bluuebunny/crossref_metadata_2025_split huggingface dataset:
PROLONGED SYSTEMIC AND REGIONAL HAEMODYNAMIC EFFECTS OF INTRACEREBROVENTRICULAR ANGIOTENSIN II IN CONSCIOUS SHEEP
Authors: May Clive N. 
Published: June 2007

SUMMARY1. The haemodynamic mechanisms by which infusion of angiotensin II (AngII), either into the lateral cerebral ventricles (i.c.v.) or intravenously (i.v.), increased arterial pressure were studied in conscious sheep.2. Sheep were previously fitted with flow probes for measurement of cardiac output and coronary, mesenteric, renal and iliac blood flows.3. Intracerebroventricular AngII (10 nmol/h for 1 h) increased arterial pressure by 11 ± 4 mmHg (P < 0.001) due to vasoconstriction, predominantly in the mesenteric vasculature. These effects developed over 30 min and took 2 h to return to control. Following the infusion renal conductance increased continuously for 3 h, resulting in a parallel increase in renal blood flow (to 75 ± 18 mL/min above control, P<0.001).4. Intracerebroventricular AngII increased plasma vasopressin from 0.8 ± 0.3 to 7.2 ± 1.8 pg/mL (P < 0.01), and reduced plasma renin concentration from 0.9 ± 0.3 to <0.4 nmol/L/h.5. The pressor effect of i.v. AngII (5, 10, 25, 50 nmol/h) also depended on peripheral vasoconstriction, but the pattern of responses was different. The greatest degree of vasoconstriction occurred in the renal, followed by the mesenteric and iliac vascular beds; these effects were rapid in onset and offset.6. In conclusion, the pressor responses to both i.c.v. and i.v. angiotensin depended on peripheral vasoconstriction, but there were contrasting regional haemodynamic changes. ICV AngII caused a prolonged pressor response, mainly due to mesenteric vasoconstriction possibly partly due to vasopressin release, and following the infusion there was a pronounced, long‐lasting renal vasodilatation. In contrast, i.v. AngII caused vasoconstriction preferentially in the renal vascular bed and its effects were short lasting.
SIGNIFICANCE OF SERINE PROTEINASE AND MATRIX METALLOPROTEINASE SYSTEMS IN THE DESTRUCTION OF HUMAN ARTICULAR CARTILAGE
Authors: Kikuchi Hiraku , Shimada Wataru , Nonaka Tohgo , Ueshima Shigeru , Tanaka Seisuke 
Published: June 2007

SUMMARY1. During the destruction of articular cartilage, fibrinolytic enzymes and matrix metalloproteinases (MMP) may contribute to the related pathology. The activities, antigens and messenger RNA (mRNA) levels of urokinase‐type plasminogen activator (uPA) and plasminogen activator inhibitor‐1 (PAI‐1) in articular cartilage were measured in patients with no history of joint diseases (control), those with osteoarthritis (OA) classified into osteophyte‐formed site (OS) and weight‐bearing site (WS), and in patients with rheumatoid arthritis (RA).2. The uPA content was higher in WS and RA compared to normal. The PAI‐1 content was higher in OS and RA compared to normal. Weight‐bearing site patients expressed a high uPA mRNA level but a low PAI‐1 mRNA level. Osteophyte‐formed site patients expressed a low uPA mRNA level but a high PAI‐1 mRNA level.3. The levels of the MMP and mRNA of tissue inhibitors of metalloproteinases (TIMP) were measured in WS, OS and RA. In WS, the levels of MMP were high and levels of TIMP mRNA expression low. In OS, the levels of TIMP were high and levels of MMP mRNA were low. In RA, the levels of MMP and TIMP mRNA were high.4. These findings suggest that regulation of fibrinolysis may play an important role in the matrix of articular cartilage with arthropathy.
SPARSE DRUG CONCENTRATION DATA ANALYSIS USING A POPULATION APPROACH: A VALUABLE TOOL IN CLINICAL PHARMACOLOGY
Authors: McLachlan Andrew J. 
Published: June 2007

