bluuebunny/crossref_metadata_2025 huggingface dataset:
CYTOCHROME P450 KNOCKOUT MICE: NEW TOXICOLOGICAL MODELS
Authors: McKinnon Ross A. , Nebert Daniel W.
Published: June 2007

1. Despite the frenetic pace of cytochrome P450 (CYP) research, important questions remain about the possible role of xenobiotic‐metabolizing CYP in development and cellular homeostasis.

2. The recent experimental development of CYP null mouse lines has provided valuable new models for addressing these issues, as well as providing novel in vivo models to study the precise role of CYP in chemical‐mediated toxicity.

3. The present review summarizes results from the three Cyp gene knockout mouse lines generated so far and looks at likely future directions of this research field.

4. Also discussed are null mouse lines with targeted mutations in genes encoding receptors having primary roles in Cyp gene regulation.
ACUTE LITHIUM ADMINISTRATION IMPAIRS THE ACTION OF PARATHYROID HORMONE ON RAT RENAL CALCIUM, MAGNESIUM AND PHOSPHATE TRANSPORT*
Authors: Carney Shane , Jackson Peggy
Published: June 2007

1. Chronic lithium (Li+) treatment commonly produces a state of hyperparathyroidism in humans and rat although the mechanism is unknown.

2. The present study evaluated the acute effect of Li+ on renal electrolyte transport, particularly Ca2+ and Mg2+ in thyroparathyroidectomized (TPTX) and intact rats.

3. The acute administration of Li+ significantly increased water, sodium, potassium and phosphate excretion in both TPTX and intact animals; however, Ca2+ and Mg2+ excretion was only increased in the intact group. Fractional excretion (FE) of Ca2+ and Mg2+ increased from 2.2±0.2 to 3.5±0.3% and 12±2 to 18±2%, respectively (P<0.01).

4. In further experiments in TPTX rats, Li+ administration inhibited the usual reduction in urine Ca2+ and Mg2+ excretion following parathyroid hormone (PTH) administration and inhibited the phosphaturia. However, supramaximal concentrations of PTH overcame this inhibitory effect. For example, an FECa of 3.8±0.2% was reduced to 1.4±0.2% and 1.7±0.2% with maximal and supramaximal PTH concentrations, respectively, while in the presence of Li+ an FEca of 4.0±0.2 was decreased to 2.8±0.2 and then 1.9±0.3% with the same PTH concentrations.

5. The inhibitory effect of Li+ was reduced with a lower plasma Li+ concentration (0.7±0.2 vs 1.6–1.8 mmol/L). The FEMg results were comparable.

6. These results demonstrate that Li+ directly inhibits PTH‐mediated renal reabsorption of Ca2+ and Mg2+ and also blunts PTH‐mediated phosphaturia. Therefore, the hyperparathyroidism in humans following Li+ treatment may be a consequence of reduced renal Ca2+ reabsorption.
IS A HYPERTENSINOGENIC FACTOR PRESENT IN THE KIDNEY OF HYPERTENSIVE DAHL RATS?
Authors: Zhou Ming Sheng , Nishida Yasuhiro , Chen Qing Hui , Murakami Hiroshi , Hosomi Hiroshi , Kosaka Hiroaki
Published: June 2007

1. Early studies suggest that hypertension in Dahl salt‐sensitive (S) rats is related to an uncommon humoral factor that may be released from the kidney.

2. To investigate whether the kidney releases a hypertensino‐genic factor for developing salt‐induced hypertension in S rats, we examined a pressor effect, or vascular contractive activity of a kidney extract from S rats using a conscious recipient rat or an isolated aortic ring.

3. Donor S and Dahl salt‐resistant (R) rats were fed a 0.4 or 8% NaCl diet for 4 weeks and were then used to provide four kinds of kidney extracts (S‐0.4%, S‐8%, R‐0.4%, R‐8%). The systolic arterial pressure (SAP) was significantly increased in donor S rats fed an 8% NaCl diet compared with other donor rat groups.

4. All four types of kidney extract increased mean arterial pressure (MAP) in a recipient rat fed a 0.4% NaCl diet. However, the increase in MAP observed following infusion of the S‐8% extract was the least of all groups. An angiotensin AT1 receptor antagonist, CV‐11974, abolished any pressor effect of all kidney extracts. In an in vitro experiment, all four types of kidney extract evoked contractile responses in aortic rings, but elicited no significant difference in aortic ring contractile force.

5. These results suggest that the kidney of S rats may not release an active hypertensinogenic factor that would cause salt‐induced hypertension.
MAGNOLOL DECREASES BODY TEMPERATURE BY REDUCING 5 HYDROXYTRYPTAMINE RELEASE IN THE RAT HYPOTHALAMUS
Authors: Hsieh MT , Chueh FY , Lin MT
Published: June 2007

1. The effects of magnolol, isolated and purified from the cortex of Magnolia officinalis Rehd. et Wils, on thermoregulation and hypothalamic release of 5‐hydroxytryptamine (5‐HT) by in vivo microdialysis were assessed in normothermic rats and in febrile rats treated with interleukin‐1β.

2. Intraperitoneal administration of magnolol (25–100 mg/kg) produced a decrease in colon temperature, an increase in foot skin temperature, a decrease in metabolic rate and a decrease in the endogenous release of 5‐HT in the rat hypothalamus.

3. Depletion of rat brain 5‐HT, produced by intracerebro‐ventricular pretreatment with 5,7‐dihydroxytryptamine, attenuated the magnolol‐induced hypothermia, cutaneous vasodilation and decreased metabolism.

4. Intracerebroventricular administration of (±)‐2,5‐dimethoxy‐4‐iodoamphetamine (a 5‐HT2 receptor agonist; 5–10 μg/5 μL) increased basal colon temperature and reversed the magnolol‐induced hypothermia.

5. The increases in both colon temperature and hypothalamic 5‐HT release produced by interleukin‐1β injection were attenuated by treatment with magnolol.

