bluuebunny/crossref_metadata_2025 huggingface dataset:
EFFECT OF PREGNANCY IN THE RABBIT ON THE PRESSOR RESPONSE TO ANGIOTENSIN AND NORADRENALINE
Authors: Joels N. , Humphreys P. W.
Published: June 2007

1. The pressor responses to angiotensin II injections of 29, 117 and 468 pmol/kg and infusion at 54 pmol/kg per min were compared in near‐term pregnant and matched non‐pregnant rabbits. The responses to noradrenaline injections of 652, 2608 and 10 432 pmol/kg and infusion at 1185 pmol/kg per min were similarly compared.

2. At all doses of angiotensin and noradrenaline, whether by injection or infusion, the response of the pregnant animals was significantly greater. However the control arterial pressures of the pregnant rabbits were lower and fell in a range where the baroreceptor reflex might be less effective. Thus less efficient buffering could contribute to the greater response to the vasoconstrictor agents.

3. To test the effect of pregnancy on the vascular response to angiotensin and noradrenaline when reflex and central effects were excluded, hexamethonium was used to produce autonomic ganglion blockade. The response to both vasoconstrictors was now less in the pregnant rabbits than in the non‐pregnant.

4. Thus in assessing the effects of pregnancy on the responses of the rabbit to angiotensin and noradrenaline the effect of pregnancy on mean blood pressure must be taken into account, since this can influence the extent to which the arterial baroreceptors may modulate the response.
STABILITY AND INTER‐RELATIONSHIPS OF HORMONE, HAEMODYNAMIC AND ELECTROLYTE LEVELS IN HEART FAILURE IN MAN
Authors: Fitzpatrick M. Andrew , Nicholls M. Gary , Ikram Hamid , Espiner Eric A.
Published: June 2007

1. Relationships between clinical status, haemodynamic measurements, hormone and biochemical indices, and maintenance diuretic dose in patients with chronic cardiac failure, are not clear. This study assessed such relationships and their stability under standardized conditions in 21 hospitalized patients.

2. The daily maintenance dose of frusemide correlated closely and in a positive fashion with plasma levels of renin activity, angiotensin II and aldosterone (P < 0.001), and to a lesser extent with plasma noradrenaline. Although there was some overlap, patients most incapacitated by their heart failure had the highest circulating levels of renin activity, angiotensin II, aldosterone and noradrenaline.

3. Plasma aldosterone correlated closely with concomitant angiotensin II levels (r= 0.70, P < 0.001) but not with its other secretagogues ACTH (as reflected by plasma cortisol) or plasma potassium. Close positive correlations between angiotensin II and plasma levels of urea and creatinine (P < 0.01) were observed. Both renin and angiotensin I1 showed positive relationships with right heart pressures, but were inversely related to cardiac index and arterial pressure.

4. These results show close relationships between clinical and haemodynamic indices on one hand, and hormones on the other. The renin‐angiotensin system appears to be the primary regulator of aldosterone under these conditions, and its activity relates closely to haemodynamic measurements and to the degree of azotaemia.
SOME CARDIOVASCULAR EFFECTS OF MONOAMINE OXIDASE INHIBITORS IN UNANAESTHETIZED RATS
Authors: Marwood John F. , Huston Vicki , Wall Kim T.
Published: June 2007

1. The effects of four monoamine oxidase (MAO) inhibitors on the blood pressure of conscious normotensive and DOC‐salt hypertensive rats were measured. Harmaline (20 mg/kg p.o.), pargyline (100 mg/kg p.o.) and tranylcypromine (10 mg/kg p.o.) all lowered blood pressure significantly in both normotensive and hypertensive rats whereas methylaplysinopsin (10 mg/kg p.o.) had no effect on blood pressure.

2. The effects of these MAO inhibitors on blood pressure responses to serotonin, tyramine and β‐phenylethylamine were determined in conscious normotensive rats. Pargyline and tranylcypromine shifted the dose‐response curves for tyramine and β‐phenylethylamine, but not serotonin, to the left, indicating inhibition of type B MAO. Harmaline and methylaplysinopsin shifted the dose‐response curves for tyramine and serotonin but not β‐phenylethylamine, to the left, indicating inhibition of type A MAO.

3. Since the four antagonists tested inhibited at least one form of MAO, and yet not all of these MAO inhibitors lowered blood pressure, we suggest that our results are consistent with the view that the hypotensive action of MAO inhibitors is not necessarily related to inhibition of MAO.
INFLUENCE OF ENDOTHELIUM ON NORADRENALINE‐INDUCED VASOCONSTRICTION IN RABBIT CENTRAL EAR ARTERY
Authors: Verrecchia C. , Sercombe R. , Seylaz J.
Published: June 2007

1. The effects of removing the endothelium of the rabbit central ear artery on the response to noradrenaline have been examined in vitro.

2. A 10 mm segment of this artery was cannulated and connected to a constant flow perfusion circuit; the endothelium of some arteries was first removed mechanically. Vasomotor activity was determined by measuring the pressure at the input to the artery.

3. Scanning electron microscopy, light microscopy and functional test with acetylcholine on intact and rubbed arteries showed that the endothelium had been effectively removed in lesioned arteries and remained intact in control arteries throughout the experiment.

4. Internal or external noradrenaline‐induced a concentration‐dependent constriction which was significantly greater in the rubbed arteries.

5. In contrast, there was no significant difference in the pressure/flow curves of control and rubbed arteries whether preconstricted with K+ or not.

6. We conclude that the endothelium in the rabbit isolated ear artery greatly influences the response to internal or external noradrenaline, and that this effect cannot be explained by changes in the physical characteristics of de‐endothelialized arteries. The endothelium thus may play an inhibitory role in noradrenaline‐induced vasoconstrictions.
ROLE OF CARDIAC AND VASCULAR AMPLIFIERS IN THE MAINTENANCE OF HYPERTENSION AND THE EFFECT OF REVERSAL OF CARDIOVASCULAR HYPERTROPHY
Authors: Korner P. I. , Jennings G. L. , Esler M. D. , Broughton A.
Published: June 2007

1. Changes in amplifying capacities of the hypertrophied heart and resistance vessels account for the characteristic evolution of haemodynamic patterns in the course of essential hypertension.

