bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inositol 1,4,5‐Trisphosphate And Reperfusion Arrhythmias
Authors: Woodcock Elizabeth A , Arthur Jane F , Matkovich Scot J 
Published: March 2003

SUMMARY1. The present review focuses on the role of the Ca2+‐ releasing second messenger inositol 1,4,5‐trisphosphate (IP3) in initiating arrhythmias during early reperfusion following a period of myocardial ischaemia.2. Evidence for an arrhythmogenic action of IP3 was provided by studies showing a correlation between the extent of the increase in IP3 and the incidence of arrhythmias in early reperfusion. In addition, phospholipase C inhibitors selective for thrombin receptor stimulation were anti‐arrhythmic only when arrhythmias were thrombin initiated.3. Mechanisms by which IP3 could initiate arrhythmias are discussed, with particular emphasis on the role of slow and unscheduled Ca2+ release.4. The reperfusion‐induced IP3 and arrhythmogenic responses can be initiated through either α1‐adrenoceptors or thrombin receptors, but endothelin receptor stimulation was ineffective. Further studies have provided evidence that the noradrenaline‐mediated response was mediated by α1A‐receptors, while the α1B‐adrenoceptor subtype appeared to be protective.5. Reperfusion‐induced IP3 responses could be inhibited by procedures known to reduce the incidence of arrhythmias under these conditions, including preconditioning, inhibiting Na+/H+ exchange or by dietary supplementation with n‐3 polyunsaturated fatty acids.6. Inositol 1,4,5‐trisphosphate generation in cardiomyocytes can be facilitated by raising intracellular Ca2+ and it seems likely that the rise in Ca2+ in ischaemia and reperfusion is responsible for the generation of IP3, which will, in turn, further exacerbate Ca2+ overload.
Microvascular Remodelling In Chronic Airway Inflammation In Mice
Authors: Thurston Gavin , Maas Kevin , LaBarbara Allyson , McLean John W , McDonald Donald M 
Published: March 2003

SUMMARY1. Chronic inflammation is associated with blood vessel remodelling, including vessel proliferation and enlargement, and changes in vessel phenotype. We sought to characterize these changes in chronic airway inflammation and to determine whether corticosteroids that inhibit inflammation, such as dexamethasone, can also reduce microvascular remodelling.2. Chronic airway inflammation was induced in C3H mice by infection with Mycoplasma pulmonis and the tracheal vessels were examined in whole mounts after Lycopersicon esculentum lectin staining.3. Neither the number nor the length of vessels changed in C3H mice after infection with M. pulmonis. Instead, vessel diameter and endothelial cell number doubled.4. Immunoreactivity for P‐selectin, a marker of venular endothelial cells, also increased after infection, indicating that the proportion of venules doubled with a corresponding decrease in capillaries.5. Whereas the average diameter of tracheal capillaries doubled in mice inoculated 10 days earlier (mean (±SEM) diameter in infected and pathogen‐free mice of 20.8±1.6 and 9.0±0.7 μm, respectively), dexamethasone treatment (0.2 mg/day, i.p.) for 7 days beginning 4 days after infection significantly decreased capillary diameter (13.0±0.7 μm). The treatment also decreased the immunoreactivity for P‐selectin and the number of adherent leucocytes (595±203 vs 2024±393 cells/ mm
2 in treated and non‐treated infected mice, respectively).6. We conclude that microvascular enlargement and changes in vessel phenotype are features of some types of chronic inflammation and, furthermore, that dexamethasone reverses the microvascular enlargement, changes in vessel phenotype and leucocyte influx associated with chronic inflammatory airway disease.
Activation Of Human Clc‐2 Cl– Channels: Implications For Cystic Fibrosis
Authors: Cuppoletti John , Tewari Kirti P , Sherry Ann M , Malinowska Danuta H 
Published: March 2003

SUMMARY1. The ClC‐2 Cl– channels are present in the adult human lung epithelia and, therefore, are a potential target for therapy in cystic fibrosis.2. Activators of ClC‐2 Cl– channels that may have physiological relevance include activation by reduced external pH, protein kinase A and arachidonic acid.3. Activators of ClC‐2 Cl– channels that have therapeutic potential include amidation and omeprazole and, perhaps, effectors of arachidonic acid metabolism.
Delayed Administration Of Jtp‐2942, A Novel Thyrotropin‐Releasing Hormone Analogue, Improves Cerebral Blood Flow And Metabolism In Rat Postischaemic Brain
Authors: Katsumata T , Katayama Y , Yonemori H , Muramatsu H , Otori T , Nishiyama Y , Yamada H , Nakamura H , Terashi A 
Published: March 2003

