bluuebunny/crossref_metadata_2025_split huggingface dataset:
SEX‐ AND AGE‐RELATED CHANGES IN URINARY CONTENTS OF α1‐MICROGLOBULIN AND ULINASTATIN IN MICE
Authors: Shikimi Tadahiro , Suzuki Shusaku , Kaku Koichi , Ishino Hiroshi , Okunishi Hideki , Takaori Shuji 
Published: March 2003

1. Using two murine strains, ICR/Jcl and senescence‐accelerated‐prone inbred mouse 1 (SAMP1), age‐associated changes in urine indices (e.g. urine volume, creatinine contents, contents of α1‐microglobulin (α1M) and ulinastatin (UT)) and the relation of urinary contents of α1M and UT were investigated.2. Sex‐related differences in the indices were not observed in ICR nor in SAMP1 mice.3. Urine indices per 24 h of ICR mice at 6 and 14 months of age were higher than those at 3 months of age, although indices of SAMP1 mice did not change with ageing. Urinary contents of α1M and UT in ICR mice at 6 and 14 months of age were higher than those in SAMP1 mice. However, contents of α1M and UT expressed as the contents per creatinine did not differ between these two strains.4. In the relation between urinary contents of α1M and UT, a positive correlation was displayed both in ICR and SAMP1 mice, and the regression slope did not significantly differ with ageing in these two strains.5. These results suggest that ageing per se is not a factor which affects the relation of urinary contents of α1M and UT.
RENAL HAEMODYNAMIC AND EXCRETORY RESPONSES TO BRADYKININ IN ANAESTHETIZED DOGS
Authors: Matsumura Yasuo , Tadano Kiyoshi , Yamasaki Tomoyuki 
Published: March 2003

1. Effects of bradykinin (BK) on renal haemodynamics and urine formation were examined in anaesthetized dogs.2. Renal arterial infusion of BK at doses of 5 or 50 ng/kg per min produced dose‐dependent increases in renal blood flow (RBF), without affecting systemic arterial pressure or glomerular filtration rate. There were also significant and dose‐dependent increases in urine flow (UF), urinary excretion of sodium (UNaV) and fractional excretion of sodium (FENa) and decreases in urine osmolality during BK infusion.3. Renal haemodynamic and excretory responses to the BK infusion were completely abolished by the simultaneous administration of Hoe 140 (icatibant, 100 ng/kg per min intrarenally), a selective BK B2‐receptor antagonist.4. In the presence of NG‐nitro‐L‐arginine (NOARG; 40 μg/kg per min intrarenally), a nitric oxide (NO) synthase inhibitor, BK‐induced renal vasodilative and natriuretic effects were markedly attenuated, although responses of UF and urine osmolality to BK remained unchanged. The water diuretic effect of BK was abolished in dogs given both NOARG and ibuprofen (12.5 mg/kg bolus injection plus 12.5 mg/kg per h of sustained infusion intravenously), a cyclooxygenase inhibitor.5. These results clearly indicate that renal haemodynamic and excretory responses to BK were mediated exclusively by the B2‐receptor. Renal vasodilative and natriuretic responses are mainly linked to NO generation, while both NO and prostaglandin biosynthesis are involved in the BK‐induced water diuresis.
Gene Transfer And Models Of Gene Therapy For The Myocardium
Authors: Alexander M Yvonne , Webster Keith A , McDonald Patricia H , Prentice Howard M 
Published: March 2003

SUMMARY1. Gene transfer into the myocardium can be achieved through direct injection of plasmid DNA or through the delivery of viral vectors, either directly or through the coronary vasculature. Direct DNA injection has proven extremely valuable in studies aimed at characterizing the activities of promoter elements in cardiac tissue and for examining the influence of the pathophysiological state of the myocardium on expression of transferred foreign genes.2. Viral vectors, in particular adenoviruses and adeno‐associated virus, are capable of transfecting genetic material with high transduction efficiencies and have been applied to a range of model systems for in vivo gene transfer. Efficient gene transfer has been achieved into the coronary vessels and surrounding myocardium by intracoronary infusion of adenovirus.3. Because the immunogenicity of viral vectors can limit transgene expression, much attention has been paid to strategies for circumventing this, including the development of new modified adenovirus and adeno‐associated virus vectors that do not elicit significant inflammatory responses. While cellular transplantation may prove valuable for the repair of myocardial tissue, confirmation of its value awaits establishment of a functional improvement in the myocardium following cell grafting.4. Because gene transfer into the myocardium can now be achieved with high efficiency in the absence of significant inflammatory responses, the ability to regulate foreign gene expression in response to an endogenous disease phenotype will enable the development of new effective viral vectors with direct clinical applicability for specified therapeutic targets.
DIFFERENTIAL BLOCKING EFFECTS OF TETRODOTOXIN ON DOUBLE‐PEAKED VASOCONSTRICTOR RESPONSES TO PERIARTERIAL NERVE STIMULATION IN CANINE ISOLATED, PERFUSED SPLENIC ARTERY
Authors: Yang XIAO‐PING , Chiba SHIGETOSHI 
Published: March 2003