6. The data suggest that magnolol decreases body temperature (due to increased heat loss and decreased heat production) by reducing 5‐HT release in rat hypothalamus.
CHARACTERIZATION OF A MAJOR SLOW OSCILLATION IN THE MESENTERIC CIRCULATION OF CONSCIOUS RATS
Authors: Létienne Robert , Julien Claude , Zhang Zhi‐Qi , Barrès Christian
Published: June 2007

1. Little is known about spontaneous slow rhythms in regional circulations. The present study was aimed at characterizing low‐frequency (LF; 78–269 mHz) oscillations in the mesenteric and hindquarter circulations of conscious rats.

2. Mean arterial pressure (MAP) and indices (pulsed Doppler technique) of mesenteric (n= 25) and hindquarter (n= 23) blood flows were recorded in conscious, freely moving rats during 1 h periods. Fast Fourier transform analysis was applied to beat‐to‐beat data after resampling at 10 Hz of consecutive 205 s time series.

3. A major oscillation centred at 164±4mHz was present in the mesenteric, but not in hindquarter, circulation. Consequently, LF power accounted for approximately 43% of the overall variability of mesenteric blood flow. Cross‐spectral analysis performed between MAP and mesenteric blood flow indicated that fractional changes in flow were approximately two‐fold of those in MAP, in pressure, at the peak frequency.

4. Acute blockade of the autonomic, renin‐angiotensin and vasopressin systems combined with noradrenaline infusion (n= 7) reduced the frequency of the mesenteric blood flow oscillation (115 ± 6 mHz) but did not change its contribution to overall flow variability (approximately 48%). A clear oscillation was still present after acute inhibition of nitric oxide (NO) synthesis with NG‐nitro‐l‐arginine methyl ester (n= 8), but was virtually absent in chronically guanethidine‐sympathectomized rats (n= 12).

5. In conclusion, the mesenteric blood flow of conscious rats exhibits a major slow oscillation that originates in the mesenteric vasculature and is not secondary to the activity of the major pressor systems or to the cyclic release of NO. Because of the strong attenuation of the oscillation in sympathectomized rats, we suggest that adrenergic vasoconstrictor tone plays a permissive role in its genesis.
SIGNAL TRANSDUCTION BY PROTEIN KINASE C IN MAMMALIAN CELLS
Authors: Kanashiro Celia A. , Khalil Raouf A.
Published: June 2007

1. The past two decades have witnessed great advances in our understanding of the role of protein kinase C (PKC) in signal transduction. The Ca2+‐activated, phospholipid‐dependent protein kinase discovered by Nishizuka's group in 1977 is now a family of at least 11 isoforms. Protein kinase C isoforms exist in different proportions in a host of mammalian cells and each isoform has a characteristic subcellular distribution in each cell type.

2. Stimulation of a specific PKC is oform often causes redistribution of the isoform from one subcellular compartment to another compartment where it complexes with and phosphorylates a specific protein substrate.

3. The interaction of a specific PKC isoform with its protein substrate may directly activate a specific function of the cell or may trigger a cascade of protein kinases that ultimately stimulates a specific response in differentiated cells or regulates growth and proliferation in undifferentiated cells.
TRANSCARDIAC 5‐HYDROXYTRYPTAMINE RELEASE AND IMPAIRED CORONARY ENDOTHELIAL FUNCTION IN PATIENTS WITH VASOSPASTIC ANGINA
Authors: Murakami Yo , Shimada Toshio , Ishinaga Yuji , Kinoshita Yoshihisa , Kin Hakutetsu , Kitamura Jun , Ishibashi Yutaka , Murakami Rinji
Published: June 2007

1. The present study was designed to test the hypotheses whether platelet degranulation across the coronary bed is detectable during non‐ischaemic periods in patients with vasospastic angina (VSA) and whether the exogenous nitric oxide (NO) donor nitroglycerin (GTN) is able to modify platelet degranulation, reflecting an impaired endothelial production of NO.

2. We studied 13 patients with VSA and 10 controls. The time course of coronary sinus (CS) plasma 5‐hydroxytryptamine (5‐HT) levels was evaluated every 4 h before and after intravenous infusion of GTN over a period of 40 h. Coronary sinus plasma 5‐HT levels were significantly higher at any measured time point in patients with VSA compared with control and were significantly decreased in patients with VSA following treatment with GTN, but not in controls. Femoral artery plasma 5‐HT levels remained almost constant throughout the study. The ratio of CS:aorta 6‐keto‐prostaglandin F1α was significantly and inversely correlated with the transcardiac plasma 5‐HT difference only in patients with VSA (r=−0.68; P < 0.02; n= 13).

3. The time course of CS 5‐HT levels confirmed significant platelet degranulation across the coronary bed supplied by the spasming artery in patients with VSA and this was modified by GTN. The present data suggest that platelet degranulation occurs during non‐ischaemic periods in patients with VSA and that prostacyclin biosynthesis may be a compensatory response to an impaired endothelial release of NO, limiting the degree of the effects of platelet degranulation.
EFFECTS OF QUANTITATIVE TRAIT LOCI FOR LIPID PHENOTYPES IN THE RAT ARE INFLUENCED BY AGE
Authors: Kovács Peter , van den Brandt Jens , Klöting Ingrid
Published: June 2007

1. Previous study on the backcross hybrids derived from a cross of the spontaneously hypertensive rat (SHR/Mol) and the spontaneously diabetic BB/OK rat demonstrated the existence of quantitative trait loci (QTL) affecting lipid phenotypes on chromosome 4 and suggestive linkage of lipid phenotypes with markers on chromosome 1. Because the previous study was performed with backcross hybrids at 12 weeks of age and it is known that lipid phenotypes can show age‐related differences, in the present study, the effect of QTL (chromosome 1 and 4) on serum triglycerides and cholesterol was longitudinally analysed between 20 and 32 weeks of age in backcross hybrids.

2. The results of the present study show that the effect of QTL on chromosome 4 (between Il‐6 and D4Mit9) for serum triglycerides was maximal at 20 weeks of age, but disappeared at 32 weeks of age. In contrast, the effect of QTL on serum total cholesterol on chromosome 4 (Npy‐Spr) was maximal at 32 weeks of age. In contrast with the first study (12 weeks), the longitudinal investigation showed significant linkage of D1Mit14 marker with lipid phenotypes on chromosome 1.

