bluuebunny/crossref_metadata_2025 huggingface dataset:
INHIBITION OF RAT GLOMERULAR MESANGIAL CELL SODIUM/HYDROGEN EXCHANGE BY HYDROGEN PEROXIDE
Authors: Shaw Sidney , Naegeli Patricia , Etter Jean‐Daniel , Weidmann Peter
Published: June 2007

1. pHi regulation In glomerular mesangial cells (GMC) includes both Na+/H+ and Cl‐/HCO3‐ exchange. As a fall in pHi may protect against H2O2‐mediated GMC damage during ischaemia‐reperfusion, the involvement of these mechanisms in the GMC pHi response to H2O2 was assessed using confluent GMC grown in RPMI medium with 20% fetal calf serum (10–15 passages).

2. Cells were loaded with BCECF‐AM and pHi evaluated using standard fluorometric‐ratio techniques. In HEPES buffer, GMC exposure to H2O2 dose‐dependently (25μmol/L‐1 mmol/L) decreased pHi over 10 rnin from 7.3 ± 0.1 to 6.7 ± 0.1 (at 100 μmol/L) partly due to rapid non‐competitive inhibition of amiloride‐sensltive Na+/H+ exchange.

3. BCECF fluorescence in free solution was unchanged by H2O2 whereas the pHi decrease was abolished by nigericin/K+ clamp. Buffer capacity by direct titration was not changed by H2O2 and averaged 100 ± 9 nmol/2.6±106 cells/pH unit. Similarly, zero‐Na+/high‐K+ buffer, used to minimize Passive H+ entry, did not prevent the fall in pHi while GMC H+‐formation/extrusion, assessed by the rate of extracellular acidification in low‐capacity buffer (0.05 mmol/L), was rapidly inhibited.

4. In contrast, following only a brief 3 min exposure to 1 mmol/L H2O2, HCO3‐/CO2 buffer potentiated the inhibition of Na+/ H+ exchange from 50 to 80% of control and reduced the acidification from pHi 6.6 ± 0.1 to 7.15 ± 00.05. This effect was reversed (to pHi 6.8 ± 0.07) by pretreatment with 200 μmol/L DIDS, an inhibitor of Cl‐/HCO3‐ exchange.

5. Thus, the decrease in GMC pHi in Fespohsë to H2O2 In HEPES, partly mediated by inhibition of Na+/H+ exchange and a possible redistribution of intraceliular H+, is antagonized in HCO3‐/CO2 through a DIDS‐sensitive Cl‐/HCO3‐ exchange mechanism. This may act to negate potentially protective effects of low pHi and potentiate oxidative damage to membrane lipids, enzymes and intracellular organelles on reperfusion.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NSAID: AN UPDATE ON THEIR ANALGESIC EFFECTS
Authors: Walker J. S.
Published: June 2007

1. The non‐steroidal anti‐inflammatory drugs (NSAID) are a group of drugs that possess both analgesic and anti‐inflammatory properties. They are used to treat a variety of painful and inflammatory disorders such as postoperative pain, dental surgery, headache, acute and chronic musculoskeletal pain.

2. There is now substantial evidence that NSAID produce analgesia by inhibiting prostaglandin (PG) synthesis both in the peripheral and central nervous system. However, other mechanisms of action should also be considered. There is a multiplicity of mediators capable of producing pain, and NSAID may act both on the peripheral and central nervous system to modulate such mediators. There is a growing body of evidence suggesting that NSAID can exert an effect on specific G‐protein dependent functions.

3. There is significant intra‐ and interpatient variability in the response to NSAID. Development of tolerance after multiple doses may provide an explanation for the unsatisfactory response to NSAID in some patients.

4. It has been suggested that the rate of decline of drug effect is characteristic of analgesia itself and indicates that an endogenous substance mediates the analgesic effect; possible candidates include serotonin.

5. NSAID remain an important therapeutic option in the management of pain.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: NEUROTRANSMITTER MECHANISMS OF RAT VAGAL AFFERENT NEURONS
Authors: Lawrence Andrew J.
Published: June 2007

1. The present study has employed anatomical and neurochemical techniques to assess whether the amino acid, l‐glutamate, may be considered as a potential neurotransmitter at rat vagal afferent neurons, with particular reference to baroreceptor afferents.

2. Slide‐mounted sections of rat nodose ganglia were incubated with a high‐titre antibody to glutamate, and visualization of the resulting immunoreactivity indicated glutamate‐positive staining in a population of vagal afferent perikarya. In contrast, interstitial cells were devoid of immunostaining.

3. Release of endogenous glutamate was measured by in vivo microdialysis in the nucleus tractus solitarius, the site of central vagal afferent terminals, and could be evoked with a depolarizing stimulus of KCl in a calcium‐dependent fashion. In addition, baroreceptor loading with an intravenous infusion of phenylephrine (30 μg/kg per min) increased the spontaneous efflux of glutamate to 148 ± 28% of basal levels, which was paralleled by an increase in mean arterial pressure (∼40 mmHg). Release of glutamate was also elevated two‐fold by intra‐cerebral administration of S‐nitroso‐N‐acetylpenicillamine (30 μmol/L), an effect that could be prevented by coadmini‐stration of methylene blue (10 μmol/L).

4. These data suggest that neuronal glutamate may be formed in a population of vagal afferent cell bodies, presumably to act on soma membrane receptors. Furthermore, the excitatory amino acid is released in a neurotransmitter‐like fashion at the terminal region of vagal afferent neurons, where glutamate release is increased as a consequence of baroreceptor loading and also following activation of soluble guanylate cyclase. Thus, glutamate may be considered a candidate neurotransmitter of vagal baroreceptor afferent neurons, which may be modulated by nitric oxide or an endogenous nitrosothiol.
Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists, 1994: SIGNALLING PATHWAYS IN CARDIAC FAILURE
Authors: Summers Roger J. , McMartin Lynne R. , Kompa Andrew , Gu Xinhua , Molenaar Peter
Published: June 2007

1. Cardiac failure in humans and in animal models is associated with a marked desensitization of the catecholamine signalling pathway.

