bluuebunny/crossref_metadata_2025 huggingface dataset:
GOOD VIBRATIONS? RESPIRATORY RHYTHMS IN THE CENTRAL CONTROL OF BLOOD PRESSURE
Authors: Pilowsky Paul
Published: June 2007

1. Arterial blood pressure is maintained, and reflexly controlled, by the activity of neurons in the medulla and spinal cord.

2. Rhythmic, automatic, respiratory activity is generated by neurons in the ventral medulla and transmitted to pre‐motoneurons and motoneurons in the medulla and spinal cord.

3. Sympathetic nerve activity often has a respiratory rhythmicity.

4. One site at which the interaction between respiratory and sympathetic neurons occurs is the ventrolateral medulla.

5. Different types of sympathetic neurons, such as muscle vasoconstrictor, sudomotor and pilo‐erector, have different patterns of respiratory rhythmicity.

6. Inputs from medullary respiratory neurons to medullary sympathetic premotor neurons may be the mechanism that co‐ordinates the activity of these two vital systems.
DEMONSTRATION OF HEREDITARILY ACCELERATED PROLIFERATION IN ASTROCYTES DERIVED FROM SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Yamagata Kazuo , Nara Yasuo , Tagamit Motoki , Yamorit Yukio
Published: June 2007

1. We examined the proliferative rates of cultured astrocytes isolated from stroke‐prone spontaneously hypertensive rats (SHRSP) and stroke‐resistant spontaneously hypertensive rats (SHRSR). Wistar‐Kyoto rats (WKY) were used as a control for SHRSP and SHRSR.

2. In the presence of 10% fetal bovine serum (FBS), the doubling time for astrocytes from SHRSP and SHRSR was significantly shorter than WKY.

3. When quiescent astrocytes derived from SHRSP or SHRSR were released from serum‐deprivation, the DNA synthesis was stimulated 13.3‐fold and 12.5‐fold, respectively, whereas only a 7.76‐fold increase was observed in WKY astrocytes.

4. Further we studied the effects of two growth factors, epidermal growth factor (EGF) and fibroblast growth factor (FGF) on astrocyte proliferation. EGF induced greater DNA synthesis in SHRSP and SHRSR astrocytes compared with WKY astrocytes, although FGF had little or no effect.

5. Total cholesterol levels in SHRSP astrocytes and SHRSR astrocytes were significantly lower than that of WKY astrocytes, which was consistent with our previous observations in cultured vascular smooth muscle cells.

6. There was no differece in morphology among the cultured astrocytes from the three strains.

7. The abnormality of growth rate and cell membranes composition of astrocytes might be closely related to the genetic phenotypes (acute death of neurons and oedema of astrocytes) of SHRSP or SHRSR.
ACUTE EFFECT OF ETHANOL ON RENAL ELECTROLYTE TRANSPORT IN THE RAT
Authors: Carney Shane L. , Gillies Alastair H. B. , Ray Cheryl D.
Published: June 2007

1. Despite human and animal studies, the direct effect of ethanol on renal water and electrolyte transport is poorly understood. The acute effect of increasing plasma concentrations of ethanol was evaluated in a water diuretic anaesthetized rat model which inhibits endogenous arginine vaso‐pressin (AVP) release.

2. Ethanol at a plasma concentration of 1.69 ±0.28 mmol/L produced an immediate increase in urine flow (174 ± 11 μL/min pre‐ethanol and 189 ± 13 and then 206 ± 12 μL/min during the ethanol infusion; P<0.001) as well as an increase in fractional sodium excretion (0.17 ± 0.04 to 0.28 ± 0.05 and 0.27 ± 0.05%; P<0.001). There was also a brief phosphaturia. These increases in electrolyte excretion had returned to control values by 20 min despite a further increase in the plasma ethanol concentration.

3. The urinary excretion of potassium, calcium and magnesium was not altered nor was glomerular filtration rate or renal plasma flow.

4. Ethanol at a mean concentration of 1.60 mmol/L did not alter the action of a maximal concentration of AVP (75 ng/kg) on water or electrolyte transport. However, the antidiuretic effect of a submaximal concentration of AVP (7.5 ng/kg) was augmented by ethanol at concentrations of 1.63 and 0.98 mmol/L.