3. The results of the present study indicate the necessity of considering the role of age in QTL analysis of lipid phenotypes.
AUGMENTED EXERCISE PLASMA NORADRENALINE WITH IMPAIRED CHRONOTROPIC RESPONSIVENESS IN PATIENTS WITH HYPERTROPHIC CARDIOMYOPATHY*
Authors: Omodani Hiroki , Kinugawa Toru , Ogino Kazuhide , Furuse Yoshiyuki , Yamaguchi Masako , Mori Masatake , Endo Akihiro , Kato Masahiko , Kato Tatsuo , Osaki Shuichi , Miyakoda Hiroyuki , Igawa Osamu , Hisatome Ichiro , Shigemasa Chiaki
Published: June 2007

1. There is controversy regarding plasma catecholamine levels in patients with hypertrophic cardiomyopathy (HCM) and few data exist on serial plasma catecholamine measurements during exercise. The present study determined whether cardiovascular and plasma catecholamine responses to exercise were altered in patients with HCM.

2. Plasma noradrenaline (NA) and adrenaline were measured at rest, at the end of each stage during exercise and immediately and 5 min after submaximal treadmill exercise in 15 patients with non‐obstructive HCM (13 males, two females; mean (±SEM) age 54 ± 3 years) and in 15 age‐ and sex‐matched controls. The ratio of the increment in heart rate (HR) divided by the increment in plasma NA during exercise (ΔHR/ΔNA) was used as an index of chronotropic sympathetic responsiveness to exercise.

3. Exercise duration was shorter (11.2 ± 0.6 vs 8.7 ± 0.6 min for control vs HCM, respectively; P<0.01) and diastolic blood pressure was significantly higher at stages I and II of modified Bruce protocol HCM.

4. Resting plasma NA levels (149 ± 17 vs 167 ± 28 pg/mL for control vs HCM, respectively; NS) were not different, but plasma NA levels at stages I and H were significantly higher in HCM than in controls (243 ± 26 vs 399 ± 69pg/mL (P<0.05) and 308 ± 30 vs 548 ± 110pg/mL (P<0.05), respectively).

5. Peak plasma NA levels were not significantly higher in HCM than in controls (578 ± 59 vs 918 ± 184 pg/mL, respectively; NS).

6. The ratio AHR/ANA was significantly lower in HCM compared with control at stages I and II (0.49 ± 0.10 vs 0.21 ± 0.05 (P<0.05) and 0.38 ± 0.06 vs 0.20 ± 0.05 (P < 0.05), respectively). There were no differences in plasma adrenaline responses during exercise between the two groups.

7. Patients with HCM had augmented plasma NA levels during submaximal exercise with a higher diastolic blood pressure response. Chronotropic sympathetic responsiveness was impaired during the early stages of exercise in patients with HCM.
EFFECT OF CROSS‐FOSTERING ON NEONATAL SODIUM BALANCE AND ADULT BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Gouldsborough Ingrid , Ashton Nick
Published: June 2007

1. The aim of the present study was to compare electrolyte handling in naturally reared neonatal spontaneously hypertensive rats (SHR) with those reared by a Wistar‐Kyoto (WKY) rat foster mother (denoted SHRX), as cross‐fostering SHR pups to a WKY rat dam lowers adult blood pressure in the SHR.

2. The electrolyte content of WKY rat and SHR dams’ milk was determined and electrolyte intake and urinary excretion rates were calculated in both naturally reared and cross‐fostered WKY rat and SHR pups.

3. The milk sodium concentration fell in both strains (WKY rat: 31.8 ± 2.0 to 15.2 ± 1.2 mmol/L; SHR 31.9 ± 2.5 to 18.2 ± 1.6 mmol/L; P < 0.001), as did potassium (P < 0.001), over lactation, but there were no differences between strains. Calcium and magnesium concentrations increased (P< 0.001), although SHR dam's milk contained less calcium (P < 0.001) than that of WKY rat dams during the third week of lactation.

4. Spontaneously hypertensive rat pups ingested less milk (P<0.05) than WKY rat pups; therefore, their cumulative sodium intake over postnatal days 4–15 was significantly lower than that of WKY rat pups (WKY rat vs SHR: 84.4 ± 3.6 vs 59.7 ± 2.6 μmol/g bodyweight, respectively; P < 0.05) and fostered SHRX pups (77.7 ± 7.0 μmol/g bodyweight; P < 0.05). Potassium and magnesium intakes were comparable between SHR, WKY rat and SHRX pups, but SHR pups ingested significantly less calcium than either WKY rat pups (136.1 ± 6.4 vs 200.1 ± 9.5p, mol/g bodyweight, respectively; P<0.05) or SHRX pups (200.0 ± 18.0 μmol/g bodyweight; P<0.05).

5. These data show that the neonatal SHR experiences a period of sodium deficiency during the developmental stage when cross‐fostering is effective in lowering blood pressure. This is consistent with the reported up‐regulation of the renin‐angiotensin system observed in SHR at this time and may have a long‐term influence on blood pressure.
MULTIPLE COMPARISON PROCEDURES UPDATED
Authors: Ludbrook John
Published: June 2007

1. A common statistical flaw in articles submitted to or published in biomedical research journals is to test multiple null hypotheses that originate from the results of a single experiment without correcting for the inflated risk of type 1 error (false positive statistical inference) that results from this. Multiple comparison procedures (MCP) are designed to minimize this risk. The present review focuses on pairwise contrasts, the most common sort of multiple comparisons made by biomedical investigators.

2. In an earlier review a variety of MCP were described and evaluated. It was concluded that an effective MCP should control the risk of family‐wise type 1 error, so as to ensure that not more than one hypothesis within a single family is falsely rejected. One‐step procedures based on the Bonferroni or Sidak inequalities do this. For continuous data and under normal distribution theory, so does the Tukey‐Kramer procedure for all possible pairwise contrasts of means and the Dunnett procedure for all possible pairwise contrasts of means with a control mean.

