bluuebunny/crossref_metadata_2025 huggingface dataset:
ENANTIOSELECTIVE DRUG ANALYSIS: PROBLEMS AND RESOLUTIONS
Authors: Nation Roger L.
Published: June 2007

1. With the increasing appreciation that the enantiomers of a chiral drug can differ pharmacokinetically and/or pharmacodynamically, there is considerable interest in methods for the resolution and quantification of enantiomers.

2. Enantiomers possess identical physical and chemical properties in a symmetrical environment and, therefore, their resolution requires the introduction of an asymmetric or chiral environment allowing diastereomeric interactions. This can be achieved using a number of chromatographic techniques, of which the most developed and widely used is high‐performance liquid chromatography (HPLC).

3. Resolution and quantification of enantiomers can be performed using HPLC by either converting the enantiomers to covalent diastereomers prior to chromatography or introducing a chiral environment to the chromatographic system, thereby allowing temporary diastereomeric interactions.

4. Antibodies are chiral molecules which can bind the enantiomers of a chiral drug in a differential manner. This is the basis of enantioselective immunoassay, which is a promising technique for the enantioselective analysis of drugs in biological fluids.

5. Each of the methods available has its limitations, advantages and potential applications in the pharmaceutical industry.
RACEMATES OR ENANTIOMERS: REGULATORY APPROACHES
Authors: Birkett D. J.
Published: June 2007

1. Racemic drugs contain enantiomers which can differ substantially in pharmacological and dispositional properties. The development of chemical methods to separate and analyse drug enantiomers has led to a growing understanding of their biological properties and a regulatory dilemma as to whether only enantiomerically pure drugs should be marketed.

2. Advantages of enantiomerically pure drugs include more selective pharmacological profiles leading to better therapeutic indices, less complex pharmacokinetics and interactions, and simpler interpretation of plasma concentration response relationships.

3. As racemic drugs that are currently marketed and reaching marketing were developed when knowledge of drug enantiomers was less sophisticated, a flexible regulatory approach is required. At present, it is probably reasonable to require substantial information on the properties of enantiomers of racemic drugs but the balance is on the side of regulatory agencies needing to justify, provided adequate information is submitted, requirements for enantiomerically pure drugs.

4. This balance will gradually change to a situation where enantiomerically pure drugs will be the standard, and a strong case will need to be put by sponsors wishing to market racemic drugs.
THE STUDY OF TACHYKININ RECEPTORS
Authors: Burcher Elizabeth
Published: June 2007

1. Three high affinity receptors (NK1, NK2 and NK3) recognizing the C‐terminal end of tachykinins have been described, with probable endogenous ligands substance P (SP‐), neurokinin A and neurokinin B, respectively.

2. Other receptors recognizing the N‐terminal regions of SP exist in adrenal medulla and central nervous system (CNS) with a low affinity receptor on mast cells.

3. NK1 receptors are associated with blood vessels, all types of smooth muscle, enteric ganglia and glands. NK2 receptors are found on gastrointestinal and urinary smooth muscle, but few peripheral NK3 receptors have been described. In contrast, NK1, NK3 but not NK2 receptors are widely distributed in the CNS.

4. Problems associated with the study of tachykinin receptors include low selectivity of endogenous tachykinins, poor antagonists and susceptibility of peptides to enzymatic degradation.
RECEPTOR ALKYLATING AGENTS: NOVEL TOOLS FOR THE STUDY OF RECEPTOR FUNCTION IN THE CENTRAL NERVOUS SYSTEM OF THE RAT
Authors: Crocker Ann D. , Cameron Donald L.
Published: June 2007

1. The use of alkylating agents to investigate receptor function in the central nervous system is discussed.

2. Examples of strategies which can be used are illustrated by studies with the irreversible dopamine receptor blocker, N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydro‐quinoline (EEDQ).

3. Recent work, in which EEDQ was injected into selected sites of the striatum and receptor loss assessed by quantitative autoradiography, is described to show how this approach can be used to elucidate dopamine receptor function in the striatum.
NEW TOOLS FOR THE LOCALIZATION OF SECOND MESSENGER SYSTEMS
Authors: Summers Roger J. , McMartin Lynne R.
Published: June 2007

1. Probes available for the localization of components of second messenger systems include G‐protein oligonucleotides which have been used to produce cDNA probes to label G‐protein mRNA by in situ hybridization histochemistry.

2. Enzymes involved in second messenger responses have been labelled with [3H]‐forskolin (Gs‐linked adenylate cyclase), [3H]‐cAMP (cAMP‐dependent protein kinase) and [3H]‐PDBu2 (protein kinase C).

3. [3H]‐Inositol 1,4,5 trisphosphate labels a site on sarcoplasmic reticulum believed to trigger Ca2+ release.

4. These probes allow the comparison of location of receptors and second messengers and the examination of changes in second messenger systems with drug treatment and disease.
PROGESTERONE ANTAGONIZES DEVELOPMENT BUT NOT MAINTENANCE OF ACTH‐INDUCED HYPERTENSION IN SHEEP
Authors: Spence Campbell D. , Reid Amanda F. , Coghlan John P. , Mills Eric H. , Whitworth Judith A. , Scoggins Bruce A.
Published: June 2007

1. This study investigated the effect of progesterone, which, under certain circumstances, can antagonize both the mineralocorticoid and glucocorticoid activities of steroid hormones, on the development and maintenance of adrenocorticotrophic hormone (ACTH)‐induced hypertension in conscious sheep.

2. Progesterone (500 mg/day) alone, for 5 days, had no effect on blood pressure, but increased urinary Na excretion by 38 ± 10 mmol/day (P < 0.05) during the first 24 h.

3. Infusion of ACTH (5 μg/kg per day), alone, for 3 days, increased mean arterial pressure by 21 ± 2 mmHg (P < 0.001) associated with hypernatraemia, hypokalaemia, urinary Na retention, and increased fasting plasma glucose concentration.