SUMMARY1. The aim of the present study was to examine the central nervous system action of JTP‐2942, a novel thyrotropin‐ releasing hormone (TRH) analogue, from the point of view of cerebral blood flow (CBF) and metabolism in the postischaemic brain.2. Left middle cerebral artery ischaemia was induced for 90 min followed by reperfusion.3. Animals were separated into four groups: (i) low‐dose (0.003 mg/kg ) JTP‐2942; (ii) high‐dose (0.03 mg/kg) JTP‐2942; (iii) cystidine diphosphate choline (500 mg/kg); and (iv) saline. The test drug or saline was administered intravenously 1 week after ischaemia.4. Local CBF and local cerebral glucose utilization were measured autoradiographically, adjacent sections were stained with haematoxylin‐eosin and infarction size was measured.5. JTP‐2942 ameliorated the reduction of local CBF and glucose utilization except in the ischaemic core. In particular, the higher dose (0.03 mg/kg) of JTP‐2942 significantly increased local CBF and glucose utilization not only in peri‐infarcted areas, but also in distal and contralateral areas.6. These results suggest that JTP‐2942 treatment may be beneficial for improving cerebral circulation and metabolism in the postischaemic brain.
The Peripheral Renin–Angiotensin System Is Not Involved In The Hypertension Of Sheep Exposed To Prenatal Dexamethasone
Authors: Peers Arianne , Campbell Duncan J , Wintour E Marelyn , Dodic Miodrag 
Published: March 2003

SUMMARY1. Fetal exposure to an adverse intrauterine environment has been linked with cardiovascular and metabolic disease later in life. We have shown previously, in sheep, that brief exposure (48 h) to maternally administered dexamethasone (0.28 mg/kg per day) at 27 days of gestation (prenatal treatment group (PTG) 1; term approximately 150 days), but not at 64 days of gestation (PTG2), produced hypertensive offspring at 40 months of age. The present study aimed to determine whether the elevated blood pressure in these sheep was associated with an altered peripheral renin–angiotensin system (RAS).2. Measurements of the basal levels of the RAS components (renin, angiotensinogen, angiotensin (Ang) I, angiotensin‐ converting enzyme (ACE), AngII and Ang‐(1–7)) were made. In addition, we studied the effect of a peripherally administered AngII type 1 (AT1) receptor antagonist (irbesartan at 1.02 mg/kg per h) on mean arterial pressure (MAP) over 4.5 h.3. There was no significant difference in basal plasma concentrations of the components of the RAS measured between control (n = 7) and PTG1 (n = 5) or PTG2 (n = 6) animals. The MAP in PTG1 was significantly higher than in the control group during both vehicle infusion and AT1 receptor blockade. The effect of 4.5 h irbesartan (1.02 mg/kg per h) infusion on blood pressure was similar between the groups.4. In conclusion, intrauterine exposure for 48 h to maternally administered dexamethasone at 27 days of gestation caused elevated blood pressure in adult sheep that does not appear to be associated with an alteration in the peripheral RAS.
KCa Channel‐Opening Activity Of Ginkgo Biloba Extracts And Ginsenosides In Cultured Endothelial Cells
Authors: Li Zy , Nakaya Y , Niwa Y , Chen X 
Published: March 2003

