bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vasomotor Effects Of ARG–Gly–ASP (RGD) Peptides Are Limited And Not Related To Endothelium‐Derived Hyperpolarizing Factor‐Mediated Relaxation In Rat Mesenteric Arteries
Authors: Bakker Erik Ntp , Balt Jippe C , Pfaffendorf Martin , Spaan Jos Ae , VanBavel Ed 
Published: March 2003

SUMMARY1. In the present study we tested the effect of arg–gly–asp (RGD) peptides on vasomotor responses in rat isolated mesenteric arteries. More specifically, the hypothesis was tested that RGD interaction with integrins mediates relaxation attributed to endothelium‐derived hyperpolarizing factor (EDHF).2. The presence of the β3 integrin subunit was shown by western blot analysis. To study its functional role, arteries (355 ± 11 μm; n = 50) were mounted in a wire myograph set‐up to measure isometric force generation. After blockade of nitric oxide synthesis with NG‐nitro‐L‐arginine (0.1 mmol/L) and prostaglandin synthesis with indomethacin (10 μmol/L), methacholine (10 μmol/L) induced a transient relaxation within 1 min of 72 ± 4.0% (as percentage of precontraction with phenylephrine; n = 27).3. These responses were inhibited by a 60 mmol/L potassium buffer (18 ± 6.0%; n = 6) or endothelium denudation (12 ± 3.2%; n = 7), consistent with EDHF.4. A function‐blocking monoclonal antibody against the integrin β3 chain did not affect relaxation.5. The RGD peptides gly–arg–gly–asp–thr–pro (GRGDTP), gly–arg–gly–asp–ser (GRGDS) and cyclic RGD, ligands for the RGD binding site of integrins, also did not affect relaxation induced by methacholine.6. Cyclic RGD increased contraction from 91 ± 3 to 98 ± 3% (as percentage of 120 mmol/L potassium).7. In conclusion, these data show that vasomotor responses related to integrins are small and not involved in hyperpolarization attributed to EDHF in rat mesenteric artery.
An Overview Of New And Novel Pharmacotherapies For Use In Traumatic Brain Injury
Authors: Vink Robert , Nimmo Alan J , Cernak Ibolja 
Published: March 2003

SUMMARY1. Although a number of interventional pharmacotherapies have undergone clinical trial in traumatic brain injury (TBI), none has shown considerable promise. The present short review will examine some of the more novel compounds that have been proposed recently as potential therapeutic agents for use in TBI.2. Previous experimental studies have demonstrated that brain intracellular free magnesium significantly declines following TBI and that the administration of magnesium salts attenuates the post‐traumatic neurological deficits. More recent studies have established that magnesium salts administered after trauma enter the brain intracellular space and reduce the size of the lesion volume. Such protection could be afforded through attenuation of both necrotic and apoptotic cell death. Magnesium salts are currently on clinical trial in TBI.3. Cyclosporine A is known to inhibit opening of the mitochondrial permeability transition pore. Administration of cyclosporine A after TBI has been shown to attenuate axonal injury and decrease the resultant lesion volume. Therefore, inhibitors of mitochondrial transition pore opening and resultant attenuation of apoptosis show some promise as neuroprotective agents.4. Recent evidence has shown that substance P antagonists may decrease lesion volume and improve neurological outcome after ischaemia. Similar findings have recently been reported in TBI. The fact that substance P antagonists are known to reduce neurogenic inflammation, oedema formation and are clinically being trialed as both antidepressants and antinociceptive agents suggests that these agents warrant further investigation as therapeutic agents following TBI.5. There are numerous contradictions in the literature regarding the potential neuroprotective effects of the hormones oestrogen and progesterone. Recent studies suggest that both hormones are protective in TBI and further studies are required to ascertain the mechanisms associated with this protection and any potential for clinical application.
Activation Of Cyclo‐Oxygenase‐2 Contributes To Motor And Cognitive Dysfunction Following Diffuse Traumatic Brain Injury In Rats
Authors: Cernak I , O'Connor C , Vink R 
Published: March 2003

