bluuebunny/crossref_metadata_2025 huggingface dataset:
ROLE OF MESANGIAL CELLS IN MACULA DENSA TO AFFERENT ARTERIOLE INFORMATION TRANSFER
Authors: Goligorsky Michael S. , Iijima Kazumoto , Krivenko Yuri , Tsukahara Hirokazu , Hu Yu , Moore Leon C.
Published: June 2007

1. Extraglomerular mesangial cells are strategically positioned between the macula densa and the afferent arteriole. These cells form a syncytium and are connected with glomerular mesangial cells via gap junctions. The model of immunoablation of mesangial cells in anti‐Thy‐1 glomerulonephritis carries the promise for understanding the function of mesangial cells as potential transmitters of information between the macula densa and the afferent arteriole.

2. The above anatomical relations between structures in the juxtaglomerular apparatus predict several possible routes of information flow. This review charts some hypothetical routes.

3. Research into the messenger systems involved in the transfer of signals from the macula densa to mesangial cells and from mesangial cells to the afferent arteriole suggests several candidate molecules to function in this capacity. Mechanisms of action for each candidate are discussed.

4. The oscillating nature of the afferent signal and efferent function in the tubuloglomerular feedback system, as well as other discoveries, offer a fertile field for future studies.
EFFECTS OF 5HT2 RECEPTOR ANTAGONISTS ON RESPONSES TO POTASSIUM DEPOLARIZATION IN RAT ISOLATED AORTA
Authors: Okoro EO , Marwood JF
Published: June 2007

1. In order to determine whether 5HT2 receptor antagonists can modify Ca2+ uptake via voltage‐operated Ca2+ channel (VOC) in arterial smooth muscle, a comparative study of the effects of selected Ca2+ uptake blockers and 5HT2 receptor antagonists on K+‐induced contractions of rat aortic strip was undertaken.

2. The antagonist drugs studied included the Ca2+ uptake blockers verapamil, nifedipine, felodipine, diltiazem and cin‐narizine, the 5HT2 receptor antagonists cyproheptadine, ritanserin, mianserin, and ketanserin and the α1‐adrenoceptor antagonist prazosin.

3. With the notable exception of prazosin, each of these compounds diminished K+‐induced aortic responses.

4. The following order of potencies (mean IC50 values in mol/L) was established: felodipine (7.0 × 10‐11) >nifedipine (4.8 × 10‐9) >verapamil (5.5 × 10‐8) >cyproheptadine (6.2 × 10‐8) > diltiazem (4.1 × 10‐7) >cinnarizine (1.3 × 10‐6) >ritanserin (1.8 × 10‐6) >ketanserin (9.0 × 10‐6) > mianserin (2.0 × 10‐5).

5. The results suggest that antagonists of 5HT2 receptors can modulate Ca2+ uptake via VOC in rat aorta.
RENAL EFFECTS OF RILMENIDINE IN VOLUME‐LOADED ANAESTHETIZED DOGS
Authors: Evans Roger G. , Shweta Amany , Malpas Simon C. , Fitzgerald Sharyn M. , Anderson Warwick P.
Published: June 2007

1. In anaesthetized, fluid expanded rats rilmenidine has diuretic and natriuretic effects. There is strong evidence that the natriuresis is mediated by putative imidazoline receptors. In contrast, in conscious euvolaemic dogs rilmenidine has a diuretic effect that is entirely attributable to activation of a2‐adrenoceptors, but no natriuretic effect. To determine whether the effects of rilmenidine are truly species dependent, or merely dependent upon the influences of anaesthesia and volume status, we tested the effects of rilmenidine in pentobarbitone anaesthetized, volume‐loaded dogs.

2. The effects of rilmenidine in anaesthetized, volume‐loaded dogs were similar to those found in conscious euvolaemic dogs. Compared with vehicle treatment, levels of glomerular filtration rate, urine flow and haematocrit were increased following rilmenidine treatment. No effect of rilmenidine on sodium excretion was observed.

3. We conclude that the renal responses to rilmenidine in dogs are largely unaffected by anaesthesia and plasma volume status. In particular, the natriuretic effect seen in rats was not observed. We conclude that putative imidazoline receptors do not have a major influence on sodium excretion in dogs.
BLOOD PRESSURE REGULATION IN BARORECEPTOR‐DENERVATED RATS
Authors: Sved Alan F. , Schreihofer Ann M. , Jr Curtis K Kost
Published: June 2007

Key words

1. Arterial baroreceptor denervation produces acute hypertension, but chronically denervated animals have an average arterial pressure that is similar to that of baroreceptor intact animals.

2. Although cardiopulmonary baroreceptors and renal compensations have been suggested to mediate the restoration of a normal average arterial pressure in sino‐aortic denervated rats, such mechanisms are inconsistent with the available data.

3. At present the processes involved in the restoration and long‐term maintenance of a normal average arterial pressure in chronic baroreceptor denervated animals are not known. An understanding of the regulation of arterial pressure that occurs in the absence of arterial baroreceptor reflexes may provide important new insights into the mechanisms underlying the long‐term regulation of arterial pressure.
ACTIONS OF ANGIOTENSIN IN THE SUBFORNICAL ORGAN AND AREA POSTREMA: IMPLICATIONS FOR LONG TERM CONTROL OF AUTONOMIC OUTPUT
Authors: Ferguson Alastair V. , Bains Jaideep S.
Published: June 2007

1. Considerable physiological and anatomical evidence indicates that circulating angiotensin II (AngII), plays important roles in the long‐term regulation of autonomic output as a result of actions in two circumventricular structures, the subfornical organ (SFO) and area postrema (AP).

2. Extracellular recordings have demonstrated excitatory actions of AngII on neurons from both of these structures which are ATi receptor mediated, maintained when cells are placed in synaptic isolation, and are dose dependent. Interestingly SFO neurons appear to be an order of magnitude more sensitive to AngII than those in AP.

