bluuebunny/crossref_metadata_2025 huggingface dataset:
WEB‐2086 AND INDOMETHACIN DO NOT MODIFY BLOOD PRESSURE FALL ON UNCLIPPING HYPERTENSIVE RATS
Authors: Smith Anthony J. , Gerkens John F. , Dosen Peter
Published: June 2007

1. Pretreatment with intravenous WEB‐2086 (0.5 mg/ kg; an antagonist of the actions of platelet activating factor; PAF) with or without indomethacin (2 mg/ kg) failed to prevent or modify the fall in blood pressure following unclipping of the renal artery of anaesthetized two‐kidney, one‐clip hypertensive rats.

2. The same medications given to two other groups of rats 60 min after unclipping when the blood pressure had fallen to stable levels failed to reverse the fall.

3. Despite evidence that both prostanoids and PAF can be detected in increased amounts in renal venous blood after unclipping, they do not appear to mediate the reduction in blood pressure in this model of reversible hypertension.
INHIBITORY EFFECTS OF VERAPAMIL ON [3H]‐ACETYLCHOLINE RELEASE IN THE CENTRAL NERVOUS SYSTEM OF SPRAGUE‐DAWLEY RATS
Authors: Tsuda Kazushi , Tsuda Seiko , Goldstein Menek , Masuyama Yoshiaki
Published: June 2007

1. The purpose of the present study was to investigate the effects of verapamil, a Ca2+ channel blocker, on acetylcholine (ACh) release in the CNS.

2. Striatal slices of rats, prelabelled with [3H]‐ACh, were superfused with Krebs'‐Ringer solution. The slices were stimulated by electrical pulses (1 Hz) or by an excitatory amino acid, l‐glutamate and the effects of verapamil on the release of ACh were examined.

3. Electrical stimulation produced an increase in [3H]‐ACh release from the striatal slices. Exposure of the slices to verapamil significantly inhibited the stimulation‐evoked [3H]‐ACh release.

4. An endogenous excitatory amino acid, l‐glutamate, also elicted the release of [3H]‐ACh. Verapamil significantly reduced the l‐glutamate‐induced release of [3H]‐ACh and the inhibitory effect of verapamil was more pronounced in the presence of Mg2+ in the medium.

5. The results of the present study demonstrate that verapamil inhibited both electrically‐ and chemically‐stimulated [3H]‐ACh release from the rat striatum. The inhibition of cholinergic transmission by verapamil might be related to the central effect of the Ca2+ channel blocker.
HETEROGENOUS ACTIVITY OF BRL 35135, A β3‐ADRENOCEPTOR AGONIST, IN THERMOGENESIS AND INCREASED BLOOD FLOW IN BROWN ADIPOSE TISSUE IN ANAESTHETIZED RATS
Authors: Takahashi Hakuo , Nakamura Shohei , Shirahase Hiroaki , Yoshida Toshihide , Nishimura Masato , Yoshimura Manabu
Published: June 2007

1. The effects of BRL 35135, a β3‐adrenergic agonist, on body temperature and regional blood flow in brown adipose tissue (BAT) were simultaneously recorded in anaesthetized rats and compared to isoproterenol.

2. BRL 35135 at doses of 0.1 and 1 μg/kg (i.v.) induced dose‐dependent increases in BAT temperature with minimal effects on systemic diastolic blood pressure (DBP), heart rate (HR) and BAT blood flow.

3. The thermogenic effect of BRL 35135 at a dose of 10 μg/kg (i.v.) was smaller than that at a dose of 1 μg/kg, and was accompanied by a marked increase in BAT blood flow.

4. Isoproterenol at doses of 0.01–1 μg/kg (i.v.) dose‐dependently increased HR and BAT blood flow and decreased DBP. It did not affect BAT temperature.

5. These findings indicate that unlike isoproterenol, BRL 35135, at the lower doses, selectively causes thermogenesis in BAT which was detectable as changes in BAT temperature, and that the vasodilator effect in BAT is not as sensitive as the thermogenic effect of β3‐adrenergic agonists.
BLOOD VOLUME MEASUREMENTS IN THE NEONATAL LAMB: VALIDATION OF A METHOD USING [51Cr]‐LABELLED RED CELLS
Authors: Moritz Karen M. , Potocnik Simon J. , Tangalakis Kathy , Wintour E. Marelyn
Published: June 2007

1. The reproducibility of blood volume measurements, using [51Cr]‐labelled red blood cells (RBC) was tested in three lambs, 79–89 days of age, and the accuracy was tested in eight lambs, 83± 0.4 days of age, in which blood volume was measured simultaneously by [51Cr]‐RBC and [125I]‐gamma globulin plus haematocrit (hct).

2. The blood volumes (mean ± s.e.) of the three lambs, on four occasions, were 64.5± 2.5, 68.8 ± 2.9 and 63.9 ± 3.7 mL/kg, respectively, and the coefficients of variation were 7.8, 8.6 and 11.6%, respectively.

3. The mean blood volume of eight lambs was 60.9 ± 3.3 mL/kg by [51Cr]‐RBC, and 60.8 ± 2.4 mL/ kg from plasma volume and hct. These were not statistically different.

4. Arterial hct was 31.2 ± 0.5%, which was not statistically different from the whole body hct of 31.2 ±2.6%.

5. It is concluded that [51Cr]‐RBC can be used to measure accurate and reproducible blood volumes in lambs.
LOW CHOLESTEROL AND IMPAIRED CARDIAC FUNCTION FOLLOWING HEART TRANSPLANTATION
Authors: Kaye David M. , Johnston Leonie , Dart Anthony M.
Published: June 2007

1. During follow‐up of 59 cardiac transplant recipients over 2 or more years, a small group of subjects was observed who displayed an unpredictable, relatively marked, reduction in plasma cholesterol.

2. A significant proportion of these subjects were subsequently observed as having experienced a marked decline in left ventricular function at the time of routine radionuclide ventriculography.