1. In the present study, we investigated the effects of progressive inhibition of neuronal sodium channels by increasing concentrations of tetrodotoxin (TTX; 1–30 nmol/L) on the double‐peaked vasoconstrictor responses to electrical periarterial nerve stimulation in the canine isolated and perfused splenic artery.2. Double‐peaked vasoconstrictions (biphasic vasoconstrictor responses) were consistently observed in following electrical stimulation with 30 s trains of pulses at 1–10 Hz. At low frequencies of stimulation (1–3 Hz), a submaximal concentration of 3 nmol/L TTX had no effect on the first phase of the contractile response, but almost completely inhibited the second‐phase response. At high frequencies (6–10 Hz), the two vasoconstrictor phases were almost equally inhibited by 50% by 3 nmol/L TTX. A three‐fold increase in the concentration of TTX used (10 nmol/L) abolished the second‐phase vasoconstriction at all stimulation frequencies tested, whereas this concentration of TTX failed to block the first‐phase response. Further increasing the concentration of TTX to 30 nmol/L completely blocked the remaining first‐phase response.3. Treatment with 0.1 μmol/L prazosin did not modify the first‐phase response to any of the stimulation frequencies in the presence of 3 nmol/L TTX. Moreover, 0.1 μmol/L prazosin had no affect on the second‐phase response at low frequencies (1–3 Hz), while at high frequencies (6–10 Hz) it slightly, but significantly inhibited the second‐phase response. The vasoconstrictor responses that persisted after 3 nmol/L TTX and 0.1 μmol/L prazosin were completely suppressed by subsequent application of 1 μmol/L α,β‐methylene ATP at all stimulation frequencies (1–10 Hz).4. In conclusion, progressive inhibition of sodium channels by increasing the concentration of TTX may exert a more preferential inhibition on adrenergic rather than purinergic components, suggesting that TTX‐sensitive sodium channels may have a more important role in determining the adrenergic rather than purinergic transmission of sympathetic nerves.
CHRONIC LEVOTHYROXIN TREATMENT IS ASSOCIATED WITH ION CHANNEL ABNORMALITIES IN CARDIAC AND NEURONAL CELLS
Authors: Dai DE‐ZAI , Hu HUI‐JUAN , Yang DONG‐MEI , Hao XUE‐MEI , Zhang GUANG‐QIN , Zhou PEI‐AI , Wu CAI‐HONG 
Published: March 2003

SUMMARY1. We investigated the ion currents responsible for repolarization of guinea‐pig isolated myocytes (ICa) and rat hippocampal CA1 neurons (IA and IK) by means of the whole‐cell holding technique.2. The rat hypertrophied heart, induced by levothyroxin, caused exaggerated cardiac arrhythmias after coronary ischaemia–reperfusion.3. We found an enhanced ICa in guinea‐pig isolated myocytes and decreased IA and IK in rat hippocampal CA1 neurons following levothyroxin treatment. Blockade of the outward K+ current and an increment in inward Ca2+ current by chronic levothyroxin treatment contributed to the delayed repolarization and aggravated cardiac arrhythmias.4. Animals treated with chronic levothyroxin may serve as pathological models for the investigation of the pattern of ion channel disorders with regard to impaired repolarization and aggravated cardiac arrhythmias.
ARSENIC‐INDUCED OXIDATIVE STRESS AND ITS REVERSIBILITY FOLLOWING COMBINED ADMINISTRATION OF N‐ACETYLCYSTEINE AND MESO 2,3–DIMERCAPTOSUCCINIC ACID IN RATS
Authors: Flora Swaran Js 
Published: March 2003