2. β1‐ and β2‐ and possibly β3‐adrenoceptors (β‐AR) are found in the hearts of humans and common laboratory animals such as rats and guinea‐pigs. In rats and guinea‐pigs chronic stimulation of cardiac β‐AR leads to a rapid loss of β2‐AR whereas heart failure in humans is associated with a loss of β1‐AR or β1‐AR and β2AR.

3. Desensitization is also associated with phosphorylation of β‐AR by β‐AR kinase β‐ARK) and uncoupling of receptors from the signalling pathway. β‐ARK but not β‐arrestin activity and mRNA are markedly increased in heart failure.

4. Chronic β‐AR stimulation and heart failure are associated with increases in Giα but little if any change in Gsα.

5. The roles of βm̀ subunits of G‐proteins, adenylate cyclase subtypes and cAMP dependent protein kinase A in heart failure are unclear at present.
EFFECTS OF PREGNANCY AND PROGESTERONE METABOLITES ON REGULATION OF SYMPATHETIC OUTFLOW
Authors: Heesch Cheryl M. , Rogers Richard C.
Published: June 2007

1. Pregnancy is characterized by a 40% increase in blood volume and cardiac output, a decrease in arterial blood pressure and thus a substantial decrease in total peripheral resistance. The aims of the experiments described in this manuscript were: (i) to determine if pregnancy resulted in alterations in baroreflex control of sympathetic outflow; and (ii) to evaluate possible mechanisms for pregnancy‐induced changes in control of sympathetic outflow.

2. Arterial baroreflex control of efferent renal sympathetic nerve activity was examined in female pregnant and non‐pregnant normotensive Sprague‐Dawley and Wistar‐Kyoto rats. In both rat strains, pregnancy was associated with a decrease in baseline arterial pressure, a shift in the baroreflex function curve to a lower operating pressure range and an attenuated ability to reflexly increase sympathetic outflow above baseline levels during a hypotensive challenge. Pregnant Sprague‐Dawley rats retained their ability to respond to a hypertensive challenge, whereas pregnant Wistar‐Kyoto rats exhibited a decreased sensitivity to hypertensive as well as hypotensive challenges.

3. The inhibitory amino acid transmitter, GABA, mediates baroreflex sympatho‐inhibition within the rostral ventral lateral medulla (RVLM) of the brainstem. Since 3α‐OH dihydroprogesterone (3α‐OH‐DHP), a major metabolite of progesterone, is elevated in pregnancy and has been reported to potentiate central nervous system GABAainhibitory responses, experiments were performed to determine if effects of this metabolite of progesterone could contribute to the pregnancy associated changes in control of sympathetic outflow. Acute intravenous administration of 3α‐OH‐DHP to virgin female Sprague‐Dawley rats resulted in progressive changes in the baroreflex function curve that mimicked the effects of pregnancy.

4. Preliminary experiments in which the GABAaagonist, isoguvacine, and 3α‐OH‐DHP were micro‐injected into the RVLM of virgin female rats suggest that the 3α‐OH metabolite of progesterone potentiates sympatho‐inhibitory effects of GABAareceptor activation in the RVLM.

5. In conclusion, acute administration of 3α‐OH‐DHP to virgin female rats mimics the effects of pregnancy on baroreflex control of sympathetic outflow. These results are consistent with potentiation of GABAergic sympatho‐inhibition by circulating levels of the major metabolite of progesterone during pregnancy.
DEGRANULATION OF RAT SALIVARY GLANDS FOLLOWING TREATMENT WITH RECEPTOR‐SELECTIVE AGONISTS
Authors: Peter Birgit , Waarde Maria A. W. H. Van , Vissink Arjan , 's‐Gravenmade Eduard J. , Konings Antonius W. T.
Published: June 2007

1. The aim of this study was to find a drug that induces an almost complete degranulation of secretory cells in rat parotid and submandibular glands.

2. Phenylephrine (α‐adrenergic), isoproterenol (β‐adrenergic) and mecholine (muscarinic cholinergic) were tested. Time and degree of maximal depletion of acinar and granular convoluted tubule cells were determined morphologically.

3. Following phenylephrine‐injection (5 mg/kg or 10.2 mg/kg, i.p.), no effect on the acinar granulation level was observed in either of the glands, while about 50–60% granular convoluted tubules were degranulated for at least 120–180 min post‐injection.

4. With isoproterenol (5, 10, 40, 70 or 100 mg/kg, i.p.), degranulation of 100% of the acinar cells in the parotid and 80% of the acinar cells in the submandibular gland was observed 90 min post‐injection. Granular convoluted tubule cells did not respond to this β‐adrenergic drug.

5. Mecholine (3.75 or 7.5 mg/kg, i.p.) induced mainly degranulation of granular convoluted tubule cells (about 50% after 120 min). Numbers of granulated acinar cells decreased only slightly in both glands (about 10%, 90–120 min).

6. From this study it appears that with a relatively low dosage (5 mg/kg, i.p.) of isoproterenol, a high level of degranulation can be induced in acinar cells of rat parotid and submandibular glands without toxic side effects. Concerning granular convoluted tubules, only moderate degranulation was observed with phenylephrine and mecholine, respectively.
SEX DIFFERENCES AND THE EFFECT OF GONADECTOMY ON MORPHINE‐INDUCED ANTINOCICEPTION AND DEPENDENCE IN RATS AND MICE
Authors: Ali B. H. , Sharif S. I. , Elkadi A.
Published: June 2007

1. Differences between sexes and the effect of bilateral surgical gonadectomy on the response to morphine analgesia and dependence were examined in rats and mice.