SUMMARY1. Extracts of Ginkgo biloba (EGb) and ginsenosides (GS) have been reported to induce vasorelaxation. In the present study, the role of K+ channels in the action of EGb and GS to activate nitric oxide synthase (NOS) activity was investigated in cultured endothelial cells.2. Nitric oxide synthase activity of cultured endothelial cells detected by the reduced nicotinamide adenine dinucleotide phosphate (NADPH) histochemistry method was significantly increased after treatment with 20 μg/mL EGb or 40 μg/mL GS plus 10 mmol/L L‐arginine. The effect was completely abolished by the addition of 0.5 μmol/L Nω‐nitro‐L‐arginine, an inhibitor of NOS, to the incubation medium and partially inhibited by 10 μmol/L tetraethylammonium (TEA), an inhibitor of Ca2+‐activated K+ (KCa) channels.3. Application of EGb to the intracellular surface of excised inside‐out patches activated K+ channels in a concentration‐dependent manner in the concentration range 1–100 μg/mL. Channel activity was also activated by application of GS at concentrations ranging from 1 to 300 μg/mL. The modulation of channel activity was inhibited by 0.5 mmol/L TEA but not by 0.5 mmol/L glibenclamide, an inhibitor of ATP‐sensitive K+ channels.4. Thus, in cultured endothelial cells, the increase in NOS activity induced by EGb or GS depends on the activity of KCa channels. These compounds may regulate nitric oxide release by changing the cell membrane potential in vascular endothelial cells.
Early Rise In Blood Pressure Following Administration Of Adrenocorticotropic Hormone‐[1–24] In Humans
Authors: Jackson RV , Nye EJ , Grice JE , Hockings GI , Strakosch CR , Walters MM , Crosbie GV , Torpy DJ , Whitworth JA 
Published: March 2003

SUMMARY1. An elevation in blood pressure has been consistently observed 24 h after adrenocorticotropic hormone (ACTH) administration and is caused by increased ACTH‐stimulated cortisol secretion, in association with increased cardiac output. The aim of the present study was to investigate the previously undefined time of onset of this increase in blood pressure in normal humans.2. Ten normal healthy volunteers received 250μg ACTH‐[1–24], in 500 mL normal saline, infused at a constant rate over 8 h. Six subjects also received a placebo infusion (normal saline only). Blood pressure, heart rate and cortisol levels were determined hourly. Adrenocorticotropic hormone (ACTH‐[1–24] plus native ACTH) was measured at 0, 1, 7 and 8 h.3. Infusion of ACTH‐[1–24] produced maximal secretion rates of cortisol, resulting in a mean peak plasma level of 985±46 nmol/L at 8 h. In response, blood pressure and heart rate rose significantly by 2 h and remained generally elevated for the duration of the infusion.4. The early onset of haemodynamic responses is consistent with classical steroid receptor‐mediated genomic mechanisms, but could be due non‐genomic mechanisms.5. The cardiovascular consequences of therapeutic use of ACTH are well recognized. This results of the present study suggest that even diagnostic administration of ACTH, delivered over a few hours, may raise blood pressure.
Adenoviral Vector‐Mediated Delivery Of Glial Cell Line‐Derived Neurotrophic Factor Provides Neuroprotection In The Aged Parkinsonian Rat
Authors: Connor Bronwen 
Published: March 2003

SUMMARY1. The long‐term delivery of neurotrophic factors to specific regions of the central nervous system via gene therapy offers a new strategy for the treatment of neurodegenerative disorders.2. The neurotrophic factor glial cell line‐derived neurotrophic factor (GDNF) is a potent dopaminergic (DA) trophic factor that ameliorates the behavioural and histological consequences of lesioning DA neurons in rodent and primate models of Parkinson’s disease.3. Glial cell line‐derived neurotrophic factor gene therapy may have a potential use in the clinical treatment of Parkinson’s disease.4. We examined whether injection of an adenoviral vector encoding human GDNF preproprotein (Ad GDNF) could protect the rat nigrostriatal DA system from progressive neuronal degeneration. Because Parkinson’s disease occurs primarily in the elderly population, we studied the effect of GDNF gene delivery in an aged rat model of Parkinson’s disease.5. In the aged (20 month) Fischer 344 rat, Ad GDNF was injected either near DA cell bodies in the substantia nigra (SN) or at the DA terminals in the striatum. One week following gene delivery, the neurotoxin 6‐hydroxydopamine (6‐OHDA) was injected unilaterally into the striatum to cause progressive degeneration of the DA neurons.6. Injection of GDNF vector into either the striatum or the SN provided significant cell protection against 6‐OHDA. However, only striatal injection of Ad GDNF protected against the development of behavioural and neurochemical changes that occur in the DA‐depleted brain.7. The results of this study are reviewed here and the behavioural and cellular effects of GDNF gene delivery into striatal versus mesencephalic sites are discussed.
Postnatal Outcomes In Term And Preterm Lambs Following Fetal Growth Restriction
Authors: Cock Ml , Camm Ej , Louey S , Joyce Bj , Harding R 
Published: March 2003

