bluuebunny/crossref_metadata_2025 huggingface dataset:
Vertebrate Agmatinases: What Role Do They Play in Agmatine Catabolism?
Authors: MORRIS SIDNEY M.
Published: March 2004

Abstract: Whereas agmatine in vertebrates may be derived from multiple sources such as the diet, endogenous synthesis via arginine decarboxylase, and possibly also from enteric bacteria, agmatinase is the only enzyme specific for agmatine catabolism. As it hydrolyzes a guanidino group within agmatine and also contains signature amino acid residues that act as ligand binding sites for the Mn++ cofactor, agmatinase is classified as a member of the arginase superfamily. Very little information is available regarding how much agmatine in vertebrate species is catabolized by agmatinase versus other enzymes such as diamine and amine oxidases. Moreover, comparisons of primary sequences of several vertebrate agmatinases demonstrate that several residues essential for catalytic activity are not conserved in the mouse. This leads to the prediction that the agmatinase protein in mouse has little or no catalytic activity, not only raising questions about the physiologic routes of agmatine disposal in this organism, but also suggesting the existence of species‐specific differences in mechanisms for regulating agmatine levels.
Agmatine: At the Crossroads of the Arginine Pathways
Authors: SATRIANO JOSEPH
Published: March 2004

Abstract: In acute inflammatory responses, such as wound healing and glomerulonephritis, arginine is the precursor for production of the cytostatic molecule nitric oxide (NO) and the pro‐proliferative polyamines. NO is an early phase response whereas increased generation of polyamines is requisite for the later, repair phase response. The temporal switch of arginine as a substrate for the inducible nitric oxide synthase (iNOS)/NO axis to arginase/ornithine decarboxylase (ODC)/polyamine axis is subject to regulation by inflammatory cytokines as well as interregulation by the arginine metabolites themselves. Herein we describe the capacity of another arginine pathway, the metabolism of arginine to agmatine by arginine decarboxylase (ADC), to aid in this interregulation. Agmatine is an antiproliferative molecule due to its suppressive effects on intracellular polyamine levels, whereas the aldehyde metabolite of agmatine is a potent inhibitor of iNOS. We propose that the catabolism of agmatine to its aldehyde metabolite may act as a gating mechanism at the transition from the iNOS/NO axis to the arginase/ODC/polyamine axis. Thus, agmatine has the potential to serve in the coordination of the early and repair phase pathways of arginine in inflammation.
Structure‐Activity Analysis of Guanidine Group in Agmatine for Brain Agmatinase
Authors: HUANG M‐J , REGUNATHAN S , BOTTA M , LEE K , MCCLENDON E , YI G B , PEDERSEN M L , BERKOWITZ D B , WANG G , TRAVAGLI M , PILETZ J E
Published: March 2004

Abstract: To identify a selective inhibitor of mammalian agmatinase, screening was performed on four analogues of agmatine with modifications directly to the guanidine group, six analogues with modifications to the carbon‐amine chain, and one analogue with modifications at both ends of the molecule. Control compounds were aminoguanidine and 7‐nitroindazole, known inhibitors of the three isoforms (i, e, n) of nitric oxide synthase (NOS), and arcaine, a known inhibitor of the glutamate NMDA receptor. These compounds were compared for inhibition of rat agmatinase and arginine decarboxylase (ADC) activities. Results were studied by ab initio Hartee‐Fock descriptors based on optimized geometries and van der Waals radii. Linear correlations were obtained using various geometric and electronic descriptors of the carbon (C), nitrogen (N), and hydrogen (H) atoms in the guanidine moiety. The best fit equation for percent activity remaining of rat agmatinase was 5 0.3225 D 1 72.76 D1916 1 64.97 D1920 2 192.58 H21 2 253.09 (r 5 0.89), where D is the calculated dipole moment, D1916 and D1920 are the N19‐N16 and N19‐N20 distances, respectively, and H21 is the charge on H21. This agmatinase equation is distinct from the equations fit for ADC, the three NOS isoforms, and inhibition of NMDA receptor binding.
Effect of Agmatine on Acute and Mononeuropathic Pain
Authors: ARICIOGLU FEYZA , KORCEGEZ EYLEM , BOZKURT AYHAN , OZYALCIN SULEYMAN
Published: March 2004

Abstract: Agmatine is a polycationic amine synthesized from L‐arginine by arginine decarboxylase in brain and several tissues. It binds to N‐methyl‐D‐aspartate (NMDA) subtype of glutamatergic, a2‐adrenergic and imidazoline (I) receptors. The present study was designed to investigate effect of agmatine on acute and mononeuropathic pain after chronic constriction injury (CCI). CCI was created by four loose ligations around the right sciatic nerve. The analgesic threshold in rats was evaluated by using thermal hyperalgesia/allodynia (THA) at 4°C. The evaluations were made preoperatively, on postoperative day 15, and after drug administration. Agmatine (10, 20, 40, 80, and 100 mg/kg) was administered intraperitoneally for 5 days beginning on postoperative day 15. Agmatine significantly reduced the hyperalgesia in all doses applied. When agmatine was injected intraperitoneally (10, 20, 40, 80, and 100 mg/kg), it increased the nociceptive threshold in the tail‐immersion test in a dose‐dependent manner, but it had no effect in the hot‐plate test. This effect of agmatine in the tail‐immersion test was blocked by both yohimbine (1 mg/kg) and idazoxan (0.5 mg/kg). When agmatine was administered intracerebroventricularly (25‐200 mg/10 mL), it increased the nociceptive threshold in the hot‐plate but not in the tail‐immersion test. We conclude that agmatine, an endogenous substance derived from arginine, can modulate both acute and chronic pain.
Is Agmatine an Endogenous Anxiolytic/Antidepressant Agent?
Authors: ARICIOGLU FEYZA , ALTUNBAS HALE
Published: March 2004

