bluuebunny/crossref_metadata_2025 huggingface dataset:
Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current
Authors: Witchel Harry J , Hancox Jules C
Published: March 2003

1. Long QT syndrome (LQTS) is a cardiac disorder characterized by syncope, seizures and sudden death; it can be congenital, idiopathic, or iatrogenic.

2. Long QT syndrome is so‐named because of the connection observed between the distinctive polymorphic ventricular tachycardia torsade de pointes and prolongation of the QT interval of the electrocardiogram, reflecting abnormally slowed ventricular action potential (AP) repolarization. Acquired LQTS has many similar clinical features to congenital LQTS, but typically affects older individuals and is often associated with specific pharmacological agents.

3. A growing number of drugs associated with QT prolongation and its concomitant risks of arrhythmia and sudden death have been shown to block the ‘rapid’ cardiac delayed rectifier potassium current (IKr) or cloned channels encoded by the human ether‐a‐go‐go‐related gene (HERG; the gene believed to encode native IKr). Because IKr plays an important role in ventricular AP repolarization, its inhibition would be expected to result in prolongation of both the AP and QT interval of the electrocardiogram.

4. The drugs that produce acquired LQTS are structurally heterogeneous, including anti‐arrhythmics, such as quinidine, non‐sedating antihistamines, such as terfenadine, and psychiatric drugs, such as haloperidol. In addition to heterogeneity in their structure, the electrophysiological characteristics of HERG/IKr inhibition differ between agents.

5. Here, clinical observations are associated with cellular data to correlate acquired LQTS with the IKr/HERG potassium (K+) channel. One strategy for developing improved compounds in those drug classes that are currently associated with LQTS could be to design drug structures that preserve clinical efficacy but are modified to avoid pharmacological interactions with IKr. Until such time, awareness of the QT‐prolongation risk of particular agents is important for the clinician.
Recent Views On Integrated Coronary Control: Significance Of Non‐Uniform Regional Control Of Coronary Flow Conductance
Authors: Quail Anthony W , Cottee David BF , Porges William L , White Saxon W
Published: March 2003

1. Previous work from this laboratory and others has shown that powerful autonomic influences modulate coronary flow. In particular, the parasympathetic nervous system produces vasodilatation when activated by baroreceptors via the vagus nerve.

2. Differences exist in baroreflex coronary vasodilator mechanisms among the right, circumflex and anterior descending coronary vascular beds in the awake chronically instrumented dog.

3. Our hypothesis is that neurogenic acetylcholine acting from the adventitial side and endothelial nitric oxide from the luminal aspect of coronary smooth muscle compete with powerful intrinsic myogenic constrictor mechanisms to regulate regional flow conductance.

4. There is also increasing evidence that heterogeneity of control systems exists in different‐sized coronary vessels within an individual coronary vascular bed.

5. It is concluded that coronary vessels in vascular beds can no longer be assumed to respond in a uniform manner to neural, myogenic, metabolic or humoral factors.

6. These new perspectives of regional control mechanisms have important implications for understanding pathophysiological mechanisms inducing and sustaining tachyarrhythmias involved in ischaemic heart disease.
Acute Effects Of Moderate Exercise On Serum Lipids, Lipoproteins And Apolipoproteins In Sedentary Young Women
Authors: Imamura H , Katagiri S , Uchida K , Miyamoto N , Nakano H , Shirota T
Published: March 2003

1. The aim of the present study was to examine the effects of moderate exercise on serum lipids, lipoproteins and apolipoproteins in seven sedentary young women under controlled conditions.

2. The subjects exercised on separate days for 30 or 60 min at an intensity of 60% of maximal oxygen uptake on a cycle ergometer. Total cholesterol, triglycerides, high‐density lipoprotein–cholesterol (HDL‐C), HDL2‐C, HDL3‐C, low‐density lipoprotein–cholesterol, apolipoproteins A‐I, A‐II and B were measured in the serum at the end of the 60 min rest period before each exercise, immediately after the performance of each exercise and at 30 min and 1, 2 and 24 h after each exercise.

3. The results showed that there were no significant differences between the pre‐ and postexercise samples for any of the parameters tested.

4. The results of the present study suggest that a single bout of exercise designed to simulate a typical training workout has no noticeable effect on serum lipids, lipoproteins and apolipoproteins in normal sedentary young women who have normal lipid profiles, are in the follicular phase of their menstrual cycle and who consume a relatively low‐fat diet.
Annual Scientific Meeting of ASCEPT, 1999 From ‘Captive’ Agonism To Insurmountable Antagonism: Demonstrating The Power Of Analytical Pharmacology
Authors: Christopoulos Arthur
Published: March 2003

1. Mathematical modelling is useful in pharmacology, allowing the investigator to obtain insights into the biological processes under study that may not always be intuitively obvious. Examples are presented in this review using the pharmacology of the muscarinic acetylcholine receptor (mAChR) agonist xanomeline.

2. Xanomeline possesses a novel mode of action that involves persistent binding to the M1 mAChR, yielding a fraction of agonist in the receptor compartment that continually activates the receptor, despite extensive washout, as assessed in functional assays measuring the cumulative production of M1 mAChR‐mediated L‐[3H]‐citrulline. This persistent effect was reversed by the antagonist atropine, but re‐established upon the removal of atropine. Thus, xanomeline may represent the first ‘captive’ agonist of the mAChR.

3. Atropine was equally potent at reversing the effect of persistently bound xanomeline and preventing the effect of added xanomeline. Application of standard quantitative equilibrium models of agonist–antagonist interaction to these data suggested that the interaction between xanomeline and atropine satisfied the criteria of competitivity in each case.