2. The analgesic response to morphine (5 mg/kg) was assessed by the hot plate and the abdominal constriction tests. Dependence was induced by injecting morphine at increasing doses (5–160 mg/kg) for 6 consecutive days and withdrawal signs elicited by injecting naloxone (2.5 mg/kg).

3. The base line reaction times in the intact control, shamoperated and gonadectomized animals of either sex were not significantly different from each other.

4. After treatment with morphine, the percentage increase in the reaction time in gonadectomized male and female rats and in gonadectomized male mice was significantly higher than in their respective controls.

5. The increase in the reaction time, after morphine treatment, was significantly higher in gonadectomized female rats than in gonadectomized male rats.

6. Naloxone‐induced withdrawal signs in morphine‐dependent gonadectomized rats and mice were not significantly different from those in sham‐operated controls. However, female rats in both groups exhibited a significantly higher number of escape jumping responses than males.
ESTERASE COMPARISON IN NEUROBLASTOMA CELLS OF HUMAN AND RODENT ORIGIN
Authors: Ehrich Marion , Veronesi Bellina
Published: June 2007

1. Activities of acetylcholinesterase (AChE), neuropathy target esterase (NTE), and carboxylesterase (CbxE) were compared in neuroblastoma cells of human origin (SH‐SY5Y) and murine origin (NB41A3).

2. Mouse neuroblastoma cells had lower specific activities of NTE and CbxE than did human neuroblastoma cells; specific activities in the murine cells correlated with specific activities in mouse brain.

3. AChE activities in mouse and human neuroblastoma cells were considerably lower than AChE activities in mouse or hen brain.

4. Inhibition of esterases did not demonstrate interspecies differences for 12 of the 17 anti‐esterase compounds tested with human and mouse neuroblastoma cells.
THE ROLE OF ANGIOTENSIN CONVERTING ENZYME AND NITRIC OXIDE IN THE ENHANCED SYSTEMIC DEPRESSOR RESPONSES TO BRADYKININ IN PREGNANT RATS
Authors: Chu Z. M. , Beilin L. J.
Published: June 2007

1. In the present study we have examined the effects of angiotensin I converting enzyme (ACE) inhibition and nitric oxide (NO) synthesis inhibition on bradykinin (BK) depressor responses in pregnancy in both Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR).

2. Ramipril (10 mg/kg, i.v.) significantly reduced mean blood pressure (MBP) in all animals. Further administration of L‐nitro‐arginine (L‐NOARG, 20 mg/kg, i.v.) increased MBP to a less extent in pregnant WKY and to a similar level in pregnant SHR compared with their non‐pregnant controls (controls), respectively.

3. Systemic depressor responses to BK were increased in pregnant WKY and were unchanged in pregnant SHR as compared with their controls. Ramipril (10 mg/kg, i.v.) potentiated BK responses in all groups, and abolished the differences between pregnant and non‐pregnant WKY. Further administration of L‐NOARG (20 mg/kg, i.v.) did not further influence BK responses in all groups.

4. The results suggest that systemic depressor responses to BK are enhanced in pregnant WKY and unchanged in pregnant SHR. Decreased ACE activity may contribute to enhanced systemic depressor responses to BK in pregnant WKY.
POSTNATAL DEVELOPMENT OF RESPONSES TO AIRFLOW OBSTRUCTION
Authors: Harding Richard , Jakubowska Alexandra E. , McCrabb Graeme J.
Published: June 2007

1. Obstruction of the upper airway could be an initiating factor in the Sudden Infant Death Syndrome (SIDS). Responses to upper airway obstruction include augmentation of respiratory efforts, active dilation of the upper airway and electrocortical arousal. Vulnerable individuals may fail to mount these responses effectively.

2. Respiratory and arousal responses to obstruction of the upper airway have been investigated in newborn lambs. In conscious lambs, nasal obstruction causes a profound augmentation of inspiratory efforts, mild asphyxiation and eventual formation of an oral airway. The ability to establish an oral airway involves both chemoreception and mechanoreception and improves with age.

3. In sleeping lambs, obstruction of tidal airflow leads to progressive hypoxaemia, augmentation of inspiratory efforts, bradycardia and arousal. Arousal occurs earlier and with less hypoxaemia and bradycardia in non‐REM sleep than in REM sleep. Arousal occurs after inspiratory efforts have increased to the same extent during both sleep states, suggesting that mechanoreception, or a sense of inspiratory effort, is important in initiating arousal.

4. Obstruction of nasal tubes tends to cause arousal from sleep earlier, and with less hypoxaemia and less augmentation of inspiratory effort, than when a more compliant face mask is obstructed. This supports the suggestion that mechanoreception, which may be involved in the perception of inspiratory effort, is a determinant of arousal.

5. With increasing postnatal age, lambs become less arous‐able in response to airflow obstruction when in REM sleep. This suggests that lambs may become progressively more vulnerable to the effects of airway obstruction during the immediate newborn period.

6. The ability to respond to upper airway obstruction is well developed at birth in normal lambs. Responses are affected by sleep‐wake states, mode of airflow obstruction and postnatal age. Future studies will determine whether prenatal compromises, such as those thought to have influenced neural development in some SIDS victims, affect the ability of the neonate to respond adequately to upper airway obstruction.
EFFECTS OF LIFESTYLE, COPING AND WORK‐RELATED STRESS ON BLOOD PRESSURE IN OFFICE WORKERS
Authors: Lindquist T. L. , Beilin L. J. , Knuiman M.
Published: June 2007

1. The relative importance of perceived stress compared with coping behaviours and ‘lifestyle’ characteristics known to influence blood pressure were studied in 337 male and 317 female office workers.

2. Males had significantly higher mean systolic (P<0.01; t‐test, 652 d.f.) and diastolic (P<0.01; t‐test, 652 d.f.) blood pressure and unhealthier lifestyles than females, particularly in the areas of alcohol intake (P<0.01; t‐test, 653 d.f.) and diet (P= 0.01; t‐test, 663 d.f.).