3. While the mechanism for this fall in cholesterol is unclear, the observation of such an unexpected reduction in total cholesterol, late after heart transplantation should be considered significant and prompt further investigation including an assessment of allograft function.
CHOLESTERYL ESTER TRANSFER PROTEIN: ITS ROLE IN PLASMA LIPID TRANSPORT
Authors: Barter Philip , Rye Kerry‐Anne
Published: June 2007

1. The cholesteryl ester transfer protein (CETP) is a hydrophobic glycoprotein which acts in plasma to redistribute cholesteryl esters and triglyceride between plasma lipoproteins.

2. CETP also plays an important role in determining the composition and particle size distribution of high density lipoproteins (HDL).

3. Activity of CETP may be regulated in four ways: By factors which influence the concentration of CETP in plasma; by the activity of CETP inhibitor proteins; by variations in the concentrations and compositions of donor and acceptor lipoproteins and by factors which influence the interaction of CETP with plasma lipoproteins.

4. The mechanism of action of CETP is uncertain. Two models have been been proposed: (i) a shuttle model in which CETP physically transports lipids between lipoprotein particles and (ii) a ternary complex model in which CETP forms a bridge between two lipoprotein particles, enabling them to exchange lipids.

5. Evidence is accumulating that CETP may be a pro‐atherogenic factor.
NO EFFECT OF KININS ON DNA SYNTHESIS IN LNCaP PROSTATE CANCER CELLS
Authors: Reid Joanna , Schrader Andrew P. , Morris Brian J.
Published: June 2007

1. Prostate has kininogenase activity and expresses members of the tissue kallikrein gene family. The present study examined the effect of exogenous and endogenous kinins on growth of LNCaP prostate adenocarcinoma cells.

2. Rate of DNA synthesis was measured by incorporation over 4 h of [3H]‐thymidine into a TCA insoluble fraction of LNCaP cells that had been cultured for 24 h.

3. Increased [3H]‐thymidine incorporation was seen in response to 10 nmol/L testosterone (4– 103 ± 5 s.e.%), dihydrotestosterone (+ 113 ± 14%) and R 1881 (+64 ± 10%) (P± 0.001; n = 4).

4. In contrast 0.05, 5 and 1000 nmol/L lysyl‐bradykinin had no effect (15 ± 4, 10 ± 9 and 5 ± 3 s.e.%, respectively; n = 7). Des‐Arg9[Leu8]‐bradykinin (a B1 receptor antagonist) and/or d‐Arg‐[Hyp3,Thi5,8,d‐Phe7]‐bradykinin (a B2 receptor antagonist), 1 nmol/L, and indomethacin, 5 μmol/L, also had little or no effect.

5. In conclusion, kallidin and endogenous kinins and prostaglandins have little or no effect on DNA synthesis and therefore on the growth of LNCaP cells in comparison to the two‐fold stimulation produced by androgens.
DIFFERENCES IN ENDOTHELIUM‐DEPENDENT RELAXATION IN VARIOUS ARTERIES FROM WATANABE HERITABLE HYPERLIPIDAEMIC RABBITS WITH INCREASING AGE
Authors: Kitagawa Satomi , Yamaguchi Yu , Sameshima Emiko , Kunitomo Masaru
Published: June 2007

1. Endothelium‐dependent relaxation in response to acetylcholine (ACh) and the calcium ionophore A 23187 was examined in aorta, coronary, basilar and renal arteries isolated from Watanabe heritable hyperlipidaemic (WHHL) rabbits of 2, 6 and 12 months of age, with normolipidaemic heterozygous WHHL rabbits as controls.

2. In the rings of WHHL rabbit aortae and coronary arteries preconstricted with vasoconstrictors, endothelium‐dependent relaxation in response to ACh was attenuated with age compared to the heterozygous WHHL rabbits. A significant negative correlation was found between the total cholesterol content and the relaxation response to ACh in the aortae or coronary arteries from 6 and 12 month old WHHL rabbits.

3. In the rings of basilar arteries, endothelium‐dependent relaxations to ACh were not modified with age. Similarly, in the rings of renal arteries, the relaxation response to ACh was not changed with age, but in the 6 and 12 month preparations, after the age of 6 months, a contraction following the relaxation appeared at higher concentrations of ACh (10−7 to 10−6 mol/L). The contraction was endothelium‐dependent and inhibited by indomethacin.

4. A 23187‐induced endothelium‐dependent relaxations were also markedly attenuated in the aorta and significantly in the coronary artery with age.

5. Endothelium‐independent relaxation to sodium nitroprusside was not changed in all arteries from WHHL rabbits of different ages.

6. These findings indicate that in the aorta and coronary artery of the WHHL rabbit, the endothelium‐dependent relaxation to ACh and A 23187 becomes impaired with increasing age (i.e., with the progression of cholesterol deposition in the arterial wall) but is preserved in the basilar and renal artery.
EFFECTS OF PROLONGED (48 H) INFUSION OF CORTISOL ON BLOOD PRESSURE, RENAL FUNCTION AND FETAL FLUIDS IN THE IMMATURE OVINE FOETUS
Authors: Dodic Miodrag , Wintour E. Marelyn
Published: June 2007

1. This study describes the effects of prolonged (48 h) infusion of cortisol into ovine foetuses (100–110 days of gestation: term is 150 days) at a time when endogenous plasma cortisol concentrations are <5 nmol/L.

2. In four chronically cannulated foetuses (107 ± 0.9 day) the infusion of saline (0.9% NaCl; w: v 0.19 mL/h, 48 h) had no effect on blood pressure, renal function, or composition of amniotic and allantoic fluids.

3. In six foetuses (107 ± 1 day) the infusion of cortisol (250 μg/h) increased plasma cortisol concentrations from 4.1 ± 0.7 to 118 ± 9 nmol/L (P < 0.001), increased mean arterial pressure from 34 ± 1 to 40 ± 1 mmHg (P < 0.001), increased glomerular filtration rate (P<0.05), urine flow rate, and free water clearance (P<0.01).

4. There was a significant increase in excretion rates of potassium and creatinine as a result of cortisol infusion, but no natriuresis, indicating some functional maturation of the fetal kidney.