SUMMARY1. Post‐traumatic inflammation may play a significant role in the development of delayed secondary brain damage following traumatic brain injury.2. During post‐traumatic inflammation, metabolic products of arachidonic acid, known as prostanoids (prostaglandins and thromboxanes) are released and aggravate the injury process. Prostanoid synthesis is regulated by the enzyme cyclo‐oxygenase (COX), which is present in at least two isoforms, COX‐1 (the constitutive form) and COX‐2 (the inducible form).3. In the present study, we examine the temporal and spatial profiles of COX‐2 expression and the effects of the COX‐2 inhibitor nimesulide on motor and cognitive outcome following diffuse traumatic brain injury in rats.4. Adult male Sprague‐Dawley rats were injured using the 2 m impact acceleration model of diffuse traumatic brain injury. At preselected time points after injury, animals were killed and the expression of COX‐2 was measured in the cortex and hippocampus by western blotting techniques.5. Increased expression of COX‐2 was found in the cortex at 3 days and in the hippocampus as early as 3 h postinjury and this persisted for at least 12 days.6. Administration of nimesulide (6 mg/kg, i.p.) at 30 min after injury and daily over a 10 day post‐traumatic neurological assessment period resulted in a significant improvement compared with vehicle (2% dimethylsulphoxide diluted in isotonic saline)‐treated controls in cognitive deficits, as assessed by the Barnes circular maze. There was also a significant improvement in motor dysfunction as assessed by the rotarod test on days 1 and 2 post‐trauma compared with vehicle‐treated controls.7. These results implicate the involvement of COX‐2 in cognitive and motor dysfunction following diffuse traumatic brain injury.
Neural Pathways From The Lamina Terminalis Influencing Cardiovascular And Body Fluid Homeostasis
Authors: McKinley MJ , Allen AM , May CN , McAllen RM , Oldfield BJ , Sly D , Mendelsohn FAO 
Published: March 2003

SUMMARY1. The lamina terminalis, a region of the brain with a high concentration of angiotensin AT1 receptors, consists of three distinct nuclei, the median preoptic nucleus, the subfornical organ and organum vasculosum of the lamina terminalis (OVLT). These latter two regions lack a blood–brain and detect changes in plasma angiotensin (Ang) II concentration and osmolality.2. Efferent neural pathways from the lamina terminalis to the hypothalamic paraventricular and supraoptic nuclei mediate vasopressin secretion in response to plasma hypertonicity and increased circulating levels of AngII.3. Studies using the neurotropic virus pseudorabies, which undergoes retrograde transynaptic neuronal transport following injection into peripheral sites, show that neurons in the lamina terminalis have efferent polysynaptic neural connections to the peripheral sympathetic nervous system. Some of these neurons have been shown to have polysynaptic connections to the kidney and to express AT1 receptor mRNA. We propose that circulating AngII acts at AT1 receptors in the subfornical organ and OVLT to influence the sympathetic nervous system. It is likely that the neural pathway subserving this influence involves a synapse in the hypothalamic paraventricular nucleus.4. The lamina terminalis may exert an inhibitory osmoregulatory influence on renin secretion by the kidney. This osmoregulatory influence may be mediated by inhibition of renal sympathetic nerve activity and appears to involve a central angiotensinergic synapse.5. The lamina terminalis exerts an osmoregulatory influence on renal sodium excretion that is independent of the renal nerves and is probably hormonally mediated.
Heterogeneity Of The Properties Of INa in Epicardial And Endocardial Cells Of Rat Ventricle
Authors: Honen Bonny N , Saint David A 
Published: March 2003

SUMMARY1. Ventricular INa heterogeneity was investigated in adult rat hearts.
Differences in transient outward potassium current (Ito) were used to
confirm isolation of subepicardial and subendocardial cells. Mean peak Ito
was 6.0 ± 0.7 and 1.6 ± 0.45 pA/pF in epicardial and
endocardial cells, respectively (P < < 0.01).2. Maximum sodium conductance was smaller in subendocardial cells compared with subepicardial cells (2.39 ± 0.11 vs 2.78 ± 0.12
nS/pF, respectively; n = 17 for both; 0.01 < P < 0.05) and 50%
activation occurred at a slightly more negative potential (–47.6 ±
0.8 vs–44.9 ± 0.9 mV, respectively; n = 10 for
both; 0.01 < P < 0.05).3. The potential for 50% inactivation was not significantly different in subepicardial compared with subendocardial cells (72.2 ± 1.0 vs
72.8 ± 2.2 mV, respectively; n = 17 for both; NS).4. Persistent sodium current density appeared smaller in subendocardial (n
= 19) compared with subepicardial (n = 11) cells (at a test potential of –25
mV current, density was 0.118 ± 0.041 vs 0.144 ± 0.085 pA/pF, respectively), although this was not statistically significant due to large variability between cells.5. Mathematical modelling of the cardiac action potential indicated that the combined effects of differences in current density and voltage dependence of sodium currents are unlikely to contribute to ventricular action potential heterogeneity between epicardial and endocardial cells.
Val‐Tyr As A Natural Antihypertensive Dipeptide Can Be Absorbed Into The Human Circulatory Blood System
Authors: Matsui Toshiro , Tamaya Kei , Seki Eiji , Osajima Katsuhiro , Matsumoto Kiyoshi , Kawasaki Terukazu 
Published: March 2003