5. These studies suggest that the ethanol induced diuresis commonly ascribed to inhibition of AVP secretion may also be due to other intrarenal effects of ethanol, possibly acting within the proximal tubule. These results also confirm recent in vitro findings that while ethanol does not inhibit the action of a maximal concentration of AVP, it does modulate the effects of lower AVP concentrations.
DECREASED SENSITIVITY TO β‐ADRENERGIC STIMULATION OF THE VENTRICULAR CELLS ISOLATED FROM THE SPONTANEOUSLY HYPERTENSIVE RAT HEART
Authors: Habuchi Yoshizumi , Lu Ling‐Ling , Okamoto Shigetaka , Komori Toshiaki , Takahashi Hakuo , Morikawa Junichiro , Yoshimura Manabu
Published: June 2007

1. The stirnulatory effects of isoproterenol on the L‐type Ca2+ current (Ic.) were compared between the control (WKY) and hypertensive (SHR) rat heart cells, using the patch‐clamp method.

2. The current density and the shape of the current‐voltage relationship for Ic. were not different between the two groups. However, the maximal percentage increase in response to isoproterenol was smaller in SHR (+ 91% in SHR and + 81% in WKY), and the ED50 was significantly higher in SHR (0.081 μmol/L in SHR and 0.020 μmol/L in WKY). IBMX, a potent phosphodiesterase inhibitor, significantly increased the isoproterenol‐stimulated Ica in SHR, but not in WKY. These results suggest an impaired CAMP production in SHR heart cells.
MOLECULAR MECHANISMS OF VASCULAR HYPERTROPHY IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Marche P. , Hérembert T. , Zhu D. L.
Published: June 2007

1. In primary hypertension, an abnormally high vascular resistance can be explained in terms of alterations in vessel wall structure. Arterial cell hypertrophy and/or hyperplasia have been implicated as playing a central role in the vascular abnormalities noted in spontaneously hypertensive rats (SHR). Cultured arterial cells appear therefore as attractive models for studying m vitro the mechanisms whereby cells originating from hypertensives exhibit hyperproliferation and/or hyper‐responsiveness.

2. This review summarized our present knowledge on growth and related biochemical events of cultured SHR‐derived vascular smooth muscle cells or aortic adventitial fibroblasts, in response to various polypeptide growth factors and vasoactive agents.

3. Exaggerated growth response to various mitogens in cultured SHR‐derived vascular cells has been well documented. However, the molecular mechanisms of abnormal growth in SHR remain unknown. This abnormality seems not to be a consequence of the alterations at the levels of receptors or of some key mitogenic events of early signalling pathways such as phospholipase C, protein kinase C and G‐proteins. Further studies should therefore focus on the more distal events related to cell growth.
ALTERATION IN THE RELEASE OF ENDOTHELIUM‐DERIVED RELAXING FACTORS BY α‐ADRENOCEPTOR STIMULATION IN THE AORTA OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Shimamura K. , Matsuda K. , Yamamoto K. , Sunano S.
Published: June 2007

1. Endothelium‐dependent relaxation by a‐adrenoceptor agonists was examined in the thoracic aorta from normoten‐sive Wistar‐Kyoto (WKY) rats and stroke‐prone spontaneously hypertensive rats (SHRSP).

2. In ring preparations from both strains, noradrenaline‐induced contraction was increased by L‐nitro arginine (L‐NNA), a NO synthesis inhibitor.

3. L‐NNA increased the contraction induced by phenyl‐ephrine, an α1‐adrenoceptor agonist. UK‐14304 and clonidine, α2‐adrenoceptor agonists, did not contract the preparations with intact endothelium. However, these agents contracted preparations when NO synthesis was inhibited.

4. In a precontracted preparation, clonidine and UK‐14304 induced relaxations. The relaxations in SHRSP aorta were smaller than those in WKY aorta.

5. These results indicate that a‐agonists release NO from endothelium in WKY and SHRSP aorta. The mechanism related to NO release by α2‐adrenoceptor agonist is impaired in SHRSP aorta.
GENE EXPRESSION OF VASCULAR NATRIURETIC PEPTIDE RECEPTOR IN THE AORTA OF HYPERTENSIVE RATS
Authors: Yoshimoto Takanobu , Naruse Mitsuhide , Naruse Kiyoko , Fujimaki Yasuko , Tanabe Akiyo , Muraki Takamura , Hagiwara Hiromi , Hirose Shigehisa , Demura Hiroshi
Published: June 2007

1. To elucidate the pathophysiologic role of vascular natriuretic peptide (NP) receptor in hypertension, we determined NP‐A and NP‐B receptor mRNA levels by means of ribonuclease protection assay in aorta of three types of hypertensive rats.

