bluuebunny/crossref_metadata_2025 huggingface dataset:
CEREBROVASCULAR CONTRACTILITY AFTER CLOT REMOVAL IN MONKEY SUBARACHNOID HAEMORRHAGE
Authors: Tsuji Tsutomu , Cook David A , Weir Bryce Ka , Handa Yuji , Chiba Shigetoshi , Kobayashi Shigeaki
Published: March 2003

1. The effects of mechanical clot removal during early surgery on pharmacological cerebrovascular reactivity after subarachnoid haemorrhage (SAH) were investigated in the monkey.

2. Contractions to potassium chloride, 5‐hydroxytryptamine and noradrenaline in rings of proximal parts of middle cerebral arteries (MCP), surrounded with clot, and basilar arteries (BAP), far from the clot, were examined 7 days after SAH, in which an autologous blood clot was bilaterally placed around major cerebral arteries.

3. Compared with the sham‐operated group, contractions in the clot removal groups at 48 and 72 h after SAH were reduced in MCP and enhanced in BAP.

4. These results suggest that divergent vascular contractility may occur according to the distance between artery and clot if the clot is removed later than 48 h after SAH.
SHORT‐ AND LONG‐TERM EFFECTS OF GLYCYRRHIZIC ACID IN REPETITIVE STRESS
Authors: Ainsah O , Nabishah Bm , Osman Cb , Khalid Bak
Published: March 2003

1. This study was carried out to determine the effect of short‐term and long‐term ingestion of glycyrrhizic acid on the response to 2 h of restraint stress by measuring locomotor activity and plasma corticosterone levels.

2. Male Sprague‐Dawley rats were randomly assigned into four groups, each group having eight rats. Group 1 (control) was given ordinary tap water, while groups 2 (short term), 3 and 4 (both long term) were given tap water containing 1 mg/mL glycyrrhizic acid to drink for 10 days, 4 weeks and 9 weeks, respectively. All the rats were subjected to 2 h of restraint stress and the locomotor activity assessed using an activity test in an open field arena followed by blood sampling to determine the plasma corticosterone level. These procedures were repeated daily for 14 days.

3. The basal locomotor activity scores for rats given glycyrrhizic acid for 10 days or 4 weeks were similar to those of controls; however, that of the rats treated long term with glycyrrhizic acid was significantly lower (21.0 ± 3.0 squares crossed; P < 0.0005). Following the first period of restraint stress there was a highly significant decrease in locomotor activity, which remained significantly lower until the seventh and subsequent periods, indicating an adaptation to the repeated stress had occurred. Although the decrease in locomotor activity was partially blocked and adaptation to repetitive stress was enhanced in the rats given glycyrrhizic acid for 10 days, this was not seen in rats treated with glycyrrhizic acid for 4 or 9 weeks. The corticosterone levels in control rats were significantly elevated for 4–5 days following the exposure to repetitive stress but decreased gradually from day 7 onwards. However, both short‐ and long‐term glycyrrhizic acid‐treated rats had higher plasma corticosterone levels than the controls (P < 0.05).

4. In conclusion, repetitive restraint stress caused decreased locomotor activity associated with increased plasma corticosterone levels, both of which, in normal rats, decreased with adaptation to stress. The stress response was partially blocked and adaptation enhanced in rats given glycyrrhizic acid for 10 days, but not in rats given glycyrrhizic acid for 4 and 9 weeks. Glycyrrhizic acid ingestion caused high plasma corticosterone.
PAEONIFLORIN REVERSES GUANETHIDINE‐INDUCED HYPOTENSION VIA ACTIVATION OF CENTRAL ADENOSINE A1 RECEPTORS IN WISTAR RATS
Authors: Cheng JUEI‐TANG , Wang CHIA‐JANE , Hsu FENG‐LIN
Published: March 2003

SUMMARY

1. Intravenous injection of paeoniflorin, a glycoside purified from the root of Paeonia lactiflora, reversed guanethidine‐induced hypotension in Wistar rats.

2. Pretreatment with the adenosine A1 receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine inhibited this effect of paeoniflorin in a dose‐dependent manner.

3. The action of paeoniflorin was not modified by 8‐(p‐ sulfophenyl)theophylline, the polar antagonist of the adenosine A1 receptor, which is not able to enter the central nervous system.

4. We conclude that paeoniflorin can reverse guanethidine‐induced hypotension via activation of adenosine A1 receptors in the brain of Wistar rats.
EXPERIMENTAL THERAPY OF A PLATELET‐ACTIVATING FACTOR ANTAGONIST (GINKGOLIDE B) ON PHOTOCHEMICALLY INDUCED THROMBOTIC CEREBRAL ISCHAEMIA IN TREE SHREWS
Authors: Li SHUQING , Meng QIANG , Zhang LINENG
Published: March 2003

1. The aim of the present study was to investigate the effects of a platelet‐activating factor (PAF) antagonist (ginkgolide B; GB) on brain oedema, ion homeostasis, monoamine neurotransmitter disturbances in ischaemic penumbra and the neuroprotective mechanisms of the PAF antagonist.

2. Photochemically induced thrombotic cerebral ischaemia in tree shrews was used as the experimental model and changes in histopathology and the content of monoamine neurotransmitters (measured by a spectrofluorometer), water content (measured by a specific gravimetric method), sodium and calcium (measured by an atomic absorption spectrophotometer) in the penumbra were observed.

3. Results show that content of noradrenaline (NA), dopamine (DA) and 5‐hydroxytryptamine (5‐HT) decreased in the penumbra, while 5‐HT metabolite 5‐hydroxyindole‐3‐acetic acid, sodium, calcium and water contents increased markedly (P < 0.01) after photochemical reaction.

4. In tree shrews treated with GB (5 mg/kg, i.v.) 6 h after photochemical reaction, cortical NA, DA and 5‐HT contents recovered to control levels and water and calcium contents decreased significantly (P < 0.01).