3. There is now a new class of MCP, based on the Bonferroni or Šidák inequalities but performed in a step‐wise fashion. The members of this class have certain desirable properties. They: (i) control the family‐wise type 1 error rate as effectively as the one‐step procedures; (ii) are more powerful than the one‐step Bonferroni or Sidak procedures, especially when hypotheses are logically related; and (iii) can be applied not only to continuous data but also to ordinal or categorical data.

4. Of the new step‐wise MCP, Holm's step‐down procedures are commended for their combination of accuracy, power and versatility. They also have the virtue of simplicity. Given the raw P values that result from conventional tests of significance, the adjustments for multiple comparisons can be made by hand or hand‐held calculator.

5. Despite the corrective abilities of the new step‐wise MCP, investigators should try to design their experiments and analyses to test a single, global hypothesis rather than multiple ones.
CAFFEINE, BUT NOT TIME OF DAY, INCREASES WHOLE‐ARM PHYSIOLOGICAL TREMOR IN NON‐SMOKING MODERATE USERS
Authors: Miller L Stephen , Lombardo Thomas W. , Fowler Stephen C.
Published: June 2007

1. Consumptive levels of caffeine significantly increased whole‐arm physiological tremor in young adult males at 3 but not 1 mg caffeine/kg bodyweight.

2. Physiological tremor was not affected by time of day (TOD) or the interaction of caffeine and TOD.

3. Findings suggest that ingestion of a single oral dose of caffeine at typical consumptive levels results in measurable changes in physiological functioning and that whole‐arm physiological tremor is a sensitive measure of physiological change due to drug effects.

4. However, the results suggest that whole‐arm physiological tremor may not detect reliably TOD changes in functioning.
THE USE OF KNOCKOUT MICE TO UNDERSTAND THE ROLE OF CYTOKINES IN FEVER
Authors: Kluger Matthew J. , Kozak Wieslaw , Leon Lisa R. , Conn Carole A.
Published: June 2007

1. In most instances, data obtained using knockout mice to dissect the role of cytokines in fever are similar to data obtained by other, more traditional experimental techniques.

2. Interleukin (IL)‐lβ appears to be critically involved in fever caused by some routes of infectiodinflammation (e.g. localized inflammation with turpentine). This cytokine has only a small role in fevers caused by i.p. injection of lipopolysaccharide (LPS). These IL‐lβ‐induced fevers in knockout mice appear to be via the induction of IL‐6, similar to LPS‐induced fevers in rats. Interleukin‐6 also appears to be critically involved in turpentine‐induced fever.

3. The precise role of tumour necrosis factor (TNF) in fever is controversial. Data obtained from knockout mice lacking both TNF receptors do not support a pyrogenic role for TNF in fever either to i.p. injection of LPS, s.c. injection of turpentine or following caecal ligation and puncture.

4. The roles of these cytokines in fevers induced by injection of LPS, IL‐lβ, turpentine and caecal ligation and puncture are summarized. The data show the complexity of the febrile response. Depending on the types of inflammatoryhnfectious stimuli, different cytokines play important roles. Because other cytokines are thought to be involved in fever (e.g. macrophage inflammatory protein, interferons), considerable work is still needed to dissect the precise roles of cytokines in fever.
ROLE OF ENDOTHELIUM AND K+ CHANNELS IN DOBUTAMINE‐INDUCED RELAXATION IN RAT MESENTERIC ARTERY
Authors: Huang Yu , Kwok Kai Hong , Chan Nickie Wai Kei , Lau Chi Wai , Chen Zhen Yu
Published: June 2007

1. In order to examine the possible involvement of the endothelium and K+ channel activation in the relaxation induced by dobutamine, a β‐adrenoceptor agonist, in rat isolated mesenteric arteries, the effects of inhibitors of nitric oxide (NO) activity, blockers of K+ channels and high extracellular K+ were studied by measuring isometric tension in both endothelium‐intact and ‐denuded arteries.

2. Dobutamine inhibited the phenylephrine (PE)‐induced sustained tension with a pEC50 of 7.40±0.08 in endothelium‐intact arteries. Removal of functional endothelium attenuated the effect of dobutamine. The relaxation induced by dobutamine was inhibited by the β1‐adrenoceptor antagonist CGP20712A (3μ.mol/L) but not by the β2‐adrenoceptor antagonist ICI 118 551 (3 μmol/L) in endothelium‐denuded arteries.

3. Pretreatment with NG‐nitro‐l‐arginine (l‐NNA; 100 μmol/L) or methylene blue (3 μmol/L) induced a similar degree of inhibition of the dobutamine‐induced relaxation in endothelium‐intact arteries, while NG‐nitro‐d ‐arginine (100 (μmol/L) and indomethacin (10 μmol/L) had no effect. In contrast, pretreatment with L ‐NNA (100 μmol/L) did not affect the relaxation induced by sodium nitroprusside (SNP) or forskolin. Methylene blue (3μmol/L) inhibited the relaxant response to SNP.

4. Charybdotoxin (CTX; 100nmol/L), iberiotoxin (IBX; 100nmol/L) and tetraethylammonium ions (TEA+; 3mmol/L) significantly reduced the dobutamine‐induced relaxation. Tetrapentylammonium ions (TPA+; 5μmol/L) markedly inhibited the relaxant effect of dobutamine. The pECso values for control and in the presence of TPA+ in endothelium‐intact arteries were 7.35±0.11 and 6.14±0.17, respectively, and 6.35±0.09 and 5.87±0.17 for control and in the presence of TPA+ in endothelium‐denuded arteries, respectively. In contrast, glibenclamide (3 μ‐mol/L) was ineffective. At 5 μmol/L, TPA+ also inhibited the relaxation induced by forskolin.

5. The maximal relaxation of PE‐contracted arteries induced by 3μmol/L dobutamine was completely abolished in the 60mmol/L K+‐contracted arteries with and without endothelium, while dobutamine at a concentration greater than 3 μmol/L induced inhibition of the high‐K+ response.