Abstract: Agmatine, an endogenous cationic amine, exerts a wide range of biologic effects, but its physiologic role is still to be determined. The aim of the present experiments was to investigate the role of agmatine in anxiety and depression. The forced swim test (FST) and the elevated plus maze (EPM) were used to determine the antidepressant and anxiolytic effects of agmatine in comparison with imipramine (30 mg/kg i.p.). Agmatine (10, 20, 40, 80, or 100 mg/kg, i.p.), saline, or imipramine was given 30 minutes before the tests. Agmatine decreased immobility time in the FST and increased the time spent in the open arms in the EPM, as compared with the saline group. As an endogenous substance, agmatine have modulatory effect on anxiety and depression.
Effect of Agmatine on Electrically and Chemically Induced Seizures in Mice
Authors: ARICIOGLU FEYZA , KAN BILGE , YILLAR OKAN , KORCEGEZ EYLEM , BERKMAN KEMAL
Published: March 2004

Abstract: Agmatine, an amine and organic cation, is formed by the decarboxylation of L‐arginine by arginine decarboxylase. It binds to a2‐adrenergic and imidazoline receptors. It blocks N‐methyl‐D‐aspartate (NMDA) subtype of glutamate receptors and inhibits nitric oxide (NO) synthase. Because the importance of NMDA receptors and the NO system are well known in seizure activity, this study was designed to investigate the effect of agmatine on electrically and chemically induced seizures by using maximal electroshock (MES) and pentilentetrazole (PTZ) models in mice. Initial studies established convulsive current 50 (CC50) for MES and effective dose 50 (ED50) for PTZ to produce seizures. Agmatine (20, 40, 80, and 100 mg/kg intraperitoneally) increased the threshold of seizures in MES dose dependently. In PTZ‐induced convulsions, the highest dose of agmatine (100 mg/kg) increased the seizure onset time and decreased percent survival. The percentage of grade V seizures was found to be increased by agmatine doses greater than 20 mg/kg.
Endogenous β‐Carbolines as Clonidine‐Displacing Substances
Authors: ROBINSON ESJ , ANDERSON NJ , CROSBY J , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: Endogenous β‐carbolines, such as harmane, are known to occur in mammalian species including humans. Radioligand binding studies have revealed that certain β‐carbolines display high affinity for both I1 and I2 imidazoline‐binding sites (IBS). Functional studies have shown that the β‐carboline harmane elicits many characteristics expected of an endogenous ligand IBS. This article discusses the evidence relating to β‐carbolines as endogenous ligands and presents a case for harmane and related compounds as endogenous ligands for IBS.
Comparative Effects of Efaroxan and b‐Carbolines on the Secretory Activity of Rodent and Human b Cells
Authors: MORGAN NOEL G. , COOPER E JANE , SQUIRES PAUL E. , HILLS CLAIRE E. , PARKER CHRISTINE A. , HUDSON ALAN L.
Published: March 2004

Abstract: The pancreatic b‐cell expresses an imidazoline‐binding site that is involved in the regulation of insulin secretion. This site is pharmacologically atypical in comparison with the I1 and I2 sites described in other tissues, and it has been classified as I3. The structural requirements for binding of ligands to the I3 site have not been fully defined, although a range of synthetic I3 ligands have been characterized in functional terms. Evidence has been presented that an endogenous I3 ligand may exist, because extracts of brain contain an active principle that stimulates insulin secretion in a manner consistent with the involvement of I3 sites. The active component has not been identified but has been equated with the long‐sought clonidine displacing substance (CDS) that is proposed as the endogenous ligand for imidazoline‐binding sites. Recent evidence has indicated that one active component of CDS may be a b‐carboline, but it is not known whether b‐carbolines can stimulate insulin secretion. Thus, we have studied the effects of b‐carbolines on insulin secretion and cytosolic Ca21 levels in rodent and human islet cells. The results reveal that harmane, pinoline, and norharmane cause a dose‐ and glucose‐dependent increase in insulin secretion but show that this response differs in a number of ways from that elicited by the well‐characterized I3‐agonist, efaroxan. Thus, b‐carbolines represent a new class of insulin secretagogues, although it remains unclear whether their action is mediated solely by I3 sites in the b cell.
Inhibitory Effect of Harmane on Morphine‐Dependent Guinea Pig Ileum
Authors: ARICIOGLU FEYZA , UTKAN TIJEN
Published: March 2004

Abstract: Studies on the occurrence and properties of b‐carbolines structurally related to harmala alkaloids have gained attention since it was hypothesized that some of these compounds play a role in processes of substance abuse and dependence. This study investigates the effects of harmane on naloxone‐precipitated withdrawal syndrome in morphine‐dependent guinea pig ileum. Segments of ilea from starved male guinea pigs were obtained and fixed at a resting tension of 1 g in an organ bath containing 1026 M morphine in Tyrode solution at 378C, which was bubbled with 95% O2 and 5% CO2. Tissues were incubated in 1026 M morphine containing Tyrode solution for 4 hours before harmane was added. Naloxone and harmane had no effect on naive ilea. Naloxone (1026 M) contracted morphine‐dependent ilea. Harmane significantly inhibited the contractile response to naloxone in a dose‐dependent manner (1027 M 5 24%; 1026 M 5 49.3%; 1025 M 5 70%). These results suggest that harmane may have beneficial effects on morphine withdrawal syndrome.
No Evidence for Activation of α2‐Adrenoceptors by Methanolic Extracts of Bovine Brain and Lung Containing Clonidine‐Displacing Substance
Authors: PINTHONG D , KENDALL DA , MACLENNAN SJ , EGLEN RM , WILSON VG
Published: March 2004

