bluuebunny/crossref_metadata_2025 huggingface dataset:
CHOLINERGIC PREJUNCTIONAL INHIBITION OF NITRERGIC NEUROTRANSMISSION IN THE GUINEA‐PIG ISOLATED BASILAR ARTERY
Authors: Jiang Fan , Li Chun Guang , Rand Michael J
Published: March 2003

1. The effects of endogenous and exogenous acetylcholine (ACh) on nitrergic relaxations elicited by electrical field stimulation (EFS) were studied in guinea‐pig endothelium‐denuded basilar artery preparations precontracted with 1 μmol/L prostaglandin F2α and a possible role of K+ channels in mediating the effects was investigated.

2. Acetylcholine (3 mmol/L) and physostigmine (10 μmol/L) produced small, yet statistically significant, inhibitions of EFS‐induced nitrergic relaxations, while atropine (1 μmol/L) slightly enhanced the nitrergic response. The ACh‐induced inhibition was atropine sensitive. Acetylcholine or atropine did not affect relaxations induced by sodium nitroprusside.

3. The inhibition of nitrergic relaxations by 3 μmol/L ACh was prevented by the K+ channel blockers tetraethylammonium and 4‐aminopyridine, but was not changed by iberiotoxin, apamin or glibenclamide.

4. Neither vasoactive intestinal polypeptide nor the α2‐adrenoceptor agonists noradrenaline and clonidine modulated nitrergic neurotransmission in the guinea‐pig basilar artery.

5. The findings show that ACh acts on prejunctional muscarinic receptors of nitrergic nerves to inhibit nitrergic neurotransmission. It is suggested that endogenous ACh may have this effect; however, the physiological significance of this prejunctional modulation is not clear due to the relatively small effect produced. The prejunctional inhibitory action of ACh may involve opening of neuronal K+ channels.
UROKINASE PLASMINOGEN ACTIVATOR SYSTEM IN HUMANS WITH STABLE CORONARY ARTERY DISEASE
Authors: Krasnikova Tl , Parfyonova YeV , Alekseeva Ia , Arefieva Ti , Mukhina Sa , Dobrovolsky Ab , Titaeva YeV , Lyakishev Aa , Resink Tj , Erne P , Tkachuk Va
Published: March 2003

1. The present study compares plasma urokinase plasminogen activator (uPA) peptide levels, plasma plasminogen inhibitor (PAI‐1) activity and urokinase receptors (uPAR) on peripheral blood monocytes of patients with stable coronary artery disease (SCAD) and healthy volunteers.

2. Urokinase plasminogen activator levels were analysed by ELISA and PAI‐1 activity was determined by a plasmin generation method using the chromogenic substrate S2390. Relative uPAR numbers and the adhesion molecules CD11b/CD18 on peripheral blood monocytes were estimated using specific antibodies and flow cytometry.

3. Patients with SCAD were found to have higher plasma uPA peptide levels than age‐matched healthy subjects (10.40±0.99 vs 8.25±0.53 pmol/L, respectively; P < 0.05).

4. Plasma PAI‐1 activity was also higher in patients with SCAD than in healthy subjects (13.6±2.5 vs 5.2±1.0 IU/mL, respectively; P < 0.05).

5. Relative uPAR and CD11b/CD18 adhesion molecules were similar on peripheral blood monocytes of patients with SCAD and in healthy subjects.

6. The data indicate a pattern of expression/activity of uPA and PAI‐1 in patients with SCAD suggestive of an impaired fibrinolytic ability.
PERTUSSIS TOXIN‐SENSITIVE G‐PROTEINS AND REGULATION OF BLOOD PRESSURE IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Jr Curtis K Kost , Herzer William A , Li Ping J , Jackson Edwin K
Published: March 2003

1. Increased Gi‐protein‐mediated receptor–effector coupling in the vasculature of the spontaneously hypertensive rat (SHR) has been proposed as a contributing factor in the maintenance of elevated blood pressure. If increased Gi‐protein‐mediated activity plays an important role in hypertension in SHR, then inhibition of Gi‐proteins by pertussis toxin would be expected to decrease blood pressure in this genetic hypertensive model. To address this hypothesis, studies were undertaken comparing the cardiovascular effects of pertussis toxin in SHR and normotensive Wistar‐Kyoto (WKY) rats.