4. Progesterone (500 mg/day) concurrently with ACTH blocked the rise in mean arterial pressure and the mineralocorticoid (urinary Na retention) but not the glucocorticoid (increase in plasma glucose concentration) effects associated with ACTH administration.

5. Progesterone (500 and 1000 mg/day) failed to reverse the hypertension and hypokalaemia in sheep pretreated for 3 days with ACTH.

6. Thus, progesterone blocked the onset but did not affect established ACTH hypertension. The mechanism by which progesterone blocked the development of ACTH hypertension appears to be related to the ability of progesterone to block the essential mineralocorticoid component of the adrenocortical steroids involved in the development of ACTH hypertension.
EFFECTS OF SODIUM RESTRICTION ON CARDIAC 3,4‐DIHYDROXYPHENYLETHYLENE GLYCOL AND CATECHOLAMINE LEVELS IN RATS
Authors: Howes L. G. , Hodsman G. P.
Published: June 2007

1. The effects of low or high sodium intake for 4 weeks on cardiac catecholamines and 3,4‐dihydroxyphenylethylene glycol (DHPG) levels were studied in adult female Wistar rats.

2. Rats receiving the low sodium diet had significantly higher plasma renin activity than rats receiving the high sodium diet.

3. Dopamine concentrations in both the right and left ventricle were significantly higher in the low salt compared with the high salt rats, but noradrenaline, adrenaline and DHPG levels did not differ significantly between the two groups.

4. These data do not support previous reports that sodium restriction reduces cardiac noradrenaline release, but suggest that alterations in sodium intake may influence cardiac noradrenaline metabolism.
EFFECT OF MAGNESIUM DEPLETION AND POTASSIUM DEPLETION AND CHLOROTHIAZIDE ON INTRACELLULAR pH IN THE RAT, STUDIED BY 31P NMR
Authors: Adam W. R. , Craik D. J. , Kneen M. , Wellard R. M.
Published: June 2007

1. Both dietary magnesium depletion and potassium depletion (confirmed by tissue analysis) were induced in rats which were then compared with rats treated with chlorothiazide (250 mg/kg diet) and rats on a control synthetic diet.

2. Brain and muscle intracellular pH was measured by using a surface coil and [31P]‐NMR to measure the chemical shift of inorganic phosphate. pH was also measured in isolated perfused hearts from control and magnesium‐deficient rats. Intracellular magnesium status was assessed by measuring the chemical shift of β‐ATP in brain.

3. There was no evidence for magnesium deficiency in the chlorothiazide‐treated rats on tissue analysis or on chemical shift of β‐ATP in brain. Both magnesium and potassium deficiency, but not chlorothiazide treatment, were associated with an extracellular alkalosis.

4. Magnesium deficiency led to an intracellular alkalosis in brain, muscle and heart. Chlorothiazide treatment led to an alkalosis in brain. Potassium deficiency was associated with a normal intracellular pH in brain and muscle.

5. Magnesium depletion and chlorothiazide treatment produce intracellular alkalosis by unknown mechanism(s).
EFFECT OF NISOLDIPINE ON STRESS‐INDUCED MYOCARDIAL DAMAGE IN THE CONSCIOUS PIG
Authors: Herbaczyńska‐Cedro K. , Lewicki Z. , Barcikowski B. , Famulski K. , Gordon‐Majszak W. , Kloś J. , Wutzen J. , Ceremużyński L.
Published: June 2007

1. The effect of the calcium channel blocker nisoldipine on the myocardial content of lipid peroxidation products (malondialdehyde (MDA), conjugated double bonds (CDB), fluorescent end‐products (RF) and mitochondrial adenine nucleotides) was investigated in conscious pigs (n= 14) subjected to 24 h of immobilization stress. Histoenzymatic and electron microscopic studies of the myocardium were also performed. Nisoldipine was given orally in a twice daily dose of 20 mg for 2 days before and on the day of the experiment. Results were compared with those obtained in immobilized untreated pigs (n= 10) and in non‐stressed treated controls (n= 8).

2. Pretreatment with nisoldipine significantly attenuated stress‐induced increase in myocardial contents of CDB and RF and prevented decline of mitochondrial adenine nucleotides. Stress‐induced myocardial histoenzymatic changes (decrease of succinic dehydrogenase, ATPase, acid phosphatase activity) and ultrastructural alterations (mitochondrial damage, lysis of myofibrils, dilatation of sarcoplasmic reticulum and endothelial swelling) were also diminished.

3. It is concluded that treatment with a Ca2+‐antagonist is beneficial to the heart exposed to environmental stress.
ACUTE MANNITOL AND SALINE VOLUME EXPANSION IN THE RAT: EFFECT ON TRANSEPITHELIAL POTENTIAL DIFFERENCE IN PROXIMAL TUBULES
Authors: Sugo E. , Györy Á. Z.
Published: June 2007

1. Transepithelial potential difference (PDte) of proximal tubules was measured in rats under control conditions (C), and mannitol‐saline and saline extracellular fluid volume expansion (MVE, SVE, respectively) under conditions of normal net lumen to basal sodium transport.

2. PDte was measured in kidneys bathed with Hartmann's solution or covered with mineral oil under both volume‐expanded conditions together with their controls.

3. PDte was significantly lower in kidneys bathed with Hartmann's solution than in those covered with oil.

4. In MVE rats, with mineral oil covering the kidneys, PDte (expressed as mean and s.e.m.) was for the control 2.20 ± 0.05 (n= 45) mV and MVE 1.97 ± 0.04 (n= 36) mV, lumen positive, a significant reduction of 10% (P<0.001). In SVE rats, with mineral oil covering the kidneys, PDte was for C = 2.42 ± 0.05 (n= 74) mV and SVE = 1.93 ± 0.03 (n= 67) mV, a significant reduction (P<0.001) of 20%.