2. Reversal of hypertrophy in established essential hypertension requires prolonged control of blood pressure. Redevelopment of hypertension on stopping drug therapy is slowest if there has been reversal of both vascular and cardiac hypertrophy. It may be possible to subsequently maintain normal blood pressure in a proportion of patients by non‐pharmacological means following the initial period of drug therapy.

3. Preliminary findings suggest that in a majority of patients the sympathetic nervous system may be overactive, whilst a smaller subset may have dysfunction of volume regulation.
IS ALDOSTERONE/RENIN RATIO USEFUL TO SCREEN A HYPERTENSIVE POPULATION FOR PRIMARY ALDOSTERONISM?
Authors: Hamlet S. M. , Tunny T. J. , Woodland E. , Gordon R. D.
Published: June 2007

1. The ratio of aldosterone to renin in plasma was measured in samples collected from 79 hypertensive patients.

2. Eighteen patients with primary aldosteronism had ratios ranging from 25 to 677 (mean 183) when measured on 34 occasions, while 16 normal subjects had ratios of 3.3–21 (mean 11.3).

3. Of the remaining 61 patients with ratios ranging from 1.8 to 184, 15 patients have ratios greater than 25 and are under investigation for primary aldosteronsim, which appears highly likely in five and has been excluded in two.

4. The aldosterone/renin ratio appears promising as a screening test for primary aldosteronism. Consistency and the effects of sodium and potassium balance and of antihypertensive medications require further study.
INCREASED RENAL PROSTANOID SYNTHESIS AFTER UNCLIPPING THE ONE‐KIDNEY, ONE‐CLIP HYPERTENSIVE RAT: EFFECT OF RENAL DENERVATION
Authors: McGowan Helen , Anderson Helen , Barden Anne , Vandongen Robert
Published: June 2007

1. Renal denervation of hypertensive one‐kidney, one‐clip (1K, 1C) rats resulted in a minor fall in blood pressure (216, s.e.m. = 4, to 182, s.e.m. =4, mmHg) 24 h later, which returned to predenervation levels within 1 week.

2. Subsequent unclipping led to a similar fall in blood pressure in denervated (202, s.e.m. = 4 to 142, s.e.m. = 3) and sham‐denervated (211, s.e.m. = 5 to 147, s.e.m. = 4) rats.

3. Unclipping also resulted in a marked rise in urinary PGE2 and 6‐keto PFG1α in both denervated and sham‐denervated animals.

4. It appears that 1K, 1C hypertension, 8 weeks after clipping, is only slightly dependent on renal nerves.

5. Unclipping results in increased renal synthesis of PGE2 and PGI2 which is not dependent on intact renal innervation.
BLOOD PRESSURE RESPONSES TO DIETARY SODIUM MANIPULATION DURING NORMOTENSIVE HUMAN PREGNANCY
Authors: McEniery P. J. , Hunyor S. N. , Cooper K. A. , Gallery E. D. M. , Gyory A. Z. , Boyce† E. S.
Published: June 2007

1. Short‐term salt loading and salt restriction in a group of normal pregnant women produced no changes in lying, sitting or standing blood pressures or heart rates.

2. Home blood pressures showed no trend to change over the periods of altered salt intake.

3. Although plasma volume and plasma renin activity changed with altered salt intake, there were no relationships between changes in these parameters and changes in mean arterial pressures (MAP) between the low and high salt diets.

4. Capillary permeability and echocardiographic dimensions were unchanged by salt intake once sodium balance had been established.
ACUTE TOLERANCE TO DIAZEPAM INDUCED BY BENZODIAZEPINES
Authors: Wong P. T. ‐H. , Yoong Y. L. , Gwee M. C. E.
Published: June 2007

1. It was observed that the effectiveness of diazepam in causing sleep, as denned by the loss of righting reflex, was significantly decreased after a single exposure to either diazepam or lorazepam.

2. RO 15‐1788, a benzodiazepine antagonist, in contrast did not induce tolerance to diazepam. The mechanism for this acute tolerance is unclear. The rapidity in its development may exclude metabolic tolerance while alterations in brain sensitivity to diazepam remain a possibility.
EFFECTS OF ACUTE VERSUS CHRONIC DELETION OF ARTERIAL BARORECEPTOR INPUT ON THE CARDIOVASCULAR RESPONSES TO EXERCISE IN THE RABBIT
Authors: Ludbrook John , Graham William F. , Potocnik Simon J.
Published: June 2007

1. These experiments were designed to confirm that at the onset of treadmill exercise in rabbits the tonic reflex depressor effects of input to the central nervous system from arterial baroreceptors is abolished, thus contributing to the rise of systemic arterial pressure (SAP) and heart rate (HR).

2. An inflatable cuff was placed around one common carotid artery after the remaining arterial baroreceptors had been surgically denervated. Transient inflation of the cuff caused reflex rises of SAP and HR, which were much reduced during the first minute of exercise. Deflation of the cuff caused a brisk fall of HR, which was completely abolished by exercise.

3. A snare was placed around one carotid sinus nerve after the remaining arterial baroreceptors had been surgically denervated. Where the snare was tightened all arterial baroreceptor reflexes were immediately and permanently abolished. This allowed the reflex effects of baroreceptor input to be calculated by difference. The magnitude of these calculated effects, at rest and during exercise, diminished according to how long after barodenervation the observations were made.

4. We conclude from the above experiments that the resting tonic reflex depression of SAP and HR caused by baroreceptor input is much reduced, rather than completely abolished, at the onset of exercise.

5. We also conclude, from the effects of partial surgical barodenervation, and of unloading the carotid baroreceptors prior to exercise by inflating the carotid cuff, that resting input from the arterial baroreceptors must be near zero before the cardiovascular response to exercise is grossly altered.
PREVENTION AND REVERSAL OF OUABAIN‐INDUCED CARDIOTOXICITY BY NALOXONE IN THE GUINEA‐PIG
Authors: Lee A. Y. S. , Unang T. W. K. , Wong T. M.
Published: June 2007

1. The effects of pre‐ and post‐treatment with naloxone on the cardiotoxicity of ouabain in the guinea‐pig were studied.

2. After pretreatment with naloxone, the dose of ouabain required to induce ventricular arrhythmias and cardiac arrest were significantly increased, in a dose‐dependent manner, compared with the control, indicating a protective effect of naloxone against digitalis intoxication.