2. Spontaneously hypertensive and WKY rats were instrumented with radiotelemetry devices and blood pressure measurements were recorded in conscious rats. Following a single injection of pertussis toxin (10 μg/kg, i.v.), mean arterial blood pressure fell from 161±3 to 146±1 mmHg in the SHR and the effect was sustained for more than 2 weeks. In contrast, 10 μg/kg, i.v., pertussis toxin produced no significant effect on blood pressure in WKY rats (103±4 vs 101±5 mmHg).

3. In a separate study, SHR and WKY rats were administered 30 μg/kg, i.v., pertussis toxin or 150 μL/kg, i.v., saline and, 3–5 days later, rats were anaesthetized and instrumented to permit measurement of blood pressure and renal function. At this higher dose, pertussis toxin reduced blood pressure in both strains of rat, although the effect was markedly greater in SHR (approximately 40 mmHg decrease) compared with WKY rats (approximately 15 mmHg decrease). In SHR, pertussis toxin increased renal blood flow (from 5.7±0.3 to 7.5±0.8 mL/min per g kidney) and decreased renal vascular resistance (from 31±2 to 19±2 mmHg/mL per min per g kidney). In WKY rats, pertussis toxin had no significant effect on renal parameters.

4. Results from these studies indicate that a pertussis toxin‐sensitive Gi‐protein‐mediated pathway contributes to the maintenance of hypertension and elevated renal vascular tone in the SHR.
DIURNAL VARIATIONS IN INSULIN SECRETION AND K+ PERMEABILITY IN ISOLATED RAT ISLETS
Authors: Delattre E , Cipolla‐Neto J , Boschero Ac
Published: March 2003

1. The effects of glucose on insulin secretion and 86Rb efflux from isolated rat islets were studied at six different times during a 24‐h period (00.00, 04.00, 08.00, 12.00, 16.00 and 20.00 h).

2. In the absence of glucose and in the presence of substimulatory concentrations (2.8 mmol/L) of the sugar, insulin secretion did not vary with the time of day. At a glucose concentration of 5.6 mmol/L the stimulated insulin secretion was greater than basal levels only at 20.00 h.

3. At a higher sugar concentration (8.3 mmol/L) the increase in insulin secretion and the reduction in 86Rb efflux rate were more marked during the dark period. No effect of the time of day on insulin secretion was observed at glucose concentrations above 8.3 mmol/L (except in 27.7 mmol/L).

4. The time of day appears to affect insulin secretion mainly at glucose concentrations close to physiological values (5.6–8.3 mmol/L).

5. This result agrees with the ability of physiological amounts of glucose to alter the 86Rb‐permeability of pancreatic B cells at the same time intervals.
PREVENTIVE NUTRITIONAL FACTORS IN EPIDEMIOLOGY: INTERACTION BETWEEN SODIUM AND CALCIUM
Authors: Mizushima Shunsaku , Tsuchida Kenichi , Yamori Yukio
Published: March 2003

1. It is generally believed, though difficult to prove, that diet plays a role in the risk of various diseases. Components of difficulties include several issues such as dietary assessment method, regression dilution bias, multicolinearity and interaction among nutrients.

2. The present study focuses on colinearity and interaction between sodium and calcium, which should be cautiously examined in nutritional epidemiological studies in relation to blood pressure and bone mineral density.

3. The World Health Organization’s International Cooperative Cardiovascular Diseases and Alimentary Comparison study showed significant multicolinearity among urinary sodium, calcium and urea nitrogen as well as urinary calcium and magnesium. Urinary sodium and calcium had significant correlation (r = 0.438, P < 0.05, n = 48) by cross‐centre analysis.