5. According to thermodynamic considerations, neither of these changes is sufficient to explain the 50% inhibition of Na transport measured previously during MVE and SVE with autologous tubular fluid. The present results offer further evidence supporting the idea that the inhibition of Na transport during MVE and SVE is largely due to inhibition of the active Na transporting step.
BODY GROWTH AND POLYCYTHAEMIA IN HYPOXIC ALBINO RATS OF FIRST AND SECOND GENERATION
Authors: Quatrini U. , Licciardi A. , Morici G.
Published: June 2007

1. In our study we followed the growth rate and the haematologic changes occurring in albino rats of Wistar strain when living in a hypoxic environment. Two generations of hypoxic rats were observed for changes in their erythrocytes (RBC), haematocrit (Hct) and haemoglobin (Hb): the first generation (H1) and the second generation (H2). A few hours after birth, the H1 rats were placed and raised in a normobaric hypoxic environment (10% O2 in N2). The H2 rats were born and raised in the environment previously described. The control group had a normoxic environment. The H1 and H2 rats had inferior growth rates in respect to their controls, but H2 were found to have a larger growth rate than the H1 group. The RBC, Hct and Hb had values significantly greater for both H1 and H2 when compared with their controls. However, we did find that the values of H2 were significantly lower than H1. We believe that these results are in relation to the degree of development of the adaptive processes to the hypoxic environment of the H2 rats.
CHANGES OF ADP‐RIBOSYLATION OF GTP‐BINDING PROTEIN BY PERTUSSIS TOXIN IN HUMAN PLATELETS DURING LONG‐TERM TREATMENT OF MANIC DEPRESSION WITH LITHIUM CARBONATE
Authors: Watanabe Y. , Morita H. , Imaizumi T. , Takeda M. , Hariguchi S. , Nishimura T. , Yoshida H.
Published: June 2007

1. The study was done to determine whether long‐term treatment with lithium carbonate affected the guanosine triphosphate (GTP)‐binding protein in platelet membranes from patients with manic depression.

2. It was found that adenosine diphosphate (ADP)‐ribosylation of inhibitory G‐proteins (40–41 kDa) by pertussis toxin, islet‐activating protein in the cell membranes increased about 45% when long‐term treatment with lithium carbonate was stopped.

3. These results support the idea that one site for the therapeutic effects of lithium ions is G‐proteins.
EFFECT OF ETHAMSYLATE ON CARRAGEENAN‐INDUCED RAT PAW OEDEMA: A COMPARISON WITH INDOMETHACIN
Authors: Gard P. R. , Trigger D. J.
Published: June 2007

1. Ethamsylate (diethylammonium 2,5‐dihydroxybenzene sulfonate, DicyneneTM), a systemic haemostatic agent with an unknown mechanism of action, was tested for anti‐inflammatory activity using the carrageenan‐induced rat paw oedema test.

2. Ethamsylate was shown to be an effective anti‐inflammatory agent with a time course and amplitude of effect similar to that of indomethacin, although the potency was only about 4% of that for indomethacin.

3. When ethamsylate and indomethacin were co‐administered they did not show additive effects, suggesting that they do not share a common mode of action. It is proposed that ethamsylate, like indomethacin, may inhibit prostaglandin synthesis.
NICOTINIC AGONIST MODULATION OF FELINE BRONCHOMOTOR TONE
Authors: Thompson David C. , Altiere Ralph J. , Diamond Louis
Published: June 2007

1. The bronchomotor actions of three nicotinic cholinoceptor agonists were investigated in anaesthetized, mechanically ventilated cats. The agonists were administered intravenously after increasing baseline airways smooth muscle tone with an infusion of 5‐hydroxytryptamine.

2. Acetylcholine induced a biphasic change in lung resistance, characterized by initial bronchoconstriction followed by bronchodilation. The specific nicotinic cholinoceptor agonists, nicotine and dimethylphenylpiperazinium (DMPP), principally induced bronchodilator responses, although initial bronchoconstrictor phases were observed occasionally.

3. All bronchoconstrictor phases were sensitive to muscarinic cholinoceptor block‐ age with atropine. DMPP‐induced bronchodilator responses were adrenergic in nature, whereas those induced by either nicotine or acetylcholine resulted from a combination of adrenergic and non‐adrenergic influences.

4. It is concluded that intravenously administered nicotinic cholinoceptor agonists exert varying actions on feline bronchomotor tone and that these actions result from activation of different autonomic inputs.
RAT DUODENAL SMOOTH MUSCLE CONTRACTILE RESPONSES TO ANGIOTENSIN II ARE DEPENDENT ON CALMODULIN
Authors: Weekley L. Bruce
Published: June 2007

1. Isolated duodenal segments were pretreated with either of the calmodulin inhibitors proadifien or trifluoroperazine and the subsequent contractile force and frequency response to angiotensin II monitored.

2. Both proadifien and trifluoroperazine decreased the spontaneous contractile force and frequency in isolated perfused duodenal segments and attenuated the force generation following exposure to angiotensin II. Proadifien and trifluoroperazine also altered the qualitative behaviour of duodenal segments.

3. These results suggest that the action of angiotensin II on duodenal smooth muscle motility is dependent on calmodulin. Furthermore, the change in qualitative behaviour of duodenal segments following treatment with calmodulin inhibitors suggest that the function of intrinsic intestinal neurons is also altered.
CHANGES IN SALINE AND WATER INTAKES IN BROMOCRIPTINE‐TREATED GENETICALLY HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: Tan B. K. H. , Hutchinson J. S.
Published: June 2007

1. We have previously reported on the effects of a 13‐day intraperitoneal infusion of bromocriptine delivered by osmotic pump on blood pressure, plasma and pituitary PRL levels in genetically hypertensive (GH) rats and their normotensive (NT) controls. This paper reports further on that study in describing the changes in saline and water intakes in rats as a result of bromocriptine (BRC) treatment.

2. In the GH rats, bromocriptine did not have any significant effect on saline or water intake.

3. In the NT rats, bromocriptine significantly decreased saline intake and increased water intake.

4. The saline intake in the vehicle‐treated GH rats was significantly lower than that in the vehicle‐treated NT rats while the water intake was not significantly different.

