea, face immersion in water and cold exposure, 18 normal subjects were exposed to these challenges separately and in various combinations.

3. Tested individually, cold and apnoea caused significant reductions in heart rate (P<0.01 and 0.002, respectively). Face immersion in thermoneutral water had no effect on heart rate.

4. The bradycardic effect of apnoea at maximal inspiration may be due to stimulation of pulmonary stretch receptors.

5. Cold exposure and voluntary apnoea applied simultaneously caused a summative effect but when tested with face immersion in water there was a synergistic response greater than the sum of individual responses.

6. The results confirm the bradycardic effect of apnoea and cold exposure, whereas immersion in thermoneutral water had little effect, a finding which has been disputed in the literature.
DIRECT EFFECTS OF ANGIOTENSIN I, ANGIOTENSIN II, AN ACE INHIBITOR AND A SERINE PROTEINASE INHIBITOR ON CULTURED HEART CELLS FROM SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kuzuo Hiroshi , Honda Masaaki , Tanaka Koichi , Kuramochi Takehiko , Morioka Shigefumi , Takabatake Toshikazu , Yamori Yukio
Published: June 2007

1. The purpose of the present study was to investigate how angiotensin 1 (AI), angiotensin II (AII), an angiotensin converting enzyme inhibitor (ACE inhibitor; ACE‐I) and a serine proteinase inhibitor contribute to the protein metabolism of cultured newborn spontaneously hypertensive rats (SHR) heart cells. We examined the uptake of [3H]‐uridine and [3H]‐proline into cultured cardiac myocytes and fibroblasts, respectively.

2. Both AI and AII increased the uptake of [3H]‐uridine into myocytes in a concentration‐dependent manner. However, the effect of AI was denied in the presence of the ACE‐I with the concentration of 10−6 g/mL. Both AI and AII increased the uptake of [3H]proline into cardiac fibroblasts in a concentration‐dependent manner. However, this effect was only partially abolished in the presence of 10−6 g/mL of the ACE‐I, which was the maximal concentration that did not exert any effect on the [3H]‐proline uptake. In the presence of AII receptor antagonist, [Sar1, Led8]‐ AII, the uptake of [3H]. proline into cardiac fibroblasts was completely inhibited. Moreover, the stimulatory effects of AI on the uptake of [3H]‐proline into cardiac fibroblasts were completely inhibited in the presence of a serine proteinase inhibitor in addition to the ACE‐I.

3. These results suggest that an ACE‐I has different effects on protein metabolism in the heart and also suggest the presence of serine proteinase in cultured cardiac fibroblasts from SHR.
DELETERIOUS EFFECTS OF SALT INTAKE OTHER THAN EFFECTS ON BLOOD PRESSURE
Authors: Antonios Tarek F. T. , MacGregor Graham A.
Published: June 2007

1. Salt intake is not only known to play an important role in determining blood pressure (BP) but has been shown to have other deleterious effects independent of BP.

2. Epidemiological and animal studies have provided evidence that salt intake may have an adverse effect on stroke mortality independent of BP.

3. Significant correlation between sodium excretion (as a measure of salt intake) and left ventricular (LV) hypertrophy has been shown in many clinical studies. Salt restriction has also been found to produce a significant reduction in LV mass.

4. In animal studies, salt restriction in uninephrectomized spontaneously hypertensive rats retarded renal glomerular injury and suppressed compensatory growth independent of hypertension. Moreover, a high sodium diet accelerated cerebral arterial disease even when no increases in BP could be detected.

5. Epidemiological data have shown an association between asthma mortality and regional purchases of table salt. Furthermore, dietary salt restriction in asthmatic patients results in improvement of symptomatology with lower consumption of bronchodilators.

6. Patients with essential hypertension are known to have increased urinary calcium excretion, and hypertension may be one factor that may increase the likelihood of osteoporosis. High salt intake is also associated with increased hydroxyproline excretion indicating increased resorption of bone. Sodium restriction reduces calcium excretion and may reduce bone demineralization and hip fractures in a similar manner to that seen with diuretics.
ALCOHOL AND HYPERTENSION
Authors: Beilin L. J.
Published: June 2007

1. Regular alcohol consumption is a significant contributor to the prevalence of hypertension in drinking communities.

2. The effect is additive to that of obesity and is partly reversible over 2–4 weeks with moderation of ethanol intake.

3. In heavy drinkers acute alcohol withdrawal may lead to more blood pressure elevation following an initial depressor response.