SUMMARY1. Intact absorption of the bioactive dipeptide Val‐Tyr (VY), with in vivo antihypertensive ability in normotensive human subjects, was investigated.2. As a result of a single oral administration of VY, the VY absorption curve occurred maximally over the second hour postprandially; a greater than 10‐fold higher increment of VY following a dose of 12 mg was observed in the plasma at 2 h compared with the baseline concentration of VY at 0 h (1934 ± 145 vs 159 ± 11 fmol/mL plasma, respectively).3. Plasma VY levels increased with dose administered (3, 6 and 12 mg), suggesting that exogenous VY could be absorbed intact into the human blood depending on the dose. The elimination half time (t1/2)
of VY was estimated to be 3.1 h. The area under the curve for the 12 mg VY dose was
9185 ± 688 fmol·h/mL plasma.
Endothelium‐Derived Hyperpolarizing Factor: Is There A Novel Chemical Mediator?
Authors: Triggle Chris R , Ding Hong 
Published: March 2003

SUMMARY1. Endothelium‐derived hyperpolarization (EDH) has been reported in many vessels and an extensive literature suggests that a novel, non‐nitric oxide and non‐prostanoid, endothelium‐derived factor(s) may be synthesized in endothelial cells.2. The endothelium‐dependent hyperpolarizing factor, or EDHF, is synthesized by the putative EDHF synthase and mediates its cellular effects by either, directly or indirectly, opening K channels on vascular smooth muscle cells or, via hyperpolarization of the endothelial cell, by facilitating electrical coupling between the endothelial and the vascular smooth muscle cell.3. The question of the chemical identity of EDHF has received considerable attention; however, no consensus has been reached. Tissue and species heterogeneity exists that may imply there are multiple EDHF. Leading candidate molecules for EDHF include an arachidonic acid product, possibly an epoxygenase product, or an endogenous cannabinoid, or simply an increase in extracellular K+.4. An increasing body of evidence suggests that EDH, notably in the resistance vasculature, may be mediated via electrical coupling through myoendothelial gap junctions and the existence of electrical coupling may negate the need to hypothesize the existence of a true endothelium‐derived chemical mediator.5. In this paper we review the evidence that supports and refutes the existence of a novel EDHF versus a hyperpolarization event mediated solely by myoendothelial gap junctions.
Pharmacological Profile Of Nociceptin/Orphanin Fq Receptors
Authors: Calo’ Girolamo , Rizzi Anna , Bigoni Raffaella , Guerrini Remo , Salvadori Severo , Regoli Domenico 
Published: March 2003

SUMMARY1. Nociceptin/orphanin FQ (NC) and its receptor (OP4) represent a novel peptide/receptor system pharmacologically distinct from classical opioid systems.2. Via OP4 receptor activation, NC regulates several biological functions,
both at peripheral and central levels; therefore, the OP4 receptor may
be viewed as a novel target for drug development. However, the pharmacology of this receptor is still in its infancy, with few molecules interacting selectively with this receptor.3. In the present article, we review the findings of studies that have investigated the pharmacological profile of ligands selective for the OP4 receptor,
these being two antagonists, the peptide [Nphe1]NC(1–13)NH2
and the non‐peptide J‐113397, and two agonists, the peptide [Arg14,Lys15]NC, and the non‐ peptide Ro 64‐6198.4. The results of these studies indicate that agents that selectively activate or block the OP4 receptor may represent new potential drugs for the treatment of human diseases.
Modulation Of [35S]‐Tert‐ Butylbicyclophosphorothionate Binding By Somatostatin In Rat Hypothalamus
Authors: Chigr F , M’hamed S Ba , Najimi M 
Published: March 2003