3. Recent calcium imaging studies have demonstrated that AngII induces increases in intracellular calcium in both SFO and AP neurons. Whole cell patch recordings have also begun to provide important information suggesting that AngII actions may modulate voltage activated ion channels in these two structures to elicit its observed actions on circumventricular organs (CVO) neurons at the blood‐brain interface.

4. Through these actions circulating AngII is thus able to influence efferent projections from these CVO which in turn influence the output of hypothalamic cells projecting to the posterior pituitary (vasopressin secretion), nucleus tractus soli‐tarius (NTS), and intermediolateral cell column of the spinal cord (to influence sympathetic preganglionics), and medullary neurons in the NTS.
EFFECTS OF ALBUMIN ON THE DISPOSITION OF MORPHINE AND MORPHINE‐3‐GLUCURONIDE IN THE RAT ISOLATED PERFUSED LIVER
Authors: O'Brien Josephine A. , Evans Allan M. , Nation Roger L.
Published: June 2007

1. The effect of albumin on the disposition of morphine and hepatically generated morphine‐3‐glucuronide (M3G) was investigated in the single‐pass rat isolated perfused liver.

1. Interest in the pharmacokinetic and pharmacodynamic properties of the enantiomers of chiral drugs has greatly increased in recent years. This is particularly so for agents used in anaesthesia.

2. Chiral compounds are those that can exist in two non‐superimposable forms. Each form is termed an enantiomer or stereoisomer. Two naming systems are in use: one uses the terms (+) and (–) to indicate the direction the compound will rotate polarized light, while the other system, based on the absolute three‐dimensional structure of the enantiomers, uses the terms R and S.

3. Investigation of the stereoisomers of the volatile anaesthetic agent isoflurane is increasing our understanding of the mechanism of general anaesthesia. Current evidence suggests a protein, rather than a lipid, receptor site.

4. Investigation of the stereoisomers of local anaesthetics is increasing the safety of these drugs.

5. For bupivacaine, a widely used amide local anaesthetic, important enantiomeric differences can be found for toxicity, clinical effect and pharmacokinetics. In particular S‐(–)‐bupivacaine has an improved central nervous system and cardiac safety profile. This is partly explained by the pharmacokinetic differences.

6. Based on these differences, ropivacaine, a propyl homo‐logue of bupivacaine, has been produced solely as the S‐(–)‐enantiomer. The available evidence suggests significantly improved safety for this agent over racemic bupivacaine.
INTERACTIONS OF Na+, H2O2 AND THE Na+‐Ca2+ EXCHANGER STIMULATE Ca2+ RELEASE IN CK1.4 CELLS
Authors: Fang Yan , Rong Mingyang , He Lianfang
Published: June 2007

1. The present study aimed to demonstrate that interactions of cations, hydrogen peroxide (H2O2) and the Na+‐Ca2+exchanger stimulate Ca2+ release and oscillations of cytosolic Ca2+ [Ca2+]i in non‐transfected Chinese Hamster Ovary (CHO) C1 cells and in transfected CHO (CK1.4) cells that contained an expression vector coding the Na+‐Ca2+ exchanger sequence.

2. The [45Ca2+] uptake assay, fura‐2 fluorescence imaging and 22 and 23 factorial orthogonal statistics provide comparative, direct, efficient, quantitative and transient methods to delineate the effects of such interactions on Ca2+ influx, Ca2+release and [Ca2+]i in C1 and CK1.4 cells.

3. In contrast to the control of either Na+‐, Ca2+‐ or H2O2‐free or CI cells, an elevated [45Ca2+] uptake was induced by Ca2+, Na+ and H2O2 individually and in combination, intracellular Ca2+ release was activated by H2O2 and by combinations of either H2O2 and Na+, H2O2 and the Na+‐Ca2+ exchanger, Na+ and the Na+‐Ca2+ exchanger or by H2O2, Na+ and the Na+‐Ca2+ exchanger and a rise in [Ca2+]i was triggered by H2O2, Na+ and a combination of Na+ and the Na+‐Ca2+exchanger.

4. These results indicate that interactions between H2O2, Na+ and the Na+‐Ca2+ exchanger stimulate intracellular Ca2+mobilization via Ca2+‐induced Ca2+ release mechanisms, ATP‐activated G‐protein coupled P2y‐purinoceptor‐sensitive pathways, Na+‐Ca2+ exchanger‐mediated Ca2+ influx and cation‐π interaction (a strong non‐covalent force between the cation and the π face of an aromatic structure in the transmembrane protein).

5. The present findings provide important clues for understanding Ca2+ signal transduction mechanisms from the plasma membrane to the endoplasmic reticulum.
EFFECT OF BLOOD FLOW AND HAEMATOCRIT ON THE RELATIONSHIP BETWEEN MUSCLE VENOUS Po2 AND OXYGEN UPTAKE IN DOG MAXIMALLY CONTRACTING GASTROCNEMIUS IN SITU
Authors: Kohzuki H. , Enoki Y. , Ohga Y. , Sakata S. , Shimizu S. , Morimoto T. , Kishi T. , Takaki M.
Published: June 2007

1. To clarify the limiting factors for peak V̇o2 (V̇o2peak)> we measured muscle venous Po2 (Pvo2) and V̇o2, peak under various O2 delivery conditions (arterial O2 concentration X flow) via the alteration of blood flow and haematocrit (Hct) in anaesthetized dog gastrocnemius muscle (n= 11) stimulated by 1 Hz isometrically and tetanically.

2. Two levels of flow (high and moderate) were maintained by using a pump (ISO and 100 mL/min per 100 g, respectively). Haematocrit was adjusted to 45 and 30% by isovolaemic haemodilution with dextran (MW 40 000).

3. The decrease in Hct induced a 31% decrease in O2 delivery (P<0.05), a 9–12% decrease in Pvo2, a 23% decrease in V̇o2, peak(P<0.05) and a 12–14% increase in O2 extraction (V̇o2/O2delivery) at both flow levels. The decrease in flow induced a 24–25% decrease in O2 delivery (P<0.05), a 15–17% decrease in Pvo2 (P<0.05), a 9% decrease in V̇o2,peak (P<0.05) and a 19–22% increase in O2 extraction (P<0.05) at both Hct levels.