5. The results suggest that PAF may play an important role in inducing calcium overload, brain oedema and secondary brain damage in penumbra and that GB produces its neuroprotective effects by inhibiting the pathological manifestation of PAF.
THE ‘ABC’ OF GABA RECEPTORS: A BRIEF REVIEW
Authors: Chebib Mary , Johnston Graham A R
Published: March 2003

1. In the mammalian central nervous system, GABA is the main inhibitory neurotransmitter. GABA is a highly flexible molecule and, thus, can exist in many low‐energy conformations. Conformationally restricted analogues of GABA have been used to help identify three major GABA receptors, termed GABAA, GABAB and GABAC receptors.

2. GABAA and GABAC receptors are members of a superfamily of transmitter‐gated ion channels that include nicotinic acetylcholine, strychnine‐sensitive glycine and 5HT3 receptors. GABAA receptors are hetero‐oligomeric Cl– channels that are selectively blocked by the alkaloid bicuculline and modulated by steroids, barbiturates and benzodiazepines. To date, 16 human GABAA receptor cDNA have been cloned.

3. GABAB receptors are seven transmembrane receptors that are coupled to G‐proteins and activate second messenger systems and Ca2+ and K+ ion channels. To date, three GABAB receptor proteins have been cloned and these resemble metabotropic glutamate receptors. GABAB receptors are hetero‐oligomeric receptors made up of a mixture of a combination of the subunits. These receptors are selectively activated by (–)‐baclofen and CCGP27492 and are blocked by phaclofen, the phosphonic acid analogue of baclofen.

4. In contrast, GABAC receptors represent a relatively simple form of transmitter‐gated Cl– channel made up of a single type of protein subunit. Two human GABAC receptor cDNA have been cloned. These receptors are not blocked by bicuculline nor are they modulated by steroids, barbiturates or benzodiazepines. Instead, GABAC receptors are selectively activated by the conformationally restricted analogues of GABA in the folded conformation cis‐4‐aminocrotonic acid and (1
S,2
R)‐2‐(aminomethyl)‐1‐carboxycyclopropane. (1,2,5,6‐Tetrahydropyridine‐4‐yl)methylphosphinic acid, a methylphosphinic acid analogue of GABA in a partially folded conformation, is a selective antagonist at GABAC receptors.
SEDATION WITH PROMETHAZINE PROFOUNDLY AFFECTS SPONTANEOUS AIRWAY PROTECTION IN SLEEPING NEONATAL PIGLETS
Authors: McKelvey George M , Post Elizabeth J , Jeffery Heather E , Wood Andrew Kw
Published: March 2003

1. Phenothiazine use in infants has been implicated in apparent life‐threatening events, sleep apnoea and Sudden Infant Death Syndrome.

2. The aim of this study was to investigate the cumulative effects of a commonly used antihistamine medication containing promethazine on airway protective mechanisms and cardiorespiratory responses in 42 healthy neonatal piglets (21 naturally sleeping, 21 sedated sleeping).

3. Sedated piglets were given 1.5 mg/kg, p.o., promethazine 2 h prior to each recording session. Control animals slept naturally with no sedative given. On three consecutive days in all piglets, physiological recordings were made during sleep; on at least one of these days, simultaneous physiological and radiological observations were made.

4. Following sedation, sleep time and time in active sleep were increased significantly (P < 0.01). The spontaneous occurrence of swallowing, arousal, body movement, gastro‐oesophageal reflux and apnoea was compared between naturally and sedated sleeping piglets. Sedation with promethazine significantly decreased the spontaneous occurrence of swallowing (P < 0.05) and arousal (P < 0.05) and increased the occurrence of both central (P < 0.05) and obstructive sleep apnoea (P < 0.0001).

5. By the third day, a cumulative effect of promethazine was seen; the rate of swallowing and body movement significantly decreased (P < 0.01).

6. In summary, a low dose of promethazine profoundly altered sleep characteristics, airway protective mechanisms and cardiorespiratory responses in normal healthy sleeping piglets. Continued use of promethazine over several days may attenuate airway protective mechanisms to a potentially life‐threatening degree. Our findings support continued caution in the use of promethazine‐containing medications for the sedation of infants.
INHIBITORY EFFECT OF NITRIC OXIDE ON THE RENIN–ANGIOTENSIN SYSTEM IN DAHL SALT‐SENSITIVE RATS
Authors: Kasuya Akira , Satoh Sachi , Yoshida Makoto , Hisa Hiroaki , Suzuki‐Kusaba Mizue , Satoh Susumu
Published: March 2003

1. To explore the role of nitric oxide (NO) in the regulation of the renin–angiotensin system (RAS) in Dahl salt‐sensitive (DS) rats, the effects of NG‐nitro‐
L‐arginine methyl ester (
L‐NAME) on plasma renin activity (PRA), and concentrations of angiotensin (Ang)I and AngII in the plasma, aorta and kidney were investigated in DS and Dahl salt‐resistant (DR) rats.

2. NG‐Nitro‐
L‐arginine methyl ester (12–18 mg/kg per day) administration for 1 week increased mean arterial pressure (MAP) in DS and DR rats fed a 0.3% NaCl diet and in DR rats fed an 8% NaCl diet compared with corresponding vehicle (water)‐treated groups. However,
L‐NAME administration did not change MAP in DS rats fed an 8% NaCl diet.

3. NG‐Nitro‐
L‐arginine methyl ester administration increased PRA in DS rats fed an 8% NaCl diet, but not in DR rats fed an 8% NaCl diet. NG‐Nitro‐
L‐arginine methyl ester administration increased AngI and AngII concentrations in plasma, aorta and kidney only in DS rats fed an 8% NaCl diet. The ratio of AngI to AngII did not change following
L‐NAME administration in any rats.