SUMMARY1. Drug concentration or pharmacological effect data collected from patients during therapy or as part of a Phase III or post‐marketing study are generally sparse (i.e. one or a few observations per patient) in nature.2. The population approach to analysing sparse drug concentration data provides a valuable tool for obtaining information about the pharmacokinetics of drugs in special patient groups (neonates, aged or critically ill), the importance of drug interactions in the clinic (using routinely collected blood concentration data) and for conducting a ‘pharmacokinetic screen’ in patients during early phase efficacy trials.3. Using a population approach to analyse drug concentration‐time data collected from patients during therapy or during an early phase investigation can complement information obtained from traditional pharmacokinetic/dynamic investigations to help gain a further insight into the factors that influence dosing guidelines.
MOLECULAR PHYSIOLOGY OF GAP JUNCTION CHANNELS
Authors: Spray David C. 
Published: June 2007

SUMMARY1. Cloning and sequencing of cDNA encoding gap junction proteins (connexins) has allowed analysis of tissue‐ and stage‐specific patterns of expression as well as the manipulation of expression of both wild‐type and mutant connexin proteins.2. These studies reveal that the 13 rodent connexins have different biophysical properties, such as unitary conductance and permeability/selectivity, are differentially sensitive to various gating stimuli and couple to one another with variable affinity. Moreover, the physiological roles of gap junction channels are being revealed, as both genetic and epigenetic human diseases are ascribed to aberrant gap junction expression, and as animal models are generated by genetic manipulation.3. This symposium brought together physiological insights achieved through the use of molecular techniques, resulting in novel appreciation of the roles of gap junction channels in normal and pathological tissue function.
WHERE ARE THE GATES IN GAP JUNCTION CHANNELS?
Authors: Dahl Gerhard 
Published: June 2007

SUMMARY1. In the formation and function of gap junction channels two types of gates ought to be discriminated: the docking gate and the channel gates proper. The docking gate is involved in the transformation of a closed hemichannel to a patent gap junction channel. By definition the trigger mechanism for this gate and maybe even the gate itself is contained within the extracellular loops of the gap junction proteins, the connexins. The channel gates proper determine the open and closed states of the complete gap junction channels.2. Probing the docking gate by mutagenesis of connexins and by synthetic peptides indicates that this gate is the consequence of complex interactions between a large fraction of the amino acids comprising the extracellular loops. Probably both inter‐ and intra‐molecular interactions are involved, and disulfide exchange may be entailed in the stabilization of the open and closed states.3. Of the various effectors on the channel gate(s) the voltage effects have obtained the most scrutiny to date. The response of gap junction channels and hemichannels is diverse, the various channels respond differently to transjunctional and membrane potential. No equivalent to the S4 segment representing the voltage sensor in other voltage dependent ion channels is present in the connexin sequences, instead mutations in various segments of connexins have been reported to affect the voltage dependence of gap junction channels. To understand the complexity of voltage effects on gap junction channels, non‐connexin peptides may need to be considered as voltage sensors or as modifiers thereof.
DOMINANT INHIBITION OF INTERCELLULAR COMMUNICATION BY TWO CHIMERIC CONNEXINS
Authors: Goliger Jefferey A. , Bruzzone Roberto , White Thomas W. , Paul David L. 
Published: June 2007

SUMMARY1. The physiological significance of communication through gap junction channels has been difficult to assess because channel activity cannot be experimentally modulated in a specific manner. To address this problem we have constructed chimeric connexins that function as dominant‐negative inhibitors of intercellular channel activity.
DIFFERENTIAL EFFECTS OF ANTIARRHYTHMIC AGENTS ON POST‐PAUSE REPOLARIZATION IN CARDIAC PURKINJE FIBRES
Authors: Wyse Kenneth R. , Bursill Jane A. , Campbell Terence J. 
Published: June 2007