Abstract: Methanolic extracts of bovine brain and lung are capable of displacing [3H]‐clonidine from α2‐adrenoceptor binding sites, indicating the presence of a clonidine‐displacing substance (CDS). We have examined α2‐adrenergic responses and the extracts in three models: [3H]‐cyclic AMP accumulation in miniprisms of guinea pig cerebral cortex, isometric tension measurements of isolated segments of the rat vas deferens, and porcine palmar lateral vein. The selective α2‐adrenoceptor agonist, 5‐bromo‐6‐2‐imidazolin‐2‐ylamino]‐quinoxaline bitartrate (UK‐14304) inhibited forskolin‐stimulated [3H]‐cyclic AMP accumulation in the cerebral cortex and elicited contractions of the porcine isolated palmar lateral vein. Clonidine (0.1–30 nM) inhibited neurogenic contractions of the rat vas deferens. Responses to both agonists were inhibited by the α2‐adrenoceptor antagonists, idazoxan or rauwolscine. Brain CDS (5 units/mL) reduced forskolin‐stimulated [3H]‐cyclic AMP accumulation in the guinea pig cerebral cortex, whereas lung CDS (1 unit/mL) increased the accumulation of the cyclic nucleotide. Neither response to the extracts was inhibited by 1 mM idazoxan. Low concentrations of both extracts (0.05 unit/mL) reduced electrically evoked contractions of the rat vas deferens by approximately 20%, but higher concentrations enhanced neurogenic contractions by approximately 50%. Again, the effect of the brain extract was not altered by 1 mM idazoxan. Lung CDS (0.02–1 unit/mL) induced contractions of the porcine palmar lateral vein that were also insensitive to rauwolscine. The results suggest that brain and lung CDS do not activate either central or peripheral α2‐adrenoceptors.
Complex Interaction of a2‐Adrenoceptor Binding Sites with Bovine Brain and Lung Extracts Containing Clonidine‐Displacing Substance
Authors: PINTHONG D , KENDALL DA , WILSON VG
Published: March 2004

Abstract: Previous studies have established that methanolic extracts of bovine brain and lung possess CDS activity with an agonist‐like profile at a2‐adrenoceptor binding sites (i.e., greater potency against [3H]‐clonidine sites than against [3H]‐RX‐821001 sites). Following prolonged reflux in ethylacetate, monovalent cations and histamine were removed from the lung extract, and the resulting extract exhibited similar potency against both radioligands, indicative of an antagonist‐like profile. These observations help explain the absence of biologic activity at a2‐adrenoceptors in the methanolic extracts as reported in our companion paper.
Endogenous Imidazoline Receptor Ligands Relax Rat Aorta by an Endothelium‐Dependent Mechanism
Authors: MUSGRAVE IAN F. , VAN DER ZYPP ANDREA , GRIGG MATHEW , BARROW COLIN J.
Published: March 2004

Abstract: Agmatine and harmane have been proposed as endogenous ligands of imidazoline receptors. Agmatine has been reported to activate nitric oxide synthetase (NOS) in endothelial cells, so we sought to determine if agmatine or harmane and an analogue of harmane, propyl harmane, produced vasodilatation through an endothelium‐dependent mechanism. The experiments were performed in endothelium‐denuded and intact rat aortic rings preconstricted with phenylephrine (0.1 mM). Agmatine (0.3–1000 mM), harmane, and propyl harmane (0.3–100 mM) relaxed endothelium‐intact rings in a concentration‐dependent manner. Removal of endothelium inhibited the relaxant effect of agmatine, harmane, and propyl harmane. The NOS inhibitor L‐NIO (100 mM) inhibited the relaxant effect of agmatine and harmane. The I1‐receptor antagonist AGN (100 mM) partly inhibited the effect of harmane but not that of agmatine. These results suggest that the endogenous imidazoline ligands are capable of stimulating NOS largely by an I1‐receptor‐independent mechanism.
I1 Imidazoline Receptors Involved in Cardiovascular Regulation: Where Are We and Where Are We Going?
Authors: BOUSQUET P , GRENEY H , BRUBAN V , SCHANN S , EHRHARDT JD , MONASSIER L , FELDMAN J
Published: March 2004

Abstract: Clonidine‐like drugs (hybrid drugs) reduce blood pressure by acting centrally at both a2‐adrenergic receptors (a2AR) and I1 receptors (I1R). Some attempts at cloning I1R have failed, probably because of the lack of selectivity of the ligands. Recently, compounds acting exclusively at I1R were synthesized: LNP 911, LNP509, and S23515. For example, LNP911 has a Kd value of 1.7 nmol/L at I1R. LNP509 and S23515 reduce blood pressure when injected centrally in anesthetized animals, whereas S23757 behaves as an antagonist of hypotensive imidazolines. LNP509 reduces blood pressure even in genetically engineered mice lacking functional a2AR. An exclusive action at central I1R is therefore sufficient to modify blood pressure. With the help of drugs selective for I1R and a‐methylnoradrenaline, selective for a2AR, we showed that imidazoline and a2‐adrenergic mechanisms interact synergistically in controlling the blood pressure. Such a synergism may explain the very powerful hypotensive effects of hybrid drugs. The new ligands selective for I1R will be very helpful to investigate the molecular features and the signaling system of I1R.
Are Centrally Acting Imidazoline Agents Appropriate Therapy for Renovascular Hypertension?
Authors: HEAD GEOFFREY A. , BURKE SANDRA L.
Published: March 2004