4. The results suggest that the limiting factor of V̇o2peak, unrelated to O2 diffusion limitation (i.e. the change in the heterogeneity of V̇o2 to O2 delivery ratio among capillaries), due to lowering Hct may be different from that due to lowering blood flow in maximally contracting muscle.
STRUCTURE AND FUNCTION OF THE ADVENTITIAL AND MUCOSAL NERVE PLEXUSES OF THE BRONCHIAL TREE IN THE DEVELOPING LUNG
Authors: Sparrow MP , Weichselbaum M.
Published: June 2007

1. The aim of the present study was first to determine when airway smooth muscle first appears in the airways of the developing foetal lung and when its contractility is mature and, second, when the airway smooth muscle becomes innervated, both structurally and functionally.

2. Narrowing and relaxation of the airways of the intact bronchial tree from the lungs of foetal pigs at varying stages of gestation was recorded by real time video microscopy. Nerves and smooth muscle were stained immunohistochemically and their spatial relationships were visualized by confocal microscopy.

3. From early in gestation (pseudoglandular stage/branching morphogenesis), airways were covered with a single layer of smooth muscle cells orientated cylindrically around the airway wall. Thick nerve trunks containing loosely packed nerves, with ganglia forming at their junctions ensheathed the airways to the growing tips, with a network of fine varicosed nerves lying on the smooth muscle cells. Some of these nerves were functional and cholinergic, as electrical field stimulation caused substantial narrowing that was blocked by atropine and by tetrodotoxin. By mid‐term, an extensive plexus of nerves, well‐defined ganglia and varicosed nerves to the smooth muscle had developed. Some nerves extended through the airway smooth muscle to form the elements of a mucosal nerve plexus in conjunction with developing vascular tissue forming a bronchial circulation. In 3 week postnatal pigs the distal and terminal airways were densely supplied with varicosed nerves to the smooth muscle. The ganglia were more centrally located.

4. An abundant network of calcitonin gene‐related peptide (CGRP) nerves with prominent nerve endings lay just below the surface of the epithelium. The nerve bundles to the terminal arterioles in the mucosa also contained CGRP‐positive fibres as well as sympathetic nerves (neuropeptide Y‐ and tyrosine hydroxylase positive). It is hypothesized that these epithelial and arteriolar CGRP nerves form the local axon reflex purported to cause neurogenic inflammation.

5. The spontaneously active tone exerted by the airway smooth muscle from early in gestation is hypothesized to provide the force across the airway wall and adjacent parenchyma that is the stimulus for lung growth in foetal life.
HUMAN MONOCYTES MAINTAINED IN CULTURE ACQUIRE FUNCTIONAL RESPONSIVENESS TO PLATELET‐ACTIVATING FACTOR THAT IS INDEPENDENT OF INCREASES IN PROTEIN TYROSINE PHOSPHORYLATION
Authors: Grigoriadis George , Stewart Alastair G.
Published: June 2007

1. Acute (day 0) stimulation with platelet‐activating factor (PAF) did not elicit superoxide anion (02‐) generation from adherent monocytes. However, by day 2 of culture, PAF induced an increase in O2‐ generation that was inhibited by pretreat‐ment with the PAF receptor antagonist WEB 2086.

2. The lack of effect of PAF on O2‐ generation was not due to the absence of receptors, as PAF stimulated an increase in tyrosine phosphorylation and intracellular calcium ([Ca2+]i) on both days 0 and 2 of culture.

3. Pretreatment with the protein tyrosine kinase inhibitor methyl 2,5‐dihydroxycinnamate inhibited PAF‐induced tyrosine phosphorylation; however, this inhibitor failed to inhibit PAF‐induced O2‐ generation. In contrast, pretreatment with the protein kinase C inhibitor staurosporine had no effect on PAF‐induced tyrosine phosphorylation, but did inhibit PAF‐induced O2‐ generation.

4. These results indicate that monocytes maintained in culture acquire a functional response to PAF through a mechanism that appears to be independent of PAF receptor expression, coupling to increases in [Ca2+]i or tyrosine phosphorylation.
PROTEIN PHOSPHORYLATION EVENTS IN EXOCYTOSIS AND ENDOCYTOSIS
Authors: Liu Jun‐Ping
Published: June 2007

1. Exocytosis and endocytosis are the continuous outward and inward vesicular transports in a cell that occur constantly for intra‐ and inter‐cellular communications. These events are accomplished with the release and uptake of chemical messages fundamental in a variety of cellular functions, such as neurotransmitter release, hormone secretion and receptor internalization.

2. Although the mechanisms underlying these events have not been fully established, it is widely accepted that they are largely mediated and controlled by a number of effector proteins. These proteins can operate individually and in concert to produce specialized machineries in the sequential steps of exocytotic and endocytic transports.

3. Protein phosphorylation, the most common covalent modification of proteins in cells, has been implicated as playing an important role in the regulation of exocytosis and endocytosis. Many proteins involved in these processes have been identified to be phosphorylated under certain conditions.

4. For instance, synapsin I, myristoylated alanine‐rich C kinase substrate and dynamin I undergo dynamic phosphorylation and dephosphorylation cycles during exocytosis and endocytosis, implying that protein phosphorylation regulates the functions of these proteins and, thus, exocytosis and endocytosis.
HISTAMINE‐STIMULATED PHOSPHOLIPASE C SIGNALLING IN THE ADRENAL CHROMAFFIN CELL: EFFECTS ON INOSITOL PHOSPHOLIPID METABOLISM AND TYROSINE HYDROXYLASE PHOSPHORYLATION
Authors: Bunn Stephen J. , Dunkley Peter R.
Published: June 2007

1. The present report gives a detailed account of histamine‐stimulated phospholipase C (PLC) activity in bovine adrenal chromaffin cells.

2. Histamine activation of Hi receptors stimulates PLC with a biphasic sensitivity to extracellular Ca2+. The initial response (the first 15 s stimulation) was not reduced by the removal of extracellular Ca2+, whereas the maintenance of PLC activity beyond this time required Ca2+ influx.