SUMMARY1. Marked action potential duration (APD) prolongation with agents such as quinidine is often a precursor of early afterdepolarizations and triggered activity, thought to be the underlying mechanism of torsade de pointes. Episodes of torsade de pointes commonly occur following a pause.2. We recently demonstrated that quinidine, but not disopyramide, produced marked further prolongation of APD immediately following pauses of 2‐10s interpolated into a basic drive train in canine Purkinje fibres.3. We report here experiments aimed at further elucidating the mechanisms of this phenomenon.4. We used standard microelectrode techniques to record action potentials from canine Purkinje fibres driven at a baseline interstimulus interval (ISI) of 1000 ms.5. We were able to reproduce the phenomenon of postpause prolongation of APD with amitriptyline, which blocks both sodium and potassium channels, as does quinidine. Furthermore, we showed that the kinetics of interaction of amitriptyline, with the sodium channel, are similar to those known to exist for quinidine (time constant of recovery from blockade 2.3±0.6s).6. In contrast, we were unable to reproduce post‐pause prolongation of APD with three pure class III antiarrhythmic agents, d‐sotalol, clofilium and dofetilide.7. We propose that quinidine and amitriptyline behave similarly, in that they both produce two separate, opposing effects on APD. During a pause, the sodium channel‐blocking action of these compounds diminishes exponentially, allowing the potassium channel blocking effect to become manifest as post‐pause prolongation of APD. None of dsotalol, clofilium or dofetilide exhibits significant sodium channel blockade and, thus, these agents do not manifest post‐pause prolongation of repolarization. Disopyramide does produce sodium channel blockade, but recovery from this effect is much slower than for quinidine or amitriptyline (time constant 12‐50s). Thus, we propose insufficient recovery occurs during the intervals under study to uncover the action potential‐prolonging effect of the unopposed potassium channel blockade for disopyramide.
11β‐HYDROXYSTEROID DEHYDROGENASE TYPE I ENZYME IN THE HEARTS OF NORMOTENSIVE AND SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Smith RE , Krozowski ZS 
Published: June 2007

SUMMARY1. The enzyme 11β‐hydroxysteroid dehydrogenase (11βHSD) converts glucocorticoids to their inactive 11‐keto metabolites. The ubiquitous expression of the NADP‐dependent isoform (11βHSD1) suggests an important role in modulating glucocorticoid action, but little is known about 11βHSD1 gene expression and enzymatic activity in the rat heart.2. In the present study rat cardiac 11βHSD1 activity and ontogeny of gene expression have been characterized. The addition of NADP, but not NAD, to heart homogenates resulted in significant increases in the metabolism of both corticosterone and cortisol, with the former substrate displaying far greater metabolism. Both 11βHSD1 gene expression and enzyme activity increased in parallel from low levels at 1 week of age to maximal levels at 8 weeks, with no further change by 16 weeks of age.3. We also compared theactivity of 11βHSD1 in the hearts of male and female spontaneously hypertensive rats (SHR) with normotensive Wistar‐Kyoto (WKY) controls. Enzyme activity in the pooled atria of female SHR was significantly higher than in male SHR atria (7.6±0.6% conversion of corticosterone vs 4.5±0.5%; P < 0.05). The left ventricles of female WKY rats contained significantly less 11βHSD activity than either male WKY rats or female SHR (8.6±0.8% conversion vs 17±1.4 and 13.6±0.5%, respectively; P < 0.05). In the right ventricle, female WKY rats also had significantly less enzyme activity than either female SHR or male WKY rats (4.9±0.7 vs 10.0±1.7 and 10.2±1.4%; P<0.05).4. These results clearly show that the rat heart contains significant amounts of the 11βHSD1 enzyme and that this activity is sexually dimorphic. Furthermore, significant differences were observed between a normotensive and hypertensive strain of rat. The relevance of these observations to the aetiology and maintenance of hypertension remains to be explored.
VESICO‐HEPATO‐RENAL CYCLING OF ACIDIC DRUGS VIA THEIR REACTIVE ACYL GLUCURONIDE METABOLITES? STUDIES WITH DIFLUNISAL IN RATS
Authors: Dickinson Ronald G. , King Andrew R. 
Published: June 2007

