bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nicotine Administration In Rabbits Using Habitrol® Nicotine Patches And Nicotine Nasal Spray
Authors: Sipe Richard V Sipe , Buck David C , Hollinger Jeffrey O 
Published: March 2003

SUMMARY1. Several methods are used to provide predictable and effective nicotine to experimental animals in scientific studies. Due to the expense and technical challenges of these methods, we sought suitable alternatives. Consequently, the purpose of the present study was to develop a reliable experimental nicotine protocol in rabbits that included either Habitrol® nicotine patches (Novartis Consumer Health Inc., Summit, NJ, USA) or nicotine nasal spray.2. Administration of one of three doses of nicotine (2.5, 5, or 10 mg) was accomplished daily on 13 rabbits divided between either the patch or spray groups. Systemic nicotine and cotinine levels at 0 h, 15 min and 8 and 24 h were assayed. Data were analysed by a Fisher’s protected least significant difference test at P = 0.05.3. Rabbits treated with Habitrol® patches exhibited consistent and predictable systemic nicotine levels. The nicotine nasal spray produced an immediate dose‐dependent response with no measurable nicotine serum levels at 8 h.4. For nicotine administration in rabbits, nicotine patches are easy to administer and provide a nicotine serum level between 5 and 25 ng/mL, which is consistent with the average daily level found in a patient who smokes cigarettes.
Effects Of Chronic Inhibition Of Nitric Oxide Synthase In The Genetically Hypertensive Rat
Authors: Tucker Elizabeth J , Ledingham Janet M , Zheng Yiwen , Laverty R 
Published: March 2003

SUMMARY1. The effects of graded inhibition of nitric oxide synthase (NOS) on blood pressure in the genetically hypertensive (GH) rat strain and NOS activity in regions of the brain (cerebellum, striatum, hippocampus, frontal cortex and medulla oblongata) as a measure of body NOS inhibition were studied.2. Male GH and normotensive (N) rats (n= 7–10 per group) were given NG‐nitro‐
L‐arginine methyl ester (
L‐NAME; 2, 5, 10 or 20 mg/kg per day in drinking water) from age 7 weeks. Age‐ and weight‐matched controls received water only. Systolic blood pressure (SBP) was measured weekly by the tail‐cuff method from age 6 weeks. By age 10 weeks, rats were killed and NOS activity was measured.3. Some GH rats that received over 5 mg/kg per day L‐NAME developed stroke‐like symptoms and were killed before the end of the treatment period.4. No difference in NOS activity was found between untreated N and GH strains but, in those that received treatment, a graded inhibition was observed with increasing L‐NAME dose levels. The frontal cortex in the GH strain given 20 mg/kg per day
L‐NAME had NOS inhibition of 90% where the N strain had 73% inhibition. Similar results were seen in the other areas of the brain.5. Left ventricular mass, weight related, was significantly greater in the GH compared with N and was further elevated by treatment with L‐NAME.6. The SBP at 10 weeks was significantly elevated in GH rats by NOS inhibition with L‐NAME in a dose‐dependent manner; 25% for 2 mg/kg per day, 31% for 20 mg/kg per day (P < 0.001). There was a non‐significant increase in BP in the N‐treated groups (average change of 7.5%).7. Nitric oxide synthase inhibition causing increased SBP in GH rats suggests an abnormality in the nitric oxide–L‐arginine pathway in this strain.
Garlic Elicits A Nitric Oxide‐Dependent Relaxation And Inhibits Hypoxic Pulmonary Vasoconstriction In Rats
Authors: Kim‐Park SangAe , Ku David D 
Published: March 2003

SUMMARY1. The aims of the present study were to determine the characteristics of garlic extract‐induced relaxation in rat isolated pulmonary arteries, its susceptibility to changes in oxygen tension and its protective effect against hypoxic pulmonary vasoconstriction.2. In normoxia, garlic extract (3–500 μg/mL) produced a dose‐ and nitric oxide (NO)‐dependent relaxation. Following 60 min hypoxia, maximum garlic relaxation was reduced compared with control (mean (±SEM) –86±3 vs–69±2% of phenylephrine (PE) precontraction, respectively), but recovered after 60 min reoxygenation (–85±3% PE precontraction).3. Acetylcholine (0.1 μmol/L)‐induced NO‐dependent relaxation was reduced from a control value of –76±1% to –46±4% during hypoxia and was further reduced to –35±2% after reoxygenation.4. In endothelium‐intact arteries, hypoxic exposure resulted in a triphasic response: early transient contraction (+24±4%), followed by transient relaxation (–37±7%) and then sustained contraction (+62±5%).5. Pretreatment with NG‐nitro‐
L‐arginine methyl ester abolished the early transient contraction, moderately attenuated the sustained contraction and had no effect on the transient relaxation. Mechanical endothelial disruption inhibited all hypoxia‐induced vascular changes.6. Garlic pretreatment had no effect on the early transient contraction (+25±4%), but inhibited the transient relaxation (–5±3%; P < 0.05) and the sustained contraction (+26±5%; P < 0.05).7. Garlic also significantly inhibited endothelin‐1‐induced contractions in a dose‐dependent manner.8. These findings show that garlic extract modulates the production and function of both endothelium‐derived relaxing and constricting factors and this may contribute to its protective effect against hypoxic pulmonary vasoconstriction.
Familial And Acquired Long QT Syndrome And The Cardiac Rapid Delayed Rectifier Potassium Current
Authors: Witchel Harry J , Hancox Jules C 
Published: March 2003

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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

SUMMARY1. 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.