bluuebunny/crossref_metadata_2025_split huggingface dataset:
ALDOSTERONE ACTION: FACT, FAILURE AND THE FUTURE
Authors: Funder John W. 
Published: June 2007

SUMMARY1. It is now 45 years since aldosterone was isolated and 25 years since its genomic action, via mineralocorticoid receptors (MR), was first described.2. Although the classic physiological role of aldosterone is to promote unidirectional transepithelial sodium transport, our ignorance of the mechanisms involved remains profound.3. Unanswered questions include: (i) the physiological significance of the equivalent, high affinity of MR for aldosterone, progesterone, corticosterone and Cortisol; (ii) the protein(s) induced as a direct transcriptional response to aldosterone; (iii) the physiological roles of MR in non‐epithelial tissues where aldosterone, in concert with salt loading, produces direct pathophysiological effects; (iv) how aldosterone occupies epithelial MR, despite the 100‐fold ‘advantage’ it enjoys over cortisol/corti‐costerone due to transcortin binding/11β‐hydroxysteroid dehydrogenase activity, as plasma glucocorticoid levels are approximately 2000‐fold higher; and (v) how epithelial MR, normally overwhelmingly occupied by glucocorticoids, are not transcriptionally active under normal circumstances in vivo, in contrast with transfection systems or the syndrome of apparent mineralocorticoid excess.4. Possible avenues for consideration of the last two of these questions are briefly proposed.
CORTISOL AND HYPERTENSION
Authors: Kelly JJ , Mangos G. , Williamson PM , Whitworth JA 
Published: June 2007

SUMMARY1. In humans, the hypertensive effects of adrenocorticotropic hormone (ACTH) infusion are reproduced by intravenous or oral Cortisol. Oral Cortisol increases blood pressure in a dose‐dependent fashion. At a dose of 80–200 mg/day, the peak increases in systolic pressure are of the order of 15mmHg. Increases in blood pressure are apparent within 24 h.2. Cortisol‐induced hypertension is accompanied by a significant sodium retention and volume expansion. Co‐administration of the type I (mineralocorticoid) receptor antagonist spironolactone does not prevent the onset of cortisol‐induced hypertension. Thus, sodium retention is not the primary mechanism of cortisol‐induced hypertension.3. Direct and indirect measures of sympathetic activity are unchanged or suppressed during Cortisol administration, suggesting that cortisol‐induced hypertension is not mediated by increased sympathetic tone.4. Preliminary evidence in humans suggests that suppression of the nitric oxide system may play a role in cortisol‐induced hypertension.5. These potential mechanisms of Cortisol action may be relevant in a number of clinical contexts, including Cushing's syndrome, apparent mineralocorticoid excess, the hypertension of liquorice abuse and chronic renal failure. There is also preliminary evidence suggesting a role for Cortisol in essential hypertension.
INTERACTION OF CIRCULATING HORMONES WITH THE BRAIN: THE ROLES OF THE SUBFORNICAL ORGAN AND THE ORGANUM VASCULOSUM OF THE LAMINA TERMINALIS
Authors: McKinley MJ , Allen AM , Burns P. , Colvill LM , Oldfield BJ 
Published: June 2007

SUMMARY1. Most circulating peptide hormones are excluded from much of the brain by the blood‐brain barrier. However, they do have access to the circumventricular organs (CVO), which lack the blood‐brain barrier. Three of the CVO, the subfornical organ (SFO), organum vasculosum of the lamina terminalis (OVLT) and area postrema, contain neurons responsive to peptides such as angiotensin II (Angll), atrial natriuretic peptide and relaxin.2. We have studied the patterns of neuronal activation, as shown by Fos expression, in the SFO and OVLT in response to systemically infused AngII, relaxin or hypertonic saline and have found subgroups of neurons activated by the different stimuli.3. Systemic infusion of relaxin or hypertonic saline activated neurons almost exclusively in the outer regions of the SFO and in the dorsal cap of the OVLT. Many of these neurons send axonal projections to regions of the brain subserving vasopressin secretion and thirst, such as the median preoptic, supraoptic and hypothalamic paraventricular nuclei.4. At moderate blood concentrations, AngII only stimulates neurons in the inner core of the SFO and lateral regions of the OVLT. Higher levels of AngII in the bloodstream activate additional neurons in the outer parts of the SFO that connect to the supraoptic, paraventricular and median preoptic nuclei and these probably mediate water drinking and vasopressin secretion induced by blood‐borne AngII. The efferent connections and the functions mediated by angiotensin‐sensitive neurons in the inner core of the SFO and lateral part of the OVLT are unknown.
REGULATION OF ALDOSTERONE BIOSYNTHESIS: THE END OF THE ROAD?
Authors: Müller Jürg 
Published: June 2007