3. Phospholipase C activity in response to a 10 min incubation with histamine was inhibited by La3+ (3 mmol/L) or SKF 96365 (10 μmol/L). Nifedipine (10 μ‐mol/L), but not ω‐agatoxin IVA (lOOnmol/L) or co‐conotoxin GVIA (300nmol/L), produced a partial inhibition of PLC activity. The response was also partially inhibited by a reduction in the extracellular CI concentration (40 mmol/L) or by the inclusion of the CL channel blocker /V‐phenylanthranilic acid (300 μmol/L).

4. Kinetic analysis of the rate of turnover of the various inositol phosphate isomers in response to histamine suggested that the inositol monophosphates were being produced from a source in addition to inositol 1,4,5‐trisphosphate (Ins(l,4,5)P3) metabolism. This conclusion was supported by the differential action of pertussis toxin and neomycin on Ins(l,4,5)P3 formation compared with inositol monophosphate formation.

5. We have attempted to identify a defined role for the intracellular Ca2+ mobilized in these cells in response to histamine. After short incubations (up to 3 min), histamine was able to regulate the site‐specific phosphorylation of tyrosine hydroxylase, the rate‐limiting enzyme in catecholamine synthesis. This observation has important implications for a possible role for the PLC signalling pathway in controlling the rate of catecholamine biosynthesis.
PROPOSAL FOR THE INTERACTION OF NON‐CONVENTIONAL PARTIAL AGONISTS AND CATECHOLAMINES WITH THE ‘PUTATIVE (β‐ADRENOCEPTOR’ IN MAMMALIAN HEART
Authors: Molenaar Peter , Sarsero Doreen , Kaumann Alberto J.
Published: June 2007

1. Evidence for a ‘putative β‐adrenoceptor’ originated over 20 years ago when cardiostimulant effects were observed to non‐conventional partial agonists. These agonists were originally described as β1‐ and β2‐adrenoceptor antagonists; however, they cause cardiostimulant effects at much higher concentrations than those required to block β2‐ and β2‐adrenoceptors. Cardiostimulant effects of non‐conventional partial agonists have been observed in mouse, rat, guinea‐pig, cat, ferret and human heart tissues.

2. The receptor is expressed in several heart regions, including the sinoatrial node, atrium and ventricle.

3. The receptor is resistant to blockade by most antagonists that possess high affinity for β1‐ and β2‐adrenoceptors, but is blocked with moderate affinity by (–)‐bupranolol and CGP20712A.

4. The receptor is pharmacologically distinct from the β3‐adrenoceptor. Micromolar concentrations of β3‐adrenoceptor agonists have no agonist or blocking activity. The receptor is also resistant to blockade by a β3‐adrenoceptor‐selective antagonist.

5. The receptor mediates increases in cAMP levels and cAMP‐dependent protein kinase (PK) A activity in cardiac tissues. Phosphodiesterase inhibition potentiates the positive chronotropic and inotropic effects of non‐conventional partial agonists.

6. The receptor mediates hastening of atrial and ventricular relaxation, which is consistent with involvement of a cAMP‐dependent pathway.

7. The non‐conventional partial agonist (–)–[3H]–CGP 12177A labels the cardiac putative β4‐adrenoceptor. Non‐conventional partial agonists compete for binding with affinities that are closely similar to their agonist potencies. Catecholamines compete for binding in a stereoselective manner with a rank order of affinity of (–)—R0363> (–)—isoprenaline > (–)—noradrenaline > (–)—adrenaline >> (+)—isoprenaline, suggesting that catecholamines can interact with the receptor.

8. The putative β4‐adrenoceptor appears to be coupled to the Gs‐adenylyl cyclase system, which could serve as a guide to its future cloning. Activation of the receptor may plausibly improve diastolic function but could also mediate arrhythmias.
LEVELS OF FRUCTOSYLLYSINE IN COLLAGEN ARE LOW COMPARED WITH THE LOSS OF LYSINE IN DIABETIC RATS: INVOLVEMENT OF OXIDATION IN INCREASED CROSS‐LINKING
Authors: Aoki Yuji , Karasawa Yasuyuki , Yazaki Kunihiko , Shirotori Katsuko , Kawa Shigeyuki , Kiyosawa Kendo
Published: June 2007

1. It is thought that early glycation products on lysine residues of collagen are re‐arranged to form collagen cross‐links (advanced glycation end‐products), which are increased in hyper‐glycaemia. We have previously reported that 4 week vitamin E supplementation in diabetic rats protected against the development of increased collagen cross‐linking. In the present study we analysed early glycation products as fructosyllysine and amino acid content of tail tendon collagen in rats.

2. The amount of lysine residues in early collagen glycation products in diabetic rats was estimated to be less than 0.2 mol/mol type I collagen, whereas in the diabetic rats the loss of lysine residues was estimated to be 2.5 mol/mol. However, vitamin E supplementation protected against the loss of lysine residues without affecting early glycation products.

3. Thus, it is demonstrated that the amount of early collagen glycation products is quite small compared with the loss of lysine residues in diabetic rats and we suggest that the oxidative modification of lysine residues may be involved in the increased cross‐linking observed in hyperglycaemia.
TACHYKININ RECEPTORS MEDIATING NON‐CHOLINERGIC CONTRACTION OF THE GUINEA‐PIG ISOLATED MAIN BRONCHUS IN RESPONSE TO FIELD STIMULATION
Authors: Heavey Melanie L. , Lau Winnie AK , Pennefather Jocelyn N.
Published: June 2007

1. The primary aim of the present study was to classify the receptors activated by tachykinins released by field stimulation of intramural nerve terminals of the guinea‐pig isolated main bronchus by using the novel non‐peptide NKi and NK2 receptor‐selective antagonists SR140333 and SR 48968, respectively.

2. Log concentration‐response curves to substance P (SP), the NKi receptor‐selective agonist [Sar9, Met(O2)11]‐SP and the NK2receptor‐selective agonist [Nle10]‐neurokinin (NK) A(4‐10) were constructed in the presence of indomethacin (2 μmol/L) and phosphoramidon (5 (μmol/L). Substance P was the least potent of these agonists.