4. Interaction between sodium and calcium on bone mineral density is studied using the data set from bone mineral density screening for 1658 females, aged 20–40 years, in Yokohama, Japan. Among those who have lower calcium intake (< 600 mg/day), higher calcium intake (%) from small fish, which is likely to be associated with a high salt diet, related to significantly lower mineral bone density.

5. Interaction between sodium and calcium on bone mineral density among young Japanese females is suggested. Moderate sodium restriction is needed for prevention of not only cardiovascular diseases but also osteoporosis.
GENETIC ANALYSIS IN DAHL SALT‐SENSITIVE RATS
Authors: Kato Norihiro
Published: March 2003

1. To investigate predisposition to hypertension in Dahl salt‐sensitive rats, genome‐wide screens were performed in F2 populations.

2. Several quantitative trait loci (QTL) for blood pressure were detected, of which some were shown to confer susceptibility genes by the construction of congenic animals carrying relevant chromosome fragments.

3. Chromosome regions homologous to one QTL (on rat chromosome 10) were recently shown to be linked to hypertension in humans. Thus, there is a possibility that a ‘common’ susceptibility gene causes hypertension in both species.
LOW DOSE INDAPAMIDE PLUS PERINDOPRIL COMBINATION EFFECTS ON CARDIOVASCULAR STRUCTURE AND FUNCTION IN GENETIC HYPERTENSION
Authors: Ibrahim Jamila , Schachter Michael , Hughes Alun D , Sever Peter S
Published: March 2003

1. Although the fixed combination preparations of thiazide and angiotensin‐converting enzyme inhibitor are gaining wide acceptance in clinical practice, data on the basic pharmacology of the combinations are relatively limited. The long‐term structural and functional effects of a fixed low dose (0.24 + 0.76 mg/kg per day) combination of indapamide + perindopril (I + P, S5590) in spontaneously hypertensive rats (SHR) were examined in the present study.

2. Male SHR (10–12 weeks) were treated with I + P or vehicle for 8 weeks. The blood pressure and heart rate were monitored by weekly measurements. At the end of the treatment period, left ventricular, aortic and intramyocardial coronary arteriole structures were assessed. Contractile and relaxant properties of mesenteric arteries were determined by wire‐myography.

3. Indapamide + perindopril combination caused a significant lowering of both systolic (P < 0.001) and diastolic (P < 0.001) blood pressures. Left ventricle plus septum:bodyweight ratio (P < 0.001), aortic medial cross‐sectional area (P < 0.05) and media:lumen ratios (P < 0.005) were all significantly reduced by I + P treatment. In contrast, the effect of I + P on intramyocardial coronary vascular structure did not reach statistical significance. There was some improvement in endothelium‐ independent vasorelaxation of mesenteric vessels but contractile responses to noradrenaline and calcium were unaffected by treatment.

4. In summary, a low dose I + P combination treatment of SHR partly normalizes both systolic and diastolic blood pressures. Cardiac and larger vessel hypertrophy was reversed but intramyocardial coronary arteriole structure was not as readily regressed by the end of the study.
CHANGES OF URINARY DOPAMINE EXCRETION EARLY AFTER BALLOON MITRAL COMMISSUROTOMY IN MITRAL STENOSIS
Authors: Hayashi Manabu , Takizawa Hideki , Tsuchihashi Kazufumi , Ura Nobuyuki , Shimamoto Kazuaki
Published: March 2003

1. In order to investigate the changes of reduced urinary free dopamine excretion (uDA) in heart failure, 15 patients with symptomatic mitral stenosis were investigated on their uDA, endogenous creatinine (Cr) clearance, urinary excretion of sodium (UNaV), fractional excretion of sodium (FENa), plasma noradrenaline (pNA) and plasma L‐dopa concentration before and early after percutaneous transvenous mitral commissurotomy (PTMC) by the clearance study. The delivery of L‐dopa to renal proximal tubules (plasma L‐dopa × Cr clearance), and the conversion ratio of plasma L‐dopa to urinary dopamine in the kidney [uDA/(plasma L‐dopa × Cr clearance)] were also estimated.