SUMMARY1. Deconjugation‐reconjugation cycling of acidic drugs is known to occur in vivo via the hydrolysis of their reactive acyl glucuronide metabolites during their circulation in the blood (systemic cycling) or during their passage through the gut after biliary excretion (enterohepatic cycling). Whether such cycling occurs after renal excretion via hydroysis in the urinary bladder followed by absorption of liberated drug (vesico‐hepato‐renal cycling) was investigated in rats using diflunisal (DF) and its acyl glucuronide. (DFAG) as model compounds.2. After administration of DF (1 mg/0.5 mL buffer, pH 7) into the bladder of anaesthetized bile‐exteriorized rats, DF appeared rapidly in plasma, achieving peak concentrations of 7 μg/mL at 1h. At 4h, 30% of the dose was recovered as metabolites, mainly DFAG and DF phenolic glucuronide (DFPG) in bile, while 30% was recovered as unchanged DF from the bladder.3. By contrast, after intravesical adminstration of an equimolar amount of DFAG at pH 7 or 5, DFAG itself was not detectable in plasma. Plasma concentrations of DF were barely detectable, with only approximately 1% of the administrered dose recovered as metabolites in bile.4. The data thus show that, although DF itself undergoes facile absorption from the urinary bladder of healthy rats, vesico‐hepato‐renal cycling of DF via DFAG appears to be of only minor quantitative importance.
HYPOTENSIVE ACTIVITY OF AQUEOUS EXTRACT OF ANDROGRAPHIS PANICULATA IN RATS
Authors: Zhang CY , Tan BKH 
Published: June 2007

SUMMARY1. The hypotensive activity of an aqueous extract of Andrographis paniculata was studied using chronic intraperitoneal (i.p) infusions by osmotic pumps. The extract exhibited a dose‐dependent hypotensive effect on the systolic blood presure (SBP) of spontaneously hypertensive rats (SHR).2. The optimum hypotensive dose determined was repeated in a study in SHR and their normotensive controls, Wistar Kyoto (WKY) rats, to demonstrate its comparative effects on the SBP, plasma and lung angiotensin‐converting enzyme (ACE) activities, as well as on lipid peroxidation in the kidneys, as measured by thiobarbituric acid (TBA) assay.3. The extract significantly lowered the SBP of both SHR and WKY rats.4. Plasma, but not lung, ACE activity and kidney TBA level were significantly lower in extract‐treated SHR when compared with vehicle‐treated SHR controls.5. Plasma and lung ACE activities as well as kidney TBA levels were not significantly different between extract‐and vehicle‐treated WKY rats.6. This study indicates that the aqueous extract of A. paniculata lowers SBP in the SHR possibly by reducing circulating ACE in the plasma as well as by reducing free radical levels in the kidneys. The mechanism(s) of hypotensive action seems to be different in WKY rats.
7th Southest Asian Western Pacific Regional Meeting of Pharmacologists Pharmacology of Natural Products
Authors: Ogle CW , Kwan CY 
Published: June 2007

Symposium PapersCardiovascular protection by ginsenosides and their nitric oxide releasing action X ChenProbing excitation‐contraction coupling in trachealis smooth muscle with the mycotoxin cyclopiazonic acid D Amoako, Y Quian, C‐Y Kwan and J‐P BourreauAntihypertensive effects of DL‐tetrahydropalmatine: An active principle isolated from Corydalis MT Lin, FY Chueh, MT Hsieh and CF ChenA family of novel actin‐inhibiting marine toxins S‐Y Saito and H KarakiIn vitro inhibitory effects of chebulinic acid on the contractile responses of cardiovascular muscles Y‐Y Guan, C‐Y Kwan, F‐L Hsu and J‐T ChengTetrandrine as a calcium antagonist H Takemura, K Imoto, H Ohshika and C‐ Y Kwan
CARDIOVASCULAR PROTECTION BY GINSENOSIDES AND THEIR NITRIC OXIDE RELEASING ACTION
Authors: Chen Xiu 
Published: June 2007