5. Cortisol infusion had no effect on the volumes of amniotic and allantoic fluids; allantoic fluid composition was unchanged; significant decreases occurred in amniotic fluid osmolality, sodium and chloride concentrations, and in lung liquid osmolality, potassium, creatinine, magnesium, glucose and fructose concentrations.

6. Thus prolonged exposure of the immature ovine foetus to elevated cortisol concentrations produced significant alterations in the water and electrolyte balance of the foetus.
CONTRASTING EFFECTS OF ISOPROTERENOL AND PHOSPHODIESTERASE I11 INHIBITOR ON INTRACELLULAR CALCIUM TRANSIENTS IN CARDIAC MYOCYTES FROM FAILING HEARTS
Authors: Honda Masaaki , Kuramochi Takehiko , Ishinaga Yuji , KUZUO Hiroshi , Tanaka Koichi , Morioka Shigefumi , Enornoto Koh‐Ichi , Takabatake Toshikazu
Published: June 2007

1. Effects of a newly developed phosphodiesterase (PDE) I11 inhibitor, E‐1020, on intracellular calcium transients were compared with those of isoproterenol (ISO) in isolated single myocytes from failing hearts secondary to pulmonary hypertension induced by monocrotaline injection. Myocytes were isolated by enzyme digestion using a Langendorff apparatus. Changes in intracellular calcium concentrations ([Ca2+]i,) were recorded using a fura‐2 fluorescence microscopic technique. Cyclic AMP contents of the hearts were measured by radio‐immunoassay.

2. Myocytes from failing hearts showed Ca2+ transients with a low peak (low amplitude) and delayed decline of Ca2+ transients. Both IS0 and E‐1020 increased peak [Ca2+]i, max +d[Ca2+]i/dt, and max − d[Ca2+]i/dt in a concentration‐dependent manner while both agents decreased T80L (time to 80% decline of amplitude from peak light). The concentrations which increased peak [Ca2+]i by 50% were 1.6 × 10‐9 mol/L of IS0 and 2× 10‐6 mol/L of E‐1020. These concentrations increased CAMP in the heart to the same levels. Analysis of the effects of both agents on peak [Ca2+], versus max ‐d[Ca2+]i/dt showed that IS0 is much more effective on peak [Ca2+], while E‐1020 is more effective on max ‐d[Ca2+]i,/dt.

3. These results showed that the effects of I S 0 and E‐1020 on the parameters of intracellular Ca2+ transients of single myocytes from failing hearts are slightly different, and suggest that E‐1020 may improve diastolic function as well as systolic function in failing hearts.
CALCIUM TRANSIENTS IN SINGLE MYOCYTES AND MEMBRANOUS ULTRASTRUCTURES DURING THE DEVELOPMENT OF CARDIAC HYPERTROPHY AND HEART FAILURE IN RATS
Authors: Kuramochi Takehiko , Honda Masaaki , Tanaka Koichi , Enornoto Koh‐ichi , Hashimoto Michio , Morioka Shigefumi
Published: June 2007

1. We examined changes in intracellular calcium transients of separated single myocytes from the right ventricle (RV) of the rat heart during the change from adaptation to maladaptation in response to a pressure overload.

2. Right ventricular hypertrophy (RVH) secondary to pulmonary hypertension was induced by a subcutaneous injection of monocrotaline. Developed tensions of the RV‐free wall were decreased as RVH progressed. Single myocytes were separated from the RV during different stages of RVH. Fura‐2/AM‐loaded cells were field stimulated, and changes in calcium transients were measured by Olympus OSP‐3 system. We also examined membranous ultrastructures (sarcoplasmic reticulum, mitochondria, surface caveolae) involved in calcium metabolism in the hearts using scanning electron microscopy.

3. We observed characteristic changes in calcium transients during the change from adaptation to maladaptation, and also found that one parameter (amplitude) of calcium transients appeared to be correlated with the changes in the number of sarcoplasmic reticulum.

4. These results provided some insights into the mechanism of calcium handling of hypertrophied heart in response to a pressure overload from adaptation to maladaptation especially when stimulatory frequency was high, and suggested that heart rate control is a very important factor for the treatment of patients with congestive heart failure.
MECHANICAL DETERMINANTS OF MYOCARDIAL OXYGEN CONSUMPTION
Authors: Gibbs C. L.
Published: June 2007

1. Recent developments which attempt to identify the mechanical determinants of myocardial oxygen consumption (mV̇o2) are considered, with emphasis being placed on the pressure‐work and pressure‐volume area (PVA) indices.

2. The difficulty of establishing a realistic in vivo basal mV̇o2 value is explained and the experimental reasons for the controversy over the magnitude of the activation metabolism are outlined.

3. The time varying elastance model of the heart is discussed including some current problems. The evidence for PVA as a satisfactory index of mV̇o2 under all physiological and pharmacological conditions is examined. Most pharmacological agents alter the intercept of the mV̇o2:PVA relationship but do not effect its slope: this result is interpreted to mean that the majority of current inotropic agents alter the energetic cost of calcium release/retrieval but not crossbridge efficiency.

4. An attempt is made to establish the likely cost of a cardiac contraction in man. The use of newer technology (i) to estimate mV̇o2 via positron emission tomography and (ii) to measure the work and potential energy output of the heart per beat with conductance catheters, is explained.
ROLE OF ATRIAL NATRIURETIC PEPTIDE IN LONG‐TERM VOLUME HOMEOSTASIS
Authors: Lohmeier Thomas E. , Mizelle H. Leland , Reinhart Glenn A.
Published: June 2007

1. Long‐term volume homeostasis is linked very closely to long‐term arterial pressure control through the renal‐body fluid feedback mechanism. A key feature of this control system is the ability of the kidneys to respond to changes in arterial pressure by altering renal excretion of salt and water, often referred to as renal‐pressure natriuresis.

2. Quantitative studies indicate that ANP secretion is relatively sensitive to changes in atrial pressure and that the rate of hormonal secretion does not adapt to continuous long‐term stimulation.