3. Administration of naloxone at the onset of cardiac arrhythmias induced by a lethal dose of ouabain restored the cardiac rhythm and consequently saved life in seven out of eight animals, indicating an antiarrhythmic effect of naloxone in digitalis‐intoxicated guinea‐pigs.

4. The protective and antiarrhythmic effects of naloxone against digitalis intoxication have clinical implications.
COMPARISON OF THE INHIBITORY EFFECTS OF SPERMINE, PAPAVERINE AND ADRENALINE UPON ISOLATED SEGMENTS OF THE RAT SMALL INTESTINE
Authors: Martin John S. , Tansy Martin F.
Published: June 2007

1. In the rat isolated duodenal and ileal segments the active baseline force and spontaneous contractile frequency were inhibited by spermine; the relative potencies, estimated as an ED50, were adrenaline papaverine spermine. The changes in baseline force, but not frequency, due to spermine were sensitive to increased calcium.

2. The duodenum was always more sensitive to papaverine and adrenaline, but the relative sensitivities of the duodenum and ileum were essentially equal for spermine.

3. Inasmuch as the gastrointestinal mucosa of most species contains an abundance of polyamines, these results suggest that, in its free form, spermine may subserve a functional role in the inhibition of gastrointestinal motility.
INTERACTION BETWEEN PLATELET‐RELEASED SEROTONIN AND THROMBOXANE A2 ON HUMAN DIGITAL ARTERIES
Authors: Young M. S. , Iwanov V. , Moulds R. F. W.
Published: June 2007

1. Synergism between the contractile effects of platelet‐derived serotonin (5HT) and thromboxane A2 (TXA2) on a human blood vessel has been investigated by incubating strips of digital arteries in subcontractile concentrations of either 5HT or the TXA2‐mimetic agent U46619.

2. Either agonist U46619 or 5HT, in subcontractile concentrations, significantly potentiated the contractile response to the other.

3. The 5HT antagonist ketanserin (10 (μmol/1), theCa2+ antagonist drugs verapamil (3 μmol/l), or nifedipine (10 nmol/l), or a Ca2+‐free bathing medium, reduced the contractile responses to 5HT, but had no effect on the potentiation mediated by U46619.

4. The interaction between TXA2 and 5HT derived from platelets was studied by measuring responses to platelets 1 min after aggregation (in the absence or the presence of ketanserin 10 μmol/l), and 20 min after aggregation. The results indicated that the response to platelets mediated by TXA2 and 5HT was greater than the sum of those mediated by TXA2 or 5HT separately.

5. It is concluded that synergism between the contractile effects of 5HT and U46619 occurs in human blood vessels; that this is mediated by enhanced utilization of intracellular, rather than extracellular calcium; and that synergism can also occur when 5HT and TXA2 are released from stimulated human platelets.
NEUROMUSCULAR BLOCKING ACTIVITY OF A CRUDE AQUEOUS EXTRACT OF IPOMOEA FISTULOSA
Authors: Abdelhadi A. A. , Elkheir Y. M. , Hassan T. , Mustafa A. A.
Published: June 2007

1. The rat phrenic nerve hemidiaphragm and chick biventer‐cervicis preparations were used to investigate the effect of a crude aqueous extract of Ipomoea fistulosa.

2. Electrically‐induced skeletal muscle twitches of the hemidiaphragm were blocked by the extract and by tubocurarine.

3. The anticholinesterase, physostigmine, intensified the blockade by the extract.

4. The extract produced contracting of the chick biventer‐cervicis preparation.

5. It is suggested that the extract possesses neuromuscular blocking activity of a depolarizing nature.
DISTINGUISHING ALDOSTERONE‐PRODUCING ADENOMA FROM OTHER FORMS OF HYPERALDOSTERONISM AND LATERALIZING THE TUMOUR PRE‐OPERATIVELY
Authors: Gordon R. D. , Hamlet S. M. , Tunny T. J. , Gomez‐Sanchez C. E. , Jayasinghed̊ L. S.
Published: June 2007

1. In 14 hypertensive patients aldosterone/cortisol ratio was always lower in a peripheral vein or low IVC than in either adrenal vein. In four patients with a right‐sided aldosterone‐producing adenoma (APA), the aldosterone/cortisol ratio in peripheral vein was always higher than in the left adrenal vein. If only the left adrenal vein is cannulated, right‐sided APA can still be diagnosed with certainty.

2. In three patients with glucocorticoid‐suppressible hyperaldosteronism, urinary excretion of both 18‐oxocortisol and 18‐hydroxycortisol was elevated. In four patients with APA excretion of 18‐oxocortisol was elevated. In two of three patients with bilateral adrenal hyperplasia (BH), excretion of both steroids was normal.

3. 75Se‐selenomethylcholesterol scanning correctly lateralized five APA, but falsely lateralized a patient with BH. Results with CT scans were often misleading.
OMEPRAZOLE: EFFECTS ON OXIDATIVE DRUG METABOLISM IN THE RAT
Authors: Henry D. A. , Gerkens J. F. , Brent P. J. , Dosen P. J.
Published: June 2007

1. Omeprazole, a substituted benzimidazole and a potent gastric antisecretory drug has been tested for inhibition of microsomal drug oxidative function in the rat.

2. A single dose of 40 mg/kg prolonged pentobarbitone sleeping times from 118 (range 73–168) min to 195 (159–222) min (P < 0.01), pentobarbitone half‐lives from 89 (63–114) to 112 (54–146) min (P < 0.05) and aminopyrine breath 14CO2 half‐lives from 43 (37–51) to 56 (49–79) min (P < 0.05). Omeprazole in doses of 20 mg/kg or less had no significant effect.

3. In prolonging pentobarbitone sleeping times omeprazole 40 mg/kg and an equimolar (30 mg/kg) dose of cimetidine were approximately equipotent.