4. Heavy drinking is also associated with an increased risk of haemorrhagic stroke and cardiomyopatby.

5. Lighter drinking habits appear to offer significant protection against ischaemic heart deaths and ischaemic strokes.

6. Antihypertensive drug treatment for alcohol related hypertension may mask some of the adverse cardiovascular effects of alcohol.

7. Arguments as to whether alcohol is a cause of essential hypertension are tautological, given the many reversible lifestyle factors now known to contribute to the rise in blood pressure with ageing.
NEW WORLD SYNDROME IN WESTERN AUSTRALIAN ABORIGINES
Authors: Gracey Michael
Published: June 2007

1. It has become clear over the past 25 years that Aborigines in Western Australia (WA) now experience very high rates of type 2 diabetes mellitus and its complications as well as hypertension and cardiovascular disease; these disorders are often associated with obesity and abnormalities of plasma lipids.

2. This experience is similar to that of Aboriginal people in other parts of Australia and to other previously traditional societies now in transition to an ubanized, Westernized existence; this is widely attributed to lifestyle factors and genetic susceptibility.

3. This so‐called ‘New World Syndrome’ is responsible for disproportionately high levels of morbidity and mortality in the Aboriginal population of WA; prevention and improved methods of screening, detection and management are needed to reduce this problem.
USE OF PRIMARY CULTURES AND CONTINUOUS CELL LINES TO STUDY EFFECTS ON ASTROCYTIC REGULATORY FUNCTIONS
Authors: Walum Erik , Eriksson Gun , Peterson Anders , Holme Elisabeth , Larsson Nils‐Göran , Eriksson Charlotta , El‐Shamy Wael
Published: June 2007

1. Current opinions on the mechanisms for glutamate‐mediated neurotoxicity are reviewed. The protective role of astrocytic high‐affinity glutamate transport is also discussed.

2. Low‐density seeding of primary astrocytes from rat hemispheres was found to result in the development of reactive‐like astrocytes. Typical glial signs of amyotrophic lateral sclerosis (ALS) could not be induced in astrocyte cultures by serum from ALS‐patients.

3. Glutamate (100 μmol/L) was found to induce an increase in respiratory activity in primary cultures of astrocytes. This stimulation appeared to be related to the co‐transport of Na2+ with glutamate and a resulting activation of Na2+/K+‐ATPase. Both basal respiration and glutamate‐stimulated oxygen consumption was inhibited by organic solvents.

4. Preliminary results show that heavy metals cause an increase in the mitochondrial DNA content at concentrations that have no effect on growth rate or morphology in a glial cell line. This increase was accompanied by an inhibition of oxygen consumption and an increased production of lactate at unaltered ATP levels.
NEUROPHARMACOLOGY OF NICOTINE: EFFECTS ON THE AUTOREGULATION OF ACETYLCHOLINE RELEASE BY SUBSTANCE P AND METHIONINE ENKEPHALIN IN RODENT CEREBRAL SLICES AND TOXICOLOGICAL IMPLICATIONS
Authors: Sastry B. V. Rama
Published: June 2007

1. The neuronal release of acetylcholine (ACh) and its autoregulation by neuromodulators, substance P (SP) and methionine enkephalin (MEK), have been studied using super‐fused rodent cerebral slices. Nicotine exerts significant effects on autoregulation of ACh release, which may have toxicological implications.

2. Positive and negative feedback systems have been postulated for autoregulation of ACh release. The components of the positive feedback system include a muscarinic (Ms) receptor, SP, and activation of Ca2+ influx. Low levels of ACh in the biophase of the cholinergic synaptic gap may trigger the positive feedback system, and high levels of ACh may trigger the negative feedback system.

3. There are also neuronal pathways for direct reciprocal regulations of SP and MEK.

4. Low concentrations of nicotine triggers the release of ACh followed by MEK and SP. Release of SP causes neurogenic inflammation.

5. Nicotine and its metabolite, cotinine, activate platelet activating factor (PAF)‐hydrolase and thereby enhance the turnover rate of PAF. This effect may contribute to tobacco‐induced arterial thrombosis in peripheral and central nervous systems.
NEUROPROTECTION IN VITRO AND IN VIVO BY CELL MEMBRANE‐PERMEANT Ca2+ CHELATORS
Authors: Tymianski Michael
Published: June 2007

1. A method of attenuating excitotoxic and hypoxic/ ischaemic neurodegeneration in vitro and in vivo using cell‐permeant Ca2+‐chelating agents is described.