SUMMARY1. Epidemiological evidence indicates that low birthweight increases the risk of a number of adult‐onset diseases. It is now apparent that many babies with a low birthweight may have been subjected to a combination of reduced growth rates in utero as well as preterm birth. However, the long‐term effects of preterm birth following intra‐uterine growth restriction (IUGR) are unknown. Thus, our objectives were: (i) to identify prenatal factors associated with preterm birth in IUGR fetuses; and (ii) to characterize postnatal effects of preterm birth following IUGR.2. We studied pregnant sheep and their offspring, in which fetal growth was restricted by umbilico–placental embolization during late gestation. Some of these animals were born at term (146 ± 1 days) and some were born prematurely (139 ± 1 days). In both groups, we have conducted longitudinal studies of postnatal respiratory function, cardiovascular function and learning ability up to 6–8 weeks of age.3. Before birth, IUGR fetuses born prematurely (P‐IUGR) were more hypoxaemic and acidaemic and had higher haemoglobin concentrations than both control fetuses and IUGR fetuses born at term (T‐IUGR). In P‐IUGR fetuses, plasma cortisol concentrations increased earlier than in the two other groups. The P‐IUGR lambs had lower birthweights than T‐IUGR lambs and both groups of IUGR lambs remained lighter than controls for 8 weeks.4. After birth, P‐IUGR lambs were hypoxaemic compared with T‐IUGR and control lambs. Pulmonary diffusing capacity (adjusted for lung volume) was significantly lower in both groups of IUGR lambs than in controls, with P‐IUGR lambs having lower values than T‐IUGR lambs. Lung compliance (adjusted for lung volume), was not different between P‐IUGR and control lambs, but values were higher in T‐IUGR lambs than in control and P‐IUGR lambs. Chest wall compliance (adjusted for lung volume) was higher in both groups of IUGR lambs than in controls.5. During the 8 week postnatal study period, both groups of IUGR lambs had lower mean arterial pressures than control lambs; this relative hypotension was greatest in P‐IUGR lambs.6. In tests of learning ability, P‐IUGR lambs took longer to complete a simple maze task at all ages and, in the second postnatal week, made a greater number of errors compared with controls. In an obstacle course, P‐IUGR lambs recorded longer trial durations; they also made more errors than control lambs.7. We conclude that preterm birth in the presence of late‐ gestational placental insufficiency and IUGR can result in specific effects on respiratory and cardiovascular development after birth, in addition to the effects of IUGR alone.
Sex, Genes And Blood Pressure
Authors: Ellis Justine A , Wong Zilla YH , Stebbing Margaret , Harrap Stephen B 
Published: March 2003

SUMMARY1. Throughout most of life, males have higher average blood pressures than females. This sexual dichotomy may be related to genetic factors including the X and Y sex chromosomes and genes that control sex steroids. Resultant physiological differences between men and women may also be relevant to the quantitative variation of blood pressure within the sexes.2. The present overview collates our published and novel sex‐related genetic data in relation to blood pressure from the Victorian Family Heart Study. These include a multipoint quantitative linkage analysis of the X chromosome and genetic association studies of single nucleotide polymorphisms (SNP) of the Y chromosome and genes encoding the androgen receptor (AR), oestrogen receptor α (ERα), 5α‐reductase types I and II (SRD5A1 and SRD5A2) and aromatase (CYP19).3. Systolic blood pressure (SBP) was linked (Z = 3.3, genome‐wide P < 0.05) to a region of the X chromosome that encompassed the AR gene and the Y chromosome was associated with diastolic blood pressure (DBP; P = 0.03). In new analyses, we observed a possible association between a SNP in AR and DBP in 369 males (84.5 vs 82.1 mmHg for genotype A vs genotype B, respectively; P = 0.06) and a significant association between haplotypes of the Y chromosome and AR SNP in males (P = 0.01) with a difference of nearly 6 mmHg DBP between extreme groups. Associations were also observed for polymorphisms of SRD5A1 and ERα with DBP and SBP in males, respectively.4. The findings indicate that genes related to sexual phenotypes may be relevant to the normal variation in blood pressure, even within the sexes. Further genetic and physiological analyses will be required to confirm these observations and to determine the mechanisms of action and the nature of any interactions.
Role Of Augmented Expression Of Intermediate‐Conductance CA2+‐Activated K+ Channels In Postischaemic Heart
Authors: Saito Takashi , Fujiwara Yoshimasa , Fujiwara Risako , Hasegawa Hitoshi , Kibira Satoshi , Miura Hiroto , Miura Mamoru 
Published: March 2003