SUMMARY1. Because aldosterone is the minority hormone of the adrenal cortex, its proper function depends on protective physiological mechanisms. These include a particular site of aldosterone biosynthesis in the zona glomerulosa of the adrenal cortex as well as a complex multifactorial control system, which adapts aldosterone production to acute and chronic changes in body sodium and potassium content, irrespective of pituitary adrenocorticotropic hormone (ACTH) secretion.2. Over the past decade, an important element of these mechanisms has been identified in the form of the enzyme involved in the final steps of aldosterone biosynthesis. In species such as the human, rat and mouse, the conversion of deoxycorticosterone to aldosterone is catalysed by an isozyme (CYP11B2) of cytochrome P450up (CYP11B1). The gene encoding this enzyme is expressed only in the zona glomerulosa. Its transcription is enhanced by sodium deficiency and potassium intake, but is suppressed by long‐term administration of high doses of ACTH.3. In contrast, the gene encoding CYP11B1 (i.e. the major (non‐aldosterone‐producing) type of the enzyme) is expressed mainly in the zona fasciculata and its expression depends on physiological concentrations of ACTH.4. In other animal species (cattle, pig, sheep), the major forms of cytochrome P45011β have an inherent aldosterone‐synthesizing activity, which is, however, selectively suppressed in mitochondria of zona fasciculata cells.5. The elucidation of the mechanisms involved in this suppression or of those mediating alterations in CYP11B2 expression in response to physiological stimuli may be important areas of future research on the regulation of aldosterone biosynthesis.
ORIGINS OF ZONATION: THE ADRENOCORTICAL MODEL OF TISSUE DEVELOPMENT AND DIFFERENTIATION
Authors: Vinson Gavin P. , Ho Mei Mei 
Published: June 2007

SUMMARY1. Although much work has addressed the functional significance of mammalian adrenocortical zonation, less attention has been paid to its developmental origins and the factors that maintain it. Recent concepts of tissue differentiation hold that cells respond to local morphogenic stimuli that are generated in a paracrine manner.2. In fact, the adrenal cortex represents an ideal mammalian in vivo model for such studies: few others exist. While several components may contribute to the establishment of a developmental polarity in the gland, including products of capsular and neural elements, compelling evidence now suggests that the tissue renin‐angiotensin system (HAS) has a critical role.3. We have examined the roles of these and other paracrine morphogens and growth factors and of specific transcription factors in adrenocortical cellular proliferation and development. From data obtained by using in situ hybridization to determine their cellular location, we propose a hierarchy of potential tissue modelling agents. These include morphogens, such as angiotensin II derived from the intra‐adrenal RAS, growth factors (e.g. basic fibroblast growth factor), which can be considered to be the paracrine amplifiers of the morphogenic signal, and, finally, transcription factors, such as C‐fos, that directly stimulate mitosis and other events of differentiation.
THE RENIN‐ANGIOTENSIN SYSTEM AND THE DEVELOPMENT OF THE KIDNEY AND ADRENAL IN SHEEP
Authors: Wintour E Marelyn , Alcorn Daine , Albiston Anthony , Boon Wah Chin , Butkus Aldona , Earnest Linda , Moritz Karen , Shandley Lynne 
Published: June 2007

SUMMARY1. The earliest form of the kidney, the pronephros, does not really occur in the ovine embryo; instead, a giant glomerulus forms at the anterior end of the mesonephros.2. In the sheep, the mesonephros is present from 11‐38% of total gestation (150 days) and produces a dilute urine, as well as expressing the genes for erythropoietin, renin, angioten‐sinogen, angiotensin‐converting enzyme and the angiotensin II (AngII) receptors AT1 and AT2.3. The ovine metanephros begins to develop at 18% of gestation and nephrogenesis is complete several weeks before birth. AH components of the renin‐angiotensin system (RAS) are expressed from at least 27% of gestation.4. Both AT1 and AT2 receptors are expressed by the adrenocortical cells early in gestation but, at mid‐gestation, exogenous AngII does not stimulate aldosterone secretion in vivo.5. Preliminary results suggest that Angll has important roles in renal development in the ovine foetus but the role(s), if any, in adrenal development, remains to be investigated.
HUMAN CYTOCHROME P450 ENZYMES EXPRESSED IN BACTERIA: REAGENTS TO PROBE MOLECULAR INTERACTIONS IN TOXICOLOGY
Authors: Gillam Elizabeth MJ 
Published: June 2007