Abstract: An increased role of the sympathetic nervous system has been suggested to be a major contributor to the chronic elevation of BP in renovascular hypertension. We assessed the effects of rilmenidine, a centrally acting antihypertensive imidazoline agent, on BP and renal sympathetic nerve activity (RSNA) in 2K1C renovascular hypertensive conscious rabbits. Rabbits were made hypertensive with a renal clip or were sham‐operated and were studied 3 and 6 weeks later. Acute treatment with rilmenidine reduced BP to a greater extent in the hypertensive rabbits. Although rilmenidine reduced the heart rate by the same extent in all groups, rilmenidine produced much less inhibition of RSNA in the hypertensive animals. These studies suggest that the contribution of the sympathetic nervous system is greater in 2K1C hypertension and that imidazoline agents may be beneficial in treating renovascular hypertension.
Cardiac Effects of Moxonidine in Spontaneously Hypertensive Obese Rats
Authors: MUKADDAM‐DAHER S , MENAOUAR A , EL‐AYOUBI R , GUTKOWSKA J , JANKOWSKI M , VELLIQUETTE RA , ERNSBERGER P
Published: March 2004

Abstract: Moxonidine, an imidazoline receptor agonist that acts centrally to inhibit sympathetic activity, has been shown to reduce effectively blood pressure, fasting insulin levels, and free fatty acids. In this study, we investigated the long‐term effects of moxonidine treatment on cardiac natriuretic peptides (ANP and BNP) in Spontaneously Hypertensive Obese Rats (SHROBs), a rat model that resembles human Syndrome X. SHROBs expressing spontaneous hypertension, insulin resistance, and genetic obesity (weight 590 6 20 g, at 30 weeks) received moxonidine in chow at 4 mg/kg/day for 15 days. Moxonidine significantly reduced not only systolic blood pressure (187 6 6 versus 156 6 5 mm Hg, P < 0.05) but also plasma ANP (1595 6 371 versus 793 6 131 pg/mL, P < 0.05) and BNP (22 6 3 versus 14 6 1 pg/mL, P < 0.04), without influencing cardiac content of either peptide. Semi‐quantitative PCR revealed that atrial ANPmRNA/GAPDHmRNA decreased to 39% 6 10% of pair‐fed controls, P < 0.03. In left ventricles, moxonidine also decreased ANP mRNA to 69% 6 7% and BNP mRNA to 74% 6 6% of control, P < 0.02, but right ventricular ANP and BNP mRNA were not affected. These findings indicate that chronic inhibition of sympathetic activity with moxonidine in SHROB is associated with decreased ventricular natriuretic peptide transcription, consistent with the cardioprotective effects of moxonidine given the role of ANP and BNP as markers of cadiac disease. Moxonidine also improves the metabolic profile in these rats, thus it may be considered the drug of choice in treatment of metabolic syndrome X.
Moxonidine Displays a Presynaptic Alpha‐2‐Adrenoceptor‐Dependent Synergistic Sympathoinhibitory Action at Imidazoline‐1 Receptors
Authors: SCHÄFER ULRICH , BURGDORF CHRISTOF , ENGELHARDT ASTRID , RAASCH WALTER , KURZ THOMAS , RICHARDT GERT
Published: March 2004

Abstract: The function of presynaptic imidazoline‐1 receptors (I1‐R) in the heart remains unclear. In rat hearts, UK14.304 and moxonidine reduced norepinephrine (NE) release. AGN192403 had no influence on NE, whereas rilmenidine, agmatine, rauwolscine, and efaroxan increased NE. These effects of moxonidine and rilmenidine were not affected by AGN192403 adminstration. Conversely, after pretreatment with UK14.304, only moxonidine displayed a pronounced inhibitory action on NE release (sensitive to AGN192403), indicating a synergistic inhibitory action at I1‐R under conditions of a stimulated alpha2‐adrenergic autoinhibition.
Norepinephrine Release Is Reduced by I1‐Receptors in Addition to a2‐Adrenoceptors
Authors: RAASCH WALTER , JUNGBLUTH BRITTA , SCHÄFER ULRICH , HÄUSER WALTER , DOMINIAK PETER
Published: March 2004

Abstract: In pithed spontaneous hypertensive rats, noradrenaline overflow was diminished by moxonidine even when a2‐adrenoceptors were blocked quantitatively using phenoxybenzamine, suggesting an I1‐receptor‐mediated mechanism of noradrenaline release. This hypothesis was confirmed, since the noradrenaline overflow was (1) increased under a2‐adrenoceptors blockade by the mixed I1/a2‐antagonists efaroxan or idazoxan, (2) still reduced by moxonidine when both a2‐ and I1‐receptors were blocked, and (3) diminished by agmatine after pretreatment with phenoxybenzamine, but not with AGN192403. An indirect ganglionic I1‐receptor‐mediated mechanism of noradrenaline release is supposed.
Normalization of Up‐Regulated Cardiac Imidazoline I1‐Receptors and Natriuretic Peptides by Chronic Treatment with Moxonidine in Spontaneously Hypertensive Rats
Authors: EL‐AYOUBI R , MENAOUAR A , GUTKOWSKA J , MUKADDAM‐DAHER S
Published: March 2004