6. The present results indicate that endothelium, probably NO but not prostacyclin, was involved in the dobutamine‐induced relaxation in rat mesenteric arteries. Activation of CTX‐, IBX‐ and TPA+‐sensitive K+ channels contributed towards the observed relaxation. Loss of the ability to relax the 60 mmol/L K+‐contracted arteries suggests that endothelium‐derived vasoactive factors affected by concentrations of dobutamine less than 3 μmol/L may also act through K+ channels in our preparations. Higher concentrations of dobutamine may have a direct, endothelium‐independent relaxant effect.
EFFECT OF TRANSMUCOSAL FLUID MOVEMENT ON ZINC AND COPPER ABSORPTION FROM THE RAT SMALL INTESTINE
Authors: Kuzuya Takafumi , Hasegawa Takaaki , Ogura Yozo , Nabeshima Toshitaka
Published: June 2007

1. The effects of transmucosal fluid movement on zinc and copper absorption from rat small intestine were investigated using an in situ recirculating perfusion method.

2. Transmucosal fluid movement was obtained by using hypo‐, iso‐ or hyperosmotic perfusate containing various concentrations of sodium chloride. Linear correlations were obtained between net fluid movement and absorption rate constants, which were calculated from the perfusion decline of zinc (n = 15; r= 0.77) and copper (n= 15; r = 0.75).

3. The changes in serum levels of these metals did not correlate with the increase in the absorption rate.

4. The present study indicates that zinc and copper absorption is dependent on transmucosal fluid movement.
PRODUCTION OF EICOSANOIDS AND ANGIOTENSIN II IN RESISTANCE VESSELS IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kunimoto Masako , Soma Masayoshi , Kanmatsuse Katsuo
Published: June 2007

1. Angiotensin II (Angll) and eicosanoids may be important in vascular remodelling and the pressor response via autocrine and paracrine mechanisms. We evaluated the influences of ageing and β‐adrenoceptor stimulation on the production of vascular Angll and eicosanoids in male spontaneously hypertensive rats (SHR), aged 5,17 and 30 weeks, and age‐matched Wistar‐Kyoto (WKY) rats.

2. All rats were weighed and their systolic blood pressure (SBP) was measured by the tail‐cuff method. Mesenteric arteries were isolated and perfused with Krebs'‐Henseleit solution. The outflows of prostaglandin E2 (PGE2), 6‐keto‐PGF1α, thromboxane B2 (TxB2) and AngII were measured by specific radioimmunoassays.

3. The SBP was higher in SHR than in WKY rats in the 17‐and 30‐week‐old groups and increased with age. Basal levels of PGE2 were significantly lower in SHR than in WKY rats. The ratios of 6‐keto‐PGF1α to TxB2 and PGE2 to TxB2 were significantly lower in 17‐week‐old SHR compared with age‐matched WKY rats. Basal Angll release did not differ between SHR and WKY rats and decreased with age. Isoproterenol stimulated the release of Angll; the magnitude of the increment was greater in WKY rats than in age‐matched SHR. These results show that there is an imbalance in the production of vasodilator and vasoconstrictor eicosanoids in the resistance vessels of SHR at ages at which hypertension developed.

4. This imbalance may contribute to the increased vasoconstrictor response and vascular remodelling in SHR. Our findings suggest that vascular Angll plays a role in the ageing process and that β‐adrenoceptor‐stimuIated release of vascular Angll is impaired in SHR.
ROLE OF AFFERENTS IN THE DEVELOPMENT AND CELL SURVIVAL OF THE VERTEBRATE NERVOUS SYSTEM
Authors: Sherrard Rachel M. , Bower Adrian J.
Published: June 2007

1. During normal development of the vertebrate central nervous system, a considerable number of neurons die. The factors controlling which neurons die and which survive are not fully understood.

2. Target populations are known to maintain their innervating neurons. However, the role of afferents in maintaining their targets is still under review.

3. In the developing nervous system, deafferentation of a neuron population is difficult to achieve because plasticity (structural re‐organization) can cause re‐innervation of the area. Re‐innervation alters, rather than removes, the afferent supply.

4. Afferent input is important for neuronal survival during development because deafferentation increases neuronal death by 20‐30% and increasing input diminishes neuronal death.

5. Deafferented neurons die at the normal time for cell death for any given population. This occurs after the arrival of afferent axons but before the completion of connectivity and the onset of unction.

6. Neuronal survival is maintained by any input, such as reinnervation by inappropriate fibres, but for optimal survival, morphological maturation and the acquisition of normal physiology, the correct input is required.

7. Afferents maintain their target neurons via a combination of electrical activity and delivery of trophic agents, which adjust intracellular calcium, thereby facilitating protein synthesis, mitochondrial function and suppressing apoptosis.

8. Evidence from animal and in vitro experiments indicates that afferents play an extremely important role in the survival of developing neurons in the immature vertebrate nervous system.
INHIBITORY MECHANISMS OF NALOXONE ON HUMAN PLATELETS
Authors: Sheu Joen‐Rong , Lee Yen‐Mei , Lee Ling‐Wen , Luk Hsiang‐Ning , Yen Mao‐Hsiung
Published: June 2007

1. In the present study, naloxone was tested for its antiplatelet activities in human platelet‐rich plasma (PRP). In human PRP, naloxone (0.1‐0.5 mmol/L) inhibited aggregation stimulated by a variety of agonists (i.e. collagen, adenosine diphosphate (ADP), U46619 and adrenaline).

2. Naloxone (0.1‐0.5 mmol/L) did not significantly affect cyclic adenosine monophosphate and cGMP levels in human washed platelets, whereas naloxone (0.5 mmol/L) significantly inhibited thromboxane B2 formation stimulated by collagen (5 μg/mL| in human washed platelets.