3. Under normal conditions, the renal‐body fluid feedback mechanism for arterial pressure control is very efficient in minimizing changes in body fluid volumes during alterations in sodium intake. Therefore, only small changes in atrial pressure and ANP secretion occur. Alterations in plasma ANP concentration within physiological levels have little effect on renal‐pressure natriuresis and, therefore, have little impact on volume homeostasis.

4. When the renal‐body fluid feedback mechanism for arterial pressure control is impaired and body fluid volumes are elevated, such as in heart failure, large increases in atrial pressure and ANP secretion occur. The resultant pathophysiological plasma levels of ANP exert sustained natriuretic effects and chronically shift renal‐pressure natriuresis to lower arterial pressures. In the absence of this chronic effect of ANP on renal‐pressure natriuresis, reduced arterial pressure in compensated heart failure would result in protracted retention of salt and water and additional increments in body fluid volumes.
POTENTIATION OF NATRIURETIC PEPTIDES BY NEUTRAL ENDOPEPTIDASE INHIBITORS
Authors: Ann Seymour Andrea , Abboa‐Offei Benoni E. , Smith Patricia L. , Mathers Parker D. , Asaad Magdi M. , Rogers W. Lynn
Published: June 2007

1. Inhibitors of neutral endopeptidase (NEP) EC 3.4.24.11 were developed to regulate endogenous levels of the natriuretic and vasodilatory hormone atrial natriuretic peptide (ANP). The selective NEP inhibitor SQ 28603 enhanced the increases in plasma ANP and urinary excretion of ANP, cyclic GMP and sodium stimulated by infusion of human ANP in conscious monkeys. SQ 28603 also potentiated the renal and depressor responses to rat brain natriuretic peptide (BNP) in conscious spontaneously hypertensive rats (SHR) and human BNP in conscious monkeys. Therefore, selective NEP inhibitors protected both natriuretic peptides from degradation in vivo and enhanced their biological activities.

2. Selective NEP inhibitors lowered blood pressure in conscious DOCA/salt hypertensive rats and SHR with antihyper‐tensive activity similar to that of exogenous ANP. Furthermore, simultaneous treatment with an angiotensin converting enzyme (ACE) inhibitor enhanced the depressor activity of the NEP inhibitor in SHR.

3. SQ 28603 stimulated urinary excretion of cyclic GMP and sodium in a dose‐related manner in conscious dogs with tachycardia‐induced heart failure. Addition of the ACE inhibitor captopril significantly reduced blood pressure and systemic vascular resistance while sustaining sodium excretion and increasing cardiac output, glomerular filtration rate and renal blood flow. Therefore, combined NEP and ACE inhibition produced a unique haemodynamic and renal profile in dogs with pacing‐induced heart failure.

4. The novel dual metalloprotease inhibitor BMS‐182657 potentiated the renal responses to exogenous ANP and suppressed the pressor response to angiotensin I in conscious monkeys, indicating in vivo inhibition of both NEP and ACE. BMS‐182657 also reduced blood pressure and stimulated natriuresis in conscious 1‐kidney 1‐clip hypertensive dogs, demonstrating efficacy in a hypertensive model characterized by normal circulating levels of ANP and renin activity. Therefore, a dual metalloprotease inhibitor may offer a unique therapeutic approach for treatment of cardiovascular disorders.
RESPONSE TO ORTHOSTATIC STRESS PREDICTS OFFICE‐DAYTIME BLOOD PRESSURE DIFFERENCE, BUT NOT NOCTURNAL BLOOD PRESSURE FALL IN MILD ESSENTIAL HYPERTENSIVES: RESULTS OF THE HARVEST TRIAL
Authors: Narkiewicz Krzysztof , Piccolo Diana , Borella Paolo , Businaro Roberto , Zonzin Pietro , Palatini Paolo
Published: June 2007

1. The aim of the present study was to evaluate whether postural blood pressure (BP) change could predict office‐daytime BP disparity and the nocturnal BP fall in young, mild essential hypertensives. We investigated 411 males aged between 18 and 45 years with never treated borderline to mild hypertension. BP was measured three times after a 5 min rest in the supine position and thereafter three times after 2 min of standing. The mean of six BP measurements obtained during two visits in the lying position was defined as office BP.

2. Twenty‐four hour ambulatory BP monitoring was performed with either the A and D TM‐2420 model 7 or the ICR Spacelabs 90207. BP values were averaged for day—and nighttime periods. The nocturnal BP fall was defined as the difference between the average day—and night‐time BP.

3. The standing‐lying difference was significantly inversely correlated with the office‐daytime difference for both systolic blood pressure (SBP) (r = ‐0.34, P 0.001) and diastolic blood pressure (DBP) (r = ‐0.24, P 0.001). These correlations did not change when the obese subjects (body mass index > 30 kg/m2) were excluded from the analysis. No significant correlation between standing‐lying difference and nocturnal BP fall was found.

4. Our results indicate that white coat hypertension assessed as the office‐daytime BP disparity is partially related (in a negative fashion) to the BP reaction to standing. The postural BP change does not predict nocturnal BP fall in young, mild essential hypertensives.
ACCELERATED ENDOTHELIAL REGENERATION AND INTIMAL HYPERPLASIA FOLLOWING A REPEATED DENUDATION OF RABBIT CAROTID ARTERIES: MORPHOLOGICAL AND IMMUNOHISTOCHEMICAL STUDIES
Authors: Azuma H. , Niimi Y. , Terada T. , Hamasaki H.
Published: June 2007

1. We compared endothelial regeneration and intimal thickening after endothelial denudation between normal and sclerotic carotid arteries (CA). Endothelial denudation of the right CA of rabbits formed intimal thickening covered with regenerated endothelial cells (EC) in 6 weeks, which was considered as the sclerosis model. Both CA were then denuded. Morphological and immunohistochemical studies using antibodies for proliferating cell nuclear antigen (PCNA), von Willebrand factor and macrophages were performed.

2. Regeneration of EC were observed 24h after denudation on both CA, but completed earlier in the double‐denuded right CA. The density of EC in both CA increased after regeneration and gradually decreased afterwards.