2. The NP‐A receptor mRNA level was higher in stroke‐prone spontaneously hypertensive rats (SHR‐SP/Izm) and deoxycorticosterone acetate‐salt hypertensive rats than that in their respective control rats. On the contrary, the NP‐A receptor mRNA level was lower in NG‐nitro‐L‐arginine‐methyl ester (L‐NAME)‐induced hypertensive rats compared with that in the control.

3. The NP‐B receptor mRNA level did not show any significant change in all three hypertensive rats compared with their respective controls.

4. The present study suggests that high blood pressure is not the major factor regulating the NP receptor gene expression and also that the receptor subtype is independently regulated from each other.
EXPRESSION OF PROTEIN KINASE C GENE IN THE BRAIN AND HEART OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Gao Ping‐jin , Zhao Guang‐sheng , Yuan Xiao‐yuan , Zhao Han‐fang , Chen Feng , Chen Shi‐shu
Published: June 2007

1. The aim of this study was to investigate protein kinase C (PKC) gene expression in spontaneously hypertensive rats (SHR).

2. Using the PKC oligodeoxyribonucleotide probes (γ, ε), we detected PKC isoforms gene expression in the heart and brain of 4 and 20 week old SHR with those of age‐matched Wistar‐Kyoto (WKY) rats by northern blot analysis.

3. In the cerebral cortex, there were significantly increased levels of expression of the Ca2+‐dependent isoform PKC‐γ in 4 and 20 weeks SHR compared with that of WKY, while Ca2+‐independent isoform PKC‐ε did not differ between SHR and WKY.

4. In ventricular myocytes, there was a significant expression of the Ca2+‐independent isoform PKC‐ε in 4 and 20 week old SHR compared with that of WKY, while Ca2+‐dependent isoform PKC‐γ could not be detected in the same extracts of SHR or WKY.

5. We conclude that both of the Ca2+‐dependent and Ca2+‐independent PKC could be involved in the pathogenesis of SHR. Ca2+‐dependent PKC‐γ may be mainly involved in the modulation of blood pressure in the level of the central nervous system, while Ca2+‐independent PKC‐ε Could be related to the genetic myocardial hypertrophy.
ANIMAL MODELS OF VASCULAR DEMENTIA WITH EMPHASIS ON STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Saito Hideya , Togashi Hiroko , Yoshioka Mitsuhiro , Nakamura Nishio , Minami Masaru , Parvez Hasan
Published: June 2007

1. Two experimental models designed to reflect different aspects of vascular dementia (rats with cerebrovascular occlusion and rats with cerebral embolization) and stroke‐prone spontaneously hypertensive rats (SHRSP) have been evaluated. The focus was on SHRSP as a model for vascular dementia.

2. Neuropathological data revealed that the cerebrovascular disorder in SHRSP was associated with lesions in their brains similar to those seen in typical human cases of multiple cerebral infarction.

3. SHRSP that died from cerebral infarction exhibited behavioural changes, including increased activity and disrupted circadian rhythms, which might correspond to the state of delirium observed in patients with dementia.

4. SHRSP displayed cognitive impairments in a step‐through passive avoidance task.

5. When compared to age‐matched Wistar Kyoto (WKY) rats, both conscious and anaesthetized SHRSP had significantly decreased cerebral spinal fluid (CSF) levels of acetylcholine (ACh).

6. These findings suggest that the SHRSP might serve as a suitable animal model for vascular dementia in humans caused by cerebrovascular lesions.
DISTINCTION OF ENDUTHELIAL CELL GROWTH AND FIBRINOLYTIC ACTIVITY BETWEEN WKY/Izm AND SHRSP/Izm IN VITRO
Authors: Ito Shigeru , Nara Yasuo , Yamori Yukio
Published: June 2007

1. In the present study, endothelial cells (EC) growth and fibrinolytic activity of WKY/Izm and SHRSP/Izm were investigated in vitro.

2. EC were isolated from the thoracic aortas of WKY and SHRSP at the age of 8–9 weeks. Proliferative activities of EC were analysed with doubling time and DNA synthesis. Fibrinolytic activity was determined by tissue type plasminogen activator (tPA) and plasminogen activator inhibitor type 1 (PAI‐1) activities in cultured medium.

3. SHRSP‐EC growth rate was significantly greater than WKY‐EC growth rate in doubling time. In the assay for DNA synthesis, 5‐bromo‐2′‐deoxy uridine incorporation rate in SHRSP‐EC was significantly increased compared with that in WKY‐EC.