SUMMARY1. Phase I metabolism of drugs is accomplished by the concerted actions of a limited number of cytochrome P450 enzymes with wide but often overlapping substrate specificities. Although metabolism generally accelerates the clearance of drugs, reactive products may also be generated that cause toxic effects.2. Because individuals vary in the range and levels of different P450 forms, it is useful to be able to determine the specific isoforms involved in a particular metabolic reaction, in order to estimate the extent of variation within a population in the pharmacokinetics of specific drugs. Such studies may also allow predictions to be made regarding the relative susceptibility of different individuals to possible adverse effects associated with drug treatment.3. Human cytochrome P450 enzymes are now routinely expressed as recombinant proteins in many different systems, including mammalian cell culture, yeast, baculovirus and Escherichia coli. The latter system is particularly useful when large amounts of protein are required for biophysical studies, but can also be adapted to routine examination of pathways of drug metabolism and toxicology.4. The present review provides an analysis of strategies used for enhancing cytochrome P450 expression in bacteria and for examining the activity of the recombinant proteins. The potential applications of recombinant P450 are discussed, with particular emphasis on investigation of the roles of cytochrome P450 forms in the metabolism and the toxicity of drugs.
A NEW METHOD FOR COMBINED ISOMETRIC AND ISOBARIC PHARMACODYNAMIC STUDIES ON PORCINE CORONARY ARTERIES
Authors: Tankó László B , Mikkelsen Erich O , Frøbert Ole , Bagger Jens P , Gregersen Hans 
Published: June 2007

SUMMARY1. The principal aim of the present study was to explore the isometric and isobaric capacity of a new intravascular technique, impedance planimetry, in basic pharmacodynamic investigations on porcine isolated epicardial coronary arteries.2. The balloon‐based catheter technique provides simultaneous measurements of luminal cross‐sectional area and pressure. Sources of errors that may influence the accuracy of measurements were evaluated in detail.3. Under isometric conditions, the stretch ratio‐tension diagram showed typical developments of resting and active tensions of the smooth muscle when exposed to alternating maximal K+ depolarization and mechanical stretching. The mean (±SEM) maximum active tension was 28.43 ± 1.72 mN/mm, which was reached at a stretch ratio of 1.26 ±0.02, corresponding to a resting tension of 10.50±0.53 mN/mm (n= 7). The concentration‐response relationship to K+ at optimal basal tension was characterized by a mean (±SEM) pD2 value of 1.67±0.01 (n= 7). 4. Under isobaric conditions in the pressure range 40‐140 mmHg, the method allowed the investigation of active vascular responses to partial K depolarization. The maximal active response to 25 mmol/L K+ was found at the transmural pressure of 60 mmHg (n= 7). To obtain full K+ concentration‐response curves, a basal tension corresponding to a transmural pressure of 120 mmHg was required. The mean (±SEM) pD2 value for the concentration‐response relationship to K+ was 1.53±0.01 (n= 10).
DECREASE WITH AGE IN FREQUENCY OF THE HOMOZYGOUS DELETIONAL ANGIOTENSIN‐CONVERTING ENZYME GENOTYPE IN HYPERTENSIVE PATIENTS*
Authors: Cheung Bernard MY , Lau Chu‐Pak , Leung Raymond YH , Tan Kathryn CB 
Published: June 2007