4. Subsequent real‐time assays of M1 mAChR‐mediated intracellular calcium mobilization found that atropine inhibited the effects of xanomeline in an insurmountable manner.

5. The discrepancy between the modes of antagonism in the various functional assays could be reconciled in a dynamic receptor model of antagonism within a transient response system and subsequent Monte Carlo simulations allowed for the development of an optimized analytical procedure to quantify antagonist potency under such conditions of response fade.

6. These types of studies exemplify the diagnostic and integrative features of analytical pharmacology.
Role Of Nitric Oxide Synthase Inhibitor In Experimental Colitis Induced By 2,4,6‐Trinitrobenzene Sulphonic Acid In Rats
Authors: Hosoi Tsutomu , Goto Hidemi , Arisawa Tomiyasu , Niwa Yasumasa , Okada Naoaki , Ohmiya Naoki , Hayakawa Tetsuo
Published: March 2003

1. The present study was designed to investigate the role of nitric oxide (NO) in modulating 2,4,6‐trinitrobenzene sulphonic acid (TNBS)‐induced colitis in rats.

2. Damage scores and NO synthase (NOS) activity were measured.

3. The damage scores and NOS activity reached a peak on the 4th day after administration of TNBS solution (day 0), thereafter gradually decreasing, and were significantly higher than in the group treated with saline throughout the experimental period.

4. Subsequently, we divided the stage of colitis into two groups, one from day 0 to day 3 after induction of colitis, and the other from day 4 onwards. We evaluated the effects of the NOS inhibitor NG‐monomethyl‐L‐arginine (L‐NMMA), on TNBS–hapten‐induced colitis and colonic mucosal blood flow. Two different methods of L‐NMMA administration, from day 0 to day 3, and from day 4 onwards, were undertaken.

5. The damage score in the early L‐NMMA treatment group was significantly higher than in the group without L‐NMMA on day 14. In contrast, the damage score in the late L‐NMMA treatment group was not significantly different from the group without L‐NMMA. Colonic mucosal blood flow in the early L‐NMMA treatment group was not significantly different from that in the late L‐NMMA treatment group.

6. These data suggest that NO is important for inhibiting inflammation during the early stages.
Growth and Differentiation Factors Derived from the N‐Terminal Domain Of Pro‐Opiomelanocortin
Authors: Denef Carl , Roudbaraki Morad , Bael Annemie Van
Published: March 2003

1. We describe a novel paracrine control system in the pituitary gland, consisting of peptides derived from the N‐terminal fragment of pro‐opiomelanocortin (N‐POMC), for example POMC(1–74) and γ3‐melanocyte‐stimulating hormone (MSH).

2. By searching the target cells of these N‐POMC fragments, using the rise of intracellular free calcium as a response system and single cell reverse transcription–polymerase chain reaction of hormone mRNA as a cell type identification method, we found that a considerable number of cells in normal rat pituitary display combinatorial expression of different pituitary hormone genes (further referred to as ‘multihormone mRNA cells’), without indication that all these cells also produce or store the respective hormones translatable from these mRNA. The N‐POMC fragments POMC(1–74) and γ3‐MSH preferentially target particular subsets of these multihormone mRNA cells.

3. We discovered a potentially novel receptor for γ3‐MSH on these cells; more precisely, on cells coexpressing growth hormone and prolactin. The putative novel receptor displays properties highly divergent from those of the known γ3‐MSH receptor (i.e. the melanocortin‐3 receptor) and even of all other melanocortin receptors cloned today.
Actions of Activins, Inhibins and Follistatins: Implications in Anterior Pituitary Function
Authors: Bilezikjian Louise M , Blount Amy L , Corrigan Anne Z , Leal Angela , Chen Yan , Vale Wylie W
Published: March 2003

1. The anterior pituitary is well documented to be under the control of central and peripheral factors that dynamically interact to affect cell‐specific modulation of pituitary functions. However, it is becoming increasingly evident that these extrinsic factors work in concert with a variety of local products that exert autocrine/paracrine control on pituitary cells.

2. These factors modulate the activity of their target pituitary cells by altering the synthesis and secretion of cell‐specific hormones and by exerting control on the growth and differentiation of cells of this tissue. Included in the list of growth factors and bioactive peptides known to be products of pituitary cells are the activins, possibly inhibins and follistatins.

3. These protein factors play an important role in the local modulation of several pituitary cell types and are crucial for the maintenance of normal follicle‐stimulating hormone production and, thus, reproductive function and fertility.
Subarachnoid Haemorrhage‐Induced Sympathoexcitation In Rats Is Reversed By Bosentan Or Sodium Nitroprusside
Authors: Lambert Gavin , Lambert Elisabeth , Fassot Céline , Friberg Peter , Elghozi Jean‐Luc
Published: March 2003

1. The roles played by nitric oxide (NO) and endothelin (ET) in the genesis of sympathetic nervous activation following experimental subarachnoid haemorrhage was investigated using spectral analysis of blood pressure rhythms.

2. Subarachnoid haemorrhage was induced in conscious rats by injecting 0.3 mL homologous blood via a catheter placed along the surface of the brain and directed towards the circle of Willis. Three hours after the insult and after sympathetic activation was evident, animals received either an acute injection of the ET antagonist bosentan (5 mg/kg, i.v.; n = 7), an infusion of the NO donor sodium nitroprusside (SNP; 18 μg/h; n = 7) or no treatment (n = 7).