Abstract: The effect of treatment with moxonidine (120 mg/kg/h sc, 4 weeks) on cardiac I1‐receptors and natriuretic peptide synthesis was evaluated in spontaneously hypertensive rats (SHR). I1‐receptor protein (85 kD) was up‐regulated in SHR atria, and normalized in right and left atria by moxonidine. Similarly, moxonidine normalized atrial and ventricular atrial natriuretic peptide messenger RNA (mRNA) and brain natriuretic peptide mRNA. This study shows that cardiac I1‐receptors are functional, being regulated by hypertension and by chronic exposure to agonist, and that cardiac natriuretic peptides may be regulated by I1‐receptor‐mediated mechanisms.
BU98008, a Highly Selective Imidazoline1‐Receptor Ligand
Authors: ROBINSON ESJ , PRICE RE , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: BU98008 (1‐(4, 5‐dihydro‐1H‐imidazol‐2‐yl)isoquinoline) is a novel isoquinoline derivative. Radioligand binding studies revealed it had high affinity for the I1 receptor in rat kidney membranes but low affinity for the I2 binding site and a2‐adrenoceptor in rat brain membranes. Further evaluation of BU98008 in vivo revealed no effect on blood pressure following peripheral administration. These preliminary data suggest BU98008 may be an antagonist at I1 receptors. Further evaluation following central administration must be performed before a hypotensive action can be excluded.
Novel Ligands for the Investigation of Imidazoline Receptors and Their Binding Proteins
Authors: HUDSON AL , TYACKE RJ , LALIES MD , DAVIES N , FINN DP , MARTÍ O , ROBINSON E , HUSBANDS S , MINCHIN MCW , KIMURA A , NUTT DJ
Published: March 2004

Abstract: New ligands for imidazoline receptors are described so that these receptors can be more fully explored and understood. BU224, (2‐(4,5‐dihydroimidaz‐2‐yl)‐quinoline, shows high affinity and is selective for the imidazoline‐2 (I2) class of receptors. BU224 was tested in the rat Porsolt forced swim paradigm where it was found to decrease time spent immobile and increase the time spent swimming, consistent with an antidepressant profile. BU224 was tritiated and, in radioligand binding studies, was found to label a single population of saturable sites with high affinity. In vitro brain autoradiography with [3H]BU224 also showed a pattern of distribution similar to the known labeling of I2 receptors. A new series of four 2BFI (2‐(benzofuranyl)‐2‐imidazoline) derivatives were investigated as potential ligands for imaging brain I2 receptors using positron emission tomography (PET). At least two, BU20012 and BU20013, retained high affinity and moderate selectivity and penetrated the brain when administered peripherally in the mouse. 2BFI has undergone the Mannich reaction to immobilized diaminodipropyl amine to fabricate an affinity column, which was used to isolate a protein from rabbit brain; this protein was sequenced and identified as the enzyme creatine kinase.
In Vivo Effects of the I2‐Alkylating Agent BU99006 on the Immunodensity of Imidazoline Receptor Proteins in the Mouse Brain
Authors: GARCIA‐SEVILLA JESUS A. , FERRER‐ALCON MARCEL
Published: March 2004

Abstract: The binding sites for imidazol(ine)/guanidine drugs (identified inter alia with [3H]‐clonidine and [3H]‐idazoxan) are heterogeneous in nature, and various pharmacologic types of imidazoline receptors (IRs) have been characterized (I1R, I2AR, I2BR, and I3R). IR‐receptor proteins have also been immunodetected using an antibody raised against an ∼70‐kD idazoxan/clonidine binding protein, which probably recognizes all types of IRs. In this study, the in vivo effects of the selective I2‐alkylating agent BU99006 (5‐isothiocyanato‐2‐benzofuranyl‐2‐imidazoline) on immunoreactive IR proteins were assessed in the mouse brain to unravel the molecular nature of the I2R subtypes. In mouse tissues (cerebral cortex, liver, testis, and kidney) this antibody revealed the presence of 30‐, 43‐, 45‐, 66‐, and/or 85‐kD IR proteins. Treatment with BU99006 (20 mg/kg, intraperitoneally, for 4 hours) significantly decreased the immunodensity of specific IR proteins in the brain (30 kD: 249%; 45 kD: 237%; 66 kD: 218%). In contrast, the immunoreactivities of 43‐kD and 85‐kD IR proteins were not altered after I2R alkylation. Prolonged treatment with BU99006 (20 mg/kg, intraperitoneally. for 8 hours) resulted in modest but significant increases in the expression of all the immunodetected IR proteins in the mouse brain (20%–36%), suggesting compensatory increases in IR protein synthesis after alkylation of I2 sites. The results indicate that the 30‐kD and 45‐kD proteins, but not the 43‐kD and 85‐kD proteins, immunodetected in the mouse brain are related to the I2R.
Effect of Postmortem Delay on Imidazoline Receptor‐Binding Proteins in Human and Mouse Brain
Authors: MA JOHN K. , ZHU HE , PILETZ JOHN E.
Published: March 2004