4. These results suggest that NO has an inhibitory role on renin release in DS rats fed a high‐salt diet.
ANGIOTENSIN II IN HUMAN VEINS: DEVELOPMENT OF RAPID DESENSITIZATION AND EFFECT OF INDOMETHACIN
Authors: Harada Kazuhiro , Ohmori Masami , Kitoh Yasuhiko , Sugimoto Koh‐ichi , Fujimura Akio
Published: March 2003

1. The present study investigated whether rapid desensitization (tachyphylaxis) develops after exposure of human hand veins to angiotensin (Ang)II and whether pretreatment with indomethacin affects its development.

2. Venoconstrictor responses to increasing (2–256 ng/min) and constant (50 ng/min) doses of AngII and noradrenaline (NA) infusion were obtained in six healthy male subjects using the dorsal hand vein technique. After pretreatment with indomethacin and placebo, venoconstrictor responses to 50 ng/min AngII infusion were obtained in eight healthy male subjects.

3. The maximal mean (±SD) venoconstrictor response to NA (obtained with 256 ng/min NA) was 93.1±4.7%, whereas that to AngII (obtained with doses between 16 and 128 ng/min) was 43.8±12.2%. Continuous infusion of NA induced constant venoconstriction, whereas the venoconstrictor response to AngII peaked 3 min after the beginning of infusion and, thereafter, was attenuated.

4. Venoconstriction in response to constant AngII infusion after indomethacin pretreatment was significantly larger than that after placebo from 6 to 18 min after the initiation of infusion.

5. These findings show that rapid desensitization to AngII develops in human hand veins and this is compatible with the hypothesis that vasodilator prostaglandins are involved in the development of this desensitization.
ROLE OF cAMP IN THE EFFECTS OF K+ ON THE STEROIDOGENESIS OF ZONA GLOMERULOSA CELLS
Authors: Tait Jf , Tait Sas
Published: March 2003

1. Investigations of the role of cAMP in the stimulation of the steroidogenesis of zona glomerulosa (ZG) cells by increased extracellular K+ concentration are reviewed.

2. Possible reasons for discrepancies in the results of different investigators on whether K+ increases the cAMP content or output of ZG tissue or dispersed cells are discussed.

3. The concentration of cAMP in the incubating media of ZG tissue or cells, rather than their cAMP content, seems to respond more sensitively to stimulation by extracellular K+, as was also found for adrenocorticotropic hormone stimulation of zona fasciculata–reticularis cells.

4. The addition of the phosphodiesterase inhibitor 1‐methyl‐3‐isobutylxanthine (IBMX) to incubations with the aim of increasing the sensitivity of the response in cAMP to extracellular K+ in ZG cells may give rise to effects, probably non‐specific, which actually inhibit the measured response.

5. The immediate stimulation in the steroidogenesis of ZG cells with raised extracellular K+ is probably mostly due to the direct effect of increases in cytoplasmic Ca2+ (arising from increases in Ca2+ influx) on mitochondrial processes. However, increases in cAMP may prolong the stimulation of steroidogenesis by increased extracellular K+. This increased cAMP is probably due to stimulation of adenylyl cyclase activity.

6. It has been concluded that the increase in Ca2+ influx output after rises in the extracellular K+ concentration of ZG cells is responsible for most of the increase in cAMP.

7. According to one group of investigators, there is weak stimulation of phospholipase C (PLC) activity after increasing the extracellular K+ concentration of rat ZG cells.

8. If there is such a stimulation of PLC activity, it seems that the action of increased extracellular K+ can potentially involve all known mechanisms for the stimulation of steroidogenesis in endocrine cells. The common primary event is probably the increase in Ca2+ influx. The relative importance of these various potential mechanisms may depend on the particular in vitro conditions used.
XENOTRANSPLANTATION: APPLICATION OF DISEASE RESISTANCE
Authors: Mueller Yvonne M , Davenport Colleen , Ildstad Suzanne T
Published: March 2003

1. Organ transplantation is now clinically routine for patients with end‐stage organ failure. One major limitation in transplantation is chronic rejection involving the loss of the graft despite the use of immunosuppressive agents. Haematopoietic stem cell (HSC) chimerism, achieved through bone marrow transplantation (BMT), induces donor‐specific tolerance to transplanted organs and prevents chronic rejection.

2. A second major limitation to organ transplantation is the donor shortage. Xenotransplantation, the transplantation of organs between different species, would have the ability to increase the availability of donor organs.

3. Current immunosuppressive therapies do not prevent the rejection of xenografts. Therefore, the only reliable method for achieving donor‐specific tolerance to xenografts may require HSC chimerism.

4. In order to justify the use of BMT to induce transplantation tolerance in patients with non‐life‐threatening diseases, the morbidity and mortality associated with current conditioning regimens must be addressed.

5. The use of partial conditioning regimens to promote engraftment of xenogeneic HSC and the development of donor‐specific tolerance may eventually make xenotransplantation in humans a clinical reality.

6. Additional advantages of xenotransplantation are the ability to genetically engineer the donor xenograft and resistance of some xenografts to infection by human viruses because of the species specificity of most viruses.

7. The clinical application of disease resistance for HIV and hepatitis B virus is the focus of the present review.
CURRENT STATUS OF XENOTRANSPLANTATION*
Authors: Platt Jl , Nagayasu T
Published: March 2003

1. The transplantation of organs and tissues from animals into humans (i.e. xenotransplantation) has been a long sought objective to allow xenotransplantation to achieve its full impact in the clinical practice of medicine.

2. The main hurdles to the application of xenotransplantation are the immunological reaction of the recipient against the transplant, the functional limitations of tissues and organs in biogenetically disparate recipients and the possibility of transferring infectious organisms from the graft into the recipient.