3. After a single denudation on the left CA, PCNA‐positive cells clearly appeared in 24h, markedly increased in 72h both in the intima and media, then greatly decreased in 4 and 6 weeks.

4. After a double denudation of the right CA, enhancement of the intimal hyperplasia was observed. PCNA‐positive cells markedly increased in 1 week and remained significantly increased in 6 weeks both in the intima and the media.

5. We concluded from these results that the repeated endothelial denudation caused more sustained proliferation of smooth muscle cells which led to an enhancement of the intimal hyperplasia.
URAEMIA IS NECESSARY FOR ERYTHROPOIETIN‐INDUCED HYPERTENSION IN RATS
Authors: Poux Jean‐Michel , Lartigue Martine , Chaisemartin Rose‐Anne , Galen Francois Xavier , Leroux‐Robert Claude
Published: June 2007

1. There is no experimental proof that renal insufficiency is a necessary condition for hypertension during erythropoietin treatment.

2. The present study compares the effect of 3 weeks treatment with r‐hu EPO (50i.u./kg) on systolic blood pressure (SBP), haematocrit and plasma cGMP in an animal model of chronic renal failure (remnant kidney model excision) and sham‐operated rats.

3. Sub‐total nephrectomy induced a significant fall in haematocrit and a significant increase in plasma creatinine levels. Treatment with r‐hu EPO resulted in a significant haematocrit increase in uraemic as well as in non‐uraemic rats. Despite this effect, r‐hu EPO treatment had no effect on SBP in sham‐operated rats. On the contrary, this treatment caused significant SBP elevation in uraemic ratq in these rats, SBP increase did not correlate with haematocrit increase.

4. Plasma cGMP concentrations were significantly higher in uraemic compared to sham‐operated rats and were not modified by r‐hu EPO treatment.

5. This study provides evidence that renal insufficiency in rats is a prerequisite for the development of hypertension during erythropoietin treatment.
24 HOUR AMBULATORY BLOOD PRESSURE PROFILES IN THE ACUTE PHASE OF STROKE
Authors: Morfis L. , Schwartz R. , Lykos D. , Zagami A. , Pryor D. , Howes L. G.
Published: June 2007

1. Twenty‐four hour ambulatory blood pressure monitoring (ABPM) was used to evaluate the blood pressure (BP) changes in acute stroke.

2. Stroke was categorized according to the probable underlying vascular mechanism into lacunar infarction (L), thrombotic infarction (T) and intracerebral haemorrhage (ICH). A total of 37 stroke patients were studied (T = 21, L = 9, ICH = 7). Control patients (n= 15) were acute medical admissions not severely ill or in significant pain. ABPM was performed on day 1 and day 7 following admission.

3. Day 1 mean ± s.d. 24h systolic BP (SBP) were L (159 ± 15.8), ICH (151 ± 33.4), T (147 ± 15.2) and controls (134 ± 17.8). Day 7 mean 24h SBP were L (138 ± 9.8), ICH (143 ± 26.9), T (138 ± 19) and controls (134 ± 14.8). In each stroke group BP fell to levels similar to control on day 7, while control mean SBP remained unchanged between days 1 and 7. The highest day 1 BP and the greatest subsequent fall on day 7 occurred for lacunar infarction. Diastolic BP showed similar changes to SBP.

4. The acute stress of hospitalization does not appear to explain elevated BP in acute stroke. Lacunar infarction appears to be particularly associated with temporary BP elevation.
PROCEEDINGS OF THE HBPRCA EFFECT OF DOSE ON TROUGH PEAK RATIO OF ANTIHYPERTENSIVE DRUGS IN ELDERLY HYPERTENSIVE MALES
Authors: Morgan T. O. , Morgan O. , Anderson A.
Published: June 2007

1. The study was undertaken in male patients aged 61–73 years with essential hypertension.

2. The patients had previously had their blood pressure controlled with the drug studied.

3. A randomized crossover study compared the effect of different drug doses on peak (3h) and trough (24h) blood pressure compared to placebo.

4. All drug doses used lowered blood pressure at peak response and the responses with different doses of angiotensin converting enzyme inhibitors were similar. The peak response to felodipine had some dose dependency.

5. Trough blood pressure was not different from placebo with enalapril, 5 and 10 mg, perindopril, 2mg, felodipine, 2.5 mg but was different with enalapril, 20 and 40 mg, perindopril, 4 and 8 mg and felodipine, 5 and 10 mg.

6. Trough peak ratio was dose dependent, with the greatest dependency seen with enalapril which has the shortest half‐life.

7. When low doses of enalapril (5 or 10 mg), perindopril (2 mg) or felodipine ER (2.5 mg) are used it is important to check blood pressure prior to the next dose to ensure that control is achieved and maintained.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: PHARMACODYNAMICS OF LEVODOPA IN PARKINSON'S DISEASE
Authors: Nutt J. G.
Published: June 2007

1. Levodopa markedly reduces parkinsonism during the first years of treatment. However, with continued therapy the response to levodopa becomes erratic and is complicated by involuntary movements. To improve the therapy of parkinsonism, the challenge is to understand why fluctuations in response develop and, once developed, what controls the moment to moment motor status.

2. In patients with a fluctuating response to levodopa, three distinct responses can be recognized: a short‐duration response, a long‐duration response and a negative response.

3. The short‐duration response, measured in minutes to hours, has a steep concentration‐response relationship such that the response appears ‘all or nothing.’ The duration of effect is dose‐responsive. The short‐duration response becomes shorter during chronic therapy, possibly because of tolerance. The onset to effect becomes briefer and the magnitude of the response becomes larger during chronic therapy, possibly because of sensitization.

4. The long‐duration response, measured in days to weeks, develops and decays slowly. The rate of decay is proportional to the severity of the parkinsonism and therefore this response may relate to dopamine storage capacity of remaining nerve terminals.

5. The negative response, measured in minutes, is a worsening of motor function as the short‐duration improvement wears off. It may reflect a biphasic concentration‐response relationship.