5. These results indicate that differences exist between the GH and NT rats with regard to their saline and water intakes and their responses to chronic bromocriptine treatment. The changes in saline and water intakes in the GH rats seem to be different from those seen in the spontaneously hypertensive rat in another study.
SOME ALDOSTERONE‐PRODUCING ADRENAL TUMOURS ALSO SECRETE CORTISOL, BUT PRESENT CLINICALLY AS PRIMARY ALDOSTERONISM
Authors: Tunny Terry J. , Klemm Shelley A. , Gordon Richard D.
Published: June 2007

1. Two patients with angiotensin‐responsive aldosterone‐producing adenoma (APA) and one with adrenal cortical carcinoma demonstrated autonomous secretion of cortisol as well as of aldosterone.

2. The response of cortisol and of aldosterone to ACTH did not differentiate between the two APA which secreted cortisol and the eight which demonstrated normal suppression with dexamethasone.

3. Concurrent autonomous secretion of cortisol as well as aldosterone may occur in patients who present clinically with primary aldosteronism.

4. Biochemical distinctions between adenomas may reflect differences in their cellular composition.
NALOXONE‐INDUCED ACTH RELEASE IN MAN IS INHIBITED BY CLONIDINE
Authors: Jackson Richard V. , Grice Jeffrey E. , Jackson A. Jane , Hockings Gregory I.
Published: June 2007

1. Adrenergic mechanisms play an important role in regulation of ACTH release. We used the α2‐adrenergic agonist, clonidine, as a central nervous system inhibitor of ACTH release to see if it would alter naloxone‐induced ACTH secretion in normal human volunteers.

2. There was a significant blunting of the mean peak level of ACTH and the mean peak change of ACTH from basal as well as the area under the ACTH‐time curve when clonidine was given prior to naloxone.

3. We conclude that clonidine, by blocking central noradrenergic pathways, which stimulate corticotropin‐releasing hormone secretion, inhibits naloxone‐induced ACTH secretion. This suggests that naloxone causes ACTH release through these same central noradrenergic pathways.
HYPOTHESIS: ISCHAEMIC PLAQUE NECROSIS AS THE INITIATOR OF UNSTABLE ANGINA/ACUTE MYOCARDIAL INFARCTION?
Authors: Boyd G. W.
Published: June 2007

1. Coronary atherosclerotic plaque complications are important in precipitating acute coronary events such as unstable angina and myocardial infarction.

2. The hypothesis is put forward that plaque complications are initiated by increases in local coronary artery tone sufficient to cut off the vasa vasorum blood supply to the plaque and result in its ischaemic necrosis.
PREVENTION OF ARTERIAL DISEASE IN EXPERIMENTAL RENAL HYPERTENSION
Authors: Yong A. C. , Boyd G. W.
Published: June 2007

XUMMARY

1. This study examined the effect of various antihypertensive agents on the development of polyarteritis nodosa lesions along the mesenteric artery system over a 10 week period after renal artery clipping in uninephrectomized rats (lKlC).

2. Of the agents, only hydralazine, enalapril and diltiazem significantly inhibited systolic blood pressure (SBP) rise over the 10 week period (P<0.001).

3. All agents except hydralazine reduced the severity of arteritic lesions compared with lKlC rats, but only with enalapril (P<0.001), nifedipine (P<0.001), diltiazem (P<0.005), propranolol (P<0.001) and reserpine (P<0.05) was this reduction statistically significant.

4. There was a positive correlation between the degree of arteritic change and SBP, but the correlation coefficient was neither high (r= 0.68) nor highly significant (P= 0.03, d.f. = 9). On examining the data, this was due on the one hand to nifedipine, propranolol and reserpine reducing the severity of lesions without significantly inhibiting SBP, and on the other to hydralazine reducing SBP without significantly affecting the extent of arteritic change.

5. These findings suggest that factors other than mere SBP alone are involved in the pathogenesis of these arteritic lesions.
CARDIOVASCULAR EFFECTS OF NICOTINE DURING PHYSICAL ACTIVITY AND FOLLOWING MEAL CONSUMPTION
Authors: Perkins Kenneth A. , Epstein Leonard H. , Stiller Richard L. , Sexton Joan E. , Marks Bonita L. , Jacob Rolf G.
Published: June 2007

1. In two separate studies using healthy male smokers as subjects, the acute cardiovascular effects of a measured dose of nicotine (15 μg/kg) were examined in conjunction with light physical activity and following consumption of a meal, conditions typical of nicotine intake via smoking.

2. Increases in heart rate and systolic blood pressure attributable to nicotine were similar during rest, physical activity, and following eating, demonstrating additivity with the cardiovascular effects of activity and a caloric load. Diastolic blood pressure was less affected by nicotine.

3. These results indicate that cardiovascular activity is acutely increased following nicotine (smoking) regardless of other influences on the cardiovascular system. Such effects may help explain increased risks of acute cardiac abnormalities due to smoking.
RELAXATION OF MESENTERIC ARTERY OF STROKE PRONE SPONTANEOUSLY HYPERTENSIVE RATS BY CALCIUM REMOVAL
Authors: Sunano S. , Shimada T. , Moriyama K. , Shimamura K.
Published: June 2007

1. The time courses of the relaxation, induced by removal of extracellular Ca2+, of K‐depolarized mesenteric artery preparations from stroke prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto rats (WKY) were compared.

2. The time course of the decline in extracellular Ca2+ was estimated from the time course of the relaxation and the concentration‐response curve of K+‐depolarized preparations to Ca2+. The time course of the decline in the intracellular free Ca2+ concentration was also estimated from the reported relation between Ca2+ concentration and the contraction of skinned vascular smooth muscle.

3. The time course of relaxation was exponential, the curve being made up of three components. The time course was slower in preparations from SHRSP, especially the first component of the relaxation curve.