Abstract: Immunoreactive proteins of 45‐kD and 29/30‐kD doublet bands are candidate imidazoline receptor binding proteins (IRBP) based on associations with I1 or I2 binding sites, respectively. It was reported that the density of cortical membrane 29/30‐kD I2 protein is diminished whereas a 45‐kD I1 protein is increased in depressed suicide victims versus controls. IRBP immunoreactive bands of similar size have been suggested to be breakdown products of the 170‐kD protein known as IRAS (putative full‐length I1 receptor). This study compares nonpathologic human brains collected and frozen after postmortem delays of 13.4 hours 6 1.7 (SEM) with brains of longer postmortem delays (26.1 hours 6 1.2). The fresher human brains possessed more full‐length IRAS (P5 0.05). In another study, the postmortem decay of IRBP bands in mouse brain was shown to be linear over time. The results are relevant to previous studies of IRBP bands in postmortem brains of depressed suicide victims.
Relationship Between Imidazoline2 Sites and Monoamine Oxidase
Authors: PATERSON LM , TYACKE RJ , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: I2 site‐selective compounds are known to interact with and inhibit monoamine oxidase (MAO), but it remains unclear as to whether this interaction occurs through an allosteric or competitive interaction. This study used the new selective, irreversible I2 ligand BU99006, to clarify the relationship between MAO and the I2 binding sites (I2‐BS). Results demonstrate that irreversible binding of BU99006 to rat brain membranes does not inhibit the enzyme or interfere with its interaction with other imidazoline enzyme inhibitors. This finding suggests that the I2 sites that react with BU99006 are not those implicated in MAO inhibition and points to the existence of at least two distinct I2 binding proteins.
Investigation of the Affinities of Two New b‐Carbolines for Rat Brain Imidazoline2 Receptors
Authors: TYACKE RJ , LAU A , GRELLA B , GLENNON RA , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: The b‐carbolines are possible endogenous ligands and modulators of the imidazoline binding sites (I‐BSs). Relatively little is known about this class of compound and its interaction with the I‐BS. Presented here are the binding data for two aryl ring substituted dihydro‐b‐carbolines at the imidazoline2 binding site (I2‐BS) and a2‐adrenoceptor: BG‐326 (5‐bromo‐4,9‐dihydro‐3H‐b‐carboline) and BG‐350 (5‐methoxy‐4,9‐dihydro‐3H‐b‐carboline). Both compounds show good affinity and selectivity for the I2‐BS.
Identification of an I2 Binding Protein From Rabbit Brain
Authors: KIMURA A , TYACKE RJ , MINCHIN MCW , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: Imidazoline‐2 binding proteins exist as a heterogeneous population. The aim of this study was to isolate and identify I2 binding proteins from rabbit brain using an affinity column synthesized with a highly selective I2 ligand, 2‐(2‐benzofuranyl)2‐imidazoline (2BFI). The results revealed an approximately 45‐kD protein to be brain creatine kinase (EC 2.7.3.2). [3H]‐2BFI (5nM) was able to bind specifically to the purified enzyme. This study has identified brain creatine kinase as a novel I2 binding protein.
In Vivo Estimation of Imidazoline2 Binding Site Turnover
Authors: PATERSON LM , ROBINSON ESJ , NUTT DJ , HUDSON AL
Published: March 2004

Abstract: Turnover of imidazoline2 (I2) binding sites in the mouse and rat brain has been measured following an acute intravenous dose of BU99006. This ligand selectively and irreversibly knocks out I2 sites, as defined by [3H]2BFI binding. Recovery was measured using radioligand binding and autoradiography to determine global and regional changes in I2 density. The density of I2 sites in brain recovered from BU99006 treatment with a half‐life of 2.1 hours in mice and 4.3 hours in rats. Monoamine oxidase (MAO) activity and MAO binding density were unaltered in the brains of BU99006‐treated animals. These data suggest that the I2 site that reacts with BU99006 recovers rapidly and is independent of MAO.
Specificity of Nonadrenergic Imidazoline Binding Sites in Insulin‐Secreting Cells and Relation to the Block of ATP‐Sensitive K1 Channels
Authors: GROSSE‐LACKMANN TIMM , ZÜNKLER BERND J. , RUSTENBECK INGO
Published: March 2004

Abstract: To characterize the specificity of nonadrenergic imidazoline binding sites of insulin‐secreting HIT cells, competitive binding of insulinotropic imidazolines and quinine was measured and compared with the effect of these compounds on native KATP channels and with a heterologously expressed variant of the pore‐forming subunit (Kir6.2 DC26). There were two nonadrenergic imidazoline binding sites for [3H]clonidine with Kd values of 61 nM and 4.5 mM, respectively. Quinine reduced specific binding incompletely (73%) with Ki values of 75 nM and 133 mM. Clonidine, N‐allyl‐clonidine (alinidine), and quinine inhibited native KATP channels as well as Kir6.2DC26 channels. Coexpression of Kir6.2DC26 and SUR1 (the regulatory subunit of KATP) did not increase the potency of quinine. There are nonadrenergic imidazoline binding sites in insulin‐secreting HIT cells which also recognize quinine. One of these sites is Kir6.2, the pore‐forming subunit of the KATP channel.
Moxonidine, a Mixed a2‐Adrenergic and Imidazoline Receptor Agonist, Identifies a Novel Adrenergic Target for Spinal Analgesia
Authors: STONE LAURA S. , FAIRBANKS CAROLYN A. , WILCOX GEORGE L.
Published: March 2004

Abstract: Moxonidine is a mixed a2‐adrenergic and imidazoline receptor agonist with an improved side effect profile compared to clonidine. Intrathecal (i.t.) moxonidine has been found to possess analgesic activity that, in contrast to the majority of a2‐adrenoceptor (a2AR) agonists, does not require activation of the a2AAR subtype, which mediates many of the side effects associated with a2AR use. In addition, moxonidine (i.t.) interacts in a synergistic manner with opioid agonists and this synergy is retained in neuropathic pain states. Moxonidine may therefore be clinically useful in the treatment of chronic neuropathic pain, either alone or as a coadjuvant with opioids.
Evidence for Nonadrenoceptor Responses to Imidazoline Derivatives in the Porcine Isolated Rectal Artery
Authors: WANG MINYAN , DUNN WR , CHAN SL , GARFIELD B , WILSON VG
Published: March 2004

Abstract: High concentrations of phentolamine, efaroxan, and idazoxan were found to produce nonadrenoceptor contractions of the porcine isolated rectal artery previously exposed to U46619 and forskolin. These responses were insensitive to the putative imidazoline I3 receptor antagonist KU‐14R, unlike those previously reported in this preparation for oxymetazoline. The pharmacologic nature of this response and the obligate requirement for preconstriction suggests that these imidazoline derivatives modulate ion channel function through a novel nonadrenergic site.
Intracellular Effect of Imidazoline Receptor on α2A‐Noradrenergic Receptor
Authors: CHEN MICHAEL J. , ZHU HE , PILETZ JOHN E.
Published: March 2004