3. Naloxone (0.5 mmol/L) significantly inhibited [3H]‐inositol monophosphate formation of [3H]‐myoinositol‐loaded platelets stimulated by collagen and U46619. Moreover, naloxone did not influence the binding of 125I‐triflavin to platelet membranes. Triflavin is an Arg‐Gly‐Asp‐containing specific fibrinogen receptor antagonist.

4. Addition of naloxone (0.5 mmol/L) to platelet preparations tagged with diphenylhexatriene (DPH) resulted in a considerable decrease in relative fluorescence intensity.

5. It is suggested that the anti‐platelet effects of naloxone may be caused, at least partly, by the induction of conformational changes in the platelet membrane initially, followed by the inhibition of thromboxane A2 formation and phosphoinositide breakdown of platelets stimulated by agonists.
PYRROLIDINE DITHIOCARBAMATE IMPROVES THE SEPTIC SHOCK SYNDROMES IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Hong Hong‐Jye , Wu Chin‐Chen , Yen Mao‐Hsiung
Published: June 2007

1. The aim of the present study was to evaluate the effect of pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor‐kB (NF‐kB), on septic shock induced by Escherichia coli lipopolysaccharide (LPS) in spontaneously hypertensive rats (SHR).

2. After injection of LPS in SHR, a marked decrease in blood pressure was observed at 3h and vascular hyporeactivity to noradrenaline (NA) was observed after 1 h. A marked increase in plasma levels of tumour necrosis factor‐et (TNF‐α) and nitrite (an indicator of nitric oxide) was also observed in SHR.

3. The delayed hypotension and hyporeactivity to NA induced by LPS were significantly reversed by pretreatment of rats with PDTC (10mg/kg). The increase in plasma levels of TNF‐α and nitrite in LPS‐treated groups was also significantly suppressed by PDTC pretreatment. In addition, the survival time of SHR treated with LPS was significantly prolonged by PDTC pretreatment.

4. The present ex vivo study demonstrates that the NA‐induced contraction is attenuated and the l‐arginine‐induced relaxation is enhanced in aortic rings obtained from LPS‐treated SHR. Both the reduction of the NA‐induced contraction and the increase of l‐arginine‐induced relaxation were reversed by pretreatment with PDTC. However, the relaxation elicited by acetylcholine (ACh) was not affected in LPS‐treated SHR when compared with sham‐operated SHR. In addition, the ACh‐induced relaxation in LPS‐treated SHR was not affected by PDTC pretreatment.

5. In normotensive Wistar‐Kyoto (WKY) rats, LPS had mild effects on blood pressure, vascular hyporeactivity and plasma levels of TNF‐α and nitrite. At a higher doses, PDTC (10 mg/kg) also prolonged survival time and improved haemodynamics in LPS‐treated WKY rats. In the ex vivo study, it was noted that the relaxation elicited by ACh was significantly (P<0.05) attenuated in LPS‐treated WKY rats. This attenuation of the ACh‐induced relaxation by LPS in WKY rats was significantly reversed by pretreatment with 10 mg/kg PDTC.

6. In conclusion, PDTC prolongs survival time in rats with endotoxaemia and improves the septic shock syndromes both in vivo and ex vivo. Thus, we propose that PDTC may be of use in septic patients.
RESPONSES OF RAT HIPPOCAMPAL SLICES IN A HIGH‐K+ MEDIUM FOLLOWING IN VIVO GLOBAL ISCHAEMIA
Authors: El‐Sabban F. , Reid KH , Jr HL Edmonds
Published: June 2007

1. We hypothesized that burst activity induced in rat hippo‐campal tissue by a high‐K+ medium in vitro would be increased by a previous episode of global ischaemia, severe enough to induce persistent neurological dysfunction.

2. Male Wistar rats that were subjected to 9 min of chest compression, sufficient to reduce blood pressure (BP) to zero, showed evidence of neurological damage attributed to a global ischaemic insult. Hindlimb function was impaired for 24‐48 h and a susceptibility to sound‐induced seizures was induced in 25 of 35 rats. The seizure susceptibility cleared spontaneously within 2 weeks in 10 of 25 rats.

3. Hippocampal slices from postischaemic rats were prepared, tested for viability and were then exposed to an 8.0 mmol/L K+ artificial cerebrospinal fluid in vitro. Spontaneous epileptiform bursting activity in the high‐K+ medium was not increased. Instead, burst size decreased with time after ischaemia.

4. The decrement in bursting activity is attributed to loss of cellular activity or integrity. These changes correlate with functional changes described by others, but not necessarily to histologically verifiable cell death. The time course of these changes was remarkably long, continuing for almost 3 weeks. Thus, a less‐than‐lethal ischaemia appears to induce neuronal changes, possibly reversible, that continue for at least 20 days after the global ischaemic insult.
REPRODUCIBILITY OF ARTERIAL COMPLIANCE AND CAROTID WALL THICKNESS MEASUREMENTS IN NORMAL SUBJECTS
Authors: Liang Yu‐Lu , Cameron James D. , Teede Helena , Kotsopoulos Dimitra , McGrath Barry P.
Published: June 2007

1. Non‐invasive techniques to measure indices of arterial function and wall thickness are frequently used as surrogate markers of cardiovascular disease. Reproducibility of measurements of arterial compliance has been infrequently reported and little is known about the interrelationships of the various indices in vivo.

2. The present study was designed to assess reproducibility and interrelationships of indices of systemic arterial compliance, pulse wave velocity, carotid compliance and intima‐media thickness (IMT).

3. Fifty healthy volunteers (20 male and 30 female; aged 20‐70 years, mean 46.5 years), participated in the present study. Each subject was studied on two occasions by the same investigators, using an identical protocol at an interval of 1‐5 weeks (mean 2.5 weeks) without lifestyle change.

4. There were no significant differences between visits for any recorded general data, except resting blood pressure, which was lower on the second occasion. There were no systematic differences within each pair over the range of measurements for any of the variables. Bland‐Altman plots of repeatability of changes in indices showed that the mean values between visits were not significantly different. All indices of central arterial compliance were significantly related to age and IMT.