2. The mechanism of neuroprotection may depend on both pre‐ and post‐synaptic effects on intracellular Ca2+ dynamics.

3. This method is unique, because it targets Ca2+ ions, the presumed triggers of neurodegeneration, rather than a specific cellular receptor.
APOPTOTIC AN IN AN IN VITRO MODEL OF NEURONAL OXIDATIVE STRESS
Authors: Ratan Rajiv R. , Baraban Jay M.
Published: June 2007

1. Oxidative stress is believed to be an important mediator of neuronal cell death but the precise mechanism by which this accurs is unknown.

2. We have developed an in vitro model of neuronal oxidative stress to study the pathways by which free radicals kill neurones.

3. We have shown that oxidative stress, cystine deprivation and glutathione depletion results in cell death with the morphological and biochemical features of apoptosis.

4. Neuronal apoptosis induced by oxidative stress can be inhibited by macromolecular synthesis inhibitors.

5. This in vitro model will be a valuable tool for defining the molecular targets of toxic free radicals in neurones and, in turn, in designing rational new therapies for free radical mediated diseases.
NITRIC OXIDE INHIBITION DOES NOT PREVENT THE HYPOTENSIVE RESPONSE TO INCREASED RENAL PERFUSION IN RABBITS
Authors: Thomas C. J. , Anderson W. P. , Woods R. L.
Published: June 2007

1. The involvement of nitric oxide (NO) and platelet activating factor (PAF) in the systemic depressor responses to increased renal perfusion pressure (RPP) were investigated.

2. In anaesthetized rabbits, the left kidney was perfused via an extracorporeal circuit which allowed RPP to be increased from 65 mmHg to 125 mmHg. The response of systemic blood pressure (SBP) to increasing RPP was measured in the same rabbits.

3. One group of rabbits (n = 5) was treated with NG‐nitro‐L‐arginine (NOLA) to inhibit NO synthase activity (20 mg/kg i.v. bolus). Another group (n= 5), received 250mmol/L NaHCO3 (4mL/kg bolus) as vehicle treatment.

4. Following an increase in RPP to 125 mmHg, SBP fell at a rate of 0.43 ± 0.06 mmHg/min in the vehicle treated rabbits. After NO synthase inhibition the rate of fall in SBP of 0.34 ± 0.07 mmHg/min was not significantly different from that in the vehicle group (P= 0.3).

5. Blockade of NO synthesis did not alter the renal blood flow, renal vascular resistance changes and pressure‐related natriuresis and diuresis responses to increased RPP to 125 mmHg.

6. PAF receptor blockade, using WEB 2086 (0.5 mg/kg plus 0.5 mg/kg/h), did not alter the systemic, renal haemodynamic or urinary responses to increasing renal perfusion pressure to 125 mmHg.

7. These findings indicate that neither NO nor PAF play an important role in the blood pressure lowering activity, intrarenal haemodynamics and urinary excretory responses observed when RPP was increased to a level within the physiological range.
ANALYSIS OF THE STEADY‐STATE DYNAMICS OF ORGANELLE MOTION IN CULTURED NEURITES: PUTATIVE INDICATOR OF NEUROTOXIC EFFECT
Authors: Chute Stewart K. , Flint Oliver P. , Durham Stephen K.
Published: June 2007

1. The objective of this study was to develop a physiologically based method to evaluate the neurotoxic potential of drug candidates in vitro. Rat embryo midbrain cells were grown in micromass culture, and the movement of mitochondria labelled with the fluorescent dye rhodamine 123 was quantified in fasciculated neurites, using a laser cytometer.

2. The rhodamine 123 signal in a defined region of fascicle was quantified and photobleached with the laser. A series of post‐photobleach scans revealed the movement of fluorescent‐labelled mitochondria into the bleached region from adjacent unbleached regions. Recovery of fluorescence is a measure of the size of the mobile pool of mitochondria relative to the total (moving plus stationary) pool.

3. The steady‐state levels of fluorescence recovery was dependent on intracellular calcium and magnesium concentrations, energy status (ATP), and microtubule integrity (post taxol or vinblastine treatment).

4. This technique may be a useful indicator of neurotoxic effect.
SUBUNIT‐DEPENDENT ACTION OF LEAD ON NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS EXPRESSED IN XENOPUS OOCYTES
Authors: Oortgiesen Marga , Zwart Ruud , van Kleef Regina G. D. M. , Vijverberg Henk P. M.
Published: June 2007

1. Pb2+ affects neuronal nicotinic acetylcholine receptors (nAChR) in NIE‐115 neuroblastoma cells in a dual manner. At nanomolar concentrations a blockade is observed, while at submillimolar concentrations this blocking effect is reversed.