SUMMARY1. The rat intermediate conductance calcium‐activated potassium channel (ImK) was cloned from a cDNA library of vascular smooth muscle cells (VSM) in rat pulmonary artery. The ImK distributes in a variety of tissue, including VSM, endothelial cells, leucocytes and fibroblasts. The ImK has a tyrosine phosphorylation consensus site in the proximal portion of the C‐terminus and motifs exist for the DNA‐binding protein AP‐1 in the promoter, suggesting this channel is upregulated and active in cell cycle functions. The aim of the present study was to examine the role of ImK in postischaemic cardiovascular remodelling in relation to the angiotensin AT1 receptor‐mediated AP‐1 signalling pathway.2. Rats underwent left coronary artery ligation for periods between 1 day and 3 weeks. The temporal profile of expression of ImK mRNA was analysed by RNase protection assay. To test the effect of AT1 receptor blockade, candesartan (3 mg/kg per day) was administered via an osmotic mini‐pump implanted in the intraperitoneal space 3 days prior to coronary occlusion.3. ImK expression in postischaemic hearts showed a significant increase with two distinct peaks; the first peak at day 3 (2.7‐fold compared with control levels; P
< 0.001) and the second after 2 weeks (1.5‐fold; P < 0.01). Reperfusion
following 30 min of ischaemia markedly accelerated and augmented the first peak at
days 1–3 (4.8‐fold), but completely abolished the second peak after 1–2
weeks (0.8‐fold). In situ hybridization of ImK mRNA and immunostaining of ImK protein with specific antibody revealed that this was not only the result of the increase in ImK expression in vascular cells, but also related to infiltration of mononuclear leucocytes and fibroblasts into the ischaemic region. Candesartan inhibited cardiac hypertrophy and perivascular fibrosis of coronary arterioles in the non‐ischaemic region. Candesartan also abrogated both peaks in ImK expression.4. These findings indicate that both the inflammatory reaction and the postischaemic cardiovascular remodelling promote increased expression of ImK in postischaemic hearts via the AT1 receptor‐mediated AP‐1 signalling pathway.
Role Of Angiotensin II Receptors In The Regulation Of Vasomotor Neurons In The Ventrolateral Medulla
Authors: Dampney RAL , Fontes MAP , Hirooka Y , Horiuchi J , Potts PD , Tagawa T 
Published: March 2003

SUMMARY1. There is a high density of angiotensin type 1 (AT1) receptors in various brain regions involved in cardiovascular regulation. The present review will focus on the role of AT1receptors in regulating the activity of sympathetic premotor neurons in the rostral part of the ventrolateral medulla (VLM), which are known to play a pivotal role in the tonic and phasic regulation of sympathetic vasomotor activity and arterial pressure.2. Microinjection of angiotensin (Ang) II into the rostral VLM (RVLM) results in an increase in arterial pressure and sympathetic vasomotor activity. These effects are blocked by prior application of losartan, a selective AT1receptor antagonist, indicating that they are mediated by AT1receptors. However, microinjection of AngII into the RVLM has no detectable effect on respiratory activity, indicating that AT1receptors are selectively or even exclusively associated with vasomotor neurons in this region.3. Under normal conditions in anaesthetized animals, AT1receptors do not appear to contribute significantly to the generation of resting tonic activity in RVLM sympathoexcitatory neurons. However, recent studies suggest that they contribute significantly to the tonic activity of these neurons under certain conditions, such as salt deprivation or heart failure, or in spontaneously hypertensive or genetically modified rats in which the endogenous levels of AngII are increased or in which AT1receptors are upregulated.4. Recent evidence also indicates that AT1receptors play an important role in mediating phasic excitatory inputs to RVLM sympathoexcitatory neurons in response to activation of some neurons within the hypothalamic paraventricular nucleus. The physiological conditions that lead to activation of these AT1receptor‐mediated inputs are unknown. Further studies are also required to determine the cellular mechanisms of action of AngII in the RVLM and its interactions with other neurotransmitters in that region.