3. In males drinking alcohol was correlated to job and home/work stress (P<0.05), and eating more atherogenic foods was correlated to home/work stress (P<0.05).

4. Coping by food and drug consumption was correlated with job and home/work stress (P <0.05) in males; avoidance/ denial coping was correlated with job stress in both males and females (P<0.001) and to home/work stress (P<0.001) in males only. Blood pressure was not correlated with stress in males or females.

5. In age‐adjusted regression analyses body mass index (BMI) and lifestyle (physical inactivity, alcohol consumption and diet) made significant contributions to systolic (P= 0.02) and diastolic (P<0.01) blood pressure and, in separate analyses, coping contributed significantly to diastolic blood pressure (P<0.01) in males. Stress made no additional contribution to blood pressure in either analysis.

6. After including age, BMI, lifestyle and coping in males ‘lifestyle’ still contributed to systolic and diastolic blood pressure and coping made a significant additional contribution to diastolic blood pressure. Neither lifestyle or coping contributed significantly to blood pressure in females.

7. Thus obesity, alcohol, physical activity and diet had dominant effects on blood pressure; while any effects of job stress were indirect and related to maladaptive coping, particularly in males.
PROLACTIN INDUCED ANALGESIA IS DEPENDENT ON ATP SENSITIVE POTASSIUM CHANNELS
Authors: Shewade D. G. , Ramaswamy S.
Published: June 2007

1. The role of ATP sensitive potassium channels in the analgesic activity of prolactin (PRL) was studied in mice using glibenclamide and minoxidil, a blocker and an opener of these channel, respectively.

2. Re‐treatment with glibenclamide attenuated the analgesic activity of PRL while treatment with minoxidil potentiated the activity.

3. It is concluded that PRL, similar to morphine, utilizes ATP sensitive potassium channels in eliciting the analgesic response.
REGIONAL DIFFERENCE OF ENDOGENOUS ATP RELEASE IN THE PULMONARY ARTERY OF RABBITS
Authors: Takeuchi Koichi , Shinozuka Kazumasa , Ishii Reiko , Hashimoto Takao
Published: June 2007

1. The release of adenyl purines such as ATP, ADP, AMP and adenosine, from the pulmonary artery trunk (PAT), extra‐pulmonary artery (EPA) and intrapulmonary artery (IPA) were compared.

2. The amount of basal overflow of adenyl purines from the PAT was significantly smaller than those from EPA and IPA. There was no significant difference between the amount of the overflow from EPA and PAT.

3. Methoxamine, an α1‐adrenoceptor agonist, significantly increased the overflow of adenine nucleotides from the PAT, EPA and IPA, but did not increase those of adenosine. Methoxamine‐induced release of adenyl purines from IPA was significantly larger than those from EPA and PAT.

4. These results suggest that an α,‐adrenoceptor‐mediated mechanism for ATP‐release is not homogeneously distributed in the pulmonary artery and a larger amount of ATP may be released in the peripheral part of the artery.
EFFECTS OF RECOMBINANT HUMAN ERYTHROPOIETIN ON BLOOD PRESSURE AND RENAL FUNCTION IN SHR WITH CHRONIC RENAL FAILURE
Authors: Kohzuki Masahiro , Yasujima Minoru , Kanazawa Masayuki , Yoshida Kazunori , Sato Tokutaro , Abe Keishi
Published: June 2007

1. The effects of chronic administration of erythropoietin (EPO) on blood pressure and renal function in rats with ablation of renal mass were assessed.

2. Spontaneously hypertensive rat were subjected to 5/6 nephrectomy (5/6Nx). Four weeks after the operation, the rats were randomly allocated to vehicle, EPO 20 IU/kg i.p., or EPO 100 W/kg i.p. (both given twice a week) for 4 weeks.

3. Marked anaemia was noted in SHR‐5/6Nx. EPO caused a significant increase in haematocrit at a high dose but not at a low dose. A dose dependent relationship was noted in the EPO‐induced rise in the systolic blood pressure.

4. EPO dose‐dependently increased urinary protein excretion. It also increased blood urea nitrogen and serum creatinine levels.

5. These results suggest that EPO ameliorates anaemia and severely accelerates renal failure in SHR‐5/6Nx. They also suggest that anaemia can be a haemodynamieally favourable adaptation to chronic renal disease and that its correction may have adverse renal haemodynamic and structural consequences.
DIFFERENCES IN CULTURED CARDIAC FIBROBLAST POPULATIONS ISOLATED FROM SHR AND WKY RATS
Authors: Klett Christoph P. R. , Palmer Abraham , Gallagher Ann‐Marie , Rioseco‐Camacho Natalia , Printz Morton P.
Published: June 2007

1. The mechanisms whereby angiotensin converting enzyme inhibitors reverse cardiac remodelling appear to involve angiotensin and/or bradykinin receptors. Previously we reported that cultured rat cardiac fibroblasts express angiotensin II (AII) receptors. In the present study we compared AII receptor binding, gene expression of angiotensinogen and the AII, Subtype 1A (AT1A) receptor, as well as morphological changes induced by selected hormonal treatments in cultured fibroblasts derived from SHRLJ or WKYLJ rats.

2. Fibroblasts were isolated from adult rat left ventricle by either collagenase B or collagenase P digestion. Collagenase B yielded cell preparations from SHRLJ which grew slower than cells from WKYLJ rats and expressed nearly two‐fold fewer AII receptors (compared to WKYLJ) while collagenase P yielded SHRLJ cells with similar binding and growth properties to WKYLJ. A good correlation was observed between receptor binding and AII receptor, type 1A (AT1A) mRNA concentrations. In the presence of steroids collagenase B cells showed a higher tendency to transform towards a preadipocyte cell type, estimated by the formation of lipid containing vacuoles/cell, while collagenase P cells, mainly the SHRLJ type, start to differentiate toward a myofibroblast‐like cell type in the presence of AII, as calculated by the expression of α‐smooth muscle actin.