4. These results contrast with studies in man in which much smaller doses of omeprazole have been shown to produce clinically significant inhibition of drug metabolism.
EFFECTS OF THREE PURINE‐RELATED COMPOUNDS ON PANCREATIC EXOCRINE SECRETION IN THE DOG
Authors: Yamagishi F. , Homma N. , Haruta K. , Iwatsuki K. , Chiba S.
Published: June 2007

1. The effects of adenosine, adenosine 5′‐triphosphate (ATP) and inosine on pancreatic exocrine secretion were investigated in the vascularly isolated and self‐hacmoperfused dog pancreas. Drugs were injected close‐arterially (i.a.) in a single bolus.

2. These three purine‐related compounds per se did not affect resting rate of pancreatic secretion and the concentrations of protein and bicarbonate in the resting juice.

3. Graded doses of adenosine (0.1–1.0 mg, i.a.) and ATP (0.1–1.0 mg, i.a.) administered 1 min prior to secretin (0.025 clinical units, i.a.) increased a secretin‐stimulated secretory volume dose‐dependently, and the effects of adenosine and ATP were reversed by pretreatments with theophylline (0.3 mg, i.a.).

4. Insoine (1.0 mg, i.a.) affected neither secretin‐ nor dopamine‐stimulated (3 μg, i.a.) pancreatic secretion. Adenosine and ATP did not affect dopamine‐stimulated pancreatic secretion.

5. These results suggest that adenosine and ATP (or terminal phosphate hydrolyzed derivatives) enhance secretin‐stimulated pancreatic exocrine secretion through ‘P1’ purine receptors in the exocrine cells, without conversion to inosine.
EFFECTS OF AROTINOLOL, AN α‐ AND β‐ADRENOCEPTOR ANTAGONIST, ON RENIN RELEASE FROM RAT KIDNEY CORTICAL SLICES
Authors: Morimoto S. , Miyawaki N. , Sasaki Y. , Matsumura Y.
Published: June 2007

1. The effects of arotinolol on changes in renin release in rat kidney cortical slices in response to isoproterenol (IP) or norepinephrine (NE), were studied in comparison with those of AC‐623, a main metabolite of arotinolol, and other typical adrenoceptor antagonists.

2. Arotinolol, at concentrations of 10−8 to 10−4 mol/l, inhibited the increasing effect of 10−6 mol/l IP on renin release, in a concentration‐dependent manner. Similar results were observed with AC‐623, propranolol or labetalol, although the inhibitory potencies of these agents were considerably lower than that of arotinolol.

3. The blocking effect of arotinolol on the 10−5 mol/l NE‐induced decrease in renin release was much less potent than seen with other α‐adrenoceptor blocking agents such as prazosin, phenoxybenzamine and labetalol.

4. These data suggest that the potent blocking effects of arotinolol and its metabolite on the increased renin release in response to β‐adrenoceptor stimulation may contribute to the antihypertensive effect of this agent.
LIPEMIC AND LIPOPROTEINEMIC EFFECTS OF NATURAL AND SYNTHETIC ANDROGENS IN HUMANS
Authors: Crist D. M. , Peake G. T. , Stackpole P. J.
Published: June 2007

1. Testosterone cypionate administration in weight‐trained subjects reduced serum high‐density lipoprotein cholesterol (HDL‐C) levels without affecting the total cholesterol (Total‐C)/HDL‐C ratio. Nandrolone decanoate administration also reduced HDL‐C levels, but elevated the Total‐C/HDL‐C ratio.

2. These findings could not be attributed to changes in exercise patterns, dietary intake, or alcohol consumption.

3. It is concluded that the synthetic androgen employed in this study produced a worsening of potential lipid‐related risk factors for ischemic heart disease and that exogenous testosterone has a much less pronounced effect on such risk factors.
CIMETIDINE AND RANITIDINE: A STUDY OF COMPETITIVE AND ION‐CHANNEL BLOCKADE IN THE TOAD ISOLATED RECTUS ABDOMINIS MUSCLE
Authors: Gwee M. C. E. , Cheah L. S. , Shoon M. L.
Published: June 2007

1. Responses of the toad isolated rectus abdominis muscle to cumulative doses of carbachol were recorded in the absence or presence of varying concentrations of cimetidine or ranitidine. The corresponding cumulative log concentration‐response curves for carbachol were then plotted for each antagonist studied.

2. Cimetidine (1 mmol/1) produced a straight and parallel 1.8‐fold shift of the carbachol curve to the right of the corresponding control curve with no significant change in the maximal response.

3. Cimetidine, at doses of 2.5 mmol/1 and 5 mmol/1, and ranitidine, at doses of 0.1 mmol/1, 0.25 mmol/1 and 0.5 mmol/1, produced a concentration‐dependent and non‐parallel shift of the carbachol curve to the right of the corresponding control curve accompanied by a marked decline of maximal responses.

4. The results provide further evidence that ion‐channel block may be involved in the neuromuscular blockade produced by cimetidine or ranitidine, the latter being more potent in this respect. Competitive antagonism may also be partly responsible for cimetidine‐induced neuromuscular blockade, especially at lower drug concentrations.
ALDOSTERONE RESPONSES TO ACTH DURING HYPOXIA IN CONSCIOUS RATS
Authors: Raff Hershel , Chadwick Karen J.
Published: June 2007

1. This study examined the aldosterone response to physiological ACTH infusion (4 ng/kg per min) and pharmacological ACTH injection (1.8 μg) in conscious Long‐Evans rats at 42 h of normoxia (21% O2) or hypoxia (10% O2).

2. Hypoxia per se (no exogenous ACTH) significantly decreased control aldosterone levels despite elevated endogenous plasma ACTH).

3. Hypoxia attenuated the aldosterone responses to ACTH infusion but not to ACTH injection.

4. It was concluded that hypoxia attenuates aldosterone responses to small increases in ACTH, and large increases in ACTH can override this apparent decrease in adrenocortical sensitivity.
EFFECTS OF SUBSTANCE P ON PANCREATIC EXOCRINE SECRETION STIMULATED BY SECRETIN, DOPAMINE AND CHOLECYSTOKININ IN DOGS
Authors: Iwatsuki K. , Yamagishi F. , Chiba S.
Published: June 2007

1. The effect of substance P (SP) on pancreatic exocrine responses to exogenous cholecystokinin, secretin, and dopamine, were studied in the isolated and blood‐perfused pancreas of dogs.