3. In left and right main bronchi, SR 140333 (lOOnmol/L) antagonized concentration‐related contractions evoked by SP yielding pKB values of 8.02 and 7.68, respectively. SR 140333 (10 nmol/L) antagonized the effects of [Sar9, Met(O2)11]‐SP on the left bronchus with a pKB value of 8.04.

4. SR 48968 (100 nmol/L) antagonized the effects of SP yielding pKB estimates of 7.88 (left bronchus) and 731 (right bronchus).

5. [Nle10]‐NKA(4‐10) was more potent in the left than in the right main bronchus. SR 48968 (0.1‐10 nmol/L) antagonized the effects of [NleI0]‐NKA(4‐10) on the left bronchus with pKBestimates of 8.26‐10.25.

6. In the presence of indomethacin (2 μmol/L), phosphoramidon (5 μmol/L) and atropine (1 (μmol/L), electrical field stimulation (EFS; 30 V, 1ms, 15 s at 1, 3, 10 and 30 Hz) produced prolonged contractions. SR 48968 (0.1 μmol/L) markedly reduced responses to stimulation, whereas SR 140333 (0.3 μmol/L) caused a small but significant rightward displacement of the log frequency‐response curve. In combination, these concentrations of SR 48968 and SR 140333 produced complete inhibition to field stimulation at 10 Hz.

7. These results indicate that: (i) both NK1 and NK2 receptor subtypes are present in the guinea‐pig main bronchi with the left bronchus being more sensitive to an NK2 receptor agonist; and (ii) EFS of the main bronchus leads to frequency dependent contractions due to the release of tachykinin(s) that predominantly activate an NK2 receptor.
AN ANGIOTENSIN‐CONVERTING ENZYME INHIBITOR PROTECTS AGAINST DOXORUBICIN‐INDUCED IMPAIRMENT OF CALCIUM HANDLING IN NEONATAL RAT CARDIAC MYOCYTES
Authors: Maeda Atsuyoshi , Honda Masaaki , Kuramochi Takehiko , Tanaka Koichi , Takabatake Toshikazu
Published: June 2007

1. The effects of doxorubicin (DOX) on intracellular calcium transients were examined in neonatal rat cultured cardiac myocytes, as were the cardioprotective effects of an angiotensin‐converting enzyme (ACE) inhibitor on DOX‐induced impairment of calcium handling.

2. Cultured cardiac myocytes isolated from neonatal Wistar‐Kyoto rats were treated with DOX for 24 h. Field‐stimulated calcium transients in single myocytes were measured in the presence or in the absence of isoproterenol using fura‐2/AM. Calcium transients were also measured after the addition of DOX to myocytes pretreated with M‐I (an active metabolite of delapril HC1, an ACE inhibitor.

3. Doxorubicin reduced the amplitude and maximum velocity of increase and decrease of calcium transients, prolonged the time‐course of calcium transients and impaired the β‐adrenoceptor responsiveness of calcium transients in a dose‐dependent manner. The DOX‐induced impairment of calcium transients and (5‐adrenoceptor responsiveness was improved by M‐I.

4. Doxorubicin impaired both the mobilization and sequestration of intracellular calcium ions in contraction‐relaxation cycles and the response of calcium transients to (3‐adrenocep‐tor stimulation. The ACE inhibitor ameliorated DOX‐induced impairment of calcium dynamics, suggesting that M‐I, an active metabolite of delapril, protects against DOX‐induced abnormal calcium handling leading to cardiac dysfunction.
PURINES AND THE NUCLEUS TRACTUS SOLITARIUS: EFFECTS ON CARDIOVASCULAR AND RESPIRATORY FUNCTION
Authors: Phillis JW , Scislo TJ , O'Leary DS
Published: June 2007

1. The roles of adenosine and adenosine 5′‐triphosphate in cardiorespiratory regulation by the nucleus tractus solitarius (NTS) have been evaluated in a range of experiments, using microinjections of selective agonists and antagonists of purinoceptors.

2. Adenosine injected into the caudal NTS decreases heart rate (HR), arterial blood pressure (BP) and respiratory frequency by an action at A2a receptors on glutamatergic nerve terminals. Microinjections of the A2a agonist CGS 21680 caused falls in arterial BPand HR which were selectively antagonized by the A2a antagonist CGS 15943. Injection of the Ai agonist CPA in the caudal NTS elevated BP and HR and its actions were selectively antagonized by the Ai antagonist l,3‐dipropyl‐8‐cyclopentylxan‐thine. Adenosine enhanced glutamate release in the NTS.

3. In the rostral NTS, adenosine administration resulted in an elevation of BP.

4. ATP microinjection into the subpostremal NTS depressed HR and BP by an action on P2x purinoceptors, which are blocked by suramin. ATP microinjections differentially affected vascular conductance in regional peripheral vascular beds, with the most marked increases in conductance in the iliac bed and lesser effects in the superior mesenteric and renal vascular beds.

5. Recordings from renal and lumbar sympathetic nerves have demonstrated marked dose‐dependent decreases in efferent activity following α, β‐methylene ATP injections into the NTS; however, only renal but not lumbar sympathetic nerve activity was inhibited following CGS 21680 injections into the same site of the NTS.

6. ATP may function as a fast‐acting neurotransmitter in the baroreceptor afferent pathway or in interneurons in the NTS. Adenosine is likely to play a role as a modulator of activity in baroreceptor and chemoreceptor pathways, fine tuning the functional output of both systems.
CENTRAL NERVOUS SYSTEM CONTROL OF CARDIOVASCULAR FUNCTION: NEURAL MECHANISMS AND NOVEL MODULATORS
Authors: Spyer KM , Lambert JH St , Thomas T.
Published: June 2007

1. Studies are described that indicate that hypothalamic stimulation, at sites eliciting the defence reaction, results in an increase in adenosine levels in both the nucleus tractus solitarius (NTS) and rostral ventrolateral medulla (RVLM) of the rat.