3. From the results obtained in this study it is evident that a subset of fibroblasts can be isolated from the SHRLJ heart using collagenase B or P which differ in growth rates, AII receptor binding, AT1A and angiotensinogen mRNA levels, morphology and steroid responsiveness when compared to fibroblasts isolated from cardiac WKYLJ tissue.
RECEPTOR DENSITY IN THE RAT HEART FOLLOWING ISCHAEMIA AND PROLONGED REPERFUSION
Authors: de Jong W. , Lukovic L. , Jones C. R. , Petty M. A.
Published: June 2007

1. The free radical scavenger MDL 73,404 decreases infarct size and improves heart performance after myocardial ischaemia and prolonged reperfusion. In the present study the possibility that changes in receptor density might contribute to the MDL 73,404‐induced increase in contractility has been investigated in rats subjected to myocardial ischaemia and 8 days of reperfusion.

2. Both in saline‐ and MDL 73,404‐treated rats a significant decrease in β1‐ and increase in β2‐adrenoceptor densities was apparent in the infarcted tissue.

3. In non‐infarcted septum and right ventricle tissue ischaemia followed by reperfusion tended to increase the density of β2‐adrenoceptors which was significantly increased after MDL 73,404 treatment.

4. The increased density of β2‐receptors in the non‐infarcted tissue may contribute to the MDL 73,404 induced improvement of cardiac performance.
FOETAL METABOLISM, PLACENTAL TRANSFER AND ORIGIN OF GASTRIN RELEASING PEPTIDE IN THE SHEEP
Authors: Shulkes Arthur , Whitley Jane , Hardy Kenneth , Giraud Andrew
Published: June 2007

1. Plasma gastrin relesing peptide (GRP) is elevated in the foetal and maternal circulations of pregnant sheep. To determine the mechanisms for this increase the synthesis, secretion rate, metabolism and placental transfer of GRP were measued.

2. Foetal metabolic clearance rate of GRP was significantly increased (P < 0.05) compared to the non‐pregnant eve (1909 ± 2.6 (s.e.m.) and 11.8 ± 2.0 mL/min per kg, respectively). Production rate of GRP in the foetus was four in the foetus was four‐fold higher than in the non‐pregnant ewe reflecting the combination of the increased basal concentration and metabolic celarance rate in the foetus.

3. Infused GRP did not cross the placenta. However, endogenous GRP was higher in the umbilical vein than in the umbilical artery, suggesting a uteroplacental origin for some of the GRP in the foetal circulation.

4. Gastrin releasing peptide mRNA was synthesized in the pregnant endometrium with lower amounts found in the pregnant myometrium. No GRP mRNA was detected in the amnoin or chorioallantois.

5. The results show that the previously reported increase in foetal concentration of GRP is from foetal and uteroplacental sources and is not a result of immaturity of clearance mechanims but rather from an increased production of GRP. With the demonstation that the uteroplacenatal unit synthesizes and stores GRP, additional studies on the regulation of GRP production from these sources are warranted.
MANUAL DEXTERITY: HOW DOES THE CEREBRAL CORTEX CONTRIBUTE?
Authors: Darian‐Smith Ian , Galea Mary P. , Darian‐Smith Corinna
Published: June 2007

1. Manual dexterity, of great evolutionary significance to the primates, ranges in complexity from the precise opposition of finger and thumb to Brendal playing Mozart. All dexterity depends on a sustained and rapid transfer of sensorimotor information between the cerebral cortex and the cervical spinal cord.

2. Multiple separate corticospinal neuron populations originate from cortical areas four, the supplementary motor area, anterior cingulate, postarcuate, parietal and insular cortex. Each corticospinal neuron population projects in parallel to all spinal segments, and has a distinctive pattern of terminations.

3. Each corticospinal neuron population has a unique thalamic input which can relay particular sensorimotor information from the sense organs, cerebellum and basal ganglia. The overall structural framework of these sensorimotor pathways, with many parallel corticospinal channels, with interconnections in the cerebral cortex and spinal cord to enable crosstalk between the channels, is that needed for parallel distributed processing, which would enable the very rapid transfer of information between the cerebral cortex and spinal cord needed for any sophisticated use of the hand.

4. Hemisection of the cervical spinal cord in the macaque results in an immediate hemiplegia, with subsequent remarkable although incomplete recovery of hand and finger movements. The only direct corticospinal input to the hemicord caudal to the hemisection, even after 3 years, is the ∼ 10% of fibres which cross the midline caudal to the lesion: the fibres ‘spared’ by the hemisection. A matching ‘sparing’ of somatosensory input from the paresed limb also occurs. No regeneration of the interrupted pathways has been visualized using modern tracer techniques.

5. Cervical hemisection permanently reduces the number of parallel channels which transmit information between cortex and spinal cord, but does not reduce their cortical origins nor the neuron populations targeted in the spinal cord. We infer that the content of the information that can be transmitted between the cortex and spinal cord is not greatly changed, but the rate of transmission of this information is sharply reduced, and is the ‘bottleneck’ that limits the complete recovery of dexterity following hemisection. The remarkable recovery that does occur presumably reflects more economic transmission of information by the few spared channels. We guess that this involves substantial synaptic reorganization not visualized by the procedures we have used.
MEMBRANE TRANSPORT AS A DETERMINANT OF THE HEPATIC ELIMINATION OF DRUGS AND METABOLITES
Authors: Evans Allan M.
Published: June 2007

1. The liver is ideally suited for the efficient uptake of drugs from sinusoidal blood. For most drugs, uptake into hepatocytes across the basolateral membrane occurs via passive diffusion, with minimal relaiance on carrier‐mediated transport systems. Often, this passive diffusion is so efficient that uptake is ratelimited by the delivery of the drug to the lvier (i.e. blood flow) rather than membrane transport per se

2. For highly polar molecules, passive diffusion no longer represents an efficient mode of hepatocellular uptake and there is an increased reliance on carrier‐mediated transport systems. For these compounds, membrane transport may dictate the overall efficiency of hepatic elimination.