SUMMARY 1. Angiotensin‐converting enzyme (ACE) genotypes in hypertensive patients were studied in order to delineate their cardiovascular risk due to the ACE gene. We hypothesized that the distribution of ACE genotypes may change with age because of the risk of myocardial infarction associated with the homozygous deletional (DD) genotype. 2. A total of 223 subjects were recruited from the Hypertension Outpatient Clinic of the Sai Ying Pun Hospital with consent. They consisted of 75 patients with newly diagnosed or documented hypertension, 46 patients with ischaemic heart disease and 102 normal controls. Genomic DNA was extracted from peripheral leucocytes and amplified by polymerase chain reaction. Insertion (I) or deletion (D) alleles were identified after electrophoresis. The frequencies of ACE genotypes and alleles were measured in three age groups: < 50 years, 50‐59 years and > 60 years. 3. A significant correlation between ACE genotype and age was found (P= 0.03). The relative frequency of the D allele in those under 50 years of age was similar in controls and hypertensive patients (0.40 vs 0.41; P = 0.94), but was significantly lower in patients ≥ 50 years compared with those patients < 50 years of age (0.22 vs 0.41; P = 0.01). 4. The observed decrease in frequency of the DD genotype in older hypertensive patients is consistent with the increase in cardiovascular risk associated with the D allele and raises the possibility that the DD genotype may increase the risk of premature death, at least in the population studied.
EFFECTS OF CHROMAN DERIVATIVES ON PLATELET AGGREGATION INDUCED BY SOME AGGREGATING AGENTS IN RABBITS
Authors: Aida Yoko , Kasama Toshio , Fukaya Hiroaki , Takeuchi Naoki , Sugiyama Kumiko , Tobinaga Seisho 
Published: June 2007

SUMMARY1. We synthesized 10 chroman derivatives (CD‐1 to CD‐10) derived from khellactone, including praeruptorin A and praeruptorin B and examined the effects of these compounds on rabbit platelet aggregation.2. These compounds exhibited an inhibitory effect on platelet‐activating factor (PAF)‐induced platelet aggregation and their effects were more potent on PAF‐induced platelet aggregation than on adenosine triphosphate (ADP)‐, arachidonate (AA)‐ or collagen‐induced platelet aggregation. In particular, (±)‐cis‐5‐methoxy‐6‐methoxycarbonyl‐2,2‐dimethyl‐3,4‐ditiglyloxychro‐man (CD‐6), (±)‐cis‐5‐methoxy‐6‐(2‐methoxycarbonylethenyi)‐2,2‐dimethyl‐3,4‐ditiglyloxychroman (CD‐8), (±)‐cis‐3,4‐diacetoxy‐5‐methoxy‐2,2‐dimethyl‐6‐propylchroman (CD‐9) and (±)‐cis‐5‐methoxy‐2,2‐dimethyl‐6‐propyl‐3,4‐ditiglyloxy‐chroman (CD‐10) showed a moderate inhibition of PAF‐induced platelet aggregation.3. From these findings, it is suggested that compounds with potent PAF antagonist activities have the following features: (i) a tiglyloxy moiety is required at the 3 and 4 positions; and (ii) the methoxy moiety is also required at the 5 position of chroman skeleton in khellactone.
THE NITRIC OXIDE SYSTEM AND CORTISOL‐INDUCED HYPERTENSION IN HUMANS
Authors: Kelly John J , Tam Sim H , Williamson Paula M , Lawson Jane , Whitworth Judith A 
Published: June 2007

SUMMARY1. The aim of the present study was to assess the role of the nitric oxide (NO) system in cortisol‐induced hypertension in humans.2. Plasma and urinary nitrate/nitrite concentrations and plasma concentrations of arginine and symmetric (SDMA) and asymmetric (ADMA) dimethyl arginine were measured in six subjects on a restricted nitrate diet who were treated with 80 mg/day Cortisol and in subjects on an unrestricted nitrate diet who were treated with Cortisol (80 mg/day, n= 6, or 200 mg/day, n= 10) for 5 days.3. Cortisol significantly increased systolic and mean arterial pressure. Significant reductions in plasma nitrate/nitrite concentrations were observed in subjects on a restricted nitrate diet on days 3, 4 and 5 of Cortisol treatment (to 11±1, 10±1, 11± pmol/L, respectively) compared with pretreatment (16±1 pmol/L; P<0.01).There were no significant changes in plasma arginine, ADMA or SDMA concentrations.4. Cortisol treatment significantly increased blood pressure and reduced plasma nitrate/nitrite concentrations. Reductions in plasma nitrate concentrations are not explained by changes in substrate availability or in endogenous nitric oxide synthase inhibitors. These data support a role for the NO system in cortisol‐induced hypertension in humans.
CEREBROVASCULAR PRESSURE TRANSMISSION ANALYSIS AS A GUIDE TO THE PATHOPHYSIOLOGY OF RAISED INTRACRANIAL PRESSURE
Authors: Lewis SB 
Published: June 2007