2. After successful PTMC, uDA, UNaV and FENa showed a significant but incomplete improvement and the changes of uDA were correlated positively with those of cardiac index (CI) (r = 0.665, P < 0.01), not with changes of pulmonary wedge pressure. While plasma L‐dopa and plasma L‐dopa × Cr clearance improved, uDA/(plasma L‐dopa × Cr clearance) was not significantly changed early after PTMC.

3. From these results, it was suggested that reduced uDA tended to increase incompletely in relation with functional recovery of heart, and that increased plasma L‐dopa and a delivery of L‐dopa to renal proximal tubules have some positive role on urinary dopamine excretion, at least, early after PTMC.
Participation Of Central and Peripheral κ1 and κ2 Opioid Receptors In Arrhythmogenesis
Authors: Lishmanov Yury B , Maslov Leonid N , Ugdyzhekova Dina S
Published: March 2003

1. The κ1 and κ2 opioid receptor agonists U‐62066 (8 mg/kg, i.p.) and (–)‐bremazocine (0.7 mg/kg, i.v.), respectively, both exhibit anti‐arrhythmic properties against adrenaline‐induced dysrhythmias in rats.

2. In contrast, (+)‐bremazocine has no effect on adrenaline‐induced dysrhythmias.

3. The κ1 opioid receptor agonists U‐50 488 (110 nmol) and [
D‐Ala
2]‐dynorphin A (20 nmol) and the κ2 opioid receptor agonist (–)‐bremazocine (30 nmol) exhibit pro‐arrhythmic properties following intracerebroventricular administration.

4. Prior administration of the κ opioid receptor antagonist nor‐binaltorphimine doses i.c.v. (14 nmol), i.p. (10 mg/kg), completely abolishes the pro‐arrhythmic (BNI, i.c.v., 14 nmol) as well as anti‐arrhythmic (BNI, 10 mg/kg, i.p.) effects of the κ opioid receptor agonists.

5. Neither hexamethonium (10 mg/kg, i.v.) nor atropine (1 mg/kg, i.v.) have any effect on the anti‐arrhythmic actions of the κ1 opioid receptor agonist U‐62066 following systemic administration.

6. It is suggested that the anti‐arrhythmic effects of U‐62066 and (–)‐bremazocine are associated with the activation of peripheral κ opioid receptors and do not depend on the activation of κ opioid receptors in the autonomic nervous system.
FOETAL FLUID BALANCE AND HORMONE STATUS FOLLOWING NEPHRECTOMY IN THE FOETAL SHEEP
Authors: Moritz Karen M , Macris Mary , Talbo Gert , Wintour E Marelyn
Published: March 2003

1. The role of the kidneys in the maintenance of normal foetal plasma (FP) composition and hormone concentrations was examined in the present study. Five ovine foetuses were chronically cannulated and nephrectomized (nephx) at 100±1 days of gestation and maintained for 14 days. These were compared to five intact control foetuses.

2. Four hours after nephx, FP renin concentrations were significantly lower than in control foetuses. By 48 h, renin concentrations in nephx foetuses were below the level of detectability of the assay. Foetal plasma aldosterone concentrations declined in nephx foetuses, but were not significantly different to those in control foetuses (P = 0.08).

3. During the second week, the nephx foetuses were significantly hypoxic, but FP erythropoietin concentrations were not increased. Adrenocorticotropic hormone (ACTH) and cortisol concentrations, when measured on day 14, were not different between the two groups. Adrenocorticotropic hormone levels were correlated with adrenal weight at post‐mortem.

4. Foetal plasma creatinine, magnesium and phosphate concentrations in nephx foetuses increased, eventually reaching values approximately twice that in controls. Foetal plasma chloride levels decreased continuously in nephx foetuses, eventually being 23 mmol/L lower than controls. Maternal plasma composition was unchanged.

5. Total foetal fluid (amniotic + allantoic) volumes were reduced when measured at post‐mortem on day 14 after nephx. The composition of both fluids was significantly altered in the nephx foetuses compared with controls.