2. The Xenopus oocyte expression system was used to examine whether the dual effect of Pb2+ is related to a differential action on nAChR subtypes. Effects of Pb2+ were investigated in oocytes expressing nAChR after co‐injection of a3 and β2 or α3 and β4 cDNA.

3. At 1–250 μmol/L, Pb2+ causes a 10–1000% increase of the response mediated by the α3β2 nAChR.

4. Pb2+ blocks ACh‐induced inward currents mediated by α3β4 nAChR. The inhibitory potency of Pb2+ greatly varies between cells. In 50% of the cells concentrations ≤μmol/L Pb2+ blocked the nicotinic response by 31–93%. In the other cells even at higher concentrations Pb2+ caused only 0–65% inhibition.

5. These results show that Pb2+ may both potentiate and block nAChR, depending on the type of nAChR subunit expressed.
USE OF DIFFERENTIATED CHOLINERGIC AND SECOND MESSENGER ENDPOINTS TO EVALUATE CHOLINESTERASE INHIBITORS
Authors: Blusztajn J. K. , Davis Ross O.
Published: June 2007

1. The effects of organophosphorus compounds on the cholinergic properties of a mouse septal neuronal cell line, SN56, were investigated. Treatment of the cells with 10 μmol/L paraoxon or 10 μmol/L diisopropylphosphorofluoridate (DFP) resulted, respectively, in rapid 27‐ and 11‐fold increases of intracellular acetylcholine content.

2. Time‐course studies showed that paraoxon maintained its efficacy whereas the effects of DFP decayed quickly, possibly due to rapid hydrolysis and inactivation of DFP in the growth medium.
NEUROTOXICITY OF BETA‐AMYLOID PROTEIN: CYTOCHEMICAL CHANGES AND APOPTOTIC CELL DEATH INVESTIGATED IN ORGANOTYPIC CULTURES
Authors: Allen Y. S. , Devanathan P. H. , Owen G. P.
Published: June 2007

1. This study is an attempt to examine in vitro the cyto chemical changes in hippocampal neurones induced by beta‐amyloid protein (β‐AP).

2. The mechanism of cell death, and the vulnerability of different regions of the hippocampus to b‐AP toxicity, has also been explored using TUNEL staining to locate fragmented DNA in both dissociated and organotypic cultures.

3. Apoptotic cell profiles and the detection by immunocytochemistry of ubiquitin and tau protein confirmed the acute neurodegenerative effects of b‐AP, and organotypic cultures revealed the dentate gyrus to be especially vulnerable.

4. A scrambled sequence of b‐AP, a peptide with similar hydrophobic groups to b‐AP, and islet pancreatic amyloidogenic peptide also showed neurodegenerative effects, although less severely than b‐AP.

5. It is concluded that organotypic cultures provide a valuable in vitro model with which to observe and characterize the neurotoxic effects of b‐AP. These effects, however, may be non‐specific and related more to the general amyloidogenicity of the b‐AP molecule.
DEVELOPMENTAL NEUROTOXICITY TO METHAMPHETAMINES
Authors: Weissman Arthur D. , Caldecott‐Hazard Sally
Published: June 2007

1. To investigate the long‐term changes caused by amphetamines in the developing brain, we used both an in vivo and in vitro model of chronic fetal exposure to methamphetamine and related drugs.

2. Offspring of rats, treated with either saline, 2 mg/kg twice a day (b.i.d.) or 10 mg/kg bid. methamphetamine throughout gestation, were examined at 30 days of age for changes in the monoamine system of their brains.

3. At the lower dose methamphetamine was neurotoxic to specific neuronal populations, mostly serotonergic. At the higher dose, methamphetamine retained its neurotoxic properties, but also stimulated the growth of axonal terminals in specific regions as evidenced by an increase in monoamine uptake sites. The neurochemical changes at the higher dose were correlated with deficits in adult behavioural measures.

4. Corresponding in vitro drug treatments of rat neuroblastomas cells also produced a dose‐related effect on cellular growth and differentiation patterns. Neurotoxic as well as stimulatory effects of methamphetamine and some related compounds were seen in culture.