6. The response to levodopa in parkinsonian patients is a complex interplay between responses with different time courses and variably affected by sensitization, tolerance and disease progression.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: HYPOTHESIS: APOPTOSIS CAUSED BY CYTOTOXINS REPRESENTS A DEFENSIVE RESPONSE THAT EVOLVED TO COMBAT INTRACELLULAR PATHOGENS
Authors: Vaux David L. , Häcker Georg
Published: June 2007

1. Over 100 different agents have been shown, under certain circumstances, to cause apoptosis, a form of cell death with characteristic morphology. In most cases, the mechanism of cell death is likely to be the same, as expression of the cell death inhibitory gene bcl‐2 can frequently prevent apoptotic changes and/or delay cell death.

2. These observations raise the question of how and why cells detect these agents and why they respond by implementing the suicide mechanism that bcl‐2 can control. Our hypothesis is that apoptosis is used as an anti‐viral strategy, and that cells interpret any metabolic disturbance as evidence of infection by a virus and thereby kill themselves in response to these toxins before they are killed by the action of the toxin itself.

3. Experiments on the effect of sodium azide upon growth factor‐dependent cells support this idea. Bcl‐2 can delay cell death caused by azide, and inhibit apoptotic changes seen by electron microscopy, but cannot prevent the eventual death of the cells.

4. These ideas suggest that drugs designed to regulate cell death may be useful for the treatment of ischaemic or neoplastic diseases. For example, human cells may activate a suicide pathway in response to sub‐lethal amounts of anoxia following a stroke or heart attack and so blocking apoptosis may be a useful therapy to limit tissue damage. On the other hand, increasing the propensity of cells to activate their physiological cell death mechanisms may enhance the effectiveness of toxins designed to kill tumour cells.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: ANIMAL MODELS OF HEART FAILURE FOR PHARMACOLOGICAL STUDIES
Authors: Einstein R. , Abdul‐Hussein N.
Published: June 2007

1. Animals for the study of congestive heart failure (HF) should have chronic, stable disease produced by methods which allow controllable damage and hence predictable disease severity.

2. Pressure and volume loading have commonly been used in the past but these methods are limited by the difficulty of controlling the disease severity.

3. HF induced by cardiotoxic agents, particularly doxorubicin, has been widely used for experimental purposes, but again, control of the degree of damage may be difficult.

4. Coronary artery ligation or occlusion produces heart failure in experimental animals, with clear clinical relevance. Disadvantages of such techniques include fatal arrhythmias and collateral vessel growth that prevents or slows the onset of HF.

5. A minimally invasive model of HF which is relatively controllable can be produced by repeated or single DC shocks across the left ventricle.

6. Chronic rapid ventricular pacing produces a technically simple, predictable, stable and controllable preparation of HF with neurohumoral and haemodynamic changes which mimic the clinical pattern. These changes are reversible in the short term but after pacing for 1 year or longer complete recovery does not occur after cessation of pacing.

7. It has recently been suggested that a single DC shock, three to seven times the threshold defibrillating current, administered to the left ventricle, might provide the basis for the development of a model of heart failure which is technically simple and controllable (Ceddeset al. 1994).
HOW DO FISH OILS AFFECT VASCULAR FUNCTION?
Authors: Chin Jaye P. F. , Dart Anthony M.
Published: June 2007

1. This is a review on the mechanisms by which fish oils affect vascular function and how such changes contribute to their documented cardioprotective effects.

2. Evidence that fish oils depress vascular responses to contractile agents will be examined. It is concluded that this effect of fish oils is mediated predominantly by alterations in prostanoid profile.

3. Effects of fish oils on arterial relaxation are discussed with particular emphasis on endothelium dependent relaxation. It is suggested that the functional impairment of endothelium dependent relaxation documented in a number of cardiovascular disease states can be reversed by dietary fish oils.

4. In addition, possible effects of fish oils on growth factors, inositol trisphosphate and lipid metabolism, the sympathetic nervous system, rheological and membrane properties and inducible nitric oxide are reviewed.
EFFECTS OF NG‐NITRO‐l‐ARGININE ON PRESSURE NATRIURESIS IN ANAESTHETIZED RABBITS
Authors: Evans Roger G. , Szenasi Gabor , Anderson Warwick P.
Published: June 2007

1. We tested the effects of blockade of nitric oxide synthesis on renal function under conditions of controlled renal artery pressure. Our hypothesis was that endogenous nitric oxide plays a role in the natriuresis that accompanies increased renal perfusion pressure. We used a novel technique which employed an extracorporeal circuit to produce step changes over a wide range of renal artery pressures in pentobarbitone‐anaesthetized rabbits.

2. Rabbits were treated with either NG‐itro‐l‐arginine (NOLA, 20 mg/kg, i.v.; n = 8) or its vehicle (n= 8). Renal artery pressure was set (by adjusting the extracorporeal circuit) at 65, 80, 95, 110 and then 130mmHg respectively, at the beginning of each of five 30 min experimental periods.

3. NOLA treatment caused profound renal vasoconstriction that was largely independent of the level of renal artery pressure, renal blood flow being 35–43% lower in NOLA‐treated than in vehicle‐treated rabbits across the range of renal artery pressures tested (P= 0.002). NOLA treatment increased filtration fraction (P = 0.02), and tended to reduce glomerular filtration rate (P= 0.09).

4. NOLA‐treatment affected sodium excretion in a manner dependent on the level of renal artery pressure, with the slope of the relationship between sodium excretion and renal artery pressure being lower in NOLA‐treated than in vehicle‐treated rabbits (P= 0.006).

5. These data provide direct evidence that in anaesthetized rabbits endogenous nitric oxide (i) tonically dilates the renal vasculature across a wide range of renal perfusion pressures, and (ii) enhances sodium excretion to a progressively greater degree as renal artery pressure is increased. It may therefore play a role in pressure‐induced natriuresis.
REGULATION OF COLLECTING DUCT Na+ REABSORPTION BY ANP 31–67
Authors: Zeidel Mark L.
Published: June 2007

1. The bulk of studies of the actions of atrial natriuretic peptides (ANP) have focussed on the carboxyterminal derivative (ANP 99–126) of the prohormone (ANP 1–126), but recent evidence indicates that an additional peptide derived from ANP 1–126, namely, ANP 31–67 also circulates, and has natriuretic actions.