3. Three hours following the induction of subarachnoid haemorrhage, the mid‐frequency components of systolic blood pressure were markedly elevated, indicating a pronounced sympathoexcitation. However, blood pressure and heart rate levels remained unchanged at this time. In the absence of treatment, the mid‐frequency components of blood pressure remained elevated for a subsequent 2 h. Treatment with a non‐hypotensive dose of SNP reversed the sympathoexcitation within 1 h. Treatment with bosentan was also effective in reducing the mid‐frequency oscillations in blood pressure associated with subarachnoid haemorrhage.

4. Our results indicate that subarachnoid haemorrhage is associated with an acute activation of the sympathetic nervous system. The degree of sympathoexcitation can be reversed by the use of either bosentan or SNP.
Increase In Gastric Intramucosal Hydrogen Ion Concentration Following Endotoxin Challenge In The Rat And The Actions Of Nitric Oxide Synthase Inhibitors
Authors: Lamarque Dominique , Whittle Brendan Jr
Published: March 2003

1. Cardiovascular events and outcome in septic shock may be predicted by monitoring the fall in intramural pH (pHi), as an index of splanchnic perfusion and mucosal ischaemia. In the present study, a small animal model for monitoring the changes of gastric pHi or intramucosal [H+] following challenge with the endotoxin lipopolysaccharide (LPS) was developed in the rat. The role of nitric oxide (NO) in these events in this model was evaluated using the non‐selective NO synthase (NOS) inhibitors NG‐nitro‐L‐arginine methyl ester (L‐NAME) and NG‐monomethyl‐L‐arginine (L‐NMMA).

2. The pHi and intramucosal [H+] were evaluated in omeprazole‐pretreated rats (30 mg/kg, i.p.) using the Henderson equation after estimating the Pco2 and the bicarbonate concentration in gastric wall. To measure gastric wall Pco2, the oesophagus was intubated and the pylorus ligated. The Pco2 was measured by a blood gas analyser in 2 mL saline instilled for 30 min in the gastric lumen to equilibrate with the gastric wall. The pHi was measured under basal conditions and 3 and 5 h after LPS (3 mg/kg) administration. Separate groups received treatment with L‐NMMA (25–50 mg/kg) or L‐NAME concomitantly or 2.5 h after administration of LPS.

3. Intravenous administration of Escherichia coli LPS provoked a significant fall in gastric pHi from 7.37 to 7.18 (median values; n = 10–19) determined after 5 h. In groups treated concurrently with LPS and L‐NAME (5 mg/kg; n = 19), there was a similar increase in intramucosal [H+] as that induced by LPS alone (n = 15) in those animals that survived. In contrast, L‐NAME (5 mg/kg; n = 12), given 2.5 h after LPS challenge, at a time at which inducible NOS is known to be significantly expressed, prevented the increase in intramucosal [H+] at 3 and 5 h after LPS challenge. Similarly, L‐NMMA (25–50 mg/kg; n = 23), given 2.5 h after LPS challenge, dose‐dependently inhibited the increase in intramucosal [H+] at 3 and 5 h.

4. In conclusion, these findings indicate that this rat model could be useful in exploring the pathophysiology of acute endotoxin shock. Delayed administration of L‐NAME and L‐NMMA abolished the increase in gastric intramucosal [H+], supporting the involvement of excess NO in the tissue dysfunction associated with endotoxin shock. This suggests the potential value of this small animal model in evaluating the therapeutic activity of novel agents for use in septic shock.
Contractile And Electrical Properties Of Sternohyoid Muscle In Streptozotocin Diabetic Rats
Authors: McGuire M , Dumbleton M , MacDermott M , Bradford A
Published: March 2003

1. The effects of diabetes on the electrical and contractile function of skeletal muscle are variable, depending on muscle fibre type distribution. The muscles of the upper airway have a characteristic fibre distribution that differs from previously studied muscles, but the effects of diabetes on upper airway muscle function are unknown. Normally, contraction of upper airway muscles, such as the sternohyoids, dilates and/or stabilizes the upper airway, thereby preventing its collapse. Diabetes is associated with obstructive sleep apnoea in which there is collapse of the upper airway due to failure of the upper airway musculature to maintain airway patency. Therefore, the purpose of the present study was to determine the effects of diabetes on the electrical and contractile characteristics of upper airway muscle.

2. Rats were treated with vehicle (sodium citrate buffer; pH 4.5) or with streptozotocin to induce diabetes, confirmed by the presence of hyperglycaemia, and the contractile and electrical properties of the sternohyoid were compared in these two groups. Isometric contractile properties and membrane potentials were determined in isolated sternohyoid muscles in physiological saline solution at 25°C.

3. Streptozotocin had no effect on sternohyoid muscle fatigue, the tension–frequency relationship or membrane potentials, but did increase contraction time, half‐relaxation time, twitch tension and tetanic tension.

4. Streptozotocin‐induced diabetes has no effect on sternohyoid muscle fatigue or the tension–frequency relationship, but does reduce contractile kinetics and increases force generation. These effects are not due to changes in resting membrane potential. These data are evidence that the association of sleep apnoea and diabetes is not due to effects on upper airway muscle contractile properties.
Pharmacological Characterization Of Bradykinin B1 and B2 Receptors In IMR‐90 and INT‐407 Human Cell Lines Using A Microphysiometer
Authors: Bentley Kim R , Jarrott Bevyn
Published: March 2003

1. In the present study, we used a microphysiometer to measure bradykinin‐induced acidification responses in IMR‐90, a human lung fibroblast cell line, and INT‐407, a human colonic epithelial cell line. Furthermore, we investigated the effect of 24 h exposure of transforming growth factor (TGF)‐α on the bradykinin response in INT‐407 cells.