Abstract: Imidazoline‐1 receptors (I1R) and α2‐noradrenergic receptors (α2AR) are known to coexist in many cell types and bind many of the same imidazoline ligands. Herein, the possibility of an interaction between these receptors was explored using a cloned cDNA that encodes a protein with I1R‐like binding properties, designated imidazoline receptor antisera‐selected (IRAS). Chinese hamster ovary (CHO) sublines permanently expressing the human subtype α2AAR cDNA were transiently cotransfected with the human IRAS cDNA (pIRAS). Saturation radioligand binding experiments on membranes isolated from the various sublines allowed distinction between I1R and α2AAR. Transfection of pIRAS into either subline led to a rise in membrane I1R‐binding sites. Immunoblotting revealed that IRAS was enriched in membranes more than in cytosolic fractions. Transfection of pIRAS in CHO cells harboring the α2AAR cDNA resulted in a twofold increase in α2AAR binding sites with no change in α2AAR binding affinity, compared with controls. Immunoblotting also revealed increased expression of membranous α2AAR by IRAS. Thus, pIRAS transfection led to I1 binding sites and to an increase in α2AAR binding sites in CHO cells expressing the human α2AAR. Although the mechanism is unclear, this increase in binding sites may explain previous imidazoline drug effects suggestive of interactions between these two receptors.
Branching morphogenesis and kidney disease
Authors: Shah Mita M. , Sampogna Rosemary V. , Sakurai Hiroyuki , Bush Kevin T. , Nigam Sanjay K.
Published: March 2004

Branching morphogenesis in the kidney is a tightly regulated, complex process and its disruption potentially can lead to a broad spectrum of diseases, ranging from rare hereditary syndromes to common conditions such as hypertension and chronic kidney failure. This review synthesizes data on branching during kidney development derived from in vitro and in vivo rodent studies and to apply them to human diseases. It discusses how the broad organization of molecular interactions during kidney development might provide a mechanistic framework for understanding disorders related to aberrant branching.
Flexural behaviour of a polyvinyl chloride-lined glass-reinforced plastic composite multi-mitred pipe bend subjected to combined loads: A comparative finite element analysis and experimental case study
Authors: Kochekseraii S B , Robinson M
Published: March 2004

The flexural behaviour of a glass-reinforced plastic (GRP) multi-mitred pipe bend (MMPB) subjected to combined in-plane bending and internal pressure is presented in this paper. After construction of a polyvinyl chloride (PVC)-lined GRP MMPB, its behaviour subjected to in-plane bending, internal pressure and combined internal pressure and in-plane bending was studied. Small-and large-displacement laminated shell finite element analysis (FEA) results using ABAQUS FE were compared with experiments on an identical specimen. When modelling an MMPB subject to individually applied pressure and bending loads, comparisons exhibited good agreement between linear small-displacement FEA with experimental data. Only large-displacement FEA agreed with experiments when modelling MMPBs subject to combined pressure and bending loads. Large-displacement FEA showed geometrically non-linear behaviour closely matching the experimental trends.
A comparison of failure prediction methods for an adhesively bonded composite beam
Authors: Abdel Wahab M. M , Ashcroft I. A , Crocombe A. D
Published: March 2004

In this paper, three different techniques are proposed to predict the failure load in two adhesively bonded composite I-beams. These methods are analytical solutions, finite element analyses (FEAs) and hybrid methods (combination of FEA and closed-form solutions). The two I-beams were tested in the three-point bending and four-point bending configurations. In the analytical solutions, simple stress analysis and fracture mechanics, based on beam theory, are used. Failure in the adhesive layer as well as failure in the skin or spar caps is considered. In the finite element (FE) approach a submodelling technique is adopted, in which a coarse model and a submodel are required. A circular flaw of 6mm radius is initiated in the adhesive layer and the strain energy release rates are extracted from the FEA results using a modified crack closure technique. In the hybrid method, a global FE model is constructed and the stresses are calculated; then an analytical solution for a circular crack is applied. Comparison between the three techniques is presented.
Critical plane modelling of fatigue initiation under rolling and sliding contact
Authors: Šraml M , Flašker J , Potrč I
Published: March 2004

Contact fatigue is a phenomenon of important practical significance for engineering applications involving localized contacts, such as gears, rail-wheel system and rolling bearings. The service lifetime of such components is related to damage, which results from the contact fatigue. The process in the material structure that causes this kind of failure is quite complicated.

The aim of the present paper is to describe a contact fatigue initiation criterion, based on the critical plane approach for the general contact problem. On the basis of contact stress analysis with modified Hertzian boundary conditions, the loading cycle of characteristic material points in the contact area is determined. The Dang Van damage initiation criterion is based on the critical plane approach, which combines the largest allowable shearing and hydrostatic stresses (tensile and compressive), with an assumed elastic shakedown behaviour and it is used in this work. The material point of initial fatigue damage is then determined at the transition of the loading cycle stresses over the critical plane. The model assumed a homogeneous and elastic material model, without any imperfections or residual stresses, and elastic shakedown is considered. A proper determination of loading cycles and their characteristic values is of significance for contact fatigue initiation analysis. Finally, determination of the most critical material point on or under the contact surface and related number of loading cycles required for fatigue damage initiation is calculated with the strain-life (ε— N) method.
Magnetic Trapping of CocoreCoOshell Nanoparticles Produced by Gas Phase Reaction
Authors: Huh Seung H , Nakajima Atsushi
Published: March 2004

The magnetic trapping of gas phase CocoreCoOshell nanoparticles of ≈160 and 5–10 nm in diameter showed unique patterns of two-dimensional circular or oval distribution and one-dimensional aggregation, respectively, suggesting that granular nanowire can be formed when shell to core ratio is less than ≈0.38 at 0.5 T.
Novel Soluble and Thermally Stable Perylene Dye with Two [60] Fullerene Units
Authors: Hua Jianli , Meng Fanshun , Ding Fang , Tian He
Published: March 2004