4. The time courses of the decline in the intracellular and extracellular Ca2+ concentrations were also exponential, being made up of three components and were also slower in the preparation made from SHRSP.

5. The wall and muscle layer of the mesenteric arteries used in the present experiments were significantly thicker in the SHRSP preparations.

6. Calculation of the half relaxation time, based on the diffusion of Ca2+ across the blood vessel wall, suggested that the slower relaxation in preparations from SHRSP is due largely to the thicker muscle layer, although differences in Ca2+ sequestration by the smooth muscle cells may also be involved.
THE EFFECT OF INHALED FENOTEROL AND IPRATROPIUM BROMIDE ON PROPRANOLOL INDUCED BRONCHOCONSTRICTION IN THE ASTHMATIC AIRWAYS
Authors: Latimer K. M. , Ruffin R. E.
Published: June 2007

1. The provocative dose of inhaled propranolol, (PC20P, mg/mL) needed to induce a 20% reduction in the forced expired volume in 1 s (FEV1, L) was determined for 15 adult asthmatics following randomized pre‐treatment with placebo, ipratropium bromide (40, 160 μg) and fenoterol (200, 800 μg) aerosols using a double‐blind protocol.

2. Fenoterol 200 μg, 800 μg increased the baseline FEV1 0.28±0.16, 0.32±0.16 L (P= 0.04, P= 0.008 respectively). Fenoterol 800 μg moved the PC20P rightwards from placebo geometric mean 10.95, 95% Confidence Intervals (95% CI) 4.43–27.22 mg/mL to mean 20.41, 95% CI 10.13 to 40.64 mg/mL (P= 0.01). Fenoterol 200 μg was not protective; mean PC20 16.22, 95% CI 7.83–34.35 mg/mL (P= 0.08). Neither 40 or 160 μg ipratropium changed the FEV1 or PC20P values compared with placebo; increase in FEV1 0.15±0.27 L (P= 0.22), 0.24±0.12 L (P= 0.14) and geometric mean PC20P 16.59±0.57 mg/mL 95% CI 8.01–34.51 mg/mL (P= 0.90), 15.48±0.66 mg/mL, 95% CI 6.72–36.05 mg/mL (P= 0.34) respectively after ipratropium treatments.

3. Bronchoconstriction induced by inhaled propranolol (P) appears to be only weakly antagonized by inhaled β‐agonist and not reduced by antimuscarinic anticholinergic aerosol. This finding argues against the activation of a cholinergic reflex to explain propranolol induced bronchoconstriction (PIB).
SHORT TERM VITAMIN E SUPPLEMENTATION HAS NO EFFECT ON PLATELET FUNCTION, PLASMA PHOSPHOLIPASE A2 AND LYSO‐PAF IN MALE VOLUNTEERS
Authors: Silbert Peter L. , Leong Lillian L. L. , Sturm Marian J. , Strophair Julie , Taylor Roger R.
Published: June 2007

1. Based largely upon in vitro studies, vitamin E has been reported to inhibit phospholipase A2 activity, to alter phospholipid metabolism and reduce platelet aggregation.

2. The effect of dietary supplementation with D‐α‐tocopherol (1500 iu/day for 14 days) was studied in nine males, 41–63 years old, comparing active treatment with a preceding placebo period.

3. Despite an increase from 2.6±0.8 (s.d.) × 10‐5 mol/L to 6.0±1.8 10‐5 mol/L in plasma vitamin E there were no significant changes in the aggregation of diluted whole blood or platelet rich plasma to adenosine diphosphate (ADP) or collagen, in plasma phospholipase A2 activity or plasma lyso‐platelet‐activating factor (lyso‐PAF) (bioassay after in vitro acetylation to PAF).

4. High dose vitamin E dietary supplementation had no effect on these phospholipid and platelet parameters.
RENOVASCULAR HYPERTENSION: INFORMATION FROM EXPERIMENTS USING CONSCIOUS DOGS
Authors: Anderson W. P. , Woods R. L. , Gao Y.
Published: June 2007

1. Evidence from experiments in conscious, instrumented dogs shows that hypertension from renal artery stenosis is due to: (i) the stimulus, the mechanical resistance of the stenosis; and (ii) the secondary responses to this, especially angiotensin II (initially) and cardiovascular hypertrophy.

2. The hydraulic resistance of the stenosis is responsible for about 20–25% of the rise in blood pressure.

3. Angiotensin II is initially the most important secondary response to the stenosis. Within days, however, other as yet undetermined factors become dominant in the maintenance of the hypertension. The most important of these factors is probably cardiovascular hypertrophy.

4. These secondary factors are homeostatic, in that they mitigate the effects of stenosis on renal function.
NON‐ADRENERGIC, NON‐CHOLINERGIC NEURAL CONTROL OF THE AIRWAYS
Authors: Stretton David
Published: June 2007

1. In addition to the classical cholinergic bronchoconstrictor and adrenergic bronchodilator neural mechanisms, there is a large volume of evidence to suggest the existence of neural pathways within the airways of a variety of species which are neither adrenergic nor cholinergic, the non‐adrenergic, non‐cholinergic (NANC) mechanisms. With respect to airway smooth muscle tone, NANC neural responses may induce either contraction (excitatory, e‐NANC) or relaxation (inhibitory, i‐NANC). Early investigations of NANC mechanisms in both human and other animal airways suggested a role for neuropeptides as the putative neurotransmitters.

2. Excitatory NANC (e‐NANC) bronchoconstrictor responses are believed to be mediated by the release of sensory neuropeptides from a subpopulation of non‐myelinated C‐fibre primary afferent neurones in the airways. e‐NANC nerves, which release tachykinins such as substance P (SP), neurokinin A (NKA) and the peptide calcitonin gene‐related peptide (CGRP, produced as a result of alternative splicing of the calcitonin gene) are selectively degenerated by the nerve toxin capsaicin (an extract from hot peppers), with the subsequent abolition of the e‐NANC responses. Tachykinin receptors have been detected by radio‐ligand receptor binding studies and visualized by autoradiographic mapping, and exogenous addition of these peptides elicits a bronchoconstrictor response in both human and other animal airways. In addition to these effects on airway smooth muscle tone, tachykinins produce an increase in microvascular permeability (and associated oedema formation), mucus hypersecretion and cause an exaggerated cholinergic bronchoconstrictor response. Thus, tachykinins may play a role in the inflammatory process and contribute to the neurogenic inflammation as seen in asthma.