SUMMARY1. The present study was designed to assess the effect of the tetradecapeptide somatostatin on the GABAA receptor complex in the rat hypothalamus.2. GABAA receptors were labelled with [35S]‐tert‐butylbicyclophosphorothionate
(TBPS), which binds in or near the chloride channel, and binding as assessed by in
vitro quantitative autoradiography using a computer‐assisted image analysis system.3. Somatostatin inhibited the binding of [35S]‐TBPS to the convulsant
site of the hypothalamic GABAA receptor complex of rat slide‐mounted hypothalamic
structures in a concentration‐dependent manner with an affinity in the micromolar
range (10–6 to 3 × 10–6 mol/L).
Somatostatin appeared to mimic the effects of the neurosteroid 5α‐pregnane‐3αol‐one
(5α3αP), GABA and picrotoxin on [35S]‐TBPS binding
in the rat hypothalamus in all structures examined. Furthermore, GABA or muscimol
(a GABAA receptor agonist), when added to the incubation medium, enhanced
the capacity of somatostatin to inhibit [35S]‐TBPS binding, with an IC50
of 10–7 mol/L. However, incubation with bicuculline (a GABAA
receptor antagonist) led to the abolition of the inhibitory effect of somatostatin
on [35S]‐TBPS specific binding in rat hypothalamus.4. The present results demonstrate the presence of a modulatory effect of somatostatin on the GABAA receptor complex in rat hypothalamic structures. Furthermore,
the data suggest that somatostatin allosterically modifies [35S]‐TBPS binding through a mechanism similar to that of GABA. Taken together, these results provide evidence for the presence of somatostatin– GABA interactions in rat hypothalamus.
Role Of CA2+‐Activated K+ Channels In The Regulation Of Basilar Arterial Tone In Spontaneously Hypertensive Rats
Authors: Kamouchi Masahiro , Kitazono Takanari , Nagao Tetsuhiko , Fujishima Masatoshi , Ibayashi Setsuro 
Published: March 2003

SUMMARY1. Ionic channels appear to play an important role in contractile responses of the cerebral arteries and, thereby, contribute to the regulation of cerebral circulation. In the present study, we investigated the role of large‐conductance Ca2+‐activated
K+ (BKCa) channels in the regulation of cerebral arterial tone during chronic hypertension.2. Ring segments of the basilar artery from spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto (WKY) rats were placed in bath chambers and the isometric tension of each ring was measured.3. Application of inhibitors of BKCa channels, namely tetraethylammonium (TEA; ≥ 0.1 mmol/L) and charybdotoxin (CTX; ≥ 0.1 nmol/L), produced spontaneous contraction with rhythmic oscillation in the basilar artery from SHR.4. The oscillatory contraction was not induced by 5‐hydroxytryptamine (0.01–10 μmol/L) or depolarization by external high K+ (20–60 mmol/L).5. The rhythmic contraction was completely abolished by either the removal of external Ca2+ or the application of nicardipine (10 nmol/L).6. The oscillation was not affected by the substitution of external Cl– by various equimolar anions (i.e. acetate, benezenesulphonate, bromide and isethianate).7. The amplitude of the oscillation was dose‐dependently increased by the vasodilators forskolin and sodium nitroprusside, as well as by stimulation of the endothelium with histamine and acetylcholine, whereas the frequency was decreased.8. In contrast, the oscillation was eliminated by depletion of Ca2+ stores by caffeine. Neither TEA (10 mmol/L) nor CTX (10 nmol/L) produced any significant contraction of the basilar artery in WKY rats.9. These results suggest that BKCa channels may play an important role in regulating the resting tone of the cerebral artery in SHR.
Effects Of Melanocortins On Cardiovascular Regulation In Rats
Authors: Ramaekers D , Beckers F , Demeulemeester H , Bert C , Denef C , Aubert AE 
Published: March 2003

SUMMARY1. Of the melanocortin peptides, γ2‐melanocyte‐stimulating hormone (MSH) has been attributed a cardiovascular effect, inducing an increase in blood pressure and heart rate. Although still controversial, this effect, based on pharmacological blockade experiments, is supposed to be mediated through sympathetic activation.2. The aims of the present study were to identify the N‐terminal pro‐opiomelanocortin (N‐POMC) fragments and melanocortins that influence blood pressure and heart rate and to investigate the real‐time changes in baroreflex sensitivity and in sympathetic and vagal modulation underlying cardiovascular effects in conscious rats without the use of pharmacological blockade.3. Intracerebroventricular administration of different melanocortins and N‐POMC induced a long‐lasting dose‐ dependent pressor response from 1 nmol onwards, with only a small initial bradycardic response with the highest dose.4. Coinciding with this pressor response, an elicitation of the low‐frequency (LF) component was observed in spectral analysis of both blood pressure variability (BPV) and heart rate variability (HRV), followed by the high‐frequency (HF) component in at least BPV. Baroreflex sensitivity remained unchanged.5. After intravenous administration, γ2‐MSH produced a short‐lasting dose‐dependent pressor and cardioaccelerator response with very rapid onset with concentrations from 1 nmol onwards.6. Continuous infusion of γ2‐MSH depressed baroreflex sensitivity and simultaneously increased both components of BPV, with a radical reduction of the LF component and a preserved vagal HF component in HRV.7. Of all the intravenously administered melanocortins, only γ2‐MSH
was active. The central effect is likely to depend on an increase of (α‐)sympathetic outflow.8. For the peripheral effect, γ2‐MSH appeared to act as a baroreceptor reflex‐blocking agent, being compatible with a role in the acute stress response.
A Rat Model Of Ischaemic Or Dilated Cardiomyopathy For Investigating Left Ventricular Repair Surgery
Authors: Nishina Takeshi , Miwa Senri , Yuasa Sadatoshi , Nishimura Kazunobu , Komeda Masashi 
Published: March 2003