2. Bradykinin (0.1–100 nmol/L) was potent in producing acidification responses in IMR‐90 cells (pEC50 8.79±0.13; Hill slope 0.96±0.04) and INT‐407 cells (pEC50 8.90±0.04; Hill slope 1.00±0.07). These responses were competitively antagonized by the bradykinin B2 receptor antagonist icatibant in both IMR‐90 cells (apparent pKB = 8.54±0.15; Hill slope = 1.09±0.13 and 1.66±0.26 in the absence and presence of 10 nmol/L icatibant, respectively) and INT‐407 cells (pKB = 8.12±0.07 (3, 10 and 30 nmol/L icatibant); Hill slope = 1.06±0.04). However, the bradykinin B1 receptor antagonist des‐Arg9Leu8‐bradykinin (3 μmol/L) had no effect on the bradykinin responses.

3. The non‐peptide bradykinin B2 receptor antagonist FR173657 selectively antagonized bradykinin‐induced acidification responses in INT‐407 cells in a competitive manner (pKB = 8.76±0.10; Hill slope = 0.92±0.05) at lower concentrations (1 and 3 nmol/L) but in an insurmountable manner at higher concentrations (10 nmol/L; Hill slope = 1.04±0.09). This compound, at concentrations of 10 and 100 nmol/L (Hill slope = 1.38±0.15), also proved to be an insurmountable antagonist in IMR‐90 cells.

4. The bradykinin B1 receptor selective agonist Lys0des‐Arg10‐bradykinin (0.1 nmol/L to 0.1 μmol/L) failed to produce acidification responses in IMR‐90 cells, even after 24 h pre‐incubation with bacterial lipopolysaccharide (0.1 μg/mL).

5. A 24 h pre‐incubation of INT‐407 cells with TGF‐α (1, 10 and 100 ng/mL) caused a significant concentration‐dependent decrease in maximal bradykinin response without affecting the pEC50.

6. In addition to this study being the first to use a microphysiometer to characterize bradykinin B2 receptors in cultured IMR‐90 human lung fibroblast cells and INT‐407 human colonic epithelial cells, we also showed that pre‐incubation of INT‐407 cells with TGF‐α caused a significant decrease in maximal acidification response mediated by bradykinin B2 receptors.
Cyclo‐Oxygenase 2 Tissue Distribution And Developmental Pattern Of Expression In The Chicken
Authors: Mathonnet M , Lalloue F , Danty E , Comte I , Lièvre C Ayer‐Le
Published: March 2003

1. Cyclo‐oxygenase 2 (COX‐2) is implicated in multiple physiopathological processes. We have studied its physiological expression during chicken embryogenesis.

2. An original procedure was set to prepare a COX‐2 probe from red blood cells. In situ hybridization, reverse transcription–polymerase chain reaction and northern blots, were performed on chick embryos from embryonic day (E) 3 to postnatal day 15.

3. In the mesonephros, the signal detected in mesonephric tubules presented a slow increase from E5 to E9, a plateau up to E12 and then a decrease, while the signal increased in the metanephros and then decreased after hatching. Transient expression of COX‐2 mRNA in endothelial cells of the infundibulum of the aorta was also detected between E12 and E17.

4. This enzyme may have important roles in kidney morphogenesis during early embryonic stages and in tubular functions during development and in adult life. In the cardiovascular system, its vasodilatory effect could modulate the vasoconstrictor effect of the systolic pressure between E12 and E17 and contribute to a normal morphogenesis of the arterial tree and heart.
Role of endothelin‐1 receptors in healthy anaesthetized rabbits
Authors: Schmitz‐Spanke S , Schipke JD
Published: March 2003

1. Many diseases are associated with elevated endothelin (ET)‐1 plasma concentrations. In order to understand the consequence of this elevation, in the present study the effects of exogenous ET‐1 on the entire organsim were investigated, in particular with respect to the role of ETA and ETB receptors in the cardiovascular system. In open‐chest rabbits, left ventricular (LV) pressure (LVPmax, LVPed), dP/dtmax and dP/dtmin were recorded in ejecting and isovolumically beating hearts to determine cardiac function. In addition, heart rate (HR), aortic pressure (AoP) and aortic flow (AoF) were measured. Total peripheral resistance (TPR) was calculated from mean AoP and AoF.

2. In the first series of experiments (n = 11), ET‐1 (0.5 nmol/kg; bolus) produced a non‐significant reduction in HR. Systolic function, in terms of AoF, LVPmax and dP/dtmax, was improved; for example, LVPmax was increased significantly (69 ± 10 vs 106 ± 20 mmHg for control and ET‐1, respectively; P < 0.05). Similarly, early relaxation (dP/dtmin) was improved. In parallel, TPR rose significantly (0.25±0.07 vs 0.35±0.1 mmHg/min per mL for control and ET‐1, respectively; P < 0.05). Isovolumic measurements showed corresponding responses.

3. In the second series of experiments (n = 7), animals were pretreated with an ETA receptor antagonist (330 nmol/min per kg FR 139317). After ETA receptor blockade, the administration of ET‐1 had no significant effect on cardiac function or vasomotion.

4. In the third series of experiments (n = 6), animals were pretreated with an ETB receptor antagonist (10 nmol/min per kg BQ 788). In this series of experiments, the effects of ET‐1 on cardiac function and vasomotion were the same as in the first series of experiments, except for the effect on HR, which decreased by 35% after ET‐1.

5. In our experimental model, exogenous ET‐1 exerted a clear‐cut positive inotropic effect, together with the anticipated peripheral vasoconstriction via ETA receptors.
Existence Of α1A‐ and α1B‐Adrenoceptor Subtypes In Canine Mandibular Alveolar Arteries
Authors: Taguchi Yuichi , Yang Xiao‐Ping , Chiba Shigetoshi
Published: March 2003

1. The present study attempted to pharmacologically characterize the α‐adrenoceptor subtypes mediating vasoconstriction in canine isolated and perfused mandibular alveolar artery (MAA).