5. Thus, under controlled experimental conditions, there was satisfactory repeatability of measurements of indices of both intrinsic and functional arterial mechanical properties (central and carotid arterial compliance and IMT). This type of information will permit the construction of sample size tables for clinical trials using these indices.

6. Central arterial compliance may be an important determinant of IMT.
PITUITARY‐ADRENAL RESPONSES TO COMBINED ORAL D‐FENFLURAMINE AND INTRAVENOUS NALOXONE IN HUMANS
Authors: Grice Jeffrey E. , Torpy David J. , Hockings Gregory I. , Walters Margaret M. , Crosbie Georgina V. , Jackson Richard V.
Published: June 2007

1. Fenfluramine is an optically active 5‐hydroxytryptamine (5‐HT) releaser and re‐uptake inhibitor. Increased brain 5‐HT mediates appetite suppression, the d enantiomer being more active than l‐ or dl‐fenfluramine. Fenfluramine also stimulates the hypothalamic‐pituitary‐adrenal (HPA) axis, leading to suggestions that this could act as a marker for its biological actions. However, the d enantiomer appears less active than a comparable dl racemate dose in animals, while effects of D‐fenfluramine on the human HPA axis remain unproven. The aim of the present study was to clarify this.

2. Seven healthy human volunteers (three male, four female; 18‐58 years) received 30 mg oral D ‐fenfluramine or placebo, followed by 125 p‐g/kg, i.v. naloxone or placebo, in randomized, double‐blinded, placebo‐controlled afternoon studies. We measured plasma adrenocorticotropic hormone (ACTH) and Cortisol levels in samples taken at intervals throughout the study period.

3. In contrast to previous results with dl‐fenfluramine, we found no dynamic responses to d ‐fenfluramine alone and no augmentation of responses to naloxone.

4. Central pathways to HPA axis activation are apparently not stimulated by d ‐fenfluramine at this dose in humans, in contrast with dl‐fenfluramine, where the l enantiomer may be more selective for proposed corticotropin‐releasing hormone‐mediated, post‐synaptic 5‐HT2 or noradrenergic mechanisms. As previously reported, d‐fenfluramine significantly blunted the circadian fall in basal plasma Cortisol, providing in vivo evidence for serotonergic involvement in circadian regulation.
AMYLIN: PHYSIOLOGICAL ROLES IN THE KIDNEY AND A HYPOTHESIS FOR ITS ROLE IN HYPERTENSION
Authors: Wookey Peter J. , Cooper Mark E.
Published: June 2007

1. There are high‐affinity binding sites for amylin in the renal cortex associated with proximal tubules. These appear to represent seven transmembrane (heptatopic) receptors that are known to form ternary complexes with G‐proteins and activate second messenger systems.

2.Amylin stimulates sodium/water reabsorption from the basolateral side of the proximal tubules and plays a role in sodium homeostasis.

3. The transient expression of amylin‐like mRNA has been detected perinatally, using in situ hybridization, in the sub‐nephrogenic zone of the metanephros and is associated with proximal tubules of the developing nephron. There it is thought to play a role as a growth factor for brush border epithelial cells in the developing kidney and in renal regrowth in the adult kidney.

4. In two models of hypertension, the spontaneously hypertensive rat (SHR) and one created surgically by subtotal nephrectomy, renal amylin receptors are activated. In the SHR, activation precedes the rise in blood pressure and suggests that activation of the amylin system may be an important event in the development of hypertension.
ROLE OF THE MESOLIMBIC DOPAMINE SYSTEM IN CARDIOVASCULAR HOMEOSTASIS. STIMULATION OF THE VENTRAL TEGMENTAL AREA MODULATES THE EFFECT OF VASOPRESSIN ON BLOOD PRESSURE IN CONSCIOUS RATS
Authors: van den Buuse Maarten
Published: June 2007

1. The possible role of the ventral tegmental area (VTA) and its dopaminergic projections in cardiovascular regulation is reviewed.

2. Our own work has shown that stimulation of the VTA by local microinjection of the substance P analogue DiMe‐C7 caused an increase in blood pressure. The mechanism of the pressor response was an interaction of central dopaminergic activation, most likely at the level of the baroreflex, with the circulatory actions of vasopressin.

3. These findings are important for a possible role of the mesolimbic dopamine system in cardiovascular homeostasis. Several studies reviewed here show that neuronal activity of the VTA and its mesolimbic projections is altered by changes in blood pressure, salt and electrolyte balance, stress and food and water intake.

4. The VTA and mesolimbic dopamine system, while playing a widely accepted role in locomotor activity, cognition and reward mechanisms, may also be involved in the integration of sensory and behavioural information with cardiovascular homeostasis.
DOPAMINE RELEASES ENDOTHELIUM‐DERIVED RELAXING FACTOR VIA α2‐ADRENOCEPTORS IN CANINE VESSELS: COMPARISONS BETWEEN FEMORAL ARTERIES AND VEINS
Authors: Segawa Tomonori , Ito Hiroyasu , Inoue Kiyoaki , Wada Hisayasu , Minatoguchi Shinya , Fujiwara Hisayoshi
Published: June 2007

1. We investigated the role of vascular smooth muscle α‐adrenoceptor subtypes in the vasoconstrictor response of femoral arteries and veins to dopamine and whether the vasoconstriction is modified by endothelium‐dependent relaxation mediated via the activation of α2‐adrenoceptors in ring preparations of femoral arteries and veins from mongrel dogs.

2. Dopamine contracted both arteries and veins in a dose‐dependent manner and this contraction was inhibited by pre‐treatment with phentolamine or prazosin. Pretreatment with yohimbine shifted the dose‐response curve for dopamine to the right in femoral veins, but not in arteries.

3. Phenylephrine contracted femoral arteries and veins in a dose‐dependent manner and this contraction was inhibited by pretreatment with prazosin.

4. Clonidine produced a bell‐shaped dose‐response curve in femoral veins and this curve was shifted upwards by pretreatment with NG‐nitro‐l‐arginine (l‐NNA). In contrast, femoral arteries were not affected by clonidine. NG‐Nitro‐l ‐arginine potentiated contractile responses to dopamine in both veins and arteries. This potentiation was inhibited by yohimbine or by the removal of the endothelium in both arteries and veins.