1. The present study examined whether arsenic induces oxidative stress in liver, brain and erythrocytes (RBC) based on the investigation of certain selected parameters. It also explored the possibility that combined administration of N‐acetylcysteine (NAC) and meso 2,3‐dimercaptosuccinic acid (DMSA) was capable of achieving better reversibility in the parameters indicative of arsenic‐induced oxidative stress than individual treatment with either of these drugs.2. Male rats were exposed to 100 p.p.m. sodium arsenite in their drinking water for 12 weeks (equivalent to 12 mg/kg As). The arsenic was then removed and rats were given NAC (1 mmol/kg per day), DMSA (1 mmol/kg per day) or a combination of the two, orally, once daily for 5 days. Animals not given arsenic and those given arsenic but not NAC or DMSA served as negative and positive controls, respectively.3. Twelve weeks of arsenic exposure was found to deplete glutathione (GSH) levels, increase oxidized glutathione (GSSG) and promote malondialdehyde (MDA) production in both liver and brain samples. In addition to a significant reduction in RBC δ‐aminolevulinic acid dehydratase (ALAD) activity and GSH levels, a marked elevation in MDA production may also contribute to arsenic‐induced oxidative stress.4. Treatment with either NAC or DMSA alone partially reversed arsenic‐induced alterations in hepatic GSH and MDA, while only brain MDA levels responded favourably to these drugs. Only DMSA appeared to restore blood ALAD, while RBC MDA levels responded favourably to both drugs. Treatment with DMSA also produced an effective depletion of blood and hepatic arsenic concentrations. In the liver, most of these parameters were more effectively reversed by combined treatment with NAC and DMSA compared with the effects of either drug alone.5. These results provide in vivo evidence of arsenic‐induced oxidative stress in liver, brain and RBC and indicate that these effects can be mitigated by pharmacological intervention that encompasses combined treatment with NAC and DMSA.
EFFECTS OF PYRUVATE ON INTRACELLULAR Ca2+ REGULATION IN CARDIAC MYOCYTES FROM NORMAL AND DIABETIC RATS
Authors: Mellors Linda J , Kotsanas George , Wendt Igor R 
Published: March 2003

SUMMARY1. Pyruvate has been shown to enhance the contractile performance of cardiac muscle when provided as an alternative substrate to glucose. The aims of the present study were to determine whether the inotropic effects of pyruvate are due to increased mobilization of intracellular Ca2+ ([Ca2+]i) and to compare the effects of pyruvate on [Ca2+]i levels in myocytes from normal and diabetic animals.2. Fura‐2 was used to monitor [Ca2+]i in ventricular myocytes isolated from control and streptozotocin‐treated male Wistar rats. The experiments were performed at 25°C, with an extracellular [Ca2+] of 1.5 mmol/L and either 10 mmol/L glucose or 10 mmol/L pyruvate as the substrate.3. In myocytes from both control and diabetic rats, increasing the stimulus frequency from 0.33 to 2.0 Hz resulted in significant increases in resting and peak [Ca2+]i as well as in the amplitude of the [Ca2+]i transient, irrespective of substrate. Compared with glucose, pyruvate significantly increased resting and peak [Ca2+]i and the amplitude of the [Ca2+]i transient at each stimulus frequency in myocytes from both control and diabetic animals. However, the extent of potentiation of the [Ca2+]i transient amplitude produced by pyruvate was significantly less in myocytes from the diabetic rats.4. The rate of restitution of the [Ca2+]i transient was used as an index of the rate of Ca2+ cycling by the sarcoplasmic reticulum (SR). Pyruvate enhanced the rate of restitution in control but not diabetic rat cells.5. The time course of decay of the [Ca2+]i transient was analysed as a measure of the rate of removal of Ca2+ from the cytosol. Pyruvate tended to increase the rate of decay in cells from control but not diabetic animals. The rate of decay was slower in cells from diabetic animals compared with controls.6. The data reveal that pyruvate increases SR Ca2+ cycling, leading to greater Ca2+ release and an increase in the amplitude of the [Ca2+]i transient. Therefore, it seems highly likely that increased [Ca2+]i mobilization is responsible for the previously reported positive inotropic actions of pyruvate. These effects of pyruvate are attenuated in diabetic rat cells, which may reflect an impaired capacity of mitochondria in diabetic hearts to oxidize pyruvate, thus limiting potential energetic benefits.
Pattern Formation And Rhythm Generation In The Ventral Respiratory Group
Authors: McCrimmon Donald R , Monnier Armelle , Hayashi Fumiaki , Zuperku Edward J 
Published: March 2003

SUMMARY1. There is increasing evidence that the kernel of the rhythm‐generating circuitry for breathing is located within a discrete subregion of a column of respiratory neurons within the ventrolateral medulla referred to as the ventral respiratory group (VRG). It is less clear how this rhythm is transformed into the precise patterns appearing on the varied motor outflows.2. Two different approaches were used to test whether subregions of the VRG have distinct roles in rhythm or pattern generation. In one, clusters of VRG neurons were activated or inactivated by pressure injection of small volumes of neuroactive agents to activate or inactivate groups of respiratory neurons and the resulting effects on respiratory rhythm and pattern were determined. The underlying assumption was that if rhythm and pattern are generated by neurons in different VRG subregions, then we should be able to identify regions where activation of neurons predominantly alters rhythm with little effect on pattern and other regions where pattern is altered with little effect on rhythm.3. Based on the pattern of phrenic nerve responses to injection of an excitatory amino acid (DL‐homocysteate), the VRG was divided into four subdivisions arranged along the rostrocaudal axis. Injections into the three rostral regions elicited changes in both respiratory rhythm and pattern. From rostral to caudal the regions included: (i) a rostral bradypnoea region, roughly associated with the Bötzinger complex; (ii) a dysrhythmia/tachypnoea area, roughly associated with the pre‐Bötzinger complex (PBC); (iii) a second caudal bradypnoea area; and, most caudally, (iv) a region from which no detectable change in respiratory motor output was elicited.4. In a second approach, the effect of unilateral lesions of one subregion, the PBC, on the Breuer–Hering reflex changes in rhythm were determined. Activation of this reflex by lung inflation shortens inspiration and lengthens expiration (TE).5. Unilateral lesions in the PBC attenuated the reflex lengthening of TE, but did not change baseline respiratory rhythm.6. These findings are consistent with the concept that the VRG is not functionally homogeneous, but consists of rostrocaudally arranged subregions. Neurons within the so‐called PBC appear to have a dominant role in rhythm generation. Nevertheless, neurons within other subregions contribute to both rhythm and pattern generation. Thus, at least at an anatomical level resolvable by pressure injection, there appears to be a significant overlap in the circuitry generating respiratory rhythm and pattern.
Development Of An Experimental Model Of Liver Cirrhosis In Rabbits
Authors: Brandão CG , Ferreira HHA , Piovesana H , Polimeno NC , Ferraz JGP , De Nucci G , Pedrazzoli J 
Published: March 2003

SUMMARY1. The aim of the present study was to develop an experimental model of liver cirrhosis in rabbits using CCl4 and phenobarbital.2. Liver cirrhosis was induced in male New Zealand white rabbits (n = 10) by intragastric administration of CCl4 once weekly starting 14 days after the addition of phenobarbital to the drinking water (50 mg/day). Controls received phenobarbital only (n = 7). Alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ‐glutamyl transpeptidase (GGT), albumin and bilirubin levels were determined throughout CCl4 treatment. The initial dose of CCl4 was 20 μg and subsequent doses were calculated to maintain AST and ALT levels between 400 and 800 IU/L for the duration of treatment (16 weeks). Indocyanine green (ICG) clearance was performed before and at the end of CCl4 treatment. Animals were killed at 16 weeks and three fragments of each liver lobe were processed for histological examination. A semiquantitative score was used to evaluate the development of fibrosis.3. Cirrhosis developed in 80% of rabbits treated with CCl4. These animals did not gain weight compared with controls (P < 0.05). A significant reduction of ICG clearance was observed in CCl4‐treated rabbits compared with controls (P < 0.05). The AST, ALT, bilirubin and γ‐GGT levels were elevated in CCl4‐treated rabbits.4. In conclusion, this model is successful in producing liver cirrhosis and may be useful in studies investigating metabolic, immunological or biochemical changes during the evolution of chronic liver disease.
Acute But Not Chronic Caffeine Impairs Functional Responses To Ischaemia–Reperfusion In Rat Isolated Perfused Heart
Authors: Rose'Meyer Roselyn B , Headrick John P , Peart Jason N , Harrison Glenn J , Garnham Bronwyn G , Willis Roger J 
Published: March 2003

SUMMARY1. The effect of acute (50 μmol/L) and chronic (0.06% in drinking water for 14 days) caffeine on the response to ischaemia–reperfusion was studied in Wistar rat isolated perfused hearts.2. Neither acute nor chronic caffeine modified normoxic heart rate or left ventricular pressures. However, acute caffeine decreased coronary flow by up to 20%, while chronic caffeine consumption increased coronary flow by approximately 15% and abolished the vasoconstrictor effect of acute caffeine (P < 0.05).3. After 15 min global ischaemia, chronic caffeine treatment did not alter the recovery of left ventricular diastolic pressure (LVDP), end‐diastolic pressure (EDP) or heart rate during reperfusion, but did enhance coronary flow rate (P < 0.05). Acute caffeine inhibited the recovery of LVDP and elevated postischaemic EDP in both caffeine‐naïve and chronic caffeine‐treated groups. Acute caffeine also significantly inhibited coronary reflow in naïve but not chronic caffeine‐treated groups and produced a transient tachycardia during reperfusion in hearts from chronic caffeine‐treated rats.4. The incidence of arrhythmias was unaltered by chronic caffeine treatment, but was increased by acute caffeine in both naïve and chronic caffeine hearts.5. In conclusion, chronic caffeine intake alone has no detrimental effects on recovery from ischaemia; however, acute caffeine worsens postischaemic contractile function in hearts from naïve and chronic caffeine‐treated rats.
Acute Opioid Receptor Desensitization And Tolerance: Is There A Link?
Authors: Borgland Stephanie L 
Published: March 2003

SUMMARY1. Morphine, used long‐term for the treatment of pain, results in drug tolerance. The therapeutic benefits, as well as side effects, of morphine are mediated predominantly via activation of μ‐opioid receptors. Although the underlying mechanisms for opioid tolerance remains unclear, early adaptive processes, such as acute receptor desensitization and receptor downregulation, have been suggested to be crucial to the development of opioid tolerance.2. Other neuroadaptations resulting from chronic opioid use include upregulation of the cAMP pathway, an increase in the cAMP response element‐binding protein and Fos‐related antigens. However, the connection between upregulation of these cellular elements and the mechanism behind the behavioural phenomenon remains unclear.3. Acute receptor desensitization is thought to occur via uncoupling of the receptor and G‐protein, which is followed by internalization of the receptor from the cell membrane. This process occurs after a few minutes of agonist exposure. Receptor–G‐protein uncoupling is mediated via phosphorylation of putative sites on the intracellular loops of activated receptors.4. Acute desensitization and downregulation of receptors both result in a reduction of agonist efficacy. These events occur early in the cascade of cellular adaptation; however, it is uncertain whether these processes contribute to the long‐term changes in receptor sensitivity that occur after repeated exposure to opioids.5. Acute desensitization may, in fact, be a protective mechanism whereby cells adapt to avoid the development of physiological drug tolerance by rapidly attenuating receptor‐mediated signalling. Those drugs that do not cause receptor internalization, such as morphine, may have higher propensities to develop tolerance.
KRH‐594, A New Angiotensin At1 Receptor Antagonist, Prevents End‐Organ Damage In Stroke‐Prone Spontaneously Hypertensive/Izm Rats
Authors: Inada Yoichi , Tazawa Shigeki , Murakami Makoto , Akahane Masuo 
Published: March 2003

SUMMARY1. In the present study, we examined whether KRH‐594, a new angiotensin AT1 receptor antagonist, would stop the progression of renal failure and end‐organ damage and improve the survival rate in salt‐loaded stroke‐prone spontaneously hypertensive rats (SHRSP/Izm).2. Oral administration of KRH‐594 (3 and 10 mg/kg per day) for 11 weeks significantly reduced systolic blood pressure, urinary total protein, blood urea nitrogen, serum creatinine and urinary N‐acetyl glucosaminidase and increased creatinine clearance in SHRSP/Izm.3. In a histological study, KRH‐594 (3 and 10 mg/kg per day) significantly improved the glomerulosclerosis, basophilic change and hyalin cast of tubules, proliferation of afferent arterioles and interlobular artery wall scores of the kidney and the cardiac fibrosis scores of the heart in SHRSP/Izm. KRH‐594 (3 and 10 mg/kg per day) also significantly inhibited cardiac hypertrophy.4. KRH‐594 (3 and 10 mg/kg per day) prevented death in SHRSP/Izm during the examination period.5. These results suggest that KRH‐594 improves hypertensive complications, such as renal failure, cardiac hypertrophy and thickening of the artery wall, and prevents death in salt‐loaded SHRSP/Izm.