2. Noradrenaline (NA) and phenylephrine (PE) induced a strong vasoconstriction in a dose‐dependent manner. The PE‐induced vascular constriction was significantly inhibited by treatment with prazosin. Xylazine evoked a moderate vascular constriction and the xylazine‐induced response was suppressed by rauwolscine. The NA‐induced response was partially inhibited by rauwolscine and the remaining response to NA was abolished by subsequent administration of prazosin.

3. Treatment of MAA with WB4101 produced a dose‐ dependent inhibition of NA‐induced vasoconstriction. Pretreatment of tissues with 10 μmol/L chloroethylclonidine produced a slight and statistically significant inhibition of NA‐induced responses. BMY 7378, a selective α1D‐adrenoceptor antagonist, failed to significantly affect vasoconstrictor responses to NA.

4. The present results suggests that: (i) both α1‐ and α2‐adrenoceptors are involved in vasoconstrictor responses in the canine MAA; and (ii) the α1‐adrenoceptors involved in the vasoconstrictor responses in the MAA are characterized as mainly of the α1A‐ and partially of the α1B‐adrenoceptor subtype.
Effects Of Optic Tract Stimulation On Baroreflex Vagal Bradycardia In Rats
Authors: Cheng Zhi Bin , Kobayashi Masayoshi , Nosaka Shoichiro
Published: March 2003

1. Arterial baroreflexes are suppressed in stressful conditions. Intense visual stimuli can cause a threatening sensation and produce defensive reactions.

2. The present study was designed to determine whether and how electrical stimulation of the optic tract (OT) affects arterial baroreflexes, especially the heart rate component, baroreflex vagal bradycardia (BVB), in rats. In chloralose– urethane anaesthetized, β‐adrenoceptor‐blocked rats, BVB was evoked by electrical stimulation of the aortic depressor nerve.

3. Electrical stimulation of the OT was found to not only increase blood pressure and heart rate, but also to inhibit BVB. To determine whether these responses were mediated by the lateral genticulate body and/or the superior colliculus, which are major target sites to which the OT projects, each was activated with electrical and chemical stimulation.

4. The lateral genticulate body did not respond to either electrical or chemical stimulation, whereas the superior colliculus increased blood pressure and heart rate while suppressing BVB following electrical stimulation. Essentially similar responses were observed following microinjection of the GABA antagonist bicuculline methiodide.

5. Optic tract‐induced inhibition of BVB was abolished by bilateral destruction of the superior colliculus. Furthermore, this inhibition was also largely attenuated by destruction of the midbrain periaqueductal grey (PAG).

6. In conclusion, electrical stimulation of the OT increases blood pressure, heart rate and inhibits BVB. These responses are not mediated by the lateral genticulate body but are mediated by the superior colliculus. The PAG may participate in the subsequent mediation of the responses to electrical stimulation of the OT and the OT‐induced inhibition of BVB may contribute to expression of a light‐induced defence reaction.
The Many Essential Interfaces Of Clinical Pharmacology
Authors: Shenfield Gillian M
Published: March 2003

1. Clinical pharmacology requires numerous skills and most activities involve interactions with other specialities, both clinical and experimental.

2. A range of experts has had a major influence on the nature and design of my research, which is illustrated by the evolution of my knowledge of adverse drug reactions and how to prevent them.

3. Clinical pharmacologists are uniquely placed to coordinate programmes to achieve quality use of medicines. but we will only achieve our aims if multiple interactions with other experts are encouraged and developed.
Fetal Growth And Programming Of The Hypothalamic–Pituitary–Adrenal Axis
Authors: Phillips David Iw
Published: March 2003

1. Epidemiological studies have shown that small size at birth is associated with an increased risk of coronary heart disease and its risk factors, including hypertension and type 2 diabetes.

2. It is suggested that these observed links between low birthweight with disease result from an imbalance between fetal nutrient demand and supply. This imbalance results in metabolic and endocrine adaptations that benefit the fetus in the short term by reducing fetal growth and increasing fuel availability but, in the longer term, are maladaptive, leading to an increased risk of coronary heart disease.

3. Experimental data in animals and recent human observations have suggested that an alteration in the set point of the hypothalamic–pituitary–adrenal axis is an important long‐term change that occurs in association with reduced fetal growth.

4. These data raise the possibility that the nature and amplitude of the stress response may be determined by intra‐uterine factors.
Is Prenatal Glucocorticoid Administration Another Origin Of Adult Disease?
Authors: Newnham John P
Published: March 2003

1. The intra‐uterine environment is now believed to play a major role in the origin of many adult diseases. Illnesses in which there is significant ‘programming’ before the time of birth include hypertension, diabetes, coronary heart disease and stroke. Acting on a genetic predisposition, intra‐uterine triggers appear to programme the individual’s metabolism and endocrine milieu and, after birth, these risk factors are then either amplified or minimized by environmental influences. The triggers operative during fetal life that have been studied most extensively are undernutrition and glucocorticoid exposure.

2. Over the past decade, a series of studies in sheep have focused on the perinatal and life‐long consequences of glucocorticoid exposure in mid‐ to late‐pregnancy. These studies in the sheep model have shown that maternal injections with glucocorticoids, in a manner similar to clinical treatment for women at risk of preterm birth, enhance fetal lung maturation, but were also associated with developmental and other functional alterations that are of concern. With weekly doses to the mother, there is restricted fetal growth, delayed myelination of the central nervous system, altered blood pressure soon after birth and increased insulin response to glucose challenge in early adulthood. If the glucocorticoids are given to the fetus by ultrasound‐guided intramuscular injection, rather than to the mother, the effects on lung maturation are similar, but growth is spared and blood pressure after birth is unaltered. Increased insulin response to glucose challenge occurs in early adulthood with glucocorticoid by either route and is independent of growth restriction.