5. Our in vivo and in vitro observations demonstrate neurotoxic effects of amphetamines and the remodelling of synaptic morphology in response.
EXAMINATION OF DEVELOPMENTAL NEUROTOXICITY BY THE USE OF TISSUE CULTURE MODEL SYSTEMS
Authors: Heller Alfred , Won Lisa , Heller Barbara , Hoffmann Philip C.
Published: June 2007

1. The rotation‐mediated three‐dimensional reaggregate culture system is uniquely suited for studies on developmental neurotoxicity. In this system, it is possible to reconstruct central neuronal pathways and follow their development.

2. Exposure to drugs of abuse including methamphetamine and methylenedioxyamphetamine or the appetite suppressant, fenfluramine, reduces monoamines in the cultures in a dose‐dependent manner and interrupts normal monoaminergic development.

3. While the monoaminergic neurones may attain normal rates of development following drug removal, the affected neurones are not capable of overcoming the drug‐induced insults and a deficiency in monoamines persists throughout development.

4. In addition, the production of immortalized monoclonal hybrid cells obtained by fusion of fetal mesencephalic neurones with a neuroblastoma has yielded cell lines expressing a dopaminergic phenotype.

5. Such cells have been useful in establishing the relationship of neurotoxicity to cell lineage and can serve as models for the study of the cellular and molecular mechanisms of neurotoxicity.
OPIOIDS AND PAIN
Authors: Kanjhan Refik
Published: June 2007

1. The central nervous system in mammals is able to react to painful stimuli at many levels that are involved in transmission, modulation and sensation of pain. Endogenous opioid peptides and their receptors are located at key points in pain pathways, and response to pain can be modulated by local application of opioids at many sites. Mechanisms of opioid analgesia at peripheral, spinal, medullary and midbrain levels are only incompletely understood; forebrain systems are even less appreciated. Local circuits in the spinal dorsal horn play a critical role in processing nociceptive afferent input and in mediating the actions of descending pain modulating systems.

2. The opioid receptors, recently cloned, exert their effects by activating G protein coupled effector systems, such as ion channels and second messenger systems. Although the receptor most commonly associated with pain relief is the μ‐receptor, specific δ‐ and k‐agonists can also mediate antinociception at spinal and supraspinal sites. Acute effects of opioids on target neurons are inhibitory, but excitatory effects have also been reported.

3. Noxious stimulation increases neuronal activity and modulates expression of genes, including immediate‐early genes and neuropeptide (i.e. opioid) genes at spinal and supraspinal levels of the somatosensory system. Opioid drugs and endogenously released opioid peptides can modulate signal transduction mechanisms and intracellular processes that lead to alterations in protein phosphorylation and gene expression. These effects of opioids at the cellular level may underlie the mechanisms of pre‐emptive analgesia and neuroplastic changes such as tolerance, dependence, sensitization, hyperalgesia, adaptation, addiction, and modulation of pain memories.
INFLUENCE OF MYOSIN ISOFORMS ON TENSION COST AND CROSSBRIDGE KINETICS IN SKINNED RAT CARDIAC MUSCLE
Authors: Rossmanith G. H. , Hamilton A. M. , Hoh J. F. Y.
Published: June 2007

1. In attempting to consolidate the role of ventricular isomyosins in regulating the contractility of the myocardium, actomyosin ATPase and crossbridge kinetics were obtained at 24°C in chemically skinned isometrically contracting cardiac muscles containing V1 and V3 isomyosins.

2. The ATPase activity was measured at various levels of Ca2+ activation by the enzymatic coupling of ATP hydrolysis with the conversion of NADH to NAD+. The crossbridge kinetics were inferred from small‐amplitude perturbations of muscle length and muscle tension, and characterized by the frequency‐domain parameter fmin.

3. The ATPase rates of V1 and V3 muscles obtained at various levels of Ca2+ activation were plotted against the corresponding proportional tensions. The ATPase vs tension plots were linear with slopes of 4.92 nmol/min‐1 per mm per mN and 1.98 nmol/min‐1 per mm per mN, respectively for, V1 and V3 muscles. Individual calculations of ATPase‐to‐tension ratios (nmol/min‐1 per mm per mN) gave corresponding averages of 4.98 ± 0.12 (s.e.m., n = 12) and 2.16 ± 0.12 (s.e.m., n = 10). The myosin isoform induced proportional change in tension cost was accompanied by a similar change in fmin (4.1 ± 0.1 Hz and 1.95 ± 0.03 Hz, means ± s.e.m., for V1 and V3 muscles, respectively).

4. The observations and other published kinetic data are discussed in the context of models of crossbridge cycling. It is suggested that the tension economy of V3 muscle arises principally from an increase in the fraction of time, during the crossbridge cycle, when the crossbridge is exerting force.