3. Advances in a variety of fields have shed new light on these hurdles and have given rise to potential solutions and prospects for the clinical application of xenotransplant and are summar‐ized in the report that follows.
Synaptic Control Of Motoneuron Excitability In Rodents: From Months To Milliseconds
Authors: Funk Gd , Parkis Ma , Selvaratnam Sr , Robinson Dm , Miles Gb , Peebles Kc
Published: March 2003

1. Motoneurons (MN) shape motor patterns by transforming inputs into action potential output. This transformation, excitability, is determined by an interaction between synaptic inputs and intrinsic membrane properties. Excitability is not static, but changes over multiple time scales. The purpose of the present paper is to review our recent data on synaptic factors important in the dynamic control of MN excitability over time scales ranging from weeks to milliseconds.

2. Developmental changes in modulation of MN excitability are well established. Noradrenergic potentiation of hypoglossal (XII) MN inspiratory activity in rhythmically active medullary slice preparations from rodents increases during the first two postnatal weeks. This is due to increasing α1‐ and β‐adrenoceptor excitatory mechanisms and to a decreasing inhibitory mechanism mediated by α2‐adrenoceptors. Over a similar period, ATP potentiation of XII inspiratory activity does not change.

3. Motoneuron excitability may also change on a faster time scale, such as between different behaviours or different phases of a behaviour. Examination of this has been confounded by the fact that excitatory synaptic drives underlying behaviour can obscure smaller concurrent changes in excitability. Using the rhythmically active neonatal rat brain‐stem–spinal cord preparation, we blocked excitatory inspiratory drive to phrenic MN (PMN) to reveal a reduction in PMN excitability specific to the inspiratory phase that: (i) arises from an inhibitory GABAergic input; (ii) is not mediated by recurrent pathways; and (iii) is proportional to and synchronous with the excitatory inspiratory input. We propose that the proportionality of the concurrent inhibitory and excitatory drives provides a means for phase‐ specific modulation of PMN gain.

4. Modulation across such diverse time scales emphasizes the active role that synaptic factors play in controlling MN excitability and shaping behaviour.
Comparative Effect Of Flunarizine In Two Animal Models Of Stroke
Authors: El‐Sabban F , Edmonds Hl Edmonds
Published: March 2003

1. A common ‘stroke model’, the rat middle cerebral artery occlusion preparation, was used to compare photocoagulation with mechanical occlusion.

2. Areas of cerebral infarction and of vascular leakage were compared using these two methods. The general pattern of damage was similar, with central infarcted areas surrounded by larger vascular leakage areas.

3. The two models differed in the extent of their vascular leakage areas and in their response to the cerebroprotective agent flunarizine.

4. We conclude that the two models are not equivalent, probably because they do not damage the vascular endothelium to the same degree.
Macromolecular Crystallography As A Tool For Investigating Drug, Enzyme And Receptor Interactions
Authors: Oakley Aaron J , Wilce Matthew Cj
Published: March 2003

1. Protein crystallography is an essential tool for the discovery and investigation of pharmacological interactions at the molecular level. It allows investigators to directly visualize the three‐dimensional structures of proteins, including enzymes, receptors and hormones.

2. Increasingly, knowledge of these interactions is being used in the drug‐discovery process. This is popularly called structure‐based drug design. The desired drug could be an enzyme inhibitor or an agonist that mimics endogenous transmitters or hormones.

3. Once the 3‐D structure of a pharmacologically relevant target is known, computational processes can be used to search databases of compounds to identify ones that may interact strongly with the target. Lead compounds can be improved using the 3‐D structure of the complex of the lead compound and its biological target.

4. The present review describes the processes involved in the determination of a structure by means of protein crystallography and the use of structures in the drug‐discovery process. A number of successful examples of structure‐based drug design are described. The limitations of the techniques are discussed.
Discrimination Of Histamine H1 and Muscarinic Receptor‐Mediated Signalling Pathways By Phorbol Ester In Human Astrocytoma Cells
Authors: Kurita Masatake , Mashiko Hirobumi , Ogata Mayumi , Kumasaka Tadanori , Niwa Shin‐ichi , Nakahata Norimichi , Takano Shizuko , Nakanishi Hironori
Published: March 2003

1. Histamine H1 receptor‐mediated signalling was compared with muscarinic receptor‐mediated signalling in 1321N1 human astrocytoma cells.

2. Short‐term (2 min) treatment of cells with phorbol 12‐myristate 13‐acetate (PMA) resulted in a reduction of increases in intracellular Ca2+ ([Ca2+]i) induced by carbachol or histamine.

3. Carbachol‐induced increases in [Ca2+]i were 10‐fold more sensitive to PMA than the histamine‐induced increases.

4. When cells were treated with PMA for 48 or 72 h (long‐term treatment), protein kinase C (PKC) was down‐regulated and PMA did not inhibit carbachol‐induced increases in [Ca2+]i.

5. Histamine‐induced increases in [Ca2+]i were significantly reduced by long‐term treatment with PMA.

6. These findings suggest that the signalling pathways mediated by histamine H1 and muscarinic receptors can be distinguished by using PKC in 1321N1 human astrocytoma cells.
Endothelium‐Independent Relaxation Induced By Histamine In Human Dorsal Penile Artery
Authors: Martínez Ac , Prieto D , Raposo R , Delgado Ja , Resel L , García‐Sacristán A , Benedito S
Published: March 2003

1. In vitro preparations of human dorsal penile arteries were used to evaluate the effect of histamine and to characterize the histamine receptors involved in the response.

2. Cumulative administration of histamine induced a concentration‐dependent relaxation in precontracted arteries. The H1 receptor agonist 2‐pyridylethylamine induced a biphasic response: contraction followed by dilation. The H2 receptor agonist dimaprit produced a marked relaxation. Mepyramine, a histamine H1 receptor antagonist, led to a slight but statistically significant change in the pD2 value corresponding to the relaxant phase of the H1 receptor agonist and the histamine curve. The H2 receptor antagonist cimetidine induced a marked shift in the dimaprit concentration–response curve without affecting the maximum response. Incubation with cimetidine led to a considerable loss in the sensitivity of the arteries to histamine and in the maximum relaxation. Combined treatment with histamine H1 and H2 receptor antagonists resulted in an additional displacement compared with the effect of each antagonist alone on the histamine response. The effects observed using a histamine H3 receptor agonist and antagonist suggest that the involvement of this receptor is unlikely.