2. Adenosine receptor antagonists applied to these sites attenuate the pressor response elicited by hypothalamic stimulation. Adenosine appears to be produced extracellularly from ATP, which is released from axon terminals in both the NTS and RVLM.

3. The implications of these observations for the pharmacology of hypothalamic actions on reflex inputs that modify cardiorespiratory function are discussed.
PATHOGENESIS OF THE INSULIN RESISTANCE SYNDROME (SYNDROME X)
Authors: Chisholm Donald J. , Campbell Lesley V. , Kraegen Edward W.
Published: June 2007

1. Insulin resistance is an early and major feature in the development of non‐insulin‐dependent diabetes mellitus (NIDDM), but it is also associated with hyperlipidaemia, hypertension, obesity and cardiovascular disease, the so‐called ‘insulin‐resistance syndrome’ (Syndrome X).

2. There is a strong genetic determination of NIDDM and insulin resistance, but the environmental factors of calorie excess, reduced activity and obesity also make a major contribution.

3. Central (abdominal) obesity is much more strongly associated with insulin resistance than is overall obesity. From twin studies, there appears to be specific genetic determinants of central abdominal fat, independent of overall obesity.

4. Calorie restriction and weight loss improve insulin sensitivity in overweight humans. Isocaloric alteration of macro‐nutrients substantially affects insulin sensitivity in rats but not, at least in the short‐term, in humans.

5. Exercise training improves insulin sensitivity via increased oxidative enzymes, glucose transporters (GLUT4) and capillarity in muscle as well as by reducing abdominal fat.

6. Metformin has been the only available drug that has been used clinically to significantly improve insulin sensitivity, but the new ‘glitazones’ (thiazolidinediones) have a more specific effect via altered lipid metabolism.
DIABETIC RETINOPATHY: EARLY FUNCTIONAL CHANGES
Authors: Alder Valerie A. , Su Er‐Ning , Yu Dao‐Yi , Cringle Stephen J. , Yu Paula K.
Published: June 2007

1. The present review reports some of the earliest physiological changes that occur in the diabetic retina prior to any clinical or anatomical changes in an animal model of diabetes.

2. Using chemically induced diabetes (by streptozotocin) in rats, retinal blood flow and vitreal and retinal oxygen tension were determined after 5 weeks of sustained hyperglycaemia. Blood flow was greater and was also redistributed in the diabetic group compared with values for the control group. At the same time, oxygen tension distribution was altered around retinal arterioles, implying an increase in retinal oxygen consumption in these early diabetic retinas.

3. The possibility that the blood flow changes could be due to altered control mechanisms in the retinal vasculature was confirmed using an isolated, perfused eye preparation. In diabetic eyes an altered reactivity to test pharmacological agents was demonstrated after 4 weeks of diabetes.

4. To further explore these vascular response changes we developed an isolated, perfused retinal arteriolar preparation in which individual segments of the vasculature can be tested. The possibility that insulin has a direct vasodilator effect on retinal arterioles was confirmed and was demonstrated to act via nitric oxide released from the vascular endothelial cells. These data may implicate the diabetic‐induced insulin changes in early retinal changes.

5. Evidence is presented that although early glucose control may be vital in stopping the onset of diabetic retinopathy, there comes a stage in the induced diabetic cascade where if the retinopathy has commenced, good glucose control cannot stop the further progression of the retinopathy.
COMPARISON OF THE EFFECTS OF OUABAIN AND BRAIN NATRIURETIC PEPTIDE IN SALINE‐LOADED SHEEP
Authors: Pidgeon Grant B. , Richards A Mark , Nicholls M Gary , Lewis Lynley K. , Yandle Timothy G. , Rademaker Miriam T. , Charles Christopher J. , Bailey Ross R. , Lynn Kelvin L.
Published: June 2007

1. It has been claimed that ouabain is an endogenous hormone that may be pivotal in the pathogenesis of some forms of hypertension and may exaggerate natriuresis in situations characterized by volume overload. We compared the haemodynamic, renal and endocrine effects of ouabain (at approximately 187 ng/kg per min for 2 h) with those of brain natriuretic peptide (BNP; at 5 pmol/kg per min for 2 h) in nine saline‐loaded sheep in a balanced, randomized, single‐blind, placebo‐controlled crossover study.

2. Brain natriuretic peptide infusion reduced mean arterial pressure whereas ouabain infusion caused no change. Haematocrit rose steadily during BNP infusion but fell during ouabain infusion. Neither ouabain nor BNP affected urine volume, sodium, potassium or creatinine excretion. Mean heart rate declined during the ouabain and placebo infusions, but was not altered during BNP infusion. Endogenous ouabain concentrations were not detectable at baseline or during BNP or placebo infusions, but rose to concentrations of 11 ± 1.3 nmol/L during the ouabain infusion.

3. These results suggest that ouabain is not an endogenous hormone present at physiologically relevant concentrations. Furthermore, ouabain does not cause natriuresis during saline‐loading in sheep and is therefore unlikely to be responsible for the exaggerated natriuresis seen in some forms of hypertension.
A STUDY OF NEUROKININS AND OTHER OEDEMA‐INDUCING MEDIATORS AND MECHANISMS IN THERMAL INJURY
Authors: Waller J , Siney L , Hoult JRS , Brain SD
Published: June 2007

1. Mechanisms involved in the plasma extravasation observed following thermal injury of rat dorsal skin were investigated.

2. Heat applied to the dorsal skin of anaesthetized rats by a temperature‐controlled skin heater (1 cm diameter) for 5 min induced temperature‐dependent plasma protein extravasation a. 48–48.5°C, measured for up to 4 h following initiation of heat.

3. A tachykini. NK1 receptor antagonist (SR140333), a bradykinin B2 receptor antagonist (HOE 140) and a cyclooxygenase inhibitor (indomethacin), when given as cotreatments prior to the selected measurement period, markedly suppressed oedema formation observed over 0–1 h (P < 0.05) but not that observed over 3–4 h after injury.