2. Intra‐arterial injection of SP had a significant biphasic effect on pancreatic secretion: an initial transient inhibition, followed by an increase in the secretion stimulated by the infusion of cholecystokinin. However, SP caused only an inhibition of secretion stimulated by the infusion of secretin and dopamine.

3. SP increased protein concentration but not bicarbonate concentration in juice stimulated by cholecystokinin, but SP did not affect significantly either protein or bicarbonate concentrations in juice stimulated by secretin and dopamine.

4. These results suggest that SP has greater effects on the pancreatic secretion stimulated by cholecystokinin than that stimulated by secretin and dopamine.
ADENOSINE RECEPTORS IN POST‐MORTEM HUMAN CEREBRAL CORTEX AND THE EFFECT OF CARBAMAZEPINE
Authors: Dodd P. R. , Watson W. E. J. , Johnston G. A. R.
Published: June 2007

1. Representative A1 site‐ and A2 site‐selective ligands for adenosine receptors were found to bind to a single class of non‐co‐operative sites in synaptic membranes prepared from pieces of normal human temporal lobe cerebral cortex obtained at autopsies performed within 24 h post‐mortem.

2. The known adenosine antagonists theophylline and 1‐isobutyl‐3‐methylxanthine also bound to these sites and could completely displace either ligand.

3. Computer analysis combining data from 21 separate experiments which used membranes prepared from seven different autopsy cases gave the following kinetic parameters for the site: equilibrium dissociation constants (KD) for l‐PIA, 4.1±0.9 nmol/1; KD for NECA, 26±4 nmol/1; KD for theophylline, 28±5 μmol/1; receptor number (Bmax), 510±77 fmol/mg protein.

4. Carbamazepine could also displace either radioligand from the sites, although solubility limits for this drug were reached at 50% receptor occupancy. The KD for carbamazepine was 138±18 μmol/1. Other anticonvulsants tested were generally ineffective at their therapeutic concentrations, although phenytoin showed a small amount of ligand binding inhibition.

5. The results are in line with earlier studies in rodent tissue preparations, and suggest a possible purinergic component in the anticonvulsant activity of carbamazepine in man.
INFLUENCE OF ALCOHOL AND CAFFEINE CONSUMPTION ON CAFFEINE ELIMINATION
Authors: George J. , Murphy T. , Roberts R. , Cooksley W. G. E. , Halliday J. W. , Powell L. W.
Published: June 2007

1. Ten healthy male volunteers were each studied on four separate occasions to assess the role of regular caffeine and alcohol intake on caffeine elimination. Antipyrine disappearance was also studied as an established quantitative test of hepatic microsomal function.

2. Regular caffeine intake in high doses for 1 week failed to alter either antipyrine or caffeine pharmacokinetics.

3. In contrast, alcohol intake of 50 g/day significantly prolonged caffeine half‐life by 72% (P<0.005) and diminished caffeine clearance by 36% (P<0.0005). However, antipyrine kinetics were unaltered.

4. These results demonstrate that alcohol, in amounts commonly consumed, is a strong inhibitor of caffeine metabolism.
ETHANOL IMPAIRS BILIARY LYSOSOMAL ENZYME RELEASE IN RATS
Authors: Sewell Richard B. , Grinpukel Susan A. , Yeomans Neville D.
Published: June 2007

1. The effects of ethanol on hepatic lysosomes are poorly documented. This study examined the biliary release of lysosomal enzymes, a marker of the hepatocyte‐to‐bile excretory pathway, after ethanol administration in the isolated perfused rat liver model.

2. At concentrations similar to those reached in human plasma during social drinking, ethanol markedly decreased biliary lysosomal enzyme output and bile flow in the rat. Ethanol did not affect hepatic activities or the release into perfusate of lysosomal and other subcellular marker enzymes.

3. Hence, ethanol may potentially inhibit hepatocyte‐to‐bile excretion of other compounds processed through lysosomes.
CONTROLLED STUDY OF THE EFFECTS OF DIETARY PROTEIN ON BLOOD PRESSURE IN NORMOTENSIVE HUMANS
Authors: Prescott S. L. , Jenner D. A. , Beilin L. J. , Margetts B. M. , Vandongen R.
Published: June 2007

1. The object of this study was to determine whether meat protein per se is responsible for the higher blood pressures (BP) in omnivores compared with vegetarians.

2. Assessments were made by a double blind randomized control trial in 64 normo‐tensive volunteers recruited from Royal Perth Hospital staff.

3. All volunteers were given a ‘meat’ substitute during the 2 week control period. Randomization was then introduced into two dietary groups: the first remained on the ‘meat’ substitute, and the other received a ‘non‐meat’ substitute of vegetable protein, for the remaining 12 weeks of the trial.

4. The content of ‘meat’ and ‘non‐meat’ substitute was designed quantitatively and qualitatively to represent the protein intake in recently studied diets of Australian omnivores and ovo‐lacto vegetarians, respectively. The levels of fats (saturated and unsaturated), fibre, energy, Na+, K+, Mg2+, Ca2+ and carbohydrate in the intervention diets were similar.

5. These dietary changes were not associated with any significant changes in BP. Significantly lower urinary 3‐methyl histidine excretions in volunteers receiving ‘non‐meat’ supplements compared with the ‘meat’ eaters confirmed the dietary changes.

6. It was concluded that BP differences between omnivores and accultured vegetarians are unlikely to be due to differences in protein intake.
CAN THE SYNTHESIS OF PLATELET‐ACTIVATING FACTOR, A POTENT VASODILATOR AND PRO‐AGGREGATORY AGENT, BE ALTERED BY DIETARY MARINE OILS?
Authors: Codde James P. , Vandongen Robert , Mori Trevor A. , Beilin Lawrence J. , Hill Kathryn J.
Published: June 2007

1. Diets enriched with n‐3 polyunsaturated fish oils, predominantly eicosapen‐taenoic acid, are associated with a lower risk of atherosclerotic vascular disease. These oils purportedly reduce plasma triglycerides, total cholesterol and impair platelet aggregation. Recently, the present authors reported that rats fed a marine oil‐enriched diet had significantly reduced levels of lyso‐PAF, the immediate precursor of platelet‐activating factor (PAF). As PAF has potent vasodilator and pro‐aggregatory properties, the purpose of this study was to examine the hypothesis that fish oils affect the biosynthesis of PAF in man.