6. Fetuses can survive in utero for 2 weeks after bilateral nephrectomy. However, there are multiple changes in plasma composition that may compromise foetal survival in the long term.
Effect Of Uranyl Nitrate‐Induced Renal Failure On Morphine Disposition And Antinociceptive Response In Rats
Authors: Crugten Jacoba T Van , Nation Roger L
Published: March 2003

1. The aims of the present study were to administer morphine (14.0 μmol/kg, s.c.) to male Hooded Wistar rats and to determine the effect of uranyl nitrate‐induced renal failure on: (i) the antinociceptive effect of morphine; (ii) the pharmacokinetics of morphine and morphine‐3‐glucuronide (M3G); and (iii) the relationship between antinociceptive effect and the pharmacokinetics of morphine in plasma and brain.

2. Renal failure was induced by a single s.c. injection of uranyl nitrate and kinetic/dynamic studies were performed 10 days after its administration, when creatinine clearance was 17% of the control group. Antinociceptive effect was measured by the tail‐flick method at various times up to 2 h post‐drug administration. Concentrations of morphine and M3G in plasma and brain and concentrations of creatinine in urine and serum were determined by specific HPLC methods.

3. After morphine administration, the area under the antinociceptive effect–time curve was decreased by 44% in renal failure rats. There were no differences between control and renal failure rats in: (i) plasma morphine concentration–time curves; (ii) brain morphine concentration–time curves; and (iii) plasma M3G concentration–time curves. Morphine‐6‐glucuronide was not detected in any plasma or brain sample from rats administered morphine and no M3G was detected in brain.

4. For both control and renal failure rats, the relationships between antinociceptive effect and plasma morphine concentration were characterized by counterclockwise hysteresis loops, probably reflecting a delay for the relatively polar morphine to cross the blood–brain barrier. The relationship between antinociceptive effect and brain morphine concentration in control rats revealed no evidence of acute tolerance and was described by a sigmoidal function. In contrast, the relationship in renal failure rats was characterized by clockwise hysteresis, which is consistent with acute tolerance development.
Congenic Rats For Hypertension: How Useful Are They For The Hunting Of Hypertension Genes?
Authors: Nabika Toru , Kobayashi Yuta , Yamori Yukio
Published: March 2003

1. Linkage studies have revealed quantitative trait loci (QTL) for blood pressure in the rat genome using genetic hypertensive rat models. To identify the genes responsible for hypertension, the construction of congenic rats is essential.

2. To date, several congenic strains have been obtained from spontaneously hypertensive or Dahl salt‐sensitive rats. The results of these studies should be interpreted according to whether the rats carry the whole QTL region or not.

3. After establishing congenic strains, three strategies are possible: (i) an orthodox positional cloning in which, using subcongenic strains, the QTL region is cut down to smaller fragments suitable for physical mapping; (ii) a positional candidate strategy in which candidate genes in the QTL regions are studied; or (iii) physiological studies in which intermediate phenotypes directly associated with the hypertension gene are explored. Several other experimental strategies are also available using congenic strains as new animal models for hypertension.

4. To make the most of advances in DNA technology, the precise evaluation of the phenotypic difference between congenic strains carrying different QTL or between a congenic and parental strain is critical.
Greater Blood Pressure‐Lowering Effect Of The Renin Inhibitor EMD 58265 Than An Angiotensin‐Converting Enzyme Inhibitor In Two‐Kidney One‐Clip Goldblatt Rabbit
Authors: Zimmerman Ben G
Published: March 2003

1. Renin inhibitors may be more advantageous than either angiotensin‐converting enzyme (ACE) inhibitors or angiotensin (Ang) antagonists in blocking the renin–angiotensin system (RAS) because they do not allow accumulation of either AngI or AngII in plasma.

2. Effects of i.v. administration of two human renin inhibitors (EMD 58265 and U 71038) were compared with the ACE inhibitor enalaprilat on mean blood pressure (BP), renal blood flow (RBF) and plasma AngI and AngII in the anaesthetized two‐kidney one‐clip Goldblatt rabbit.