A novel fullerene derivative in which perylene group is attached to two C60 through a pyrrolidine ring has been prepared and found to exhibit good solubility, high thermal stability and broad visible-light absorption with high coefficients, and photophysical studies shows that photo-induced energy transfer from the perylene moiety to C60.
Effects of Head-Slaved Navigation and the Use of Teleports on Spatial Orientation in Virtual Environments
Authors: Bakker Niels H. , Passenier Peter O. , Werkhoven Peter J.
Published: March 2004

The type of navigation interface in a virtual environment (VE)---head slaved or indirect---determines whether or not proprioceptive feedback stimuli are present during movement. In addition, teleports can be used, which do not provide continuous movement but, rather, discontinuously displace the viewpoint over large distances. A two-part experiment was performed. The first part investigated whether head-slaved navigation provides an advantage for spatial learning in a VE. The second part investigated the role of anticipation when using teleports. The results showed that head-slaved navigation has an advantage over indirect navigation for the acquisition of spatial knowledge in a VE. Anticipating the destination of the teleport prevented disorientation after the displacement to a great extent but not completely. The time that was needed for anticipation increased if the teleport involved a rotation of the viewing direction. This research shows the potential added value of using a head-slaved navigation interface---for example, when using VE for training purposes---and provides practical guidelines for the use of teleports in VE applications.
Modeling the Effect of Task and Graphical Representation on Response Latency in a Graph Reading Task
Authors: Peebles David , Cheng Peter C.-H.
Published: March 2004

We report an investigation into the processes involved in a common graph-reading task using two types of Cartesian graph. We describe an experiment and eye movement study, the results of which show that optimal scan paths assumed in the task analysis approximate the detailed sequences of saccades made by individuals. The research demonstrates the computational inequivalence of two sets of informationally equivalent graphs and illustrates how the computational advantages of a representation outweigh factors such as user unfamiliarity. We describe two models, using the ACT rational perceptual motor (ACT-R/PM) cognitive architecture, that replicate the pattern of observed response latencies and the complex scan paths revealed by the eye movement study. Finally, we outline three guidelines for designers of visual displays: Designers should (a) consider how different quantities are encoded within any chosen representational format, (b) consider the full range of alternative varieties of a given task, and (c) balance the cost of familiarization with the computational advantages of less familiar representations. Actual or potential applications of this research include informing the design and selection of appropriate visual displays and illustrating the practice and utility of task analysis, eye tracking, and cognitive modeling for understanding interactive tasks with external representations.
Steps toward Building Mathematical and Computer Models from Cognitive Task Analyses
Authors: Schweickert Richard , Fisher Donald L. , Proctor Robert W.
Published: March 2004

Typically, detailed quantitative and computer models of human operators performing real world tasks cannot easily be developed. We propose a technique that more easily allows for that development. We propose that when a cognitive task analysis has been carried out, a computer simulation model useful for approximations of task completion time is often within reach. The first step is to construct an activity network or order-of-processing diagram from the task analysis. Second, activity durations are found in the literature or approximated through multidimensional scaling. Finally, equations are written for calculating task completion time, or a program is written for simulations to estimate this time. Resulting models can be useful for optimizing system design. The approach is illustrated with an activity network by W. D. Gray, B. E. John, and M. E. Atwood (1993) for a telephone operator task. Simulations demonstrate the feasibility of using multidimensional scaling to obtain approximate activity durations. The approach is also illustrated with an order-of-processing diagram representing drivers reading roadside message displays. We point out that if a more detailed picture of unobservable mental processes in a task is needed, techniques have been developed for this through analysis of response times. Actual or potential applications of this research include system design, human-computer interaction, message comprehension, and simulation of information-processing tasks.
New Alternative Methods of Analyzing Human Behavior in Cued Target Acquisition
Authors: Maltz Masha , Shinar David
Published: March 2004

Target acquisition tasks in natural environments are often augmented by cuing systems that advise human observers during the decision process. With present technological limitations, cuing systems are imperfect, so the question arises whether cuing aids should be implemented under all conditions. We examined target acquisition performance under different levels of task complexity and cuing system reliability. We introduce here two new methods to help define observer behavior trends in cued target acquisition: a quantitative measure of observer search behavior in a temporal sense and a measure of the extent of observer reliance on the cue. We found that observer reliance on the cue correlated with task difficulty and the perceived reliability of the cue. Cuing was generally helpful in complex tasks, whereas cuing reduced performance in easy tasks. Consequently, cuing systems should be implemented only when the task is difficult enough to warrant the intrusion of a cue into the task. Actual or potential applications of this research include the design and implementation of imperfect automated aids dealing with augmented reality
Weatherwise: Evaluation of a Cue-Based Training Approach for the Recognition of Deteriorating Weather Conditions during Flight
Authors: Wiggins Mark , O'Hare David
Published: March 2004

Inappropriate and ineffective weather-related decision making continues to account for a significant proportion of general aviation fatalities in the United States and elsewhere. This study details the evaluation of a computer-based training system that was developed to provide visual pilots with the skills necessary to recognize and respond to the cues associated with deteriorating weather conditions during flight. A total of 66 pilots were assigned to one of two groups, and the evaluation process was undertaken at both a self-report and performance level. At the self-report level, the results suggested that pilots were more likely to use the cues following exposure to the training program. From a performance perspective, there is evidence to suggest that cue-based training can improve the timeliness of weather-related decision making during visual flight rules flight. Actual or potential applications of this research include the development of computer-based training systems for fault diagnosis in complex industrial environments.