2. Supplementation of a normal diet for 3 weeks with fish oil containing the equivalent of 2.7 g of eicosapentaenoic acid daily, increased the eicosapentaenoic acid content of platelet phospholipids as well as depleting the arachidonic acid. Platelet aggregation to PAF (measured in whole blood by impedance aggregometry) was significantly impaired and whole blood thromboxane suppressed.

3. Two weeks after ceasing supplements, platelet aggregation remained impaired although thromboxane had reverted to baseline levels. There was a transient but significant fall in whole blood lyso‐PAF apparent within 2 days of commencing supplements but returning to baseline levels by the end of the treatment period. Whole blood PAF followed a similar trend.

4. The effects of dietary fish oil on whole blood aggregations to PAF, on thromboxane and plasma lyso‐PAF levels may be relevant to the prevention of vascular disease and the treatment of disorders in which PAF could be an inflammatory mediator.
ATRIAL NATRIURETIC FACTOR IN CHRONIC RENAL FAILURE: STUDIES IN MAN AND THE RAT
Authors: Hodsman G. P. , Jackson B. , Debrevi L. M. , Ogawa K. , Johnston C I.
Published: June 2007

1. Plasma concentration and atrial content of atrial natriuretic factor (ANF) were measured in rats with chronic renal failure induced by subtotal nephrectomy.

2. Plasma ANF was higher, and atrial ANF content lower in rats with renal failure when compared with sham‐operated controls.

3. Plasma renin activity (PRA) and ANF were elevated at 1 week following subtotal nephrectomy. After 1 month plasma ANF had risen further, but PRA was suppressed to below control values.

4. Plasma ANF was also measured in six patients with chronic renal failure undergoing routine haemodialysis.

5. Elevated plasma ANF levels in patients with renal failure were lowered by haemodialysis, although extraction of ANF across the dialysis membrane was negligible.

6. Secretion of ANF is increased in chronic renal failure in man and the rat, possibly mediated by increased intravascular volume.
EFFECTS OF NEUROPEPTIDE Y ON LEFT VENTRICULAR FUNCTION IN THE CONSCIOUS RABBIT
Authors: Minson R. B. , McRitchie R. J. , Chalmers J. P.
Published: June 2007

1. Changes in arterial pressure, heart rate and left ventricular contractility induced by intravenous injections of neuropeptide Y (NPY; 1–30 μg/kg) were studied in the conscious rabbit.

2. NPY has a brief pressor effect associated with a bradycardia, an increase in left ventricular end diastolic pressure, and a prolonged fall in peak left ventricular dP/dt (LVdP/dt).

3. The haemodynamic changes increase substantially with increasing doses up to 10 μg/kg. Beyond 10 μg/kg there are only slight effects on heart rate or peak LV dP/dt.
AIRWAY RESPONSES IN VITRO FOLLOWING C5A DES ARG‐INDUCED HYPER‐RESPONSIVENESS IN VIVO IN RABBITS
Authors: Armour C. L. , Black J. L. , Vincenc K. S. , Johnson P. R. A. , Ward H. , Berend N.
Published: June 2007

1. The mechanism of C5a des Arg‐induced airway hyper‐responsiveness in rabbits was investigated.

2. Airway smooth muscle from rabbits which had been pretreated in vivo, was studied in vitro. Tracheal rings, segmental bronchial rings, subsegmental bronchial spirals and lung parenchymal strips were all prepared from each rabbit lung.

3. Although C5a des Arg produces hyper‐responsiveness to histamine in vivo, which is inhibited by indomethacin, the airway smooth muscle responses in vitro from control, C5a des Arg and C5a des Arg plus indomethacin pretreated rabbits did not differ.

4. The neutrophil counts in the tracheal and subsegmental bronchial specimens were increased in the C5a des Arg‐treated group. Indomethacin significantly (P<0.05) inhibited the neutrophil influx in the subsegmental bronchi.

5. It is concluded that intrinsic smooth muscle function is unaltered following C5a des Arg‐induced hyper‐responsiveness in vivo.
THE EFFECT OF CORTICOSTEROID PRETREATMENT IN VIVO ON THE CONTRACTION OF GUINEA‐PIG ILEUM AND DUODENUM
Authors: Morat Paden , Khalid B. A. K. , Merican Z. , Idid S. Z. , Alias A. K.
Published: June 2007

1. The effects of corticosteroid pretreatment on the contraction caused by acetylcholine or electrical stimulation of guinea‐pig ileum and duodenum were studied.

2. The acetylcholine dose‐response curves for steroid pretreated ileum but not duodenum were significantly shifted to the right; evidence that pretreated ileum required higher dose of acetylcholine than normal to cause 50% maximal contraction.

3. Naloxone enhanced the contraction of normal ileum caused by acetylcholine given at the dose of ED50, but not that of normal duodenum.

4. The dose of morphine required to abolish electrically induced contraction was higher in steroid pretreated ileum than in normal ileum.

5. Hence, corticosteroid pretreatment may affect intestinal contractility via opioidergic mechanisms which are found in the ileum but not in the duodenum.
HIGH‐AFFINITY ALDOSTERONE BINDING IN RAT LIVER—A RE‐EVALUATION
Authors: Zaini Anuar , Pearce Paul , Funder John W.
Published: June 2007

1. The use of sodium molybdate as a stabilizing agent, and a RU26988 to exclude [3H]aldosterone from Type II glucocorticoid receptors, has enabled us to characterize high affinity Type I aldosterone binding sites in rat liver cytosol.

2. In liver cytosols from male rats aldosterone bound with an affinity (Kd‐22°C) of 0.6 nmol/l (range 0.3–0.8 nmol/l), and Nmax 1.7 fm/mg protein (s.e.m. = 0.4); specificity of binding was similar to that for Type I sites in classical aldosterone target tissues (aldosterone ≥ corticosterone > dexamethasone).

3. Hepatic Type I receptor levels were relatively constant in both male and female rats aged 30–120 days, with levels significantly higher in females.