3. The findings in experimental animals are supported by studies of children in the Western Australian Preterm Infant Follow‐up Study. Multivariate analyses have shown that increasing the number of glucocorticoid exposures, for the purpose of enhancing lung maturation prior to preterm birth, is associated with reduced birthweight and behavioural disorders at 3 years of age.

4. The results of these animal and clinical studies provide further support for a role of prenatal glucocorticoid exposure in triggering predisposition to adult disease. Further exploration of these models is expected to uncover the mechanisms and lead to effective strategies that may underpin clinical interventions.
Possible Involvement Of P‐Glycoprotein In The Biliary Excretion Of Grepafloxacin
Authors: Zhao Ying Lan , Cai Shao Hui , Wang Li , Kitaichi Kiyoyuki , Tatsumi Yasuaki , Nadai Masayuki , Yoshizumi Hideo , Takagi Kenji , Takagi Kenzo , Hasegawa Takaaki
Published: March 2003

1. In the present study, we have examined the effects of the quinolones norfloxacin (NFLX), enoxacin (ENX), ofloxacin (OFLX), tosufloxacin (TFLX), lomefloxacin (LFLX), sparfloxacin (SPFX) and grepafloxacin (GPFX) on the efflux of doxorubicin from mouse leukaemia P388/ADR cells expressing P‐glycoprotein. The relationship between their partition coefficients (hydrophobicity) and effluxing potencies was also elucidated.

2. Both TFLX and SPFX strongly increased the intracellular accumulation of doxorubicin (5 μmol/L) in P388/ADR cells, but had no effect on P388/S cells not expressing P‐glycoprotein. The rank of order of the potency of the quinolones (TFLX > SPFX > GPFX > NFLX) was not related directly to their hydrophobicity. These results suggest that some quinolones can reverse anticancer drug resistance.

3. Because GPFX is more highly excreted into the bile than other known quinolones, the effects of doxorubicin (10 mg/kg) or the well‐known inhibitors of P‐glycoprotein, namely cyclosporine A (10 mg/kg) and erythromycin (100 mg/kg), on the biliary excretion of GPFX at steady state was studied in rats.

4. Doxorubicin, cyclosporine A and erythromycin significantly decreased the biliary clearance of GPFX. Cyclosporine A and erythromycin had a much stronger inhibitory effect on the biliary excretion of GPFX than doxorubicin. These results suggest the possibility that GPFX is, at least in part, excreted into the bile by a P‐glycoprotein‐mediated transport mechanism.
Dendroaspis Natriuretic Peptide Administered Intracerebroventricularly Increases Renal Water Excretion
Authors: Lee JongUn , Kim Soo Wan
Published: March 2003

1. The effects of intracerebroventricular (i.c.v.) infusion of Dendroaspis natriuretic peptide (DNP) on renal function were examined in anaesthetized rats. The results were compared with those obtained following intravenous (i.v.) infusion of the same dose of DNP.

2. Urine volume was increased four‐ to six‐fold over basal values by i.c.v. infusion of DNP (6 pmol/min). Urine osmolality was decreased, whereas sodium excretion was not significantly altered. Intravenous infusion of the same dose of DNP had little effect on urinary water excretion. Neither arterial pressure nor heart rate was changed significantly by either i.v. or i.c.v. infusion of DNP. Glomerular filtration rate, measured by creatinine clearance, remained unaltered.

3. The diuretic response to i.c.v. DNP was markedly attenuated in rats that were deprived of their water supply for 3 days before the experiment.

4. These results suggest that DNP can act within the central nervous system to increase renal water excretion.
Sympathoinhibitory Action Of Nociceptin In The Rat Spinal Cord
Authors: Brailoiu GC , Lai CC , Chen CT , Hwang LL , LIN HH , Dun NJ
Published: March 2003

1. Whole‐cell patch recordings were made from antidromically identified sympathetic preganglionic neurons (SPN) of immature rat spinal cord slices. Bath application of nociceptin (0.1–1 μmol/L) suppressed excitatory postsynaptic potentials (EPSP) and hyperpolarized a population of SPN; these effects were naloxone (1 μmol/L) insensitive.

2. Nociceptin suppressed the amplitude of EPSP without causing a concomitant change in glutamate‐induced depolarizations, suggesting a presynaptic inhibitory action.

3. Analysis of current–voltage relationships showed that nociceptin hyperpolarized SPN by increasing an inwardly rectifying K+ current.

4. Intrathecal injection of nociceptin (3, 10 and 30 nmol) to urethane‐anaesthetized rats dose‐dependently reduced the mean arterial pressure and heart rate; these effects were not prevented by prior intravenous injection of naloxone (1 mg/kg).

5. Results from our in vitro and in vivo experiments suggest that nociceptin suppresses spinal sympathetic outflow either by attenuating excitatory synaptic responses or hyperpolarizing SPN.
Neutrophil Migration During Liver Cirrhosis In Rabbits
Authors: Penteado FC , Ferreira HHA , Calafatti SC , Bernascconi G , Piovesana H , Pedrazzoli J
Published: March 2003

1. The aim of the present study was to investigate neutrophil chemotaxis during the induction of liver cirrhosis in rabbits.

