bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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.