3. Drug metabolites, particularly conjugated metabolites, such as sulphates and glucuronides, are invariably more polar than their precursors and are more likely to experience hepatocyte membranes as diffusional barriers. In the presence of such a barrier, the hepatocellular disposal of a locally formed metabolite will depend critically on the presence and activity of carrier‐mediated transport systems for sinusoidal efflux and biliary excretion. Transporters of current interest include P‐glycoproteins, which are responsible for the biliary excretion of a rage of organic cations, and the canalicular multispecific organic anion transporter.

4. Intracellular trapping of hepatically formed metabolites, secondary to low membrane permeability, is clinically important as many metabolites are potentially hepatotoxic and/or capable of interfering with the hepatic transport of endogenous compounds or other durgs and metabolites. In addition, if the metabolite is unstable, intracellular accumulation can lead to the regeneration of the precursor and ‘futile cycling’ within hepatocytes.

5. An increased understanding of the factors influencing the intracellular concentrations of drugs and hepatically formed metabolites in the lvier will improve our ability to specifically treat liver disorders, such as hepatocellular carcinoma and malaria, and minimize the risk of hepatotoxicity from drugs and other xenobiotics.
PERMEABILITY OF MYOCARDIAL CAPILLARIES TO HYDROPHILIC DRUGS: THE PARACELLULAR PATHWAY
Authors: Morgan Denis J.
Published: June 2007

1. As the majority of drug molecules are relatively small and lipophilic, capillary uptake in those regions with a continuous endothelium, such as the heart, has generally been regarded as taking place by flow‐limited transcellular capillary transport. Little attention has been paid to myocardial paracellular capillary transport of hydrophilic drugs, despite efficient transport of hydrophilic solutes, such as sucrose, inulin and EDTA, by this route.

2. The paracellular pathway is formed by the cleft between adjacent endothelial cells and its permeability properties are determined by the tight junction, a region of restricted diameter within the cleft. Paracellular capillary permeability is modulated by circulating macromolecules, such as albumin, by an unknown mechanism thought to involve the intra‐endothelial cell Ca2+ concentration.

3. Studies in perfused rat heart have shown that capillary permeability of quinidine does not vary when perfusate pH is varied from 7.0‐8.0, suggesting that capillary transport involves the ionized as well as unionized moiety. Addition of albumin to the perfusion medium reduced quindine capillary permeability, which is consistent with paracellular transport of quinidine ions.

4. Paracellular transport increases in capillary inflammation. Therefore, if there is significant paracellular transport of hydrophilic drugs, an increase in uptake of such drugs in areas of inflamed myocardium associated with acute myocardial infarction would be expected to result.
IRINOTECAN (CPT‐11): A BRIEF OVERVIEW
Authors: Rivory Laurent P.
Published: June 2007

1. Irinotecan (also known as CPT‐11) is a water soluble, semi‐synthetic analogue of 20(S)camptothecin (CPT) with promising activity against a range of tumour types.

2. As with all other active analogues of CPT, irinotecan causes cell toxicity by stabilizing a ternary complex between the nuclear enzyme topoisomerase I (topo I) and doublestranded DNA. This leads to replication fork‐arrest, double DNA strand breaks and, possibly, illegitimate recombination of vital genes.

3. This activity is much greater for its metabolite SN‐38 and irinotecan is widely considered to be a prodrug of SN‐38.

4. The anti‐topo I activity of CPT is stereoselective at C‐20 and irinotecan is synthesized from 20(S)CPT to ensure maximal activity. In aqueous solutions, the lacton ring of CPT under goes reversible and spontaneous hydrolysis to a ring‐opened and inactive carboxylate form. In patients, it has been shown that the lactone is the predominant form of SN‐38 in plasma, whereas the opposite is true for irinotecan.

5. The transformation of irinotecan to SN‐38 is catalysed by carboxylesterases. However, this conversion appears relatively inefficient in man.

6. Irinotecan and SN‐38 show evidence of other metabolic reactions (type I and II), some of which could be subject to pharmacogenetic variablity.

7. Therapy with irinotecan is associated with unusual toxicities, such as an acute cholinergic‐like syndrome and delayed onset diarrhoea. Although the mechanism for the diarrhoea remains to be defined, the cholinergic toxicity appears to be due to an inhibition of acetylcholinesterase.
POTASSIUM CHANNELS IN VASCULAR SMOOTH MUSCLE
Authors: Brayden Joseph E.
Published: June 2007

1. Regulation of smooth muscle membrane potential through changes in K+ channel activity and subsequent alterations in the activity of voltage‐dependent calcium channels is a major mechanism of vasodilation and vasoconstriction, both in normal and pathophysiological conditions. The contribution of a given K+ channel type to this mechanism of vascular regulation depends on the vascular bed and species examined.

2. Multiple K+ channels are present in most vascular smooth muscle cells and these different K+ channels play unique roles in regulating vascular tone. Voltage‐dependent K+ (Kv) channels are activated by depolarization, may contribute to steady state resting membrane potential and are inhibited by certain vasoconstrictors. Calcium‐activated K+ (KCa) channels oppose the depolarization associated with intrinsic vascular tone and are activated by some endogenous vasodilators. Small‐conductance, apamin‐sensitive KCa channels may be activated by endothelium‐derived hyperpolarizing factor. ATP‐sensitive K+ (KATP) channels are activated by pharmacological and endogenous vasodilators. Inward rectifier K+ (Kir) channels are activated by slight changes in extracellular K+ and may contribute to resting membrane potential.