SUMMARY1. In an animal model in vivo, ginsenosides (GS), saponins from Panax ginseng, were shown to protect against myocardial ischaemia/reperfusion damage with concomitant increased 6‐keto‐PGF1α and decreased lipid peroxidation.2. In perfused rabbit lung in situ and isolated rabbit aortic rings, GS protected the pulmonary and aortic endotheluim against electrolysis‐induced free radical injury. Purified components of GS, Rb1 and especially Rg1, relaxed pulmonary vessels and this effect was eliminated by nitro‐L‐arginine, an inhibitor of nitric oxide (NO) synthase.3. In cultured bovine aortic endothelial cells, GS enhanced the conversion of [14C]‐L‐arginine to [14C]‐L‐citrulline, indicating an increased release of NO.4. As the neurotransmitter inducing penile erection, NO release was shown to be enhanced by GS in rabbit corpus cavernosum (CC) in vitro. Ginsenosides enhanced both acetylcholine‐induced and transmural nerve stimulation‐activated relaxation associated with increased tissue cGMP. The latter effect was eliminated by tetrodotoxin and was associated with decreased tissue cGMP. Ginsenoside‐enhanced CC relaxation was attenuated by nitro‐L‐arginine and oxyhaemoglobin, and enhanced by superoxide dismutase.5. It is postulated that cardiovascular protection by GS may be partly mediated by the release of NO, a potent antioxidant, and that the GS‐enhanced release of NO from endothelial cells, especially from perivascular nitric oxidergic nerves in the CC, may partly account for the aphrodisiac effect of Panax ginseng used in traditional Chinese medicine.
IN VITRO INHIBITORY EFFECTS OF CHEUBULINIC ACID ON THE CONTRACTILE RESPONSES OF CARDIOVASCULAR MUSCLES
Authors: Guan Yong‐Yuan , Kwan Chiu‐Yin , Hsu Feng‐Lin , Cheng Juei‐Tang 
Published: June 2007

SUMMARY1. The effects of chebulinic acid, which has been shown to elicit blood pressure lowering effect in rats, on aortic vascular contraction as well as cardiac contraction were studied in rats.2. Chebulinic acid had no effect on KCI‐induced aortic contraction, but irreversibly inhibited the contractile responses to phenylephrine in an apparently non‐competitive manner. Chebulinic acid also inhibited contractile responses of rat aorta to 5‐hydroxytryptamine and angiotensin II.3. Chebulinic acid inhibited the binding of [3H]‐prazosin to dog aortic microsomal membranes in a concentration‐dependent manner with an IC50 value of 0.34 mmol/L. Results of saturation binding experiments suggest a mixed mode of inhibition by chebulinic acid (i.e. a decrease in both the maximal number of binding sites and the affinity for prazosin).4. Chebulinic acid concentration‐dependently and reversibly inhibited the maximal left ventricular pressure of rat heart in a Langendorff preparation with 50% inhibition occurring at a concentration of 0.3 nmol/L.5. We conclude that chebulinic acid exerts non‐specific inhibitory actions in vascular preparations. Its inhibitory effect on cardiac contraction was reversible and three orders of magnitude more potent than that on vascular contraction. We suggest that the hypotensive effect of chebulinic acid is probably mediated via the decrease in cardiac output resulting from reduced left ventricular contraction.
EFFECT OF ARTERIAL CHEMORECEPTOR STIMULATION WITH ALMITRINE BISMESYLATE ON PLASMA RENIN ACTIVITY, ALDOSTERONE, ACTH AND CORTISOL IN ANAESTHETIZED, ARTIFICIALLY VENTILATED CATS
Authors: Honig A. , Wedler B. , Oppermann H. , Gruska† S. , Schmidt M. 
Published: June 2007

SUMMARY1. Changes in plasma renin activity (PRA) and in the plasma concentration of aldosterone, adrenocorticotrophic hormone (ACTH) and cortisol in response to an intravenous infusion of the chemoreceptor stimulant almitrine bismesylate (0.2 mg/kg) were studied in two groups of anaesthetized, paralysed and constantly ventilated cats. In one group, the peripheral arterial chemoreceptors remained innervated, whereas in the other they were denervated by bilateral cervical vagotomy and section of the carotid sinus nerves.2. Animals with innervated chemoreceptors (n= 16) reacted to almitrine bismesylate with a significant (P < 0.05) increase in both ACTH and cortisol. These responses were not present in cats in which the peripheral arterial chemoreceptors had been surgically denervated (n= 16).3. Plasma renin activity and plasma aldosterone increased with time during experiments on both the chemoreceptor‐intact and chemoreceptor‐denervated cats. Almitrine did not affect the time course of the rise in PRA and plasma aldosterone in either group of animals.4. These data indicate that, under the conditions of our experiments, almitrine induced arterial chemoreceptor reflex mechanisms stimulate ACTH and cortisol release, but has no chemoreceptor‐dependent influence on PRA or plasma aldosterone.
INFLUENCE OF EXTRACELLULAR pH, SODIUM PROPIONATE AND TRIMETHYLAMINE ON EXCITATION‐CONTRACTION COUPLING IN THE RAT TAIL ARTERY
Authors: Achike Francis I. , Ballard Heather J. , Ogle Clive W. 
Published: June 2007