3. At doses of 2–2.5 mg/kg, i.v., EMD 58265 and 5–10 mg/kg, i.v., U 71038, both drugs decreased BP approximately 10 mmHg more than enalaprilat (2–4 mg/kg, i.v.) when given either before or after the ACE inhibitor. None of the three agents had any significant effect on RBF in the face of the lowered BP; however, renal vascular resistance was decreased. A higher dose of enalaprilat (10 mg/kg, i.v.) had no further effect on BP than the lower doses but did cause a marked increase in RBF.

4. Both renin inhibitors markedly decreased plasma AngI, but the high basal level of AngII was less consistently and only modestly affected. Enalaprilat, in either the low dose range or at the high dose, was also not effective in significantly decreasing AngII.

5. The results indicate that renin inhibition in the rabbit with a high circulating AngII level is more effective in lowering BP than ACE inhibition. A high dose of the ACE inhibitor may be required to block the intrarenal RAS, which may account for the increase in RBF.
Calcium‐Activated Potassium Currents In Mammalian Neurons
Authors: Sah Pankaj , Davies Phil
Published: March 2003

1. Influx of calcium via voltage‐dependent calcium channels during the action potential leads to increases in cytosolic calcium that can initiate a number of physiological processes. One of these is the activation of potassium currents on the plasmalemma. These calcium‐activated potassium currents contribute to action potential repolarization and are largely responsible for the phenomenon of spike frequency adaptation. This refers to the progressive slowing of the frequency of discharge of action potentials during sustained injection of depolarizing current. In some cell types, this adaptation is so marked that despite the presence of depolarizing current, only a single spike (or a few spikes) is initiated. Following cessation of current injection, slow deactivation of calcium‐activated potassium currents is also responsible for the prolonged hyperpolarization that often follows.

2. A number of macroscopic calcium‐activated potassium currents that can be separated on the basis of kinetic and pharmacological criteria have been described in mammalian neurons. At the single channel level, several types of calcium‐activated potassium channels also have been characterized. While for some macroscopic currents the underlying single channels have been unambiguously defined, for other currents the identity of the underlying channels is not clear.

3. In the present review we describe the properties of the known types of calcium‐activated potassium currents in mammalian neurons and indicate the relationship between macroscopic currents and particular single channels.
Extrarenal Renin–Angiotensin Systems Are Unable To Maintain Blood Pressure In Sheep
Authors: Bonnet Jeanne‐Marie , Boivin Robert , Bernard Nicole , Sassard Jean
Published: March 2003

1. The present study was designed to assess the participation of extrarenal tissue renin–angiotensin systems (RAS) in pressure homeostasis in sheep.

2. The effect of the administration of an angiotensin II type 1 receptor antagonist (losartan; 30 mg/kg, i.v.) on mean arterial blood pressure (MABP) was investigated in eight intact (controls) and 10 binephrectomized sheep haemodialysed every 2 days for 10 days.

3. In control sheep, losartan decreased blood pressure and this decrease was significantly more marked after furosemide‐induced water and salt depletion. After nephrectomy and throughout the anephric period, losartan lost its hypotensive effect, while the plasma renin concentration fell to undetectable levels. Baseline MABP became significantly lower than at the beginning of the anephric period after 7 days. The inability to maintain blood pressure after several volume‐depleting haemodialysis sessions proved that an efficient system for blood pressure regulation was lacking after nephrectomy.

4. Renin gene expression measured by reverse transcription– polymerase chain reaction was found in liver, adrenal and arterial wall tissue. Neither nephrectomy nor sodium depletion enhanced this tissue renin gene expression.

5. In conclusion, the present work allows us to exclude an active role of extrarenal RAS in the maintenance of blood pressure. In addition, haemodialysis technology in nephrectomized sheep can be used as a good model for the study of extrarenal control of blood pressure.
Inositol 1,4,5‐Trisphosphate And Reperfusion Arrhythmias
Authors: Woodcock Elizabeth A , Arthur Jane F , Matkovich Scot J
Published: March 2003

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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.