4. Parallel studies on hepatoma H4 cells showed levels of Type I sites similar to those in normal liver, suggesting a general distribution of such sites throughout liver parenchyma, rather than a concentration in a specific cell type.

5. The function of such Type I sites, and whether or not they are aldosterone‐selective in vivo and can thus act as mineralocorticoid receptors, remains to be determined.
PLASMA ATRIAL NATRIURETIC PEPTIDE IS INCREASED DURING ATRIAL PACING IN CONSCIOUS RABBITS
Authors: Morris M. J. , Pilowsky P. M. , Cain M. D. , Chalmers J. P.
Published: June 2007

1. The effect of increases in heart rate on plasma atrial natriuretic peptide (ANP) concentrations was investigated in conscious rabbits.

2. Plasma ANP concentrations were significantly increased following abrupt increases in heart rate produced by atrial pacing at 400 beats/min. Pacing at 300 beats/min resulted in smaller increases in plasma ANP concentration.

3. Stepwise increases in heart rate produced by atrial pacing at 250, 300, 350 and 400 beats/min resulted in increases in plasma ANP concentrations at 400 beats/min only.

4. The increase in plasma ANP concentration during atrial pacing correlated significantly with the increase in heart rate achieved.
INVOLVEMENT OF SYMPATHETIC NERVOUS SYSTEM INHIBITION IN THE HYPOTENSIVE EFFECT OF BROMOCRIPTINE IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kanayama Y. , Kohno M. , Takaori K. , Itoh S. , Yasunari K. , Takeda T.
Published: June 2007

The hypertensive effect of bromocriptine in young (6 week old) spontaneously hypertensive rats (SHR) was studied. Blood pressure and plasma norepinephrine level in bromocriptine‐treated SHR were significantly lower than those in vehicle‐treated SHR after 3 weeks of treatment (5 mg/kg per day, i.p.), while no significant decrease of blood pressure or plasma norepinephrine level was observed after 2 weeks of treatment. These results suggest the involvement of sympathetic nervous system inhibition in the hypotensive effect of bromocriptine in SHR.
AMANTADINE RESTORES IMPULSE CONDUCTION ACROSS DEMYELINATED NERVE SEGMENTS
Authors: Schauf C. L.
Published: June 2007

SUMMARY

1. Drugs can be identified that relieve clinical symptoms of demyelinating diseases such as multiple sclerosis based on their ability to alter voltage‐dependent ion channels in membranes and restore conduction in demyelinated nerve. Beneficial drugs either slow inactivation of membrane Na+ channels or block K+ channels.

2. Amantadine, an antiviral drug that slows Na+ inactivation in Myxicola giant axons, restores conduction in frog and rat sciatic nerves partially demyelinated by disruption of the perineurium (the ‘perineurial window') loose ligatures, or lysolecithin.

3. A positive effect of amantadine on several different animal models supports the need for clinically oriented studies of amantadine and related inactivation‐blocking agents in diseases such as multiple sclerosis.
SYMPATHETIC NERVOUS SYSTEM MEDIATES URINARY KALLIKREIN EXCRETION IN CONSCIOUS RATS
Authors: Albertini R. , Vargas L. , Oliveri P. , Pardo F. , Paredes M. C.
Published: June 2007

1. The influence of the sympathetic nervous system on urinary kallikrein excretion (UKal) was investigated in conscious rats during stress produced by inserting a silastic catheter through the urethra into the bladder. The effect of this stress on blood glucose (BG), mean arterial pressure (MAP), urinary volume (Uv), urinary sodium (UVNa), and glomerular filtration rate (GFR) was also studied.

2. In intact animals stress of 120 min duration produced a non‐significant increase of MAP, a significant increase of BG and a decrease of UNa (P < 0.001 t‐test, 9 d.f.), but it did not affect Uv and GFR. In stressed rats UKal was considerably lower (52 milli Amidasic Units [mAU] per 100 g bodyweight, s.e.m. = 5, n= 6) than in control rats (170 mAU per 100 g, s.e.m. = 21, n= 5). The inhibitory effect on UKal was also observed when kallikrein was measured by the kininogenase method.

3. Adrenal medullectomy, performed 1 week before the experiment, suppressed the stress hyperglycaemia but did not affect the reduction of urinary kallikrein or the anti‐natriuresis.

4. Intracerebroventricular (i.c.v.) injection of saline also had no effect in the control or in the stressed rats, while i.c.v. d‐l‐propranolol decreased MAP, suppressed the stress hyperglycaemia and the anti‐natriuresis and stimulated UKal, without changes in Uv and GFR. Non‐stressed control rats i.c.v. injected with saline excreted considerably less kallikrein than rats i.c.v. injected with d‐1‐propranolol (control saline: 162, s.e.m. = 14, n= 6; vs control d‐l‐propranolol: 559, s.e.m. = 20, n= 6). Even in stressed rats this difference was registered (stressed saline: 56, s.e.m. = 8, n= 6; vs stressed d‐l‐propranolol: 554 mAU per 100 g, s.e.m. = 33, n= 6).

5. Peripheral sympathectomy with 6‐hydroxydopamine (6‐OHDA) did not suppress the hyperglycaemic response to stress, but it stimulated UKal. Kallikrein excretion was similar in 6‐OHDA stressed (534 mAU per 100 g, s.e.m. = 30, n= 6) than in 6‐OHDA control rats (491 mAU per 100 g, s.e.m. = 34, n= 6). No differences were observed on UNa and GFR between control 6‐OHDA treated rats and stressed 6‐OHDA treated rats.

6. The present results suggest strongly that urinary kallikrein excretion is modulated by sympathetic activity. Results after central β‐adrenergic blockade and peripheral sympathectomy led to the hypothesis that normal sympathetic tone in the kidney inhibits the release of kallikrein into the urine.
GASTRIC MUCOSAL DEFENCE MECHANISM DURING STRESS OF PYLORIC OBSTRUCTION IN ALBINO RATS
Authors: Somasundaram K. , Ganguly A. K.
Published: June 2007

1. The integrity of the gastric mucosa and its ability to secrete mucus are believed to be essential for protection of gastric mucosa against ulceration induced by aggressive factors active in any stress situation. This study involves a three‐compartmental analysis of gastric mucosal barrier in pylorus‐ligated albino rats.