2. Liver cirrhosis was induced in male New Zealand white rabbits. The study consisted of three experimental groups: (i) group A (n = 16) served as the control and
received only normal chow and all rabbits in this group were killed at 16 weeks;
(ii) group B rabbits (n = 8) were killed immediately after the chemotaxis
assay, which was performed 24 h after CCl4 administration, at weeks 2,
4, 6 and 8; and (iii) in group C rabbits (n = 19), the chemotaxis assay was
performed every second week on the day before CCl4 administration for 16 weeks and all animals in this group were killed at 16 weeks.

3. Four of six rabbits in group B had liver cirrhosis at week 8. In group C, liver cirrhosis occurred in seven of eight animals. All rabbits with liver cirrhosis had an inflammatory infiltrate of neutrophils. In group B, there was a significant increase in polymorphonuclear cells and neutrophil chemotaxis and a significant reduction in mononuclear leucocytes at week 8. The rabbits in group C showed a significant increase in total leucocyte and polymorphonuclear numbers at week 10. A significant increase in neutrophil chemotaxis was also observed from week 2 through to week 6.

4. The presence of neutrophils in the liver of all rabbits with cirrhosis, associated with an increase in polymorphonuclear cell chemotaxis during this process, supports the view that this cell type has an important role in the development of toxic liver damage.
Oxidative Stress And Potassium Channel Function
Authors: Liu Yanping , Gutterman David D
Published: March 2003

1. Modulation of K+ channel activities by cellular oxidative stress has emerged as a significant determinant of vasomotor function in multiple disease states.

2. Evidence from in vitro and in vivo studies suggest that superoxide
(O2–) and hydrogen peroxide (H2O2)
enhance BKCa channel activity in rat and cat cerebral arterioles; however,
activity is decreased by peroxynitrite (ONOO–) in rat cerebral
arteries. The mechanisms of changes in BKCa channel properties are not fully understood and may involve oxidation of cysteine residues that are located in the cell membranes.

3. Studies further suggest that O2– increases KATP
channel activity in guinea‐pig cardiac myocytes, but decreases opening in cerebral
vasculature. Both H2O2 and ONOO– enhance
KATP channel activity in the myocardium and in coronary, renal, mesenteric
and cerebral vascular beds. Alteration of KATP channels by free radicals may be due to oxidation of SH groups or changes in the cytosolic concentration of ATP.

4. It does appear that O2– produced by either reaction
of xanthine and xanthine oxidase or elevated levels of glucose reduces Kv channel activity and the impairments can be partially restored by free radical scavengers, superoxide dismutase and catalase.

5. Thus, redox modulation of potassium channel activity is an important mechanism regulating cell vascular smooth muscle membrane potential.
Cellular Coupling And Conducted Vasomotor Responses
Authors: Neild TO , Crane GJ
Published: March 2003

1. The present brief review examines the concept of spreading vasodilator responses in arteriolar trees, its physiological relevance and possible mechanisms.

2. The most likely mechanisms involve spread of hyperpolarization through tissues in the vessel wall, made possible by electrical coupling between the cells. It is generally agreed that there is coupling between cells within the muscle and endothelial layers, but coupling between the two layers is not always present.

3. The passive electrical properties of arterioles can be modelled, using different techniques depending on the complexity of branching of the arteriolar tree. Comparison of experimental results with the model indicates that hyperpolarization can spread further than expected from passive properties alone, implying that spreading vasodilatation may be an active process.
Vasopeptidase Inhibition In A Canine Model Of Exercise‐Induced Left Ventricular Dysfunction
Authors: Holzgrefe Henry H , Arthur Susan R , Powell James R
Published: March 2003

1. The present study compared the acute efficacies of vasopeptidase inhibition with omapatrilat, nitroglycerin and angiotensin‐converting enzyme (ACE) inhibition in exercise‐induced myocardial dysfunction. Omapatrilat, a vasopeptidase inhibitor, inhibits both neutral endopeptidase and ACE. Whereas vasopeptidase inhibitors have demonstrated clinical efficacy in hypertension and heart failure, their effects in myocardial ischaemia remain unclear.

2. Omapatrilat (0.3 mg/kg) was compared with vehicle (saline), an ACE inhibitor (fosinoprilat; 0.44 mg/kg) and nitroglycerin (8.0 μg/kg per min), in an established canine model of exercise‐induced myocardial dysfunction induced by progressive closure of an ameroid constrictor placed about the proximal circumflex coronary artery. Maximal treadmill exercise tests, terminated when heart rate failed to increase with increasing workload or failure to continue exercise, were performed in chronically instrumented dogs.

3. During exercise, omapatrilat and nitroglycerin similarly increased ischaemic wall thickening (P≤ 0.0001, ANOVA, 12 d.f.), whereas fosinoprilat and vehicle were without effect. Ischaemic zone ST changes were decreased with nitroglycerin (P = 0.0006, ANOVA, 12 d.f.) and tended to decrease with omapatrilat (P = 0.07, ANOVA, 12 d.f.). Peak exercise capacity was increased with nitroglycerin (9.7 ± 1.1 vs 11.2 ± 1.0 kcal, control vs 4 h, respectively; n = 6) and omapatrilat (9.7 ± 0.8 vs 11.4 ± 0.6 kcal, control vs 4 h, respectively; n = 6) and was unchanged with ACE inhibition (9.0 ± 1.2 vs 9.5 ± 1.1 kcal, control vs 4 h, respectively; n = 7). Omapatrilat differentially increased double product during exercise (P = 0.001, ANOVA, 12 d.f.) compared with other treatments.