SUMMARY1. Raised intracranial pressure (ICP) is a major factor associated with morbidity and mortality in patients with severe head injury. Identifying the mechanisms responsible for raised ICP may be difficult and, as a result, treatment prescribed may be non‐specific and often ineffective.2. Research aimed at obtaining more information from measurement of ICP was initially focused on measurements of compliance. This was achieved by introducing fluid volume into the craniospinal compartment and measuring the response. Although shown to be clinically useful, associated technical problems have precluded the routine use of these measurements.3. Cerebrovascular pressure transmission (CVPT) analysis has been suggested as an alternative method of deriving more information from the ICP wave‐form. Pressure transmission across the cerebrovascular bed is assessed by a systems analysis approach whereby blood pressure and ICP wave‐form pairs are resolved by fast Fourier transform analysis into component harmonic frequencies, each with a specific amplitude and phase. These are expressed as a ratio or ‘transfer function’ for each harmonic peak.4. Laboratory models have identified specific CVPT patterns associated with various causes of raised ICP. These studies have been extended to clinical practice and have been used to define patterns of CVPT in head‐injured patients, which may be used to identify mechanisms responsible for raised ICP, thus assisting in directing treatment strategy. Clinical usefulness of this technique in patient management is currently under investigation.
THE CONSEQUENCES OF DEAFNESS AND CHRONIC INTRACOCHLEAR ELECTRICAL STIMULATION ON THE CENTRAL AUDITORY PATHWAYS
Authors: Hardie Natalie Anne 
Published: June 2007

SUMMARY1. Auditory deprivation can result in significant morphological and physiological changes within the central auditory nervous system. These changes are generally more pronounced when the onset of deafness occurs early in development, as is the case with congenitally deaf children.2. A review of the auditory plasticity literature suggests that some of these deafness‐induced changes may be preventable or partially reversible by electrical stimulation of the auditory nerve.3. With the increasing application of cochlear implants in congenitally deaf children, it is important to evaluate the consequences of introducing electrical stimulation to the developing auditory nervous system.
PROPOFOL BLOCK OF CARDIAC SODIUM CURRENTS IN RAT ISOLATED MYOCARDIAL CELLS IS INCREASED AT DEPOLARIZED RESTING POTENTIALS
Authors: Saint David A , Tang Yulu 
Published: June 2007

SUMMARY1. The effect of propofol on cardiac whole‐cell sodium currents and single sodium channels in rat isolated ventricular myocytes was examined using patch‐clamp techniques.2. Propofol caused a block of the whole‐cell sodium current, the potency of block depending on the holding potential. When cells were held at ‐90 mV, the EC50 was 2.8 μg/mL. When cells were held more hyperpolarized (at ‐140 mV), the EC50 increased to 44.0 μg/mL.3. Although the degree of block produced by the same concentration of propofol was different at different holding potentials, the time course of onset and recovery from block was the same.4. The current/voltage relationship for the sodium current showed a pronounced block of peak current by propofol (40–50 % block of the maximum current by 30 μg/mL propofol), with a minimal shift in the voltage dependence of activation and no shift in reversal potential.5. The voltage dependence of the steady state inactivation curve was shifted to more hyperpolarized potentials by propofol (shift of 18 and 8 mV by 30 and 10 μg/mL propofol, respectively).6. Single channel records showed that propofol caused a shortening of the mean channel open time (from a mean of 0.59 to 0.38 ms by 10 μg/mL propofol), but no change in the channel amplitude.7. It is concluded that propofol produces a block of sodium currents in cardiac myocytes at concentrations that are comparable to those that may be attained during anaesthesia.
BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS
Authors: Yoneda Hikaru , Yamada Hiroshi , Yano Koji , Nishiyama Shinsuke , Naito Kazuaki 
Published: June 2007

SUMMARY1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing.2. Changes in plasma ANP, renal function and haemody‐namics during rapid cardiac pacing were studied in anaesthetized closed‐chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min.3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four‐ and three‐fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing.4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but not at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.