3. Removal of the endothelium was unable to reverse the histamine response. Pretreatment with NG‐nitro‐
L‐arginine methyl ester,
L‐arginine and indomethacin had no effect on the histamine control curve.

4. In conclusion, the vasodilation of human dorsal penile artery induced by histamine seems to be mainly mediated by muscular histamine H2 receptors, without the intervention of key intracellular mediators, such nitric oxide or relaxant prostanoids. A minor population of relaxant histamine H1 receptors cannot be excluded.
Effects Of NKH477 On Endothelin‐1‐Induced Renal Responses In Anaesthetized Dogs
Authors: Hara Sunao , Tanahashi Masayuki , Yoshida Makoto , Suzuki‐Kusaba Mizue , Hisa Hiroaki , Satoh Susumu
Published: March 2003

1. Intrarenal arterial infusion of a direct adenylate cyclase activator (NKH477; 300 ng/kg per min) increased renal blood flow, urine flow rate and urinary sodium excretion in anaesthetized dogs.

2. Intrarenal arterial infusion of endothelin (ET)‐1 (2 ng/kg per min) reduced basal values of these parameters and glomerular filtration rate, which were recovered by the addition of NKH477 during ET‐1 infusion.

3. These results demonstrate that NKH477 can counteract ET‐1‐induced antinatriuresis, mainly by restoring glomerular filtration.
Blockade Of Central Angiotensin II Does Not Affect The Reduction In Renal Sympathetic Nerve Activity Following A Volume Load In Heart Failure Rabbits
Authors: Badoer E , McGrath BP
Published: March 2003

1. We investigated the role in sympathetic nerve regulation of endogenous angiotensin (Ang)II in the brain in heart failure by examining the effect of losartan on the resting mean arterial blood pressure (MAP), heart rate (HR) and renal sympathetic nerve activity (RSNA) and the reflex reduction in RSNA elicited by acute volume expansion in conscious rabbits.

2. Heart failure was induced with doxorubicin (1 mg/kg, i.v., twice weekly for 6 weeks). On the experimental day, MAP, HR and RSNA were recorded in conscious rabbits before and after losartan (10 μg; n = 6) or Ringer’s (control; n = 5) injected in the fourth brain ventricle. Animals were then administered an acute volume load with the plasma expander Haemaccel (Hoechst Marion Roussel, Lane Cove, NSW, Australia; 2 mL/min, i.v., for 30 min).

3. Losartan did not significantly affect the resting basal levels of MAP, HR and RSNA. There was no significant difference between losartan‐ and Ringer’s‐treated animals.

4. Volume expansion in the control group elicited a significant reduction of 40% in RSNA. In the losartan‐treated group, a similar reduction (42%) was observed. There was no significant difference between the treatments. The administration of losartan did not significantly affect MAP and HR during volume expansion compared with the control group.

5. We conclude that AngII in the brainstem does not play a major role in the maintenance of resting MAP, HR and RSNA or in the reflex reduction in RSNA elicited by volume expansion in the conscious rabbit with doxorubicin‐induced heart failure.
In Vivo Manipulation And Continuous Measurement Of Muscle Blood Flow With Venous Effluent Sampling
Authors: Zheng D , Upton RN
Published: March 2003

1. An acute in vivo hindlimb skeletal muscle preparation was developed in anaesthetized sheep in order to facilitate studies of the effects of altered blood flow states on drug kinetics in skeletal muscle.

2. A continuous index of blood flow was recorded via ultrasonic Doppler probes on the femoral artery and vein. Skeletal muscle effluent blood was sampled via a catheter in the femoral vein proximal to the probe. Low‐ and high‐blood flow states were achieved by direct femoral artery infusion of adrenaline (0.002–0.006 mg/min) or magnesium (0.4–1 mmol/min), which produced mean (±SD) stable flow states of 25±12 and 185±56% (both n = 5) of baseline, respectively. The correlation coefficients between arterial and venous Doppler frequency shifts in five sheep during and after adrenaline infusion were 0.96 (indicating these vessels probably supplied and drained common tissue).

3. The venous Doppler frequency shifts were calibrated against timed collections of the femoral vein outflow to provide estimates of the low and normal blood flow states (mean flows of 2.8±1.7 and 9.3±5.7 mL/100 g per min; both n = 3) and against an indirect Kety–Schmidt method during low‐ and high‐blood flow states (mean flows of 2.2±1.3 and 18.2±7.0 mL/100 g per min; both n = 5). There was a generally good agreement between the two methods.

4. The tissue was neither hypoxic nor acidotic in the low‐ or high‐flow states and altering the flow produced no change in muscle oxygen consumption, suggesting the flow changes were largely due to changes in resistance vessel tone.

5. Postmortem femoral artery dye injection and dissection of stained tissues showed the artery supplied 657±96 g (n = 5) of skeletal muscle and 42±20 g (n = 5) of other tissues.

6. It is concluded that the method is suitable for sampling predominantly muscle effluent blood at low‐ or high‐blood flow states according to experimental requirements.
Delayed Hypotensive Effect Of The Thromboxane A2/Prostaglandin H2 Receptor Antagonist S‐1452 in Spontaneously Hypertensive Rats
Authors: Sugimoto Koh‐ichi , Shiga Tsuyoshi , Fujimura Akio
Published: March 2003

1. Several lines of evidence indicate that thromboxane (Tx) A2 may contribute to the development and maintenance of hypertension. The present study was undertaken to evaluate the role of TxA2 in the development of hypertension in spontaneously hypertensive rats (SHR) by using an orally active, highly specific TxA2/prostaglandin H2 receptor antagonist S‐1452.