4. These results indicate that although neurokinins, bradykinin and cyclo‐oxygenase products may be important for the early response to thermal injury, they do not appear to play an important role in the ongoing oedem. response.

5. Neutrophils accumulate at the inflammatory site by 4h after thermal injury. Therefore, the effect of depletion of circulating neutrophils by a rat anti‐neutrophil antiserum on oedema formation over the 0–4 h period was investigated. The results show that oedema formation was similar in control and antineutrophil‐treated rats.

6. In conclusion, the data from the present study indicate that neuropeptides as well as other vasoactive mediators play a role in the acute plasma extravasation observed after thermal injury, but not in the ongoing inflammatory injury. Neutrophils, despite their presence at sites of thermal injury, do not appear to be involved in mediating the oedema formation observed up to 4 h after thermal injury.
PEROXYNITRITE: A MEDIATOR OF INCREASED MICROVASCULAR PERMEABILITY?
Authors: Greenacre S , Ridger V , Wilsoncroft P , Brain SD
Published: June 2007

1. Increased expression of inducible nitric oxide synthase (iNOS) and subsequent elevation of nitric oxide (NO) levels at inflammatory sites have led to the suggestion that peroxynitrite (the reaction product of superoxide and NO) is involved in proinflammatory processes. The present study has investigated the ability of peroxynitrite to induce oedema formation in the rat cutaneous microvasculature.

2. Peroxynitrite was synthesized from hydrogen peroxide and acidified nitrite. Spectrophotometry was used to measure the concentration and breakdown of peroxynitrite. It was also used to determine maximum amounts of hydrogen peroxide and sodium nitrite remaining after synthesis.

3. Oedema formation in response to intradermall. (i.d.) injected peroxynitrite, hydrogen peroxide and sodium nitrite was measured by the extra vascular accumulation of i.v. [125I]‐albumin in the anaesthetized rat.

4. Peroxynitrite (40,100 and 200 nmol/site) acted in a dose‐dependent manner to cause a mean (± SEM) increase in plasma extravasation of 24 ± 2,55 ± 5 and 69 ± 6 μL, respectivel. (n= 4), with resulting inflammatory oedema. Peroxynitrite induced significantly larger plasma extravasation than equivalent vehicle controls at doses of 100 (P > 0.05) and 200 nmol (P > 0.001). This increased extravasation appears to be a direct microvascular response to peroxynitrite administration and not due to either a raised pH, necessary to stabilize the peroxynitrite, or contaminating concentrations of hydrogen peroxide or sodium nitrite from which peroxynitrite is formed.

5. These results suggest that peroxynitrite acts to increase microvascular permeability and oedema formation. Therefore, peroxynitrite may mediate vascular pro‐inflammatory effects in addition to its direct cytotoxic activity.
EFFECT OF DIETARY FAT REDUCTION AND INCREASED AEROBIC EXERCISE ON CARDIOVASCULAR RISK FACTORS
Authors: Nolte Leanne J. , Nowson Caryl A. , Dyke Ann C.
Published: June 2007

1. The combined effect of dietary fat reduction and increased aerobic exercise on coronary heart disease (CHD) risk factors was investigated in healthy, normolipidaemic, normotensive, sedentary individuals.

2. After a baseline period of 2 weeks, 21 subjects were randomly allocated to one of two intervention groups (low fat exercise (LFEX) or low fat control (LFQ) for 8 weeks. Both groups were counselled to reduce their dietary fat intake to 20–25% energy from fat. The LFEX group was also required to commence an aerobic exercise programme (4X45 min per week).

3. In both groups, the falls in total cholesterol seen at week 4 were not maintained at the end of the study; however, the LFEX group maintained a fall in low‐density lipoprotein (LDL) o. 0.21±0.11 mmol/L. At the end of the study, the LFC group experienced a fall in high‐density lipoprotein (HDL)‐cholesterol of 0.16±0.05 mmol/L, due to a 0.19±0.07 mmol/L fall in the HDL2 subfraction. The LFEX group experienced no change in HDL (−0.09 ±0.06 mmol/L) or HDL2 (−0.09 ±0.05 mmol/L).

4. At the end of the study the LFEX and LFC groups experienced a 7±3 and 5±lmmHg fall in systolic blood pressure, respectively, while the LFEX group also observed a 4±2 mmHg fall in diastolic bloo. pressure.

5. The benefits of a low‐fat diet combined with aerobic exercise include a reduction in LDL and blood pressure, while maintaining HDL through th. HDL2 subfraction.
STRUCTURE AND FUNCTION OF URIDINE DIPHOSPHATE GLUCURONOSYLTRANSFERASES
Authors: Meech Robyn , Mackenzie Peter I.
Published: June 2007

1. The uridine diphosphate (UDP)‐glucuronosyltransferases (UGT) are a family of enzymes that catalyse the covalent addition of glucuronic acid to a wide range of lipophilic chemicals. They play a major role in the detoxification of many exogenous and endogenous compounds by generating products that are more polar and, thus, more readily excreted in bile or urine.

2. Inherited deficiencies in UGT forms are deleterious, as exemplified by the debilitating effects of hyperbilirubinaemia and neurotoxicity in subjects with mutations in the enzyme that converts bilirubin to its more pola. glucuronide.

3. The UGT protein can be conceptually divided into two domains with the amino‐terminal half of the protein demonstrating greater sequence divergence between isoforms. This region apparently determines aglycone specificity. The aglycone binding site is presumed to be a ‘loose’ fit, as many structurally diverse substrates can be bound by the same UGT isoform. The carboxyl‐terminal half, which is more conserved in sequence between different isoforms, is believed to contain a binding site for the cosubstrate UDP glucuronic acid (UDPGA).

4. Uridine diphosphat. glucuronosyltransfera.se is localized to the endoplasmic reticulum (ER) and spans the membrane with a type I topology. The putative transmembrane domain is located near the carboxyl terminus of the protein such that only a small portion of the protein resides in the cytosol. This cytosolic tail is believed to contain an ER‐targeting signal. The major portion of the protein is located in the ER lumen, including the proposed substrate‐binding domains and the catalytic site.