3. Inhibitory NANC (i‐NANC) bronchodilator responses were believed to be due to the release of peptides such as vasoactive intestinal peptide (VIP) and peptide histidine isoleucine/methionine (PHI/M). VIP is believed to be co‐localized to cholinergic nerves in the airways and is co‐released upon cholinergic nerve stimulation. Recent evidence, however, would suggest that, together with VIP and related peptides, another substance may mediate i‐NANC responses in the airways. Nitric oxide (NO), which is formed from arginine in a reaction catalysed by the enzyme NO synthase, has been shown to mediate bronchodilator responses evoked in both human and other animal airway smooth muscles following nerve stimulation in vitro.

4. NANC neural mechanisms play an important role in the maintenance and regulation of bronchomotor tone, either via the direct effects of the transmitters released or by neuromodulation of autonomic control mechanisms. The study of NANC nerves in the airways has led to a greater understanding of the interaction between different nerve types in the respiratory tract and provided new insights into, and understanding of, the pathogenesis of airway disease.
EFFECT OF STRESS ON SEROTONIN, NOREPINEPHRINE, EPINEPHRINE AND CORTICOSTERONE CONTENTS IN THE SOFT‐SHELLED TURTLE
Authors: Mahapatra Manjula S. , Mahata Sushil K. , Maiti Biswaranjan
Published: June 2007

1. Adult soft‐shelled turtles were exposed to hyperosmotic and dehydration stresses.

2. Acute treatment for 0.5, 1 or 2 h with sodium chloride (3.6%, single intramuscular injection, 2 mL volume) caused depletion of pineal serotonin contents followed by elevation of norepinephrine and epinephrine levels. In addition, it depleted corticosterone and norepinephrine from the adrenal gland.

3. The serotonin level also decreased with a concomitant increase of 5‐hydroxyindoleacetic acid but without any discernible change in catecholamine content after chronic treatment with sodium chloride (3.6%, 0.5 mL daily for 7 days).

4. Dehydration for 7 days brought about depletion of serotonin and epinephrine levels and elevation of norepinephrine level.

5. The findings suggest that hyperosmotic stress has a definite influence on pineal‐paraphyseal serotonin, 5‐hydroxyindoleacetic acid, norepinephrine and epinephrine concentrations, and adrenal corticosterone and norepinephrine contents in Lissemys turtles. Dehydration stress also modulates pineal‐paraphyseal serotonin, norepinephrine and epinephrine concentrations.
COMPARISON OF INOTROPIC AND CHRONOTROPIC RESPONSES IN RAT ISOLATED ATRIA AND VENTRICLES
Authors: Brown Lindsay , Sernia Conrad , Newling Ross , Fletcher Peter
Published: June 2007

1. The positive inotropic and chronotropic responses to adrenoceptor agonists (noradrenaline, phenylephrine), to compounds which increase cAMP by post‐adrenoceptor mechanisms (forskolin, theophylline and dibutyryl cAMP) and to calcium chloride were measured in isolated rat atria and papillary muscles from both ventricles.

2. Noradrenaline produced similar maximal inotropic responses to calcium chloride in all tissues. Forskolin gave similar responses to calcium chloride in atrial but not ventricular tissues; the reverse was observed with dibutyryl cAMP. Phenylephrine and theophylline produced significantly smaller inotropic responses than calcium chloride in all tissues, especially in ventricular tissues.

3. Maximal chronotropic responses to noradrenaline, theophylline and dibutyryl cAMP were similar. Forskolin produced significantly greater responses while calcium chloride and phenylephrine produced significantly smaller responses than noradrenaline.

4. These results show that the maximal positive inotropic response of some agonists is markedly dependent on the tissue chosen. Further, chronotropic responses in right atria do not mimic inotropic responses in left atria.
NEUROPEPTIDE Y RADIO‐IMMUNOASSAY: CHARACTERIZATION AND APPLICATION
Authors: Allen Roberta , Boublik Jaroslav , Hauger Richard L. , Scott Neal , Rivier Jean , Brown Marvin R.
Published: June 2007

1. A sensitive and specific neuropeptide Y (NPY) radio‐immunoassay has been developed. This radio‐immunoassay does not detect the NPY‐related peptides pancreatic polypeptide or peptide YY. NPY extracted from rat plasma using sequential C18 sorbent and affinity chromatography co‐eluted with synthetic rat NPY when applied to high pressure liquid chromatography.

2. The procedure of stabilization of platelets followed by high speed centrifugation reduced basal values of NPY by 60%, and this may be consistent with removal of platelets that release NPY. Administration of the cholinesterase inhibitor physostigmine (0.3 mg/kg), intravenously, produced a small but significant increase (39%) from basal concentrations of NPY.

3. NPY concentrations in young (2‐3‐month‐old) Sprague‐Dawley and Fisher 944 rats were similar; however, NPY concentrations were significantly increased (55%) in 2‐year‐old Fisher 944 rats. Similar to plasma concentrations of noradrenaline, NPY levels increase with age.
CARDIOVASCULAR DISEASE RISK FACTORS IN AUSTRALIAN ABORIGINES
Authors: O'Dea Kerin
Published: June 2007

1. Aborigines from all over Australia develop unusually high prevalence rates for obesity, non‐insulin dependent diabetes mellitus (NIDDM) and cardiovascular disease when they make the transition from their traditional hunter‐gatherer lifestyle to a Westernized lifestyle.