2. Vehicle (1% arabic gum solution) alone was given orally to Wistar‐Kyoto (WKY) rats (n = 15) and SHR (n = 14), while S‐1452 (10 mg/kg per day, twice daily) was administered orally to SHR (n = 16) for 18 weeks (from 5 to 23 weeks of age).

3. No significant difference was observed in tail‐cuff blood pressure (BP) between vehicle‐ and S‐1452‐treated SHR before and at 5 and 11 weeks after treatment. Thereafter, BP was further elevated in vehicle‐treated SHR, but was significantly blunted in SHR treated with S‐1452 at 15 (224 ± 8 vs 211 ± 13 mmHg; P < 0.01) and 18 weeks (227 ± 9 vs 206 ± 10 mmHg; P < 0.001); this was associated with reduced proteinuria.

4. Urinary TxB2 in vehicle‐treated SHR, especially during the early period, was significantly greater than that in WKY rats, while no significant difference was observed in urinary 6‐keto‐prostaglandin F1α (6‐keto‐PGF1α) between the two groups. Treatment with S‐1452 reduced urinary excretion of TxB2 at 18 weeks.

5. The present study shows that S‐1452, at the dose used, does not reduce BP during the early period of the development of hypertension. These results suggest that the role of enhanced TxA2 production in the development of hypertension is small, if any, in SHR. Delayed response of BP may be independent of the direct pharmacological effects of S‐1452.
Nicorandil Stimulates Release Of Adenyl Purines From Porcine Coronary Artery
Authors: Sasaki Tetsuya , Hashimoto Michio , Nosaka Seishi , Hanada Tomoki , Saitoh Yuhei , Yamauchi Masanobu , Nakayama Kengo , Masumura Sumio , Tamura Katsuhiro
Published: March 2003

1. To clarify the mechanism of the cardioprotective effect of nicorandil (2‐nicotinamidoethyl‐nitrate ester), the effects of nicorandil and nitric oxide (NO) donors on the release of ATP, ADP, AMP and adenosine from arterial segments and cultured endothelial cells of the porcine coronary artery were examined.

2. Nicorandil significantly increased the release of total adenyl purines from arterial segments and from cultured endothelial cells.

3. Cromakalim, an ATP‐sensitive K+ channel opener, did not affect the release of total adenyl purines from coronary artery segments.

4. S‐Nitroso‐N‐acetyl‐
D,
L‐penicillamine and isosorbide dinitrate, NO donors, significantly increased the release of total adenyl purines from coronary artery segments.

5. These results demonstrate that nicorandil stimulates ATP release from the coronary artery by acting not as an ATP‐sensitive K+ channel opener, but as a nitrate, thus suggesting the cardioprotective properties of nicorandil.
Inhibition Of Cytokine Release By And Cardiac Effects Of Type Iv Phosphodiesterase Inhibition In Early, Profound Endotoxaemia In Vivo
Authors: Tofovic Stevan P , Zacharia Lefteris C , Carcillo Joseph A , Jackson Edwin K
Published: March 2003

1. In rats, inhibition of type IV phosphodiesterase (PDE4) attenuates acute renal failure and early (hours) mortality induced by high‐dose endotoxin. Because it is unlikely that protection of renal function accounts for improved early survivability, most likely PDE4 inhibition exerts multiple beneficial effects in endotoxaemia and the purpose of the present study was to test this hypothesis.

2. In study 1, we determined, in anaesthetized rats, the effects of endotoxin (30 mg/kg, i.v.) on cardiac performance parameters (heart rate (HR), ventricular peak systolic pressure (VPSP), maximum positive change in left ventricular pressure with respect to time (+dP/dt), maximum negative change in left ventricular pressure with respect to time (–dP/dtmax), ventricular end‐diastolic pressure (VEDP), ventricular minimum diastolic pressure (VMDP) and HR–pressure product), plasma catecholamine levels, plasma renin activity (PRA) and plasma levels of inflammatory cytokines (tumour necrosis factor (TNF)‐α and interleukin (IL)‐1β).

3. In study 2, we determined, in anaesthetized rats, whether inhibition of PDE4 attenuates lipopolysaccharide (LPS)‐induced changes in the aforementioned parameters of heart performance and neurohumoral status. We compared the changes in these parameters induced by endotoxaemia in animals treated with either RO 20‐1724 (10 μg/kg per min; a selective PDE4 inhibitor) or its vehicle (DMSO; 1.35 μL/min).

4. At 90 min postadministration, endotoxin significantly increased HR and reduced –dP/dtmax and VEDP and caused a several‐fold increase in plasma levels of TNF‐α, IL‐1β, noradrenaline, adrenaline and PRA. RO 20‐1724 significantly blunted the endotoxin‐induced reduction in –dP/dtmax and decreased endotoxin‐induced increases in TNF‐α and IL‐1β, without significantly altering endotoxin‐induced changes in HR, VEDP, catecholamine levels and PRA.

5. Results from these studies indicate that, in addition to preserving renal function, PDE4 inhibition attenuates inflammatory cytokine release caused by high‐dose endotoxin and may have protective effects on diastolic function in early profound endotoxaemia.
Heart–Lung Interactions: The Sigh And Autonomic Control In The Bronchial And Coronary Circulations
Authors: Porges William L , Hennessy Edward J , Quail Anthony W , Cottee David BF , Moore Peter G , McIlveen Stephen A , Parsons Gibbe H , White Saxon W
Published: March 2003

1. The Darwin hypothesis that human and animal expressions of emotion are the product of evolution and are tied to patterns of autonomic activity specified to progress the emotion remains under challenge.

2. The sigh is a respiratory behaviour linked with emotional expression in animals and humans from birth to death. The aim of the present study was to explore Darwin’s hypothesis with respect to tied autonomic activity underlying sigh‐induced changes in the bronchial and coronary circulations.