2. The effects of ANP 31–67 on inner medullary collecting duct (IMCD) Na+ transport have been examined in freshly prepared suspensions of rabbit IMCD cells. Like ANP 99–126, ANP 31–67 reduces Na+ transport in these cells.

3. However, unlike ANP 99–126, this effect is not mediated by cGMP, and does not result from inhibition of apical Na+ channels. Rather, ANP 31–67 inhibits basolateral Na/K‐ATPase, probably via the stimulation of PGE2 synthesis.

4. These results are discussed in the context of other natriuretic substances (interleukin 1 and endothelin), which also inhibit Na+ reabsorption by PGE2 ‐mediated inhibition of Na/K‐ATPase.
PREGNANCY ATTENUATES ACTIVITY OF THE BARORECEPTOR REFLEX
Authors: Brooks Virginia L. , Quesnell Rebecca R. , Cumbee Sharon R. , Bishop Vernon S.
Published: June 2007

1. Pregnancy‐induced changes in acute blood pressure regulation are reviewed.

2. Pregnant animals are less able to maintain arterial pressure during haemorrhage than non‐pregnant animals.

3. Baroreceptor reflex‐mediated increases in heart rate, renal sympathetic activity, vasopressin, ACTH and cortisol are reduced during pregnancy. Therefore, one explanation for the subnormal ability of pregnant animals to regulate arterial pressure during haemorrhage is that the baroreceptor reflex is not as effective.

4. Chronic increases in oestrogen levels in non‐pregnant rabbits do not reduce the gain of baroreflex control of renal sympathetic activity. This and other findings suggest that oestrogen alone does not mediate the blunted baroreflex activity observed during pregnancy.
NITRIC OXIDE BIOSYNTHESIS DURING PREGNANCY: IMPLICATIONS FOR CIRCULATORY CHANGES
Authors: McLaughlin Margaret K. , Conrad Kirk P.
Published: June 2007

1. The biosynthesis of NO and its second messenger, cGMP, increases from pre‐pregnant levels during rat gestation. An increase in plasma level and urinary excretion of cGMP is also evident during human pregnancy. However, the relative contribution of the maternal vasculature and other tissues to increased NO and cGMP biosynthesis during gestation is uncertain. Consensus is lacking about the contribution of NO to reduced maternal vascular tone and reactivity during gestation in various organ beds; clearly, further investigation is still needed. That NO may also regulate vascular smooth muscle behaviour during pregnancy by altering membrane potential is another intriguing possibility.

2. The syncytiotrophoblast of the human placenta expresses significant NO synthase activity, and along with the fetoplacental endothelium undoubtedly contributes to NO production during pregnancy.

3. Finally, it should be emphasized that vascular studies in gravid animal models need to be extended to pregnant women.
VEGETARIAN DIET COMPONENTS, PROTEIN AND BLOOD PRESSURE: WHICH NUTRIENTS ARE IMPORTANT?
Authors: Beilin L. J. , Burke V.
Published: June 2007

1. Evidence that vegetarian dietary patterns lower blood pressure (BP) comes from both population studies and randomized controlled trials in normotensive and hypertensive subjects.

2. The effect has been shown most clearly in those who keep to a strict lacto‐ovo vegetarian diet characterized by a relatively low intake of saturated fat, a high polyunsaturated/saturated fat ratio, and a high intake of fruit, vegetables and other fibre containing products. Randomized controlled dietary trials suggest the effects are independent of dietary sodium, additive to that of calorie restriction, and not due to the absence of meat protein per se. Indeed, recent population studies suggest an inverse relationship between dietary protein and BP.

4. Dietary fats, fibre, potassium, magnesium and calcium do not independently seem to account for the effects. A possible role for complex carbohydrate in conjunction with the other dietary factors has yet to be fully explored.
AMBULATORY BLOOD PRESSURE MONITORING FOR EVALUATING THE RELATIONSHIPS BETWEEN LIFESTYLE, HYPERTENSION AND CARDIOVASCULAR RISK
Authors: Pickering Thomas G. , Schwartz Joseph E. , James Gary D.
Published: June 2007

1. Ambulatory monitoring provides a unique opportunity for studying the temporal relationships between lifestyle factors and blood pressure (BP). These include physical activity, mental activity, environmental stressors, substances ingested for pleasure such as smoking, alcohol and caffeine, and nutrition.

2. Changes in physical activity play a major role in determining the diurnal profile of BP, whereas the influence of mood is small.

3. Environmental stress, in the form of job strain, has been shown to be associated with a sustained increase of BP throughout the day and night in men, and also with an increased left ventricular mass. The effects are most marked in men who drink alcohol regularly. Job strain does not appear to influence BP in women.

4. Although it is recognized that smoking raises BP acutely, its long‐term effects have been unclear. Ambulatory monitoring shows that smokers have a larger diurnal swing of BP than non‐smokers, because of a higher daytime pressure. Alcohol also increases the diurnal swing of BP.

5. Ambulatory monitoring has been used relatively little for evaluating nutritional factors, but has the possibility of quantifying their effects on BP more reliably than traditional methods, and also elucidating the underlying mechanisms.
ALTERED LIPID PEROXIDATION/GLUTATHIONE RATIO IN EXPERIMENTAL EXTRAHEPATIC CHOLESTASIS
Authors: Panozzo M. P. , Basso D. , Balint L. , Biasin M. R. , Bonvicini P. , Metus P. , Infantoho D. , Plebani M.
Published: June 2007

1. Lipid peroxidation can occur in the presence of a cellular antioxidant‐oxidant imbalance, but the role of lipid peroxides in cholestasis is not well understood.

2. This study was undertaken in order to: (i) evaluate the behaviour of a product of lipid peroxidation (thiobarbituric acid‐reactive species), and of an important antioxidant tripeptide, reduced glutathione, in the course of experimental extrahepatic cholestasis; and (ii) ascertain whether there was a link between this aspect and the alterations in liver morphology.