2. There is no evidence that they experienced these diseases as hunter‐gatherers. Data from the few extant traditionally orientated groups in very remote areas of northern Australia indicate that they were very lean (BMI < 20 kg/m2), with low blood pressure, and that neither blood pressure nor BMI rose with age.

3. In addition, fasting glucose and cholesterol levels were low (usually below 4 mmol/L). However, in view of their extreme leanness and regular physical activity, fasting insulin and triglyceride levels were inappropriately elevated, suggestive of insulin resistance.

4. When Westernized diabetic Aborigines reverted temporarily to a traditional hunter‐gatherer diet and lifestyle, all of the metabolic abnormalities of diabetes were greatly ameliorated (fasting glucose and triglyceride levels fell markedly and glucose tolerance and insulin secretion improved). In addition, they lost weight and there was a reduction in the major risk factors for cardiovascular disease (reduction in hypertriglyceridaemia and blood pressure, increase in bleeding time).

5. The hunter‐gatherer lifestyle was associated with increased physical activity and a low‐fat, high‐fibre diet of low‐energy density and high‐nutrient density derived from very lean wild meat, and uncultivated vegetable foods. It has important therapeutic implications for the treatment and prevention of many of the chronic degenerative diseases of affluent Western societies.
CARDIOVASCULAR RESPONSES TO NIFEDIPINE IN ANAESTHETIZED RATS WITH ABNORMAL BLOOD GAS/PH LEVELS
Authors: Achike Francis I. , Dai Soter
Published: June 2007

1. Blood pressure and pulse rate responses to intravenously (i.v.) administered nifedipine were studied in chloralose‐anaesthetized rats subjected to hypoxaemia, hyperoxaemia, alkalosis, acidosis, hypocarbia with alkalosis, or hypercarbia with acidosis, or hypercarbia with acidosis.

2. Ventilation with a gas mixture of 17% O2, 28% O2, or 23% O2 with 5% CO2 at a fixed stroke volume (10 mL/kg) and rate (80 strokes/min) induced hypoxaemia, hyperoxaemia or hypercarbia, respectively. Hypocarbia was induced by ventilation with 17% O2 at 160 strokes/min. Acidosis or alkalosis was produced by intravenous infusion of 1 mol/L HCl or 1 mol/L NaHCO3, respectively, in animals ventilated with room air.

3. There were significant decreases in blood pressure and pulse rate during acidosis, and increases in pulse rate during alkalosis and hypercarbia. No marked changes in these parameters were observed under the other experimental conditions.

4. The control animals showed a dose‐dependent decrease in blood pressure without marked changes in pulse rate in response to nifedipine injection.

5. Significant reductions in the hypotensive effect of nifedipine were observed in rats subjected to alkalosis, acidosis, or hypercarbia. A similar tendency was also found during hypocarbia while the responses to nifedipine during hypoxaemia and hyperoxaemia were statistically the same as those in the controls.

6. It is concluded that alterations of blood pH reduce the hypotensive effect of nifedipine, and we suggest that blood pH changes probably play a more important role than PO2 or PCO2 abnormalities in altering the cardiovascular responses to nifedipine in hypoventilated or hyperventilated rats.
THROMBOXANE A2 RECEPTOR STIMULATION SIMILARLY POTENTIATES PRESSOR RESPONSES TO 5‐HYDROXYTRYPTAMINE IN PERFUSED HINDQUARTERS OF NON‐DIABETIC AND ALLOXAN DIABETIC RATS
Authors: Sikorski Bogdan W. , Hodgson Wayne C. , King Roger G.
Published: June 2007

1. Dose‐response curves were obtained to bolus injections of 5‐hydroxytryptamine (5‐HT) in Krebs'‐perfused hindquarters of male Wistar rats. Vasoconstrictor responses to 5‐HT (5.7–363 nmol/kg) were significantly attenuated in hindquarters of alloxan‐treated 14 day diabetic rats compared with non‐diabetics.

2. Infusion of the thromboxane A2 (TxA2)‐mimetic U46619 (317 and 31.7, but not 3.17 nmol/L) significantly potentiated vasoconstrictor responses to 5‐HT in Krebs'‐perfused hindquarters of non‐diabetic and diabetic rats. The degree of potentiation was similar for both groups.

3. In Krebs'‐perfused hindquarters of non‐diabetic rats, infusion of the α1‐adrenoceptor agonist methoxamine (8.96 μmol/L, which caused a rise in perfusion pressure intermediate in magnitude to that produced by infusion of 31.7 and 317 nmol/L U46619) did not significantly affect responses to bolus injections of 5‐HT.

4. The same concentration of methoxamine did not cause a significant potentiation of vasoconstrictor responses to 5‐HT (except for the two highest 5‐HT doses, 182 and 363 nmol/kg) in hindquarters of diabetic rats. This potentiation was significantly less than that due to 317 nmol/L U46619, although there was no significant difference between the rise in basal perfusion pressures produced by these concentrations of methoxamine and U46619.

5. Infusion of the TxA2 receptor antagonist AH23848 (111 nmol/L) inhibited the potentiating effect of U46619 (317 nmol/L) on responses to 5‐HT in both non‐diabetic and diabetic rats.

6. These results indicate that the potentiation of constrictor responses to 5‐HT by U46619 is mediated by activation of TxA2/prostaglandin H2 (PGH2) receptors, and suggest that a synergistic interaction of TxA2 and 5‐HT could be of importance in both normal and diabetic vasculature.
CLINICAL AND PATHOLOGICAL DIVERSITY OF PRIMARY ALDOSTERONISM, INCLUDING A NEW FAMILIAL VARIETY
Authors: Gordon Richard D. , Stowasser Michael , Tunny Terry J. , Klemm Shelley A. , Finn Wendy L. , Krek Anton L.
Published: June 2007

1. Of 93 patients with primary aldosteronism seen during a 20 year period, 52 had an aldosterone‐producing adenoma (APA) removed (five more await surgery), 14 had bilateral adrenal hyperplasia (BAH), three had glucocorticoid‐suppressible hyperaldosteronism (GSH), one had adrenal carcinoma and 18 are yet to be categorized.