5. These results suggest that dopamine contracts femoral arteries via stimulation of α1‐adrenoceptors and contracts femoral veins via stimulation of both α1‐ and α2‐adrenoceptors and that these contractions are attenuated by the vasodilator action of dopamine via α2‐adrenoceptor‐mediated release of endothelium‐derived relaxing factor.
FUNCTIONAL ASSESSMENT OF α1‐ADRENOCEPTOR SUBTYPES IN PORCINE CORONARY ARTERY
Authors: Yan Ming , Zhang Youyi , Du Xiao‐Jun , Han Chide
Published: June 2007

1.α1‐Adrenoceptors are known to play an important role in vasoconstriction in response to adrenergic stimulation. However, the functional importance of α1‐adrenoceptor subtypes at the epicardial coronary artery remains unclear. We examined α‐adrenoceptor subtypes by comparing functional affinities for α‐adrenoceptor antagonists on noradrenaline (NA)‐induced vasoconstriction in porcine denuded right coronary arteries.

2. Noradrenaline induced a dose‐dependent vasoconstriction in incubated vessel rings. Prazosin and phentolamine were potent and competitive antagonists for NA‐induced contraction (pA2 10.27 and 9.03, respectively). In contrast, the selective α2‐adrenoceptor antagonist yohimbine had a low affinity (pA2 6.13). Two selective α1A‐adrenoceptor antagonists, WB 4101 and 5‐methyl urapidil, were potent and competitive antagonists of α1‐adrenoceptor‐induced contraction (pA2 10.67 and 8.90, respectively) and the selective α1D‐adrenoceptor antagonist BMY 7378 had a low affinity (pA2 6.06). Noradrenaline‐induced contraction was insensitive to the alkylating effects of chlorethyl‐clonidine. These observations indicate that the vasoconstriction is predominantly mediated by the α1A‐adrenoceptor subtype. This was also supported by a good correlation between pA2 values from the present study and reported binding affinities (pKi) of various α‐adrenoceptor antagonists with cloned human α1A‐adrenoceptors (r= 0.98), but not for α1B‐ or α1D‐adreno‐ceptor subtypes (r= 0.77 and 0.41, respectively).

3. Our results indicate that the α1A‐adrenoceptor is the main functional receptor subtype in porcine denuded coronary arteries.
METABOLIC EFFECTS OF THIOCTIC ACID IN RODENT MODELS OF INSULIN RESISTANCE AND DIABETES
Authors: Black Kelly , Qu Xianqin , Seale J Paul , Donnelly Richard
Published: June 2007

1. The antioxidant thioctic acid (TA) has been used in the treatment of diabetic neuropathy and recent studies have suggested that TA also has pancreatic and peripheral effects that improve glucose transport and metabolism. In the present study, the metabolic effects of TA were evaluated in rodent models of insulin resistance (fructose‐fed Sprague‐Dawley rat) and insulin deficiency (streptozotocin (STZ)‐induced diabetic rat). Oral and intravenous glucose tolerance tests (OGTT and IVGTT, respectively) were performed in conscious rats after treatment with 50 mg/kg per day TA or vehicle for 5 days.

2. Fructose feeding for 7 days induced insulin resistance and impaired glucose tolerance and hypertriglycerideaemia. Treatment of fructose‐fed rats with TA had no significant effect on fasting or stimulated glucose levels or on fasting triglyceride concentrations (e.g. the area under the curve for glucose (AUCglu) following OGTT was 1233 ± 67 and 1284 ± 59 in fructose‐fed rats treated with either TA (n= 12) or vehicle (n= 12), respectively). Similarly, TA had no significant effect on IVGTT profiles in fructose‐induced insulin resistance.

3. Low‐dose STZ (80 mg/kg, i.p, over 2 days) induced hyper‐glycaemia, but TA had no significant glucose‐lowering effects in STZ‐diabetic rats (AUCglu (OGTT) following oral administration was 5507 ± 27 and 5450 ± 27 in TA (n= 12) and vehicle‐treated (n= 12) rats, respectively). Nor did pretreatment with TA affect the diabetogenic response to STZ.

4. In contrast with previous in vitro studies reporting favourable metabolic effects of TA, the present study shows that after short‐term oral therapy there are no significant improvements in glucose tolerance in rodent models of insulin resistance and insulin deficiency. Thioctic acid is unlikely to be of therapeutic benefit as an anti‐diabetic drug in clinical practice.
EVOLUTION OF SURFACE ACTIVITY RELATED FUNCTIONS OF VERTEBRATE PULMONARY SURFACTANT
Authors: Daniels Christopher B. , Lopatko Olga V. , Orgeig Sandra
Published: June 2007

1. Pulmonary surfactant is a mixture of lipids and proteins that lines the air‐liquid interface of the lungs of all vertebrates. In mammals, it functions to reduce and vary surface tension, which helps to decrease the work of breathing, provide alveolar stability and prevent alveolar oedema. The present review examines the evolution and relative importance of these surface activity related functions in the lungs of vertebrates.

2. The surface activity of surfactant from fish, amphibians, birds and most reptiles is generally very low, correlating with a low body temperature and a low disaturated phospholipid content of their surfactant. In contrast, the surfactant of those reptiles with a higher preferred body temperature, as well as that of birds and mammals, has a much higher surface activity.

3. The two main functions of surfactant in mammals are to provide alveolar stability and to increase compliance of the relatively stiff bronchoalveolar lung. As the respiratory units of most non‐mammalian vertebrates are up to 1000‐fold larger and up to 100‐fold more compliant, surfactant is not required for these functions.

4. In non‐mammals, surfactant appears to act as an anti‐glue preventing the adhesion of respiratory surfaces that may occur when the lungs collapse (e.g. during diving, swallowing of prey or on expiration). Surfactant also controls lung fluid balance. These functions can be fulfilled by a surfactant with relatively low surface activity and may represent the primitive functions of surface active material in vertebrate lungs.