5. The microsomal membrane impedes the access of UDPGA to the active site, resulting in latency of UGT activity in intact ER‐derived microsomes. Active transport of UDPGA is believed to occur in hepatocytes, but the transport system has not been fully characterized. Uridine diphosphate glucuronosyltransfer‐ase activity is also highly lipid dependent and the enzyme may contain regions of membrane association in addition to the transmembrane domain.
MANAGEMENT OF BRANCH PULMONARY ARTERY STENOSIS: BALLOON ANGIOPLASTY OR ENDOVASCULAR STENTING
Authors: Chau Adolphus KT , Leung Maurice P.
Published: June 2007

1. The surgical outcome of congenital heart diseases may be adversely affected by residual branch pulmonary artery stenosis, which is difficult to treat surgically.

2. The objective of the present study was to evaluate the effectiveness, safety and follow‐up results of two transcatheter procedures, balloon angioplasty and endovascular stenting, for treatment of branch pulmonary arter. stenosis.

3. From December 1988 to March 1997, 22 children (group 1) underwent 30 balloon angioplasties and 12 children (group 2) underwent 14 endovascular stent implantations. The overall success rates for groups 1 and 2 were 67 (20/30) and 93% (13/14), respectively, with significant increases in vessel diameter (P < 0.001, t‐test, 29d.f.; P= 0.0001, Mest, 12d.f., respectively) and decreases in pressure gradient (P < 0.0001, Mest, 29d.f.; P= 0.001; t‐test, 12 d.f., respectively). One death (3.3%) in group 1 was due to post‐dilation reactive pulmonary hypertension. No mortality occurred in group 2 children, but two migrated stents required re‐implantation of another stent. Mean follow‐up periods were 28.2 and 26.3 months for groups 1 and 2, respectively. For group 1, no significant change in vessel diameter or pressure gradient was noted on recatheterization in 12 patients. Restenosis occurred in four of 16 (25%) initial successes. Balloon redilation in four vessels were all successful. For group 2 children, although vessel diameter remained unchanged, a significant increase in pressure gradient (P= 0.02; t‐test, 11 d.f.) was noted on recatheterization. Balloon dilations on two narrowed stents caused by intimal proliferation showed only partial improvements.

4. In conclusion, both balloon angioplasty and endovascular stent implantation are effective and safe, with satisfactory intermediate‐term results, for the treatment of branch pulmonary artery stenosis. Balloon angioplasty is the choice for initial treatment, whereas stent implantation, the long‐term outcome of which remains to be determined, should be reserved for older children after repeated failures with balloon dilation.
REDUCED INHIBITORY ACTIONS OF ADENOSINE A1 AND K1‐OPIOID RECEPTOR AGONISTS ON β‐ADRENOCEPTORS IN SPONTANEOUSLY HYPERTENSIVE RAT HEART
Authors: Yu X‐C , Wang H‐X , Wong TM
Published: June 2007

1. The modulatory actions of both adenosine A1 and K1‐opioid receptor agonists on β‐adrenoceptor stimulation in the heart of both spontaneously hypertensive rats (SHR) and nor‐motensive Wistar‐Kyoto (WKY) rats were compared.

2. In both types of rats, bot. R(‐)‐N6‐(2‐phenyliso‐propyl)adenosine (R‐PIA), an adenosine A1 receptor agonist, and U50 488H, a K1‐opioid receptor agonist, inhibited the stimulatory effects of β‐adrenoceptor activation on electrically induced [Ca2+]i transients measured by a spectrofluorometric method with fura‐2/AM as the calcium indicator. The effects of these two agonists were blocked by their respective antagonists, namely 8‐cyclopentyl‐l,3‐diprolxanthine and norbinaltorphimine.

3. The inhibitory actions of both R‐PIA and U50488H on β‐adrenoceptor augmentation of electrically induce. [Ca2+]i transients in the heart were more significantly reduced in SHR than in WKY rats, suggesting the negative modulatory actions of endogenous substances on 3‐adrenoceptors were impaired in SHR, which may contribute to hypertension.
NEW INSIGHTS INTO THE TREATMENT OF HYPERTENSION
Authors: Tomlinson Brian
Published: June 2007

1. The choice of initial pharmacological therapy is one area where the different hypertension management guidelines vary in recommending either the use of diuretics and beta‐blockers as preferred drugs or choosing from any of the five major classes of antihypertensives.

2. Improvement in cardiovascular morbidity and mortality may have been shown most conclusively with diuretics and beta‐blockers, but the effects on coronary events with these drugs were less than predicted and the other agents have a number of theoretica. advantages.

3. Recent worries regarding the possible adverse effects of calcium antagonists have led to a reappraisal of the risks and benefits of these drugs and antihypertensives i. general.

4. Many patients, particularly the elderly, have other conditions that influence the choice of first‐line therapy and ethnic variations in the effects of hypertension or the efficacy or side effects of drugs should also be taken int. account.

5. There is considerable heterogeneity within the major categories of antihypertensive drugs, so it is important to distinguish the different subgroups, dosages and formulations that may b. used.
PASSIVE SMOKING AND CORONARY HEART DISEASE: A BRIEF REVIEW
Authors: Lam Tai Hing , He Yao
Published: June 2007

1. Whether passive smoking or environmental tobacco smoke (ETS) can cause coronary heart disease (CHD) is controversial. We have undertaken a comprehensive review of the epidemiological studies regarding the relationship between ETS and CHD.

2. We searched for all original papers and reviews and calculated pooled odds ratio using the Mantel‐Haensze. method.

3. Ten prospective studies, nine case‐control studies and one cross‐sectional study were found. Almost all studies showed positive associations between ETS and CHD and a few were statistically significant, with dose‐response relationships being evident. Six review papers calculated pooled estimates of the relative risks, which ranged from 1.23 to 1.51. Other studies also showed that ETS could have other cardiovascular effects.

4. The association observed is likely to be real. The criteria for causation of time sequence, consistency, coherence and biological plausibility are satisfied. We conclude that ETS may cause CHD, particularly in women who have never smoked.