SUMMARY1. The effects of left ventricular repair (LVR) surgery for ischaemic or dilated cardiomyopathy are not fully understood. The development of a proper animal model will help to resolve this issue.2. The ischaemic cardiomyopathy (ICM) model used was as follows. Twenty‐six rats developed ICM with a large akinetic left ventricular (LV) area after ligation of the left anterior descending artery (LAD). Four weeks after surgery, 13 rats underwent LVR by placating the akinetic area (LVR group), while 13 underwent rethoracotomy alone (sham group).3. The dilated cardiomyopathy (DCM) model is as follows. Six Dahl salt‐sensitive (DS) rats were fed an 8% NaCl diet from the age of 9 weeks and developed DCM. These rats had LVR by plicating the LV area between the papillary muscle bases (LVR group), while other rats underwent rethoracotomy alone (sham group).4. Before LAD ligation in the ICM model or starting the high‐salt diet in the DCM model and just before and after LVR or sham surgery, LV dimensions were measured by echocardiography and the heart rate and systolic blood pressure were recorded by the tail‐cuff method.5. In the ICM model, all rats survived the second surgery, after which LV end‐diastolic diameter (EDD) decreased, LV fractional shortening (FS) increased (both P < 0.001 vs sham) and heart rate increased (P < 0.05) in the LVR group.6. In the DCM model, LV EDD decreased and LV FS increased (both P < 0.001) in the LVR group.7. Both models developed LV dilatation, tolerated LVR and enable reproducible physiological evaluation of the LV. Because the rats survived thereafter, both models may provide a useful tool for various investigations.
Antihyperglycaemic And Anti‐Oxidant Properties Of Anoectochilus Formosanus in Diabetic Rats
Authors: Shih Chun‐Ching , Wu Yueh‐Wern , Lin Wen‐Chuan 
Published: March 2003

SUMMARY1. In the present study, we investigated aqueous extracts of Anoectochilus formosanus (AFE) for antihyperglycaemic and anti‐oxidant effects in diabetic rats induced by streptozotocin (STZ).2. Diabetic rats were randomly divided into groups and treated orally by gavage with vehicle (distilled water) or AFE (1 and 2 g/kg), once a day for 21 days.3. At the end of the 21 day period, AFE (2 g/kg) significantly reduced fasting blood glucose, serum fructosamine, triglycerides and total cholesterol compared with vehicle‐treated diabetic rats. In vehicle‐treated diabetic rats, levels of renal lipid peroxidation were increased, whereas glutathione concentrations were not affected. Renal lipid peroxidation levels were significantly lower and renal reduced glutathione (GSH) concentrations were significantly higher in AFE‐treated diabetic rats compared with vehicle‐treated diabetic rats. The diabetic kidney in the vehicle‐treated group showed a decrease in catalase, but the activity of glutathione peroxidase (GSH‐Px) was increased.4. The activity of catalase, but not GSH‐Px, was significantly reversed by AFE treatment. These results indicate that AFE (1 and 2 g/kg) not only possesses an antihyperglycemic effect, but that it may also reduce oxidative stress in diabetic rats.
Molecular moulds with multiple missions: Functional sites in three‐finger toxins
Authors: Kini R Manjunatha 
Published: March 2003

Summary1. Snake venoms are complex mixtures of pharmacologically active peptides and proteins.2. These protein toxins belong to a small number of superfamilies of proteins. The present review describes structure–function relationships of three‐finger toxins.3. All toxins share a common structure of three β‐stranded loops extending from a central core. However, they bind to different receptors/acceptors and exhibit a wide variety of biological effects.4. Thus, the structure–function relationships of this group of toxins are complicated and challenging.5. Studies have shown that the functional sites in these ‘sibling’ toxins are located on various segments of the molecular surface.