2. Seventy‐three presented with hypertension and hypokalaemia. Others had markedly suppressed renal venous plasma renin activity (PRA) or elevated plasma aldosterone (PA)/PRA ratio, in new or resistant hypertensives.

3. The PA/PRA ratio was the most reliable screening test.

4. Diagnosis depended on the failure of suppression of aldosterone by salt loading and fludrocortisone.

5. Differentiation of BAH from APA depended on adrenal venous sampling comparing adrenal and peripheral venous PA/cortisol ratios.

6. A new familial variety of primary aldosteronism is described, with two affected members in each of three families.

7. Primary aldosteronism should be looked for in resistant and low‐renin hypertension as well as in hypertension with hypokalaemia, and other family members should have PA/PRA measured if they are hypertensive.
EFFECTS OF ENDOTHELIN‐1 ON ARTERIAL PRESSURE AND MYOCARDIAL CONTRACTILITY IN THE CONSCIOUS NORMOTENSIVE RABBIT
Authors: Roberts‐Thomson P. , McRitchie R. J. , Chalmers J. P.
Published: June 2007

1. We studied the effects of an intravenous bolus of endothelin‐1 on arterial pressure and myocardial contractility in the conscious rabbit.

2. Endothelin produced an initial fall in arterial pressure accompanied by an increase in heart rate. This was followed by a dose‐dependent increase in arterial pressure, peaking about 7 min after injection, accompanied by a reciprocal fall in heart rate.

3. Left ventricular rate of change of pressure (LV dP/dt) increased with endothelin except at higher doses (0.8 and 1.6 nmol/kg), where in some animals it decreased.
SECRETION OF MEDULLIPIN I BY ISOLATED KIDNEYS PERFUSED UNDER ELEVATED PRESSURE
Authors: Muirhead E. E. , Brooks B. , Byers L. W. , Brown P. , Pitcock J. A.
Published: June 2007

1. Medullipin I (Med I) is a hormone extracted from renal papillae and its renomedullary interstitial cells (RIC). Med I is stimulated by elevation of the renal artery perfusion pressure.

2. When isolated normal rat kidneys were perfused either with oxygenated blood or with 5% albumin bubbled with O2 at elevated perfusion pressures, Med I appeared to be secreted into the renal venous effluent (RVE). Addition of Tween 20, treatment of the assay rat with SKF 525A, inhibitor of cytochrome P‐450 and removal of the liver from the systemic circulation prevented vasodepression of both the RVE and extracted Med I. The lipid in the RVE gave the same dose–response as extracted Med I.

3. Lowering the renal artery perfusion pressure below normal inhibited the secretion of Med I. As the perfusion pressure was elevated Med I secretion appeared to increase.

4. Previous observations and the present study support the view that the renin–angiotensin system and the Medullipin system are double feedback systems involved in blood pressure control.
INCREASE IN REACTIVITY OF HUMAN PLATELET GUANYLATE CYCLASE DURING AGGREGATION POTENTIATES THE DISAGGREGATING CAPACITY OF SODIUM NITROPRUSSIDE
Authors: Chirkov Y. Y. , Belushkina N. N. , Tyshchuk I. A. , Severina I. S. , Horowitz J. D.
Published: June 2007

1. Basal and stimulated guanylate cyclase activity during ADP‐induced human platelet aggregation in comparison with the actions of sodium nitroprusside (SNP) on platelets was investigated.

2. Sodium nitroprusside exhibited both ex vivo and in vitro antiplatelet effects, as assessed by inhibition of subsequent ADP‐induced aggregation in platelet‐rich plasma. A strong correlation between decrease in aggregation and increase in platelet guanylate cyclase activity in the presence of SNP was obtained.

3. When SNP was administered after the induction of aggregation, it caused acceleration of disaggregation (in reversible aggregation) and produced disaggregation (under conditions of otherwise irreversible aggregation) which was time‐dependent.

4. Platelet aggregation was accompanied by a transient increase in platelet cyclic GMP content and guanylate cyclase activation by the nitric oxide (NO) donor SNP. Changes in guanylate cyclase activity were haem‐associated and probably reflected saturation of enzyme by haem.

5. Maximal SNP disaggregating effect coincided with peak guanylate cyclase responsiveness to SNP.

6. The present investigation provides evidence that increased responsiveness of platelet guanylate cyclase to NO during aggregation facilitates disaggregation in the presence of SNP. Thus, availability of NO (endogenous or exogenous) at sites of incipient platelet aggregation in vivo may play a pivotal role regarding limitation of this process.
DEVELOPMENT OF TOLERANCE TO KAVA IN MICE
Authors: Duffield P. H. , Jamieson D.
Published: June 2007

1. The development of tolerance to the aqueous extract of kava, and to the lipid soluble extract (kava resin) was tested in mice.

2. Tolerance to the unknown pharmacologically active ingredient(s) developed very rapidly, given parenterally, in the aqueous extract. A minimally effective daily dose (50 mg/kg) of the aqueous extract for 3 days was sufficient to produce tolerance to a test dose of 150 mg/kg, which is close to the ED50. As tolerance was evident at the first test period it can be assumed to be physiological tolerance.

3. Kava resin decreased spontaneous motility and caused a loss of muscle control. A minimally effective daily dose of kava resin (100 mg/kg) did not produce tolerance to the above effects of a weekly test dose of kava resin (166 mg/kg) within 7 weeks. In a further experiment the dose was raised to 150 mg/kg twice daily and this schedule caused partial tolerance to occur within 3 weeks, but very little further tolerance developed over the ensuing 2‐week period.

4. To try to induce learned (behaviourally acquired) tolerance a dose of 166 mg/kg kava resin was injected daily and animals were tested each day while under the influence of the drug. However, even under these conditions, there was no tolerance evident within 3 weeks, when the experiment was terminated.

5. It appears difficult to induce the development of physiological or learned tolerance to kava resin in mice.