3. Forty‐five male Sprague‐Dawley rats (250–300 g) were double bile duct ligated and followed from 1 to 28 days. At the end of each experimental period, blood and liver samples were collected for thiobarbituric acid‐reactive species and glutathione determinations.

4. Bile duct ligated rats showed a marked increase in liver weight which was related to cholestasis duration and to some anatomical alterations such as bile duct proliferation and dilation and liver fibrosis (periportal, perivenular, perineoductular and parenchymal).

5. An increase in serum lipid peroxidation was also observed but this was not linked to hepatic thiobarbiturie acid‐reactive species. Erythrocyte and hepatic glutathione decreased in relation to cholestasis duration. Serum lipid peroxides and erythrocyte glutathione were correlated with liver cell necrosis.

6. In conclusion, experimental extrahepatic cholestasis determines bile duct proliferation and fibrosis, the degree of which is directly related to the duration of cholestasis itself and to liver cell necrotic phenomena. Furthermore, extrahepatic cholestasis is associated with increased lipid peroxide formation and with a depletion of reduced glutathione both in the liver and in the erythrocytes. The alteration in the oxidative balance may be a contributory factor in necrotic liver cell phenomena.
USING NEUROBLASTOMA CELL LINES TO ADDRESS DIFFERENTIAL SPECIFICITY TO ORGANOPHOSPHATES
Authors: Ehrich Marion
Published: June 2007

1. Organophosphates can cause acute toxicity, which follows inhibition of ncetylcholinesterase (AChE), or delayed neuropathy, which follows inhibition of neuropathy target esterase (NTE).

2. Human neuroblastoma SH‐SY5Y cells contain AChE and NTE.

3. Organophosphates actively able to inhibit AChE in animal models inhibited AChE in neuroblastoma cells.

4. Inhibition of NTE in neuroblastoma cells could identify active organophosphates capable of causing delayed neuropathy in animal models and distinguish these organophosphates from those that do not cause delayed neuropathg in animal models.
EFFECTS OF SELECTED ORGANIC SOLVENTS ON THE ASTROCYTE MEMBRANE ATPase IN VITRO
Authors: Vaalavirta Leila , Tähti Hanna
Published: June 2007

1. The present study deals with astrocyte cultures as a model for studying the membrane‐mediated central nervous system‐depressing effect of organic solvents.

2. The primary astrocyte cultures were prepared from neonatal rat cerebella. The cells were cultured in modified essential medium. The astrocyte membranes isolated from the cultures were exposed to solvents in incubation mixture at different dose levels (3, 6 and 9 mmol/L) for 1h. The physiologically important integral proteins Na+, K+‐ATPase and Mg2+‐ATPase were studied.

3. The aromatic hydrocarbons (benzene, toluene, styrene, xylene and ethylbenzene) inhibited the ATPase activities according to their lipid solubilities. n‐Hexane and cyclohexane clearly had less effect than aromatic hydrocarbons, despite their greater lipid solubilities.

4. Astrocytes were shown to be sensitive targets to the effects of organic solvents, measured as the inhibition of the integral enzymes Na+, K+‐ATPase and Mg2+‐ATPase.
EXCITOTOXICITY AS A STOCHASTIC PROCESS
Authors: Dubinsky J. M.
Published: June 2007

1. Neuronal death following excitotoxic insult appears to be a stochastic process involving transition through an intermediate biochemical state.

2. Hydrogen ion accumulation in the hours after toxic glutamate exposure may indicate that this transition has occurred.
INVOLVEMENT OF CYTOSKELETAL PROTEINS IN THE MECHANISMS OF ORGANOPHOSPHORUS ESTER‐INDUCED DELAYED NEUROTOXICITY
Authors: Abou‐Donia Mohamed B.
Published: June 2007

1. Organophosphorus ester‐induced delayed neurotoxicity (OPIDN) is a neurodegenerative disorder characterized by the presence of swellings in the distal parts of large axons in the central and peripheral nervous systems with subsequent axonal degeneration and paralysis.

2. An early change in OPIDN is enhanced activity and autophosphorylation of Ca2+/calmodulin‐dependent kinase II.

3. In OPIDN, there is also a dose‐ and time‐dependent increase in Ca2+/calmodulin‐dependent kinase mediated phosphorylation of the cytoskeletal proteins, α‐ and β‐tubulin, microtubule associated protein‐2, neurofilament triplet proteins and myelin basic protein.

4. Anomalous hyperphosphorylation of neurofilaments decreases their transport rate down the axon relative to their rate of entry resulting in their accumulation.

5. Consistent with the neurochemical results is the presence of anomalous aggregations of phosphorylated neurofilaments in early stages of OPIDN.

6. These findings suggest that aberrant hyperphosphorylation of cytoskeletal proteins is a post‐translational modification involved in the pathogenesis of OPIDN.
USE OF TISSUE CULTURE MODELS TO STUDY ENVIRONMENTAL‐GENETIC INTERACTIONS RELEVANT TO NEURODEGENERATIVE DISEASES
Authors: Durham Heather D. , O'Brien Catherine , Nalbantoglu Josephine , Figlewicz Denise A.
Published: June 2007

1. Clonal cell lines, primary cultured neurones and transgenic animals expressing mutant genes linked to familial forms of neurodegenerative diseases provide models in which to examine the interaction between expression of a predisposing gene and exposure to neurotoxic chemicals. Methods of establishing these models are reviewed.

2. Mutations in the gene encoding Cu/Zn‐superoxide dismutase (SOD‐1) have been identified in cases of familial amyotrophic lateral sclerosis linked to chromosome 21. We report that in clonal lines of PC12 cells, the cytotoxicity of a glutathione‐depleting epoxide, styrene oxide, varied with SOD activity in a manner similar to that previously demonstrated for redox cycling chemicals. These preliminary data suggest that either low or high SOD‐1 activities may be associated with greater toxicity of a variety of neurotoxic chemicals and their metabolites.