4. During exercise‐induced myocardial dysfunction, acute ACE inhibition did not attenuate ischaemic changes and failed to improve exercise capacity. Increased exercise capacity with omapatrilat was accompanied by a differential increase in double product, consistent with increased oxygen supply and demand. Improvements in ischaemic function were comparable between omapatrilat and nitroglycerin, suggesting that omapatrilat may represent a novel therapy in demand‐induced ischaemia.
Cardiovascular Responses During Stimulation Of Hindlimb Skeletal Muscle Nerves In Anaesthetized Rats
Authors: Ishide Takeshi , Pearce William J , Ally Ahmmed
Published: March 2003

1. Cardiovascular responses during static skeletal muscle contraction in anaesthetized rats appear to be contradictory. The present study attempted to explain such variations by stimulating different peripheral nerves supplying the hindlimb skeletal muscles using anaesthetized Sprague‐Dawley rats.

2. Muscle contractions were evoked by a 30 s stimulation of the sciatic, tibial, peroneal nerves or the sciatic nerve with transected peroneal branch at threefold the motor threshold, 0.1 msec duration and 40 Hz frequency.

3. Contractions during stimulation of the tibial or the sciatic nerve with severed peroneal branch evoked similar increases in arterial pressure and heart rate. Following stimulation of the tibial nerve, blood pressure, heart rate and muscle tension increased by 23 ± 3 mmHg, 31 ± 5 b.p.m. and 789 ± 34 g, respectively. For the sciatic nerve with transected peroneal branch, increases the respective increases were 27 ± 5 mmHg, 32 ± 6 b.p.m. and 802 ± 43 g. In contrast, peroneal nerve stimulation produced depressor and bradycardic responses of –22 ± 5 mmHg and –40 ± 9 b.p.m., respectively. Interestingly, intact sciatic nerve stimulation elicited pressor, depressor or no responses (average being –10 ± 8 mmHg), along with a consistent increase in heart rate of 24 ± 7 b.p.m.

4. The results demonstrate that static muscle contraction following stimulation of the tibial or sciatic nerve with transected peroneal branch, elicits consistent increases in blood pressure and heart rate. Furthermore, stimulation of the peroneal nerve elicits a depressor response, while stimulation of the intact sciatic nerve evokes variable cardiovascular responses. Overall, anaesthetized rats can be excellent models to study the variable cardiovascular responses during activation of group III and/or group IV muscle afferents.
Effects of dopamine and nitric oxide on arterial pressure and renal function in volume expansion
Authors: Costa MA , Loria A , Marchetti M , Balaszczuk AM , Arranz CT
Published: March 2003

1. The aim of the present study was to investigate the role of dopamine (DA) in the hypotensive and renal effects of l‐arginine during extracellular fluid volume expansion (10% bodyweight).

2. Animals were randomized to non‐expanded and expanded groups. Both groups received different treatments: l‐arginine (250 mg/kg, i.v.), NG‐nitro‐l‐arginine methyl ester (l‐NAME; 1 mg/kg, i.v.), haloperidol (3 mg/kg, i.p.) and l‐arginine + haloperidol (n = 8). Mean arterial pressure (MAP), diuresis, natriuresis, kaliuresis, glomerular filtration rate, renal plasma flow (RPF) and nitrite and nitrate (NOx) excretion were determined.

3. The increase in MAP induced by l‐NAME was greater in expanded than in non‐expanded rats (42 ± 3 vs 32 ± 3 mmHg, respectively; P < 0.01). Administration of haloperidol did not modify the l‐arginine hypotensive effect.

4. Blockade of nitric oxide synthase diminished urine flow in non‐expanded (4.15 ± 0.56 vs 0.55 ± 0.11 µL/min per 100 g; P < 0.01) and expanded animals (24.42 ± 3.67 vs 17.85 ± 2.16 µL/min per 100 g; P < 0.01). Diuresis induced by l‐arginine was reduced by DA blockade in both non‐expanded (17.15 ± 2.11 vs 6.82 ± 0.61 µL/min per 100 g; P < 0.01) and expanded animals (44.26 ± 8.45 vs 25.43 ± 5.12 µL/min per 100 g; P < 0.01).

5. Sodium excretion decreased with l‐NAME treatment in non‐expanded (0.22 ± 0.03 vs 0.06 ± 0.01 µEq/min per 100 g; P < 0.01) and expanded animals (3.72 ± 0.70 vs 1.89 ± 0.23 µEq/min per 100 g; P < 0.01). Natriuresis induced by l‐arginine was diminished by haloperidol both in non‐expanded (0.94 ± 0.13 vs 0.43 ± 0.04 µEq/min per 100 g; P < 0.01) and expanded rats (12.77 ± 0.05 vs 3.53 ± 0.75 µEq/min per 100 g; P < 0.01). Changes in kaliuresis changes seen following treatment with l‐arginine, l‐NAME and l‐arginine + haloperidol followed a pattern similar to that observed for sodium excretion in both groups of rats.

6. l‐Arginine enhanced RPF in non‐expanded animals (11.96 ± 0.81 vs 14.52 ± 1.05 mL/min per 100 g; P < 0.01). Glomerular filtration rate was increased by extracellular volume expansion (3.08 ± 0.28 vs 5.42 ± 0.46 mL/min per 100 g; P < 0.01).

7. The increase in NOx induced by acute volume expansion (0.18 ± 0.03 vs 0.52 ± 0.08 nmol/min per 100 g; P < 0.01) was diminished following the administration of haloperidol (0.52 ± 0.08 vs 0.26 ± 0.06 nmol/min per 100 g; P < 0.01).

8. Although DA does not participate in the actions of nitric oxide on vascular tone, both systems would play an important role in renal function adaptation during extracellular fluid volume expansion.