SUMMARY1. The effects of extracellular or intracellular pH changes on agonist‐ or depolarization‐induced contractions of the rat tail artery were investigated.2. Vessels were perfused initially (25 min) with physiological salt solution (PSS) at a pressure of 30 mmHg. Perfusion was then continued with calcium‐free PSS containing either 3.0 μmol/L noradrenaline (NA) or 100 mmol/L K+, which had been made either acidotic or alkalotic. Contractile responses to graded concentrations of calcium were assessed.3. A reduction in the intracellular or extracellular pH was induced by the addition of a weak acid (30 mmol/L sodium propionate) or reduction of the concentration of HCO3‐ in the PSS, respectively; an elevation of the intracellular or extracellular pH was produced by the addition of a weak base (10 mmol/L trimethylamine) or by increasing HCO3‐, respectively. The PSS was bubbled with 5% CO2/95% O2.4. Lowered intracellular pH did not alter NA‐ or K+‐stimulated contractions. During lowered extracellular pH, contractile responsiveness and peak response were significantly reduced in K+‐stimulated arteries, but were not affected in NA‐stimulated arteries.5. Elevated intracellular pH did not alter NA‐induced contraction, but reduced the sensitivity to K+‐stimulated contractions. Elevated extracellular pH had little effect on the magnitude of K+‐induced contractions, but slightly enhanced (although not significantly) NA‐induced contractions.6. It is concluded that reduced contractile responses to K+ during extracellular acidosis are due to the modulation of potential‐operated calcium channels (POC). Alkalotic vasodilatation is mediated by intracellular events and is POC‐modulated, whereas alkalotic vasoconstriction appears to be due to extracellular events and is modulated by receptor‐operated calcium channels (ROC).
HIGH‐LEVEL EXPRESSION OF RAT D1A DOPAMINE RECEPTOR cDNA IN MOUSE FIBROBLAST LTK‐ CELLS BY n‐BUTYRATE
Authors: Horiuchi Akira , Felder Robin A. 
Published: June 2007

SUMMARY1. In order to develop a simple, efficient system for the high‐level expression of dopamine receptors in eukaryotic cells, we have studied the effects of n‐butyrate on the expression of rat D1A dopamine receptor cDNA in mouse fibroblast LTK‐ cells as compared with those of n‐butyrate on endogenous D1 receptor levels in opossum kidney cells.2. In the transfected LTK‐ cell membranes with pRc/CMV‐D1A receptor cDNA, a selective D1 dopamine antagonist, [3H]‐SCH 23390, exhibited a K4 of 0.9 ± 0.1 nmol/L and a Bmax of 0.35 ± 0.05 pmol/mg protein (n= 5).3. Addition of n‐butyrate (2–10 mmol/L) to the culture medium for 48 h dose‐dependently increased the D1A receptor level up to 1.5 ± 0.3 pmol/mg protein (n= 7), although the K4 values were not affected. The increase in receptor level was accompanied by an elevation of selective D1 agonist‐induced adenylyl cyclase activity.4. In contrast, n‐butyrate treatment (2–10 mmol/L) did not affect either endogenous D1 receptor levels or fendoldopam‐induced adenylyl cyclase activity in opossum kidney cells.5. These results suggest n‐butyrate is a useful tool for obtaining high‐level expression of D1A dopamine receptor cDNA in mouse fibroblast LTK‐ cells.