3. Membrane potential and diameter are determined, in part, by the integrated activity of several K+ channels, which are regulated by multiple dilator and constrictor signals in vascular smooth muscle.
EVIDENCE FOR A RENOMEDULLARY VASODEPRESSOR HORMONE
Authors: Thomas Collen J. , Woods Robyn L. , Evans Roger G. , Alcorn Daine , Christy Irene J. , Anderson Warwick P.
Published: June 2007

1. Recent physiological experiments have established that increasing the perfusion pressure of the kidney causes the release of a vasodepressor substance from the renal medulla.

2. The substance is not a platelet activating factor, a prostaglandin or nitric oxide and the vasodepressor response to increased renal perfusion pressure is not due simply to inhibition of renin release.

3. The mechanisms by which the renomedullary vasodepressor substance lowers arterial pressure remain to be determined. Sympathoinhibition may account for part of the response, but the hypotension still occurs in autonomic ganglion blocked animals.

4. The source of the substance appears to be the renomedullary interstitial cells, though the control of the production and release of the substance remain to be determined.

5. The substance may be a lipid but it is yet to be fully isolated and identified.

6. The threshold for release of the substance appears to be close to normal resting arterial blood pressure.

7. Despite strong evidence that the renal medulla releases a vasodepressor hormone in response to increased renal perfusion pressure, much is still to be determined regarding the physiology of this hormone and its involvement in the aetiology of hypertension.
NEUROHUMORAL ACTIVATION IN HEART FAILURE: ROLE OF PARAVENTRICULAR NUCLEUS
Authors: Patel Kaushik P. , Zhang Kun
Published: June 2007

1. A number of neurohumoral processes are activated in heart failure (HF), including an increase in the plasma concentration of noradrenaline.

2. Few studies have been performed to examine the role of the central nervous system (CNS) in the activation of sympathetic outflow during HF. In the present paper we review the limited studies performed to examine the role of the CNS in the activation of sympathetic outflow, with particular emphasis on our recent study that examined the activity of discrete regions of the brain as assessed by histological localization and photodensitometric quantification of the metabolic enzyme hexokinase during HF.

3. There were significant increases in hexokinase activity in the parvocellular (pPVN) and magnocellular (mPVN) divisions of the paraventricular nucleus of the hypothalamus and in the locus coeruleus (LC) in rats with HF. No changes in hexokinase activity were observed in the median preoptic area, supraoptic nucleus (SON) or posterior hypothalamus.

4. We conclude that HF is associated with changes in specific areas in the brain and that alterations in the activation of neurons in the pPVN, mPVN and LC are likely to be related to alterations in vasopressin production, blood volume regulation and sympathoexcitation observed in the HF state.
OESTROGEN AND ENDOTHELIAL CELL ANGIOGENIC ACTIVITY
Authors: Schnaper H William , McGowan Kelly A. , Kim‐Schulze Seunghee , Cid Maria C.
Published: June 2007

1. Increasing evidence suggests that oestrogens protect women from cardiovascular disease during their reproductive years. Although most studies by others have examined the effect of oestrogen on vascular smooth muscle cells, we have evaluated the effect of oestrogen on the angiogenic behaviour of endothelial cells.

2. Oestrogen enhances endothelial cell attachment, proliferation, migration and organization into capillary‐like structures in vitro. In vivo, oestrogen augments experimental angiogenesis.

3. As the same endothelial cell behaviours that are important in angiogenesis in small vessels are also important in the healing response to injury of large vessels, it is likely that the effect of oestrogen on these endothelial cell functions contributes significantly to the cardioprotective effects of oestrogen in women.
INDOMETHACIN DAMAGE TO RAT GASTRIC MUCOSA IS MARKEDLY DEPENDENT ON LUMINAL pH
Authors: Elliott Susan L , Ferris Rebekah J , Giraud Andrew S , Cook Gregory A , Skeljo Maryanne V , Yeomans Neville D
Published: June 2007

1. There is good evidence that acid is a prerequisite for aspirin induced gastric mucosal damage; however, there is inconsistent information available for non‐salicylate NSAID. The present study examines the effect of gastric luminal pH on indomethacin‐induced gastric mucosal damage.

2. Macroscopic gastric mucosal damage induced by indomethacin (40 mg/kg) or vehicle, administered intraduodenally to male pylorus‐ligated rats (n= 5–10/group), was assessed at four different levels of luminal pH (2,4,5.5 and 7) by means of digital planimetry.

3. There was a marked difference in the extent of damage induced by indomethacin at the different luminal pH levels (P= 0.001). There was no difference between the percentage of haemorrhagic lesions at pH 2 and 4 (P>0.05), nor between pH 5.5 and 7 (P>0.05). However, the damage at the high levels of luminal acidity (pH 2 and 4) was strikingly different from that at pH 5.5 and 7 (P<0.05).

4. Gastric mucosal damage induced by indomethacin, a non‐salicylate NSAID, is augmented by the presence of high concentrations of acid in the gastric lumen. The main finding, that indomethacin injury is markedly less above pH 4, may have clinical implications in the prevention of NSAID‐induced mucosal injury.
ALTERED REACTIVITY OF THE INFERIOR VENA CAVA TO NORADRENALINE AND ACETYLCHOLINE FOLLOWING THE BLOCKADE OF EDRF‐BIOSYNTHESIS WITH NG‐NITRO‐l‐ARGININE METHYL ESTER
Authors: Schwarzacher Severin , Krejcy Kurt , Ferber Wolfgang , Weidinger Franz
Published: June 2007

1. Endothelium‐derived relaxing factor (EDRF) has been shown to influence arterial tone, but controversial results have been obtained studying veins. The present study was performed to determine the importance of EDRF for the inferior vena cava in the rabbit and whether blockade of the synthesis of EDRF with NG‐nitro‐l‐arginine methyl ester may influence the reactivity of the inferior vena cava to noradrenaline.

2. The inferior vena cava was excised in six New Zealand white rabbits and 12 rings were prepared for organ bath studies. Concentration‐response curves were constructed for acetylcholine (10−9‐10−4mol/L) and noradrenaline (10−9‐10−4mol/L) before and following the administration of NG‐nitro‐l‐arginine methyl ester.