2. Quantitative analyses of histologically identifiable gastric mucosal epithelial neutral glycoproteins and gastric adherent mucus from oxyntic and pyloric gland areas, and components of non‐dialysable mucosubstances in gastric secretion were made under stress of pyloric obstruction for 4, 8, and 16 h durations. Epithelial mucin was identified by periodic acid‐Schiff (PAS) staining technique and assessed from the ratio of gastric mucosal thickness to the depth of PAS positive materials in it. The remaining visible mucus adhered to the gastric mucosa was estimated by Alcian blue binding technique. The results were compared with that of identical control groups.

3. A significant reduction in mucosal epithelial PAS positive materials after 8 or 16 h of pylorus ligation was observed.

4. The Alcian blue binding capacity of the pyloric gland area was increased significantly after 4 h of pylorus ligation, while after 8 or 16 h it was reduced in both oxyntic and pyloric gland areas.

5. Significant reductions in the rate of gastric secretion and volume, as well as concentration of the components of non‐dialysable mucosubstances, were observed, indicating decreased synthesis of mucus glycoproteins.

6. Disruption of the mucosal barrier may have occurred due to decreased mucus synthesis and acid‐pepsin accumulation; both could be due to stress associated with gastric distension.

7. The present findings confirm the role of mucus in protecting the underlying gastric epithelium during stress. The adherent mucus offers a first line of defence and epithelial mucus a second line of defence.
DISSOCIATION BETWEEN CORTICOTROPHIN AND CATECHOLAMINE RESPONSES TO ISOPRENALINE IN HUMANS
Authors: Eisenhofer G. , Goldstein D. S. , Stull R. W. , Gold P. W. , Keiser H. R. , Kopin I. J.
Published: June 2007

1. The pituitary‐adrenocortical, sympathoadrenomedullary and renin‐angiotensin‐aldosterone systems contribute to circulatory and metabolic homeostasis during stress. One possible site of co‐ordination of these systems is the β‐adrenoceptor.

2. To determine whether circulating β‐adrenoceptor agonists can act hormonally to stimulate these systems simultaneously, plasma concentrations of corticotrophin (ACTH), noradrenaline, adrenaline and plasma renin activity were measured during graded intravenous infusions of isoprenaline in 20 people.

3. Administration of isoprenaline caused dose‐related increases in noradrenaline (94% at the highest dose) and renin activity (189%), but decreases in ACTH (25%) and adrenaline (20%), findings inconsistent with simultaneous activation of these systems by circulating β‐adrenoceptor agonists.
HUMAN VASCULAR α‐ADRENOCEPTORS: THE RELEVANCE OF SUBTYPES
Authors: Moulds R. F. W. , Stevens M. J. , Jenkin R. A.
Published: June 2007

SUMMARY

1. The post‐receptor mechanisms of α1 and α2‐adrenoceptor subtypes in guinea‐pig aorta and human digital arteries have been explored.

2. Nifedipine antagonized contractile responses of human digital arteries to TL99 and methoxamine to a similar degree, thus suggesting that neither the α1 nor the α2 receptor is preferentially linked to calcium entry through voltage‐operated channels of the cell membrane.

3. In the guinea‐pig aorta, which contains only α1‐adrenoceptors, methoxamine‐stimulated inositol phosphate (IP) production at similar concentrations was required to produce contractile responses.

4. In the human digital artery, noradrenaline also produced a significant increase in IP formation, but preliminary experiments have suggested that both TL99 and methoxamine stimulate IP production.

5. Thus, the present authors have been unable as yet to confirm, in a tissue which contains both α1‐and α2‐adrenoceptors, that the post‐receptor mechanisms of the α subtypes are different.
TIME DEPENDENT CONVERSION FROM α1‐ to β‐ADRENOCEPTOR‐ MEDIATED GLYCOGENOLYSIS IN ISOLATED RAT HEPATOCYTES: ROLE OF MEMBRANE PHOSPHOLIPASE A2 AND PROTEIN KINASE C
Authors: Ishac E. J. N. , Kunos G.
Published: June 2007

SUMMARY

1. Incubation of isolated rat liver cells in a serum‐free buffer leads to the reduction of the glycogenolytic effect of phenylephrine and the simultaneous emergence of the response to isoprenaline within 4 h.

2. Inhibitors of phospholipase A2 reverse the adrenergic activation of phosphorylase a from a β‐ to an α1‐receptor‐mediated event. Conversely activators of phospholipase A2 enhance the conversion.

3. In vitro incubation of hepatocytes leads to a translocation of protein kinase C from the cytosol to the membrane which can be mimicked by phorbol 12‐myristate 13‐acetate (PMA), an activator of protein kinase C. PMA is also associated with transformation from α1 to β‐adrenoceptor‐mediated glycogenolysis.

4. It is proposed that coupling of hepatic α1 and β‐adrenoceptors to postreceptor pathways are regulated by changes in membrane phospholipase A2 and protein kinase C activity.
NATURE OF THE GASTRIC ACID‐GASTRIN FEEDBACK LOOP IN THE FETAL SHEEP
Authors: Shulkes Arthur , Chick Patricia , Hardy Kenneth J.
Published: June 2007

1. The neonates of sheep and other species have a decreased gastric acid secretion but an elevated plasma gastrin concentration.

2. Since low gastric acid secretion is a stimulus for gastrin release in mature animals the present study examined whether the relative hypochlorhydria in the sheep fetus was sustaining the hypergastrinaemia.

3. Fetal plasma gastrin was measured following fetal gastric acidification (pentagastrin infusion) and gastric neutralization (parietal cell blockade with the proton pump inhibitor omeprazole) in chronically cannulated fetal sheep from 101 days until term (145 days).

4. Acutely raising gastric pH with omeprazole increased plasma gastrin in the mature sheep. However, in the fetus increasing the pH with omeprazole or decreasing pH with pentagastrin had no effect on fetal plasma gastrin. This was true for fetuses from all age groups.

5. The results indicate that the gastric acid‐gastrin feedback loop is not functional in the fetus and that the hypergastrinaemia at birth is therefore not the result of the relative hypochlorhydria.

6. The time after birth when the gastric acid‐gastrin feedback loop matures remains to be determined.