4. The tPA activity in cultured medium of WKY‐EC was 2‐fold greater than that of SHRSP‐EC, while PAI‐1 activities were nearly equal in them.

5. These physiological distinctions of EC of SHRSP/Izm from that of WKY/Izm with close genetic background could be contributory genetic factors to hypertension‐related vascular diseases in SHRSP.
HMG‐COA REDUCTASE INHIBITOR AFFECTS BLOOD PRESSURE AND VASCULAR REACTIVITY
Authors: Li N. , Sawamura M. , Nara Y. , Kizawa K. , Ikeda K. , Usui H. , Kurahasi K. , Yamori Y.
Published: June 2007

1. To investigate the effect of endogenous cholesterol synthesis on blood pressure and vascular response, a HMG CoA reductase inhibitor, pravastatin (1 or 10 mg/kg) was administered orally for 2 or 4 weeks to 8–13 week old spontaneously hypertensive rats (SHR/Izm) and normotensive Wistar‐Kyoto (WKY/Izm) rats.

2. Blood pressure was significantly increased in the pravastatin‐treated groups of both strains, but the elevation was observed in WKY after a longer treatment than in SHR.

3. After the thoracic aorta from 10–12 week old SHR and WKY was pretreated with pravastatin (10‐4 mol/L), the vascular response to norepinephrine was increased in pravastatin‐treated SHR aorta but not in the WKY aorta in both contractivity and sensitivity.

4. These experiments suggest that the vascular response is affected by intracellular cholesterol synthesis pathway.
EFFECTS OF CHRONIC TREATMENT WITH CARVEDILOL ON ABNORMALITIES OF ENDOTHELIUM‐DEPENDENT RELAXATION AND STRUCTURE OF ENDOTHELIUM IN RESISTANCE ARTERIES OF SHRSP
Authors: Sasaki F. , Yamamoto K. , Shimamura K. , Shibutani T. , Hashimoto H. , Tanaka M. , Sunano S.
Published: June 2007

1. This study investigated the effects of chronic treatment with carvedilol, a β‐blocking agent with an α‐blocking activity, on blood pressure, endothelium‐dependent relaxation and the endothelial structure of the mesenteric resistance artery in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. Chronic treatment with carvedilol at a dose range of 30–120 mg/kg per day lowered systolic blood pressure of SHRSP from 234.9 ± 3.3 to 198.7 ± 3.1 mmHg at 16 weeks of age.

3. Acetylcholine‐induced endothelium‐dependent relaxation was impaired in the mesenteric artery from SHRSP and high concentrations of acetylcholine produced contractions. The impairment of the relaxation was abolished in the presence of indomethacin. Carvedilol treatment improved the impairment in the preparation from SHRSP. The structural abnormality of endothelium was observed in the preparation from SHRSP. The abnormality could be prevented by the antihypertensive treatment.

4. These results suggest that the impairment of endothelium‐dependent relaxation in the preparation from SHRSP is due to the corelease of an endothelium‐derived contracting factor which is considered to be a product of cyclo‐oxygenase pathway of arachidonic acid cascade and that the impairment can be prevented by the antihypertensive treatment with carvedilol.
SUPPRESSIVE EFFECTS OF BENIDIPINE ON THE DEVELOPMENT OF HYPERTENSION AND RENAL LESIONS IN SALT‐LOADED STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Nito M. , Sato H. , Hara T. , Karasawa A. , Yamada K. , Ohta Y.
Published: June 2007

1. The effects of benidipine hydrochloride (benidipine), a long‐acting dihydropyridine calcium antagonist, on the development of hypertension and renal lesions were examined in stroke‐prone spontaneously hypertensive rats (SHRSP).

2. SHRSP were fed with 8% NaCl diet for 3 weeks from 13 weeks of age, and benidipine (1 or 3 mg/kg per day) was orally administered during the same period.

3. The high salt diet accelerated an increase in urinary excretions of total protein and albumin, and caused marked arteriole, glomerular and tubular lesions in the kidney.

4. Benidipine significantly inhibited these changes, and also suppressed the elevation of blood pressure in salt‐loaded SHRSP.

5. These results reveal that benidipine has protective effects against the development of hypertension and the progression of renal lesions induced by the high salt diet in SHRSP.
HYPOTENSIVE EFFECTS OF A NEW TRANSDERMAL DELIVERY SYSTEM FOR CLONIDINE (M‐5041T) IN SