bluuebunny/crossref_metadata_2025 huggingface dataset:
ENDOTHELIN IN THE CENTRAL CONTROL OF CARDIOVASCULAR AND RESPIRATORY FUNCTIONS
Authors: Kuwaki T , Ling Gy , Onodera M , Ishii T , Nakamura A , Ju Kh , Cao Wh , Kumada M , Kurihara H , Kurihara Y , Yazaki Y , Ohuchi T , Yanagisawa M , Fukuda Y
Published: March 2003

1. Exogenously administered endothelin (ET) modulates the activity of cardiovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a physiological role(s) for endogenous ET in the CNS has not been elucidated. To address this question, we examined ABP and ventilation in mutant mice deficient in ET‐1, ETAand ETBreceptors and endothelin‐ converting enzyme‐1, which were made by gene targeting.

2. Respiratory frequency and volume was measured in mice by whole body plethysmography when animals breathed normal room air and hypoxic and hypercapnic gas mixtures. A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia. On the following day, the ABP of awake mice was measured through the indwelling catheter and heart rate was calculated from the ABP signal. After 2 h ABP measurement, arterial blood was collected through the catheter and pH and the partial pressures of O2and CO2were measured by a blood gas analyser.

3. Compared with corresponding controls, the mean (±SEM) ABP in ET‐1+/–and ETB‐deficient mice was significantly higher (118±2vs106±3 mmHg for ET‐1+/–(n= 22) and ET‐1+/+(n= 17) mice, respectively; 127±3vs109±4 mmHg for ETB–/s(n= 9) and ETB+/s(n= 9) mice, respectively;P<0.05 for both). In ET‐1+/–mice,PCO2tended to be higher andPO2was significantly lower than corresponding values in ET‐1+/+mice. Under resting conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increases of ventilation to hypoxia and hypercapnia were significantly attenuated in ET‐1+/–, ET‐1–/–and ETA–/–mice.

4. In another series of experiments in ET‐1+/–mice, we found that sympathetic nerve activity (SNA) was augmented and reflex excitation of phrenic nerve activity (PNA) in response to hypoxia and hypercapnia was blunted. Attenuation of the reflex PNA response to hypercapnia was also observed in the medulla–spinal cord preparation from ET‐1–/–mice.

5. Elevation of ABP in ETB‐deficient mice was most likely due to a peripheral mechanism, because SNA and respiratory reflexes were not different from those in control animals.

6. We conclude that endogenous ET‐1 plays an important role in the central neural control of circulation and respiration and that ETAreceptors mediate this mechanism.
ENDOTHELIN AND POST‐GANGLIONIC SYMPATHETIC NEURONS
Authors: Damon Deborah H
Published: March 2003

1. The present report documents evidence suggesting that endothelin (ET) is a mediator and modulator of post‐ganglionic sympathetic neuronal development.

2. Endothelin is produced by post‐ganglionic neurons and by cells adjacent to these neurons.

3. Post‐ganglionic sympathetic neurons express functional receptors for ET.

4. Endothelin promotes the survival of cultured post‐ ganglionic sympathetic neurons and modulates the morphological and biochemical differentiation of these neurons.

5. Endothelin enhances the activity of nerve growth factor and modulates the release of neurotransmitter from post‐ ganglionic sympathetic nerve terminals.
Long‐Term Oestrogen Therapy Is Associated With Improved Endothelium‐Dependent Vasodilation In The Forearm Resistance Circulation Of Biological Males*
Authors: New Gishel , Duffy Stephen J , Harper Richard W , Meredith Ian T
Published: March 2003

1. The aim of the present study was to determine the effects of long‐term oestrogen on resistance vessel reactivity in biological males.

2. Recent studies have demonstrated that long‐term oestrogen therapy favourably alters the lipid profile and improves vasodilator function in the conduit arteries of biological males. Whether a similar benefit is exerted on the resistance circulation is not known. Therefore, we examined the effects of long‐term oestrogen therapy on skeletal muscle resistance vessel function in biological males and the potential mechanisms by which it may exert its effects.

3. Forearm blood flow (FBF) and resistance were compared in 15 male‐to‐female transsexuals being prescribed oestrogen, with 14 age‐matched healthy males, at rest and in response to the endothelium‐dependent nitric oxide (NO) vasodilator acetylcholine (ACh), the endothelium‐independent but NO‐mediated vasodilator sodium nitroprusside (SNP), the endothelium‐ independent and non‐NO‐mediated vasodilator verapamil (VER) and the endothelium‐independent vasoconstrictor phenylephrine (PE).

4. Basal blood flows were similar in the two groups. However, the male‐to‐female transsexuals had a significant upward and leftward shift in FBF responses to ACh compared with males, with a 52% increase in FBF responses at the highest dose of ACh used. Forearm blood flow in transsexuals rose from a mean (±SEM) baseline level of 3.02±0.25 to a maximum of 19.5± 2.59 mL/min per 100 mL forearm tissue (compared with 3.24±0.41 and 9.43±1.97 mL/min per 100 mL forearm tissue, respectively, in males) with the highest dose of ACh (+2.73 μg/min per 100 mL; P < 0.0005). Forearm vascular resistance was also significantly reduced in transsexuals compared with males (P < 0.05). Vasodilator responses to SNP, VER and PE were similar in both groups.

5. There were no differences observed in total cholesterol and low‐density lipoprotein–cholesterol levels. However, male‐ to‐female transsexuals had 20% higher high‐density lipo‐protein–cholesterol levels compared with males (1.57±0.11 vs 1.26±0.08 mmol/L, respectively; P < 0.05) and 47% higher triglyceride levels (P < 0.005). Serum testosterone levels (an index of oestrogen therapy) was a predictor of responses to endothelium‐dependent vasodilation (rs = –0.50; P < 0.01).

6. Long‐term oestrogen therapy enhances endothelium‐dependent vasodilation in the skeletal muscle microcirculation of biological males. The effects appear to be selective because endothelium‐independent vasodilation and vasoconstriction are not altered.
Effect Of Chronic Lithium Administration On Endothelium‐Dependent Relaxation In Rat Aorta
Authors: Dehpour Ahmad Reza , Aghadadashi Hamid , Ghafourifar Pedram , Roushanzamir Farshad , Ghahremani Mohammad Hossein , Meysamee Farnoush , Rassaee Nastaran , Koucharian Armen
Published: March 2003

1. The effects of chronic lithium administration on the relaxant responses of rat thoracic aortic rings in the presence of indomethacin (a cyclo‐oxygenase inhibitor) and/or NG‐nitro‐L‐arginine (L‐NOARG; a nitric oxide synthase inhibitor) to acetylcholine (ACh) or sodium nitroprusside were investigated in the present study.

2. Acetylcholine produced a concentration‐dependent relaxation in vessels precontracted by phenylephrine (PE), while in lithium‐treated rats the maximal relaxation was significantly increased.

3. Indomethacin (20 μmol/L) significantly potentiated the ACh‐induced relaxation in lithium‐treated and control rats.

4. NG‐Nitro‐L‐arginine (1 μmol/L) decreased the ACh‐induced relaxation in both control and lithium‐treated rats. In contrast, indomethacin (20 μmol/L) reversed the inhibitory effect of L‐NOARG.

5. Sodium nitroprusside produced similar concentration‐dependent relaxations of vessels from both control and lithium‐treated rats, which was not affected by indomethacin. In endothelium‐denuded rings, indomethacin (20 μmol/L) caused a rightward shift in the concentration–contraction curve to PE.

6. These data support evidence for a possible increase in endothelium‐dependent relaxation induced by ACh during long‐term administration of lithium in rat aortic rings.
Oxidative Status And Anti‐Oxidant Enzyme Activity During Calcium Paradox In The Rat Isolated Heart
Authors: Lazou Antigone , Seraskeris Stelios , Tsiona Vasiliki , Drossos George
Published: March 2003

1. The effect of calcium paradox on oxidative status and the activity of anti‐oxidant enzymes were studied in the rat isolated heart. Glutathione status, sulphydryl group contents and lipid peroxidation in the myocardium, as well as the release of oxidized and reduced glutathione from the heart, were taken as indices of oxidative events.

2. Reperfusion with calcium after calcium‐free perfusion induced a significant decrease in the myocardial content of reduced and oxidized glutathione and non‐protein sulphydryl groups. At the same time, a significant release of both forms of glutathione from the heart was observed. However, the ratio of oxidized to reduced glutathione remained unchanged and was not different from control. Increased lipid peroxidation was observed only after 30 min of reperfusion with calcium.

3. Increased anti‐oxidant activity during the reperfusion period was observed. Mitochondrial Mn‐superoxide dismutase (SOD) activity was increased throughout the reperfusion period, while cytoplasmic Cu,Zn‐SOD and glutathione peroxidase activity showed a transient increase at 5 min reperfusion.

4. The results do not support an important role of oxygen free radicals in cell damage observed during calcium paradox in the rat isolated heart. Production of oxygen free radicals may occur during the reperfusion period, but the quantity produced is insufficient to exceed the anti‐oxidant capacity of the heart.
Krn2391: Dual Action On Rat Pulmonary Artery And No Loss Of Potency In Pulmonary Hypertension
Authors: Wanstall Janet C , Gambino Agatha , Thomas Bronwyn J
Published: March 2003

1. The pulmonary vasorelaxant properties of KRN2391 (N‐cyano‐N′‐(2‐nitroxyethyl)‐3‐pyridinecarboximidamide) were examined in isolated ring preparations of main (MPA) and intralobar (IPA) pulmonary artery from control and pulmonary hypertensive rats (exposure to hypoxia, 10% oxygen, for 1 week).

2. On both MPA and IPA, pulmonary vasorelaxant responses were inhibited by methylene blue (10 μmol/L) or glibenclamide (1 or 10 μmol/L). Thus, KRN2391 has the properties of both a nitric oxide (NO) donor and a KATP channel opener on rat pulmonary arteries.

3. KRN2391 was more potent and gave a greater maximum relaxation on MPA (–log EC50 6.47; maximum 92% reversal of induced contraction) than on IPA (–log EC50 6.09; maximum 58% reversal of induced contraction). Comparable differences between MPA and IPA were seen for SIN‐1 (NO donor) and levcromakalim (KATP channel opener).

4. KRN2391 was equipotent in MPA from control and pulmonary hypertensive rats but, when glibenclamide (10 μmol/L) was present, KRN2391 was six‐fold less potent in preparations from pulmonary hypertensive than control rats. An eight‐fold reduction in potency was seen for SIN‐1 (no glibenclamide) in arteries from pulmonary hypertensive rats, confirming previous findings with other NO donors.

5. It is concluded that the dual mechanism of action of KRN2391 accounts for the finding that this drug is equally potent in pulmonary arteries from pulmonary hypertensive and control rats. In the context of pulmonary hypertension, this property of the drug could give it an advantage over drugs that act solely as NO donors because these decline in potency, at least in animal models of this disease.
Functional Evidence For Anti‐Oxidant Action Of Fluvastatin On Low‐Density Lipoprotein Using Isolated Macrophages And Aorta
Authors: Kagota Satomi , Yamaguchi Yu , Nakamura Kazuki , Kunitomo Masaru
Published: March 2003

1. Fluvastatin has been reported to have not only a hypocholesterolaemic effect, but also a protective effect on low‐ density lipoprotein (LDL) from oxidation. We functionally evaluated the anti‐oxidant effect of fluvastatin on oxidation of LDL by copper ions in vitro using mouse macrophages and rabbit aorta preparations.

2. After native LDL (N‐LDL) from rabbit plasma had been pre‐incubated in the presence or absence of fluvastatin (10 μmol/L) for 4 h, the N‐LDL was mildly oxidized by incubation with 5 μmol/L CuCl2 for 5 h and two oxidized LDL, fluvastatin‐pretreated (Flu‐OxLDL) and ‐non‐treated (OxLDL), were prepared. The level of thiobarbituric acid‐reactive substances (TBARS) in Flu‐OxLDL and OxLDL markedly increased compared with N‐LDL. The degree of increment was significantly less in Flu‐OxLDL than OxLDL.

3. When macrophages were incubated with Flu‐OxLDL or OxLDL, the amount of cholesteryl ester that accumulated in the macrophages markedly increased compared with N‐LDL. The degree of increment was significantly less in Flu‐OxLDL than OxLDL.

4. Acetylcholine‐induced endothelium‐dependent relaxations in rabbit aortic rings were impaired in the presence of either Flu‐OxLDL or OxLDL. The degree of impairment was significantly less in Flu‐OxLDL.

5. The increased TBARS level, facilitated cholesteryl ester accumulation in macrophages and impaired endothelium‐dependent relaxation elicited by OxLDL were not affected by simultaneous treatment with fluvastatin (10 μmol/L).

6. These findings indicate that fluvastatin can protect plasma LDL from oxidative modification and, thereby, prevent cholesterol accumulation in macrophages and endothelial dysfunction in blood vessels. This additional anti‐oxidative effect of fluvastatin may be beneficial for preventing the progression of atherosclerosis.
Effects Of Experimental Obstructive Jaundice On Contractile Responses Of Dog Isolated Blood Vessels: Role Of Endothelium And Duration Of Bile Duct Ligation
Authors: Utkan Zafer N , Utkan Tijen , Sarioglu Yusuf , Gönüllü Nuri N
Published: March 2003

1. We examined the effects of experimental obstructive jaundice caused by bile duct ligation (BDL) on vascular smooth muscle function, as well as the underlying mechanisms involved, by recording responses to noradrenaline (NA), 5‐hydroxytryptamine (5‐HT) and acetylcholine (ACh) in canine isolated renal arteries and to NA in isolated mesenteric arteries in vitro. All studies were performed 7 days after the onset of BDL in renal arteries and 3, 7 and 15 days after the onset of BDL in mesenteric arteries.

2. The maximum contraction evoked by both NA and 5‐HT was significantly attenuated with no change in agonist potency (pD2 value) in renal arteries with endothelium obtained from 7 day BDL dogs when compared with those from sham‐operated controls (SO). However, the reduction almost disappeared when the endothelium was removed. In contrast, no change in the responsiveness of renal arteries to KCl could be detected at 7 day BDL. Endothelium‐dependent relaxations produced by ACh were significantly increased in renal artery rings from 7 day BDL dogs, but the endothelium‐independent relaxations produced by papaverine in BDL preparations were not changed when compared with SO controls.

3. At 7 and 15 days after BDL, the Emax values of the mesenteric ring of BDL dogs to NA were significantly lower than that of SO controls, whereas 3 days after surgery there was no significant difference. The pD2 values in arteries obtained from 15 day BDL animals were significantly lower than those obtained from SO control animals. However, no significant changes in pD2 values were seen 3 and 7 days after the onset of BDL.

4. In conclusion, it is suggested that enhanced production and/or release of nitric oxide, mainly of endothelial origin, is associated with reduced vascular responses to contractile agents in experimental obstructive jaundice and that this effect is related to the duration of obstructive jaundice. These results may explain, at least in part, a cause of hypotension that leads to renal failure in patients with obstructive jaundice.
Brain Versus Peripheral Angiotensin Ii Receptors In Hypovolaemia: Behavioural And Cardiovascular Implications
Authors: De Luca Laurival A , Sugawara Alexandre M , Menani José V
Published: March 2003

1. Angiotensin (Ang)II is involved in responses to hypovolaemia, such as sodium appetite and increase in blood pressure. Target areas subserving these responses for AngII include the cardiovascular system in the periphery and the circumventricular organs in the brain.

2. Conflicting data have been reported for the role of systemic versus brain AngII in the mediation of sodium appetite.

3. The role for systemic AngII and systemic AngII receptors in the control of blood pressure in hypovolaemia is well established. In contrast with systemic injections, i.c.v injections of AngII non‐peptide AT1 and AT2 receptor antagonists, such as losartan and PD123319, do not reduce arterial pressure in sodium‐depleted (furosemide injection plus removal of ambient sodium for 24 h) rats. Thus, brain AngII receptors are likely not important for cardiovascular responses to hypovolaemia induced by sodium depletion.

4. Intracerebroventricular injections of losartan or PD123319 increase arterial pressure when injected at relatively high doses. This hypertensive effect is unlikely to be an agonist effect on brain AngII receptors. Increases in arterial pressure produced by i.c.v. losartan are attenuated by lesions of the tissue surrounding the anterior third ventricle (AV3V). The hypertensive effect of i.c.v. AngII is abolished by lesions of the AV3V.

5. Hypertension induced by AngII receptor antagonists is consistent with hypotension induced by AngII acting in the brain. However, the full physiological significance of this hypotensive effect mediated by brain AngII receptors remains to be determined.
Neuroexcitatory Effects Of Morphine And Hydromorphone: Evidence Implicating The 3‐Glucuronide Metabolites
Authors: Smith Mt
Published: March 2003

1. Morphine is recommended by the World Health Organization as the drug of choice for the management of moderate to severe cancer pain.

2. Education of health professionals in the past decade has resulted in a large increase in the prescribing of opioids, such as morphine, and in the magnitude of the doses administered, resulting in an improvement in the quality of pain relief available for many cancer patients.

3. However, the reported incidence of neuroexcitatory side effects (allodynia, myoclonus, seizures) in patients administered large doses of systemic morphine or its structural analogue, hydromorphone (HMOR), has also increased.

4. Clinically, increasing the magnitude of the morphine or HMOR dose administered to patients already exhibiting neuroexcitatory opioid related side effects, results in an exacerbation rather than an attenuation of the excitatory behaviours.

5. In contrast, cessation of the opioid or rotation to a structurally dissimilar opioid (e.g. from morphine/HMOR to methadone or fentanyl), usually results in a restoration of analgesia and resolution of the neuroexcitatory opioid side effects over a period of hours to days.

6. To explain the clinical success of ‘opioid rotation’, it is essential to understand the in vivo metabolic fate of morphine and HMOR.

7. Following systemic administration, morphine and HMOR are metabolized primarily to the corresponding 3‐glucuronide metabolites, morphine‐3‐glucuronide (M3G) and hydromorphone‐3‐glucuronide (H3G), which are not only devoid of analgesic activity but evoke a range of dose‐dependent excitatory behaviours, including allodynia, myoclonus and seizures, following intracerebroventricular (i.c.v.) administration to rats.

8. Several studies have shown that, following chronic oral or subcutaneous morphine administration to patients with cancer pain, the cerebrospinal fluid (CSF) concentrations of M3G exceed those of morphine and morphine‐6‐glucuronide (analgesically active morphine metabolite) by approximately two‐ and five‐fold, respectively.

9. These findings suggest that when the M3G concentration (or H3G by analogy) in the CSF exceeds the neuroexcitatory threshold, excitatory behaviours will be evoked in patients.

10. Thus, rotation of the opioid from morphine/HMOR to a structurally dissimilar opioid, such as methadone or fentanyl, will allow clearance of M3G/H3G from the patient central nervous system over hours to days, thereby producing a time‐dependent resolution of the neuroexcitatory behaviours while maintaining analgesia with methadone or fentanyl.
First Report Of Active Renin In Rat Amniotic Fluid
Authors: Caragounis Aphrodite , Koutsis Kathy , Wlodek Mary E , Wilkinson‐Berka Jennifer La , Nicolantonio Robert Di
Published: March 2003

1. Epidemiological studies indicate that a reduced birthweight increases the likelihood of human cardiovascular disease later in life. The role of hormonal factors in this finding is not known. Given that angiotensin II is believed to be a fetal regulator of growth, we have examined in the hypertensive Ren‐2 transgenic rat whether it has active renin in its amniotic fluid and whether this is associated with fetal underdevelopment.

2. We found that while the Sprague‐Dawley rat contained no active renin in its amniotic fluid near term (20 days), Ren‐2 amniotic fluid contains high levels of active renin and is associated with a reduced fetal weight.

3. This is the first report of active renin in the rat and allows the possibility that renin overproduction plays a role in reduced fetal growth and the prenatal ‘programming’ of essential hypertension that has been proposed to occur in humans.
Reversal of Anticancer Drug Resistance by Macrolide Antibiotics in Vitro and in Vivo
Authors: Wang Li , Kitaichi Kiyoyuki , Hui Cai Shao , Takagi Kenji , Takagi Kenzo , Sakai Miyuki , Yokogawa Koichi , Miyamoto Ken‐ichi , Hasegawa Takaaki
Published: March 2003

1. The combined effects of the macrolide antibiotics erythromycin, josamycin, clarithromycin and YM17K (3,4′‐dideoxy mycaminosyl tylonolide hydrochloride) on in vitro intracellular accumulation of vinblastine or cyclosporine (Cs)A and on the in vivo antitumour activity of vinblastine were investigated using mouse leukaemia P388 cells (P388/S) and anticancer drug‐resistant (P388/ADR) cells. These effects were compared with those of a calcium antagonist (verapamil) or immunosuppressants (FK506 and CsA).

2. All tested macrolide antibiotics increased the accumulation of both vinblastine and CsA in P388/ADR cells in a dose‐ dependent manner, but their potency was lower than that of verapamil, CsA or FK506.

3. When vinblastine (200 μg/kg) was administered intraperitoneally with each of the macrolide antibiotics (10 or 100 mg/kg) or with verapamil (25 mg/kg) once a day for 10 days in P388/ADR‐bearing mice, combined effects of vinblastine with the macrolide antibiotics (erythromycin, clarithromycin and YM17K) or verapamil were observed.

4. The present study suggests that macrolide antibiotics may overcome anticancer drug resistance by inhibiting the binding of vinblastine or CsA to P‐glycoprotein in P388/ADR cells.

5. We believe that these results are encouraging for combination chemotherapy to overcome P‐glycoprotein‐dependent anticancer drug‐resistant tumours in clinical practice.
Effects Of The New Hydroxy‐3‐Methylglutaryl Coenzyme A Reductase Inhibitor Fluvastatin On Anti‐Oxidant Enzyme Activities And Renal Function In Streptozotocin‐Induced Diabetic Rats
Authors: Kurusu Atsushi , Shou Ichiyu , Nakamura Shinji , Fukui Mitsumine , Shirato Isao , Tomino Yasuhiko
Published: March 2003

1. The effects of 11 week treatments with the new hydroxy‐3‐methylglutaryl coenzyme A (HMG‐CoA) reductase inhibitor fluvastatin on renal intrinsic anti‐oxidant enzyme (AOE) activities and renal function were evaluated in streptozotocin (STZ)‐induced diabetic rats.

2. Renal intrinsic AOE activities, creatinine clearance and urinary albumin excretion were examined in STZ‐induced diabetic rats. The levels of total cholesterol (TC), triglyceride (TG) and phospholipid (PL) were also examined.

3. In general, renal AOE activities and function were lower in diabetic rats than in non‐diabetic Sprague‐Dawley rats.

4. Decreases in TC, TG and PL levels and urinary albumin excretion by the HMG‐CoA reductase inhibitor fluvastatin improved renal function and produced a non‐uniform alteration in renal AOE; only glutathione peroxidase (GSH‐Px) activity increased significantly with fluvastatin treatment.

5. It appears that the improvement in renal function and albuminuria may be related to increases in GSH‐Px activity, but there was no correlation between changes in renal function and changes in the activity of Mn‐superoxide dismutase or catalase.
Relevance Of Cytochrome P450 Levels In The Actions Of Enflurane And Isoflurane In Mice: Studies On The Haem Pathway
Authors: Buzaleh Ana Maria , Martinez Maria del Carmen , Batlle Alcira Maria del Carmen
Published: March 2003

1. The effect of the fluorinated ether anaesthetics enflurane and isoflurane in mice on haem metabolism and regulation in different metabolic states, such as depression and induction of cytochrome P450 produced by allylisopropylacetamide (AIA) and imidazole, respectively, was investigated.

2. Mice previously treated with AIA (350 mg/kg, i.p.) or imidazole (400 mg/kg, i.p.) received a single dose (1 mL/kg, i.p.) of enflurane or isoflurane and were killed 20 min after anaesthetic administration.

3. Induction of δ‐aminolevulinic acid synthetase (ALA‐S) activity was found, as expected, in animals receiving AIA and also in animals treated with AIA plus anaesthesia, but no change in the activity of either porphobilinogenase (PBGase) or porphobilinogen deaminase (PBG‐D) activities was detected in these two groups of animals. An additional increase in haem destruction was observed in the AIA plus isoflurane‐treated group. When mice were injected with imidazol alone or in combination with the anaesthetics, ALA‐S activity was increased 50–90% in all groups, but again no change in PBGase or PBG‐D activity was observed. Haem oxygenase was diminished in mice receiving imidazole and anaesthesia.

4. In conclusion, neither enflurane nor isoflurane caused additional disturbances in haem metabolism to those produced by AIA or imidazole alone.
Tachykinin NK1 and NK3 Receptors In The Prefrontal Cortex Of The Human Brain
Authors: Tooney Paul A , Au Gough G , Chahl Loris A
Published: March 2003

1. The tachykinins are neuropeptides found in both the central and peripheral nervous systems that play a role in inflammation and pain mechanisms and some autonomic reflexes and behaviours.

2. Although the distribution of the tachykinin receptors has been described in the brains of various animal species, little is known about the distribution of the NK1 and NK3 receptors in the human brain.

3. The present paper examines the distribution of the NK1 and NK3 receptors in the prefrontal cortex of formalin‐fixed post‐mortem human brain tissue by immunohistochemical techniques.

4. The majority of NK1 receptor immunoreactivity appeared as a thin band of punctate staining at the pial surface, with dark brown dots of NK1 receptor immunoreactivity predominantly scattered across the mid to upper cortical layers.

5. The NK3 receptor immunoreactivity was found in the glia limitans at the pial surface, where astrocytes and beaded fibres were intensely stained. Dots of NK3 receptor immunoreactivity were scattered across all cortical layers. In the white matter, astrocytes and beaded fibres displayed NK3 receptor immunoreactivity, particularly in areas surrounding blood vessels.
Lymphatic Vasomotion
Authors: Helden Dirk F Van , Zhao Jun
Published: March 2003

1. Experimental findings in the past decade have greatly advanced present understanding of electrical/mechanical rhythmicities in smooth muscle, including vasomotion. Lymphatic vessels show strong vasomotor activity and have provided a key experimental system to study these processes.

2. Evidence from lymphatic vessels, blood vessels and other smooth muscles indicates that rhythmical contractions arise through a Ca2+ store‐controlled pacemaker mechanism, which can function to cause smooth muscle constriction.

3. Such a model fits with observations that vasomotion can be near synchronous over large vessel lengths involving many cells.

4. The alternative interpretation that smooth muscle rhythmicities are generated by a cardiac‐like electrical pacemaker mechanism has not been substantiated in any smooth muscle preparation under normal physiological conditions. However, elements of this latter mechanism are likely to be present at least in some smooth muscles, serving to modulate pacemaking.
Quantitative Analysis Of Vascular To Cardiac Selectivity Of L‐ And T‐Type Voltage‐Operated Calcium Channel Antagonists In Human Tissues
Authors: Angus Ja , Sarsero D , Fujiwara T , Molenaar P , Xi Q
Published: March 2003

1. Classical L‐type voltage‐operated calcium channel (VOCC) antagonists dilate blood vessels, depress myocardial contractility and slow cardiac conduction.

2. We compared four L‐type VOCC antagonists and a novel tetralol derivative, mibefradil, reportedly 10‐fold more selective for T‐ (transient) over L‐type VOCC in two in vitro assays of human tissue, namely isolated small arteries from the aortic vasa vasorum in a myograph and right atrial trabeculae muscle under isometric force conditions.

3. In arteries contracted with K+ (62 mmol/L), the relaxation pIC50 values for the VOCC antagonists felodipine, nifedipine, amlodipine, verapamil and mibefradil were 8.30, 7.78, 6.64, 6.26 and 6.22, respectively. In atrial trabeculae, the pIC50 values to inhibit the inotropic response to a submaximal concentration of isoprenaline (6 nmol/L) for felodipine, nifedipine, verapamil, amlodipine and mibefradil were 7.21, 6.95, 6.91, 5.94 and 4.61, respectively.

4. Taking the anti‐log (pIC50 vessel – pIC50 atrium) the vascular relaxation to cardiac depression potency ratios for mibefradil, felodipine, nifedipine, amlodipine and verapamil were 41, 12, 7, 5 and 0.22, respectively.

5. We conclude that, in human tissue assays, perhaps T‐ over L‐type VOCC selectivity confers the most favourable vascular selectivity on mibefradil. Alternatively, splice variants of L‐type VOCC in the vasculature (CaV1.2b) may be more sensitive to mibefradil than the splice variants in the heart (CaV1.2a).
Proceedings of the Australian Neuroscience Society Symposium: Schizophrenia A PREDICTED CORTICAL SEROTONERGIC/CHOLINERGIC/GABAERGIC INTERFACE AS A SITE OF PATHOLOGY IN SCHIZOPHRENIA
Authors: Dean Brian
Published: March 2003

1. The pathological process that precipitates schizophrenia has yet to be identified. However, many lines of evidence suggest that a change in the functioning of the frontal cortex is an important abnormality that underlies schizophrenia.

2. Studies in Brodmann’s area 9, obtained post‐mortem, have shown changes in 5‐hydroxytryptamine 5‐HT2A, muscarinic M1 and GABAA receptors in tissue from subjects with schizophrenia.

3. Animal studies suggest a site in the cortex where there would be an interaction between serotonergic and cholinergic innervation and that this interaction would involve the 5‐HT2A and the M1 receptor. This site, in turn, would be a potent modulator of GABA activity and, hence, levels of GABAA receptors.

4. From combining these data, a theoretical site is proposed that, if proven to exist in human cortex, is likely to be central to the pathology of that illness.
Experimental Biology 2000 Symposium on Differential Control of Sympathetic Outflow DIFFERENTIAL REGULATION OF BROWN ADIPOSE AND SPLANCHNIC SYMPATHETIC OUTFLOWS IN RAT: ROLES OF RAPHE AND ROSTRAL VENTROLATERAL MEDULLA NEURONS
Authors: Morrison Shaun F
Published: March 2003

1. The medullary premotor neurons determining the sympathetic outflow regulating cardiac function and vasoconstriction are located in the rostral ventrolateral medulla (RVLM). The present study sought evidence for an alternative location for the sympathetic premotor neurons determining the sympathetic nerve activity (SNA) controlling brown adipose tissue (BAT) metabolism and thermogenesis.

2. The tonic discharge on sympathetic nerves is determined by the inputs to functionally specific sympathetic preganglionic neurons from supraspinal populations of premotor neurons. Under normothermic conditions, BAT SNA was nearly silent, while splanchnic (SPL) SNA, controlling mesenteric vasoconstriction, exhibited sustained large‐amplitude bursts.

3. The rostral raphe pallidus (RPa) contains potential sympathetic premotor neurons that project to the region of sympathetic preganglionic neurons in the thoracic spinal cord. Disinhibition of neurons in RPa elicited a dramatic increase in BAT SNA, with only a small rise in SPL SNA.

4. Splanchnic SNA was strongly influenced by the baroreceptor reflex, as indicated by a high coherence with the arterial pressure wave, a significant amplitude modulation over the time‐course of the cardiac cycle and a marked inhibition of SPL SNA during a sustained increase in arterial pressure. When activated, the bursts in BAT SNA exhibited no correlation with arterial pressure and were not affected by increases in arterial pressure.

5. Because these characteristics and reflex responses in sympathetic outflow have been shown to arise from the on‐going or altered discharge of sympathetic premotor neurons, the marked differences between SPL and BAT SNA provide strong evidence supporting the hypothesis that vasoconstriction and thermogenesis (metabolism) are controlled by distinct populations of sympathetic premotor neurons, the former in the RVLM and the latter, potentially, in the RPa.
Central Nervous System Regeneration: Mission Impossible?
Authors: Fry Elizabeth J
Published: March 2003

1. Attempts to induce clinical repair after central nervous system injury, such as spinal cord damage, are likely to involve several protocols because eliciting a regenerative response from an injured central neuron is a complex task. Future treatments, applied when a window of opportunity exists, address the requirements for regeneration.

2. Application of trophic support to the lesion site for axotomized neurons aims to initiate and maintain a cell body response conducive to axonal regrowth.

3. Surgical intervention may provide a bridge across the injury site that contains either Schwann cells or olfactory bulb ensheathing cells derived from the patient’s own tissue.

4. The application of antibodies may block the inhibitory action of myelin‐associated molecules and other glial elements.

5. Gene therapy may induce the correct cascade of guidance molecules to be released at appropriate times.

6. Physical rehabilitation may ensure that muscle wastage is reduced and encourages functional reconnection.
β‐Adrenoceptor Blocking Activities Of Nipradilol And Its Optical Isomers In Pig Coronary Artery
Authors: Itomine Tatsushi , Matsuzaki Toshihiro , Sakanashi Mayuko , Hobara Norio , Sakanashi Matao
Published: March 2003

1. β‐Adrenoceptor blocking activities of nipradilol, its four optical isomers (RR, RS, SR, SS) and denitro nipradilol were evaluated using pig isolated coronary arteries.

2. (–)‐Isoprenaline produced concentration‐dependent relaxations of the arteries, which were antagonized by nipradilol, its four optical isomers or denitro nipradilol under KCl‐induced contracture.

3. The order of pA2 values for β‐adrenoceptor blocking activities was SR > nipradilol > SS ≥ denitro nipradilol > RR > RS.

4. The nitroxy group in nipradilol appears to enhance its β‐adrenoceptor blocking activity, because the β‐adrenoceptor blocking activity of nipradilol was more potent than that of denitro nipradilol.

5. Isomers that have the S configuration (SR, SS) at the 2′ position (having a hydroxyl group) in the aryloxypropanolamine showed more potent β‐adrenoceptor blocking activity than isomers that have the R configuration (RR, RS).

6. Isomers that have the R configuration (SR, RR) at the 3 position (having a nitroxy group) in the benzopyran ring showed more potent β‐adrenoceptor blocking activity than those with the S configuration (SS, RS).

7. It is suggested that the difference in configuration of the chemical structure of nipradilol may result in variations of binding affinity for the β‐adrenoceptor.
The Lung Is The Major Site That Produces Nitric Oxide To Induce Acute Pulmonary Oedema In Endotoxin Shock
Authors: Lee Ru Ping , Wang David , Kao Shang Jyh , Chen Hsing I
Published: March 2003

1. The present study was undertaken to determine the locus of nitric oxide (NO) production that is toxic to the lung and produces acute pulmonary oedema in endotoxin shock, to examine and compare the effects of changes in lung perfusate on endotoxin‐induced pulmonary oedema (EPE) and to evaluate the involvement of constitutive and inducible NO synthase (cNOS and iNOS, respectively).

2. Experiments were designed to induce septic shock in anaesthetized rats with the administration of Escherichia coli lipopolysaccharide (LPS). Exhaled NO, lung weight (LW)/bodyweight (BW) ratio, LW gain (LWG) and lung histology were measured and observed to determine the degree of EPE 4 h following LPS. The EPE was compared between groups in which LPS had been injected either into the systemic circulation or into the isolated perfused lung. The lung perfusate was altered from whole blood to physiological saline solution (PSS) with 6% albumin to test whether different lung perfusions affected EPE. Pretreatment with various NOS inhibitors was undertaken 10 min before LPS to investigate the contribution of cNOS and iNOS to the observed effects.

3. Endotoxin caused profound systemic hypotension, but little change in pulmonary arterial pressure. The extent of EPE was not different between that induced by systemic injection and that following administration to isolated lungs preparations. Replacement of whole blood with PSS greatly attenuated (P < 0.05) EPE. In blood‐perfused lungs, pretreatment with NOS inhibitors, such as Nω‐nitro‐L‐arginine methyl ester, aminoguanidine and dexamethasone, significantly prevented EPE (P < 0.05).

4. The major site of NO production through the whole blood is in the lung. The NO production mediated by the iNOS system is toxic to the endothelium in the pulmonary microvasculature. Inhalation of NO for patients with sepsis may be used with clinical caution. Therapeutic consideration of lung extracorporeal perfusion with PSS and pharmacological pretreatment with iNOS inhibitors may be warranted.
Circumventricular Organs: Gateways to the Brain Role Of Circumventricular Organs (CVO) In Neuroendocrine Responses: Interactions Of Cvo And The Magnocellular Neuroendocrine System In Different Reproductive States
Authors: Summy‐Long Joan Y , Kadekaro Massako
Published: March 2003

1. Magnocellular neurons, which release oxytocin (OT) or vasopressin (VP) into the circulation in response to hyperosmolality, hypovolaemia and cholecystokinin (CCK), undergo a resetting during pregnancy and lactation that involves circumventricular organs.

2. During gestation, there is a similar lowering of the osmotic thresholds for stimulation of OT and VP release, whereas the responsiveness of both neuroendocrine systems to hyperosmolality is attenuated by lactation. These osmotic changes in the magnocellular system are mediated by depletion of hormone (OT) stores in the neurohypophysis (lactation), as well as by alterations in afferent stimulation via pathways involving the subfornical organ, organum vasculosum lamina terminalis and median preoptic nucleus.

3. During gestation, both the VP and OT systems are reset such that the expanded blood volume is maintained and defended as ‘normal’ in response to hypovlaemia. Thus, in virgin animals, only a 0–5% reduction in blood volume is needed to activate VP release, whereas 23–25% is required for stimulation of the oxytocinergic system. Thereafter, incremental changes in plasma levels of both hormones with increasing loss in blood volume are similar in virgin and pregnant animals. However, during lactation, the apparent hypovolaemic threshold for both hormones becomes significantly elevated to 20.4% (VP) and > 25% (OT) blood volume depletion, resulting in a decreased responsiveness of the magnocellular system to hypovolaemia.

4. The OT response to CCK is attenuated in lactating animals and circulating VP is unaffected in pregnant rats given the peptide.
General practitioner participation in the second australian national blood pressure study (ANBP2)
Authors: Reid Christopher M , Ryan Phillip , Nelson Mark , Beckinsale Paul , McMurchie Marilyn , Gleave David , DeLoozeƒ Fred , Wing Lindon M
Published: March 2003

1. The second Australian National Blood Pressure Study (ANBP2) is an outcome trial of the treatment of hypertension in the elderly conducted entirely in general practices across Australia. Prior to ANBP2, no study of this size and nature had been undertaken in Australian general practice and the response of General Practitioners (GPs) to becoming involved in long‐term cardiovascular research was unknown.

2. Academic departments and Divisions of General Practice were approached to support the project. General Practitioners were approached by letter of invitation and contacted by a regional medical coordinator (RMC) either at a face‐to‐face meeting or by telephone.

3. At the close of recruitment to ANBP2, 1938 GPs from 950 practices had registered as investigators. Sixty‐two Divisions of General Practice were approached to support the study in five mainland Australian states with 39 (63%) participating, although participation by state was highly variable (range: 18–100%). Thirty divisional or promotional dinner meetings were held, with 56% (368/658) of those attending registering as investigators. Of the 8098 GPs sent a letter of invitation to participate in the study, 1357 (17%) expressed interest and eventually enrolled as investigators, ranging from 8% in Queensland to 28% in New South Wales. Ninety‐six per cent of GPs who had a personal face‐to‐face contact (696/724) with the RMC registered in the study.

4. The GP recruitment phase of ANBP2 has been successfully completed. Peer‐to‐peer recruitment was the most successful strategy; however, success varied between states. General Practitioner recruitment to long‐term clinical trials appears to be successful with a multifactorial approach focusing on peer‐to‐peer recruitment.
Proceedings of the Australian Physiological and Pharmacological Society Symposium: New Frontiers in Muscle Research Hybrid skeletal muscle fibres: a rare or common phenomenon?
Authors: Stephenson Gabriela MM
Published: March 2003

1. The main aim of the present review is to raise awareness of the molecular complexity of single skeletal muscle fibres from ‘normal’ and ‘transforming’ muscles, in recognition of the many types of hybrids that have been observed in vertebrate skeletal muscle. The data used to illustrate various points made in the review were taken from studies on mammalian (mostly rat) and amphibian muscles.

2. The review provides a brief overview of the pattern and extent of molecular heterogeneity in hybrid muscle fibres and of the methodological problems encountered when attempting to identify and characterize such fibres. Particular attention is given to four types of skeletal muscle hybrids: (i) myosin heavy chain (MHC) hybrids; (ii) mismatched MHC–myosin light chains (MLC) hybrids; (iii) mismatched MHC–regulatory protein hybrids; and (iv) hybrids containing mismatched MHC–sarcoplasmic reticulum protein isoforms.

3. Some of the current ideas regarding the functional significance, origin and cognitive value of hybrid fibres are examined critically.
Blood Pressure Variability And Organ Damage
Authors: Su Ding‐Feng , Miao Chao‐Yu
Published: March 2003

1. Blood pressure variability (BPV) is expressed as the standard deviation of the average blood pressure (BP). Blood pressure variability is increased in hypertensive patients and animals. However, BPV is not necessarily related to the BP level.

2. For nearly any level of 24 h mean BP, hypertensive patients in whom the BPV is low have a lower prevalence and severity of organ damage than patients in whom the 24 h BPV is high. This observation has been confirmed further in spontaneously hypertensive rats with direct pathological analysis for organ damage.

3. In sinoaortic‐denervated (SAD) rats, 24 h average BP is normal and BPV is markedly increased. Myocardial damage, renal lesions and vascular remodelling are seen in these animals 4 weeks after SAD.

4. Haemodynamic effects and activation of the renin– angiotensin system are hypothesized to contribute to organ damage induced by increased BPV.

5. Blood pressure variability is of potential importance in antihypertensive therapy.
Fendiline Mobilizes Intracellular Ca2+ In Chang Liver Cells
Authors: Cheng Jin‐Shiung , Chou Kang‐Ju , Wang Jue‐Long , Lee Kam‐Chung , Tseng Li‐Ling , Tang Kwong‐Yui , Huang Jong‐Khing , Chang Hong‐Tai , Su Warren , Law Yee‐Ping , Jan Chung‐Ren
Published: March 2003

1. The effects of the antianginal drug fendiline (N‐[3,3‐diphenylpropyl]‐α‐methyl‐benzylamine) on intracellular free Ca2+ levels ([Ca2+]i) in Chang liver cells were evaluated using fura‐2 as a fluorescent Ca2+ indicator.

2. Fendiline (1–100 μmol/L) increased [Ca2+]i in a concentration‐dependent manner, with an EC50 of 25 μmol/L.

3. The [Ca2+]i response was composed of an initial rise and a slow decay to a sustained phase. Removal of extracellular Ca2+ partly reduced the [Ca2+]i signals.

4. Fendiline (10 μmol/L)‐induced release of intracellular Ca2+ was reduced by 65% following pretreatment with 1 μmol/L thapsigargin (an endoplasmic reticulum Ca2+ pump inhibitor) to deplete Ca2+ stored in the endoplasmic reticulum.

5. After pretreatment with 10 μmol/L fendiline in Ca2+‐free medium for several minutes, addition of 3 mmol/L Ca2+ induced an increase in [Ca2+]i of a magnitude four‐fold greater than control. This increase in [Ca2+]i was not reduced by 10 μmol/L SKF96365, econazole, nifedipine or verapamil.

6. Fendiline (10 μmol/L)‐induced release of intracellular Ca2+ was not altered by inhibition of phospholipase C with 2 μmol/L 1‐(6‐((17β‐3‐methoxyestra‐1,3,5(10)‐trien‐17‐yl)amino) hexyl)‐1H‐pyrrole‐2,5‐dione (U73122).

7. The results of the present study show that fendiline induces an increase in [Ca2+]i in Chang liver cells by releasing stored Ca2+ in an inositol 1,4,5‐trisphosphate‐independent manner and by causing extracellular Ca2+ influx.
Effect Of Age On Renal Functional And Orthostatic Vascular Response In Healthy Men
Authors: Adachi Toshiyuki , Kawamura Minoru , Owada Masahiko , Hiramori Katsuhiko
Published: March 2003

1. Few studies have been reported concerning the effect of ageing on renal functional and vascular responses to various stresses during ordinary life. In the present study, we examined the effect of age on changes in renal sodium handling and renal vascular resistance (RVR) in response to standing from a supine position in subjects with normal renal function.

2. We selected 43 healthy males in the second through to the seventh decade of life and gave them a constant dietary sodium intake before the study period. Renal function was estimated by standard clearance methods with the subject in a state of euvolaemia.

3. The mean daily urinary excretion of sodium was 236 ± 22 mEq. Standing from a supine position was associated with significant decreases (P < 0.0001) in creatinine clearance (from 125 ± 18 to 117 ± 19 mL/min per 1.73 m2), sodium excretion (from 178 ± 29 to 97 ± 23 μEq/min) and fractional excretion of sodium (from 1.02 ± 0.19 to 0.60 ± 0.13%). A significant increase (P < 0.0001) in the RVR index (from 0.11 ± 0.03 to 0.14 ± 0.04 units) was noted. Univariate analysis indicated that while the change in RVR associated with standing was significantly diminished (P < 0.05) in older subjects, orthostatic changes in other parameters associated with standing were minimally influenced by age.

4. In conclusion, although the renal vascular response is impaired in advanced age, the renal functional response to orthostasis is otherwise maintained in healthy elderly subjects under conditions of normal sodium intake and clinical euvolaemia.