3. Awake dogs were prepared using pulsed ultrasonic flow probes on the right bronchial artery, parent intercostal artery and brachial artery, or on the right, circumflex and anterior descending coronary arteries. Central venous (CVP) and arterial pressures (AP) were measured; heart rate and flow conductances were derived. Three spontaneous sighs were monitored before and during random blockade of individual and combinations of cholinoceptors, α‐adrenoceptors and β‐adrenoceptors using methscopolamine, phentolamine and propranolol infusions. The data were subject to a 2
3 factorial analysis.

4. A spontaneous sigh is marked by a transient fall and return (< 3 s) in CVP of 18 mmHg (from 4±1 to –14±2 mmHg), usually followed by apnoea lasting 23±2 s. There is an immediate tachycardia and small rise in AP (phase 1) then, during apnoea, bradycardia and a fall in AP (phase 2). During phase 2, bronchial and coronary blood flow and conductance rise two‐ to three‐fold over 30 s (peak at 8 s). The vascular changes are absent in parent intercostal and brachial beds.

5. The phase 1 tachycardia is entirely cholino/adrenoceptor in origin and is due to cholinoceptor withdrawal and positive β‐adrenoceptor plus β‐adrenoceptor/cholinoceptor interaction activity, in the ratio 1.75 : 1. The phase 2 bradycardia is entirely cholinoceptor. However, only 17% of the peak rise in bronchial conductance is due to α‐/β‐adrenoceptor interactions (sympathetic withdrawal); 83% is due to non‐cholino/adrenoceptor mechanisms. In a separate four animals, the total sigh‐induced conductance rise is virtually abolished by prior infusion of NG‐nitro‐
L‐arginine methyl ester.

6. Therefore, the mechanism of the sigh‐induced bronchial and conductance effects may be an efferent nitrergic component of an arterial chemoreceptor reflex induction of sighing. An alternative hypothesis invokes local stretch‐sensitive C‐fibre sensory nerve endings releasing substance P–calcitonin gene‐related peptide–neurokinin A in response to cardiovascular distortion secondary to the sudden transmural pressure rise when intrapleural pressure falls. Whatever the case, these effects and the cholino/adrenoceptor base for the heart rate and broncho/coronary changes support the Darwin hypothesis.
Bronchovascular Role In Pulmonary Congestion
Authors: McIlveen SA
Published: March 2003

1. A postulated role for the bronchial circulation in the development of pulmonary congestion may be based on recent studies of bronchovascular control.

2. The bronchial circulation is the nutrient blood supply of the conducting airways and, therefore, plays an important role in the function of the bronchial mucosa. Mucosal swelling secondary to elevation of mucosal capillary hydrostatic pressure may decrease airway calibre, increase resistance to airflow and precipitate symptoms of pulmonary congestion.

3. Resting mucosal capillary hydrostatic pressure is relatively constant due to autoregulation of bronchial blood flow and is maintained low by nett bronchovascular constriction due to the dominance of autonomic vasoconstriction over nitric oxide‐dependent vasodilatation.

4. Bronchial blood flow is also regulated by cardiac afferent reflexes. Stimulation of cardiac vagal and spinal afferents produces vasodilatation and vasoconstriction, respectively. Tonic activity of cardiac spinal afferents probably contributes to the resting autonomic vasoconstriction.

5. Therefore, mild heart failure, which is associated with abnormal cardiovascular reflex function, may decrease cardiac spinal afferent‐mediated bronchial vasoconstriction and produce active dilatation due to stimulation of cardiac vagal afferents by excessive myocardial stretch, leading to bronchial mucosal swelling and pulmonary congestion.
In Situ Generation Of Nitric Oxide By Myenteric Neurons But Not By Mononuclear Cells Of The Human Colon
Authors: Tomobuchi Motoi , Oshitani Nobuhide , Matsumoto Takayuki , Kitano Atsuo , Seki Shuichi , Arakawa Tetsuo
Published: March 2003

1. Production of nitric oxide (NO) is implicated in the pathogenesis of inflammatory bowel disease. However, the cells responsible for the production of NO in situ in the human colon remain unknown.

2. Surgical samples from 12 patients with ulcerative colitis, eight patients with Crohn’s disease and 10 controls were studied. Possible generation of NO was visualized by reduced nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase activity in human colon. Immunohistological staining for various NO synthase (NOS) isoforms (endothelial, neuronal and inducible), nitrotyrosine and interleukin‐2 was also performed.

3. Reduced NADPH diaphorase activity was not found in lamina propria mononuclear cells, but was found in colonic epithelium, endothelium and myenteric neurons and their processes.

4. The NADPH‐diaphorase activity positive processes were significantly less common in colon from patients with Crohn’s disease compared with control colon.

5. Endothelial NOS was constitutively expressed on colonic endothelium.

6. Neuronal NOS was constitutively expressed on myenteric neurons.

7. Expression of inducible NOS (iNOS) was increased in the epithelium and endothelium of the colon of patients with ulcerative colitis.

8. No correlation was found between expression of iNOS and NADPH diaphorase activity.

9. Nitrotyrosine was expressed by lamina propria leucocytes, but not by epithelium.

10. Interleukin‐2 was expressed on both leucocytes and myenteric neurons.

11. Colonic epithelium, endothelium and myenteric neurons synthesize NO. Myenteric neurons were principally responsible for NO production and NO may act as a neurotransmitter in the enteric nervous system.
Association Of Serum Tumour Necrosis Factor‐α With Serum Low‐Density Lipoprotein–Cholesterol And Blood Pressure In Apparently Healthy Japanese Women
Authors: Ito Hiroyuki , Ohshima Akiko , Tsuzuki Misako , Ohto Naoko , Takao Kaoru , Hijii Chiga , Yanagawa Mami , Ogasawara Masashi , Nishioka Kazuo
Published: March 2003

1. The pro‐inflammatory cytokine tumour necrosis factor (TNF)‐α is considered to be involved in the development of atherosclerosis by inducing local inflammatory responses in the vascular wall. Because TNF‐α is also known to affect lipid and glucose metabolism, the association between the circulating concentration of TNF‐α and atherogenic risk factors was examined in 82 apparently healthy Japanese women (aged 19–69 years; mean age 48.5 years).