3. All rings showed concentration‐dependent relaxation to acetylcholine (mean maximum: 57 ± 9%) following precon‐traction with noradrenaline (EC50: 10−6mol/L). Following NG‐nitro‐l‐arginine methyl ester, this dilation was significantly reduced to a mean maximum relaxation of 13 ± 6% (P<0.01).

4. Contraction of the inferior vena cava to increasing doses of noradrenaline reached a maximum of 5.8 ± 2.8 g before NG‐nitro‐l‐arginine methyl ester (basal tension 1.0 ± 0.5 g). NG‐nitro‐l‐arginine methyl ester did not affect basal tension, but the constrictor response to noradrenaline was enhanced significantly to a maximum of 9.1 ± 3.8 g (P<0.01).

5. Although it cannot be ascertained definitively from the present results, it is suggested that EDRF is mediating vasodilation of the inferior vena cava and that this vasoactive agent may also contributes significantly to the modulation of the reactivity to catecholamines.
Proceedings of the Symposium ‘Angiotensin AT1 Receptors: From Molecular Physiology to Therapeutics’: ROLE OF AT1 RECEPTORS IN THE CENTRAL CONTROL OF SYMPATHETIC VASOMOTOR FUNCTION
Authors: Head Geoffrey A
Published: June 2007

In a number of species, high concentrations of angiotensin II (AngII) receptors have been found in the rostral ventrolateral medulla (RVLM) in the hindbrain, which is an important region involved in the modulation of sympathetic vasomotor tone. The present review describes studies in which the contribution of angiotensin receptors in the brainstem to cardiovascular regulation, in particular sympathetic vasomotor reflexes, has been examined in conscious and anaesthetized rabbits.

In conscious rabbits, fourth ventricular infusions of AngII produced dose‐dependent pressor responses as doses 400 times less than equipressor intravenous doses. Chronic baroreceptor denervation increased the sensitivity to AngII by 1000‐fold. Administration of prazosin i.v. blocked the pressor response, suggesting that the mechanism involved sympathetic vasoconstriction.

The pattern of haemodynamic changes in response to AngII injected into the fourth ventricle (4V) involved decreased total peripheral conductance and mesenteric conductance, but a rise in hindlimb conductance. Sinoaortic denervation changed the hindlimb fall in conductance to an increase, suggesting that muscle vasomotor pathways were particularly inhibited by baroreceptor feedback mechanisms.

In anaesthetized rabbits, infusion of AngII into the RVLM increased blood pressure and transiently increased resting renal sympathetic nerve activity. The renal sympathetic baroreflex curves were shifted to the right and the upper plateau of the sympathetic reflex increase was markedly increased.

The pressor actions of 4V AngII were blocked by administration of a peptide antagonist injected into the RVLM or by the angiotensin AT1 antagonist losartan injected into the 4V. These results suggest that mainly AT1 receptors are involved and that the RVLM is a likely candidate site for the modulation of the renal sympathetic baroreflex.

Losartan administration into the 4V in conscious rabbits increased resting renal sympathetic tone and enhanced renal sympathetic baroreflex and chemoreflexes.

Our studies suggest that there are sympathoexcitatory AT1 receptors in the RVLM accessible to AngII from the cerebrospinal fluid. In addition, an AT1 receptor pathway normally inhibits the sympathoexcitation produced by baroreceptor unloading or chemoreceptor activation. The effect of losartan suggests that there is greater tonic activity within the sympathoinhibitory pathways. These two actions suggest that angiotensin receptors in the brainstem modulate sympathetic responses to specific afferent inputs, thus forming part of a potentially important mechanism for the integration of characteristic autonomic response patterns.
AUTORADIOGRAPHIC LOCALIZATION OF ACTIVE RENIN IN THE JUXTAGLOMERULAR APPARATUS OF THE DOG KIDNEY: EFFECTS OF SODIUM INTAKE
Authors: Zhuo Jialong , Anderson Warwick P , Song Keifu , Mendelsohn Frederick AO
Published: June 2007

1. The effects of dietary sodium intake on active renin binding in the juxtaglomerular apparatus (JGA) of superficial and juxtamedullary cortex of the dog kidney were examined by quantitative in vitro autoradiography using a radiolabelled renin inhibitor [125I]‐H77, which has high affinity for dog renin.

2. Changes in sodium intake resulted in marked alterations of active renin binding in the radiolabelled JGA. In comparison with the control kidney (190.8 ± 7.7 Bq/mm3), a higher density of binding occurred in the labelled JGA of sodiumdepleted kidney (277.7 ± 6.2 Bq/mm3), while a lower density of binding was found in the labelled JGA of sodium‐loaded kidney (99.3 ± 7.4 Bq/mm3).

3. Active renin binding in the labelled JGA was significantly higher in superficial JGA than in their juxtamedullary counterparts, irrespective of sodium intake.

4. Pre‐incubation with trypsin (0.5mg/mL), a procedure known to activate prorenin, markedly increased active renin binding in the labelled JGA of control (+∼ 35%; P < 0.01), and sodium‐loaded kidneys (+∼ 75%; P < 0.01), but had little effect on binding in the labelled JGA of the sodium‐depleted kidney (± 5–10%; NS). The proportions of active renin as a percentage of total renin were 60, 75 and 95% in the labelled JGA of sodium‐loaded, control, and sodium‐depleted kidneys, respectively.

5. Emulsion microscopic autoradiography revealed that the binding was exclusively localized in the JGA, including the afferent and efferent arterioles, macula densa and extraglomerular mesangium. Labelling extended to the interlobular arteries in sodium depleted kidney.

6. These results indicate that autoradiography combined with the in vitro binding of radiolabelled renin inhibitors may provide a useful tool to measure active and prorenin renin and thereby study the physiological regulation of renin in the kidney.