2. The mean (±SD) serum TNF‐α concentration was 2.7±0.9 pg/mL (range 1.4–5.9 pg/mL). The TNF‐α concentration showed significant correlations with age (r = 0.28; P = 0.01), body mass index (r = 0.27; P = 0.01), the waist–hip ratio (r = 0.41; P = 0.0002), percentage body fat (r = 0.30; P = 0.006), systolic (r = 0.32; P = 0.004) and diastolic (r = 0.24; P = 0.03) blood pressure, total cholesterol (r = 0.27; P = 0.02) and low‐ density lipoprotein–cholesterol (LDL‐C; r = 0.36; P = 0.001), while the correlations with high‐density lipoprotein–cholesterol (r = –0.20; P = 0.08) and insulin resistance estimated by the homeostasis model assessment (HOMAIR; r = 0.16; P = 0.15) were not statistically significant.

3. When adjusted for age and menopause, TNF‐α was significantly associated with systolic blood pressure (r = 0.25; P = 0.02) and LDL‐C (r = 0.27; P = 0.02). The association between TNF‐α and LDL‐C remained significant when adjustment was made for age, menopause and the waist–hip ratio (r = 0.24; P = 0.03).

4. Our results indicate that TNF‐α may play a role in modulating blood pressure and LDL‐C.
Structure‐Specific Membrane‐Fluidizing Effect Of Propofol
Authors: Tsuchiya H
Published: March 2003

1. While recent studies about the pharmacological mechanism of the intravenous anaesthetic propofol (2,6‐diisopropylphenol) have focused on its interaction with functional proteins, there is the possibility that propofol alters membrane properties to produce anaesthesia. In the present study, the structure‐specific effects of propofol on liposomal model membranes were studied.

2. The effect of propofol on the phase transition of membrane phospholipid was analysed spectrophotometrically using 1,2‐dipalmitoyl‐L‐α‐phosphatidylcholine liposomes. Propofol (50–200 μmol/L) lowered the phase transition temperature to fluidize membranes.

3. Membrane fluidization was also analysed by measuring fluorescence polarization of liposomes consisting of 1,2‐ dipalmitoyl‐L‐α‐phosphatidylcholine, 1‐palmitoyl‐2‐oleoyl‐L‐ α‐phosphatidylcholine and cholesterol with different probes. Propofol fluidized all liposomal membranes in the concentration range 5–500 μmol/L by acting on both the inner and outer layers of the membranes.

4. The membrane effects of propofol were compared with those of 2,6‐dialkylphenols, 1,3‐dialkylbenzenes, 2‐alkylphenols and alkylbenzenes. Although the membrane‐fluidizing effects were shared by a series of structural analogues, propofol was most effective in fluidizing membranes, especially liposomal membranes consisting of 20 mol% cholesterol and 80 mol% 1‐palmitoyl‐2‐oleoyl‐L‐α‐phosphatidylcholine.

5. Lipophilicity was compared between propofol and its structural analogues using their capacity factors, determined by reverse‐phase high‐performance liquid chromatography. The potency of propofol to fluidize membranes was much greater than anticipated from its lipophilicity.

6. At 0.125–1.0 μmol/L, almost corresponding to clinically relevant concentrations, propofol significantly enhanced membrane fluidity of cholesterol‐containing 1‐palmitoyl‐2‐oleoyl‐L‐α‐phosphatidylcholine liposomes.

7. These results indicate that propofol fluidizes membranes in a structure‐specific manner through an interaction with membrane lipids. Such a membrane effect may be responsible for the mode of anaesthetic action of propofol.
Effect Of Metabolic Control On Nitrite And Nitrate Metabolism In Type 2 Diabetic Patients
Authors: Francesconi Federica , Mingardi Roberto , DeKreutzenberg Saula , Avogaro Angelo
Published: March 2003

1. The measurement of nitrite and nitrate levels in plasma and urine is an approach to assess the activity of the endogenous nitric oxide (NO) system. The aim of the present study was to evaluate whether metabolic control may affect plasma levels and urinary excretion of nitrates and nitrites in type 2 diabetic patients.

2. Twenty consecutive type 2 diabetic patients were studied twice: first (study 1), under poor metabolic control; and, second, after improved metabolic conditions. Determinations of the main metabolic parameters and of plasma nitrates and nitrites (NOX) were performed in the fasting state. A 24 h urinary specimen was obtained for glycosuria, NOX and creatinine. Diet compliance and home blood glucose monitoring was evaluated on a weekly basis until study 2 was performed after 32 ± 7 days: then, an identical protocol was repeated (study 2).

3. Fasting plasma glucose was lower in study 2 (8.27 ± 2.11 vs 10.77 ± 3.88 mmol/L, respectively; P < 0.05); similarly glycosylated haemoglobin (HbA1c) improved significantly. Plasma NOX levels were similar between the first and second studies (14.3 ± 7.8 vs 13.5 ± 8.1 μmol/L, respectively); nor were any differences observed in urinary NOX excretion rates (726 ± 607 vs 689 ± 444 μmol/day, respectively). The urinary excretion fraction of NOX was higher during study 1 than during study 2 (3.22 ± 2.38 vs 1.88 ± 1.98%, respectively; P = 0.031). A relationship was observed between fasting plasma glucose levels and the urinary excretion fraction of NOX (r2 = 0.12; P = 0.026).

4. In type 2 diabetic patients, plasma and urinary levels of NOX do not change after improvement of metabolic control. A worse metabolic control is associated with an increased urinary fraction excretion of NOX: thus, changes in plasma NOX concentration may reflect the effect of hyperglycaemia in the renal handling of these compounds rather than the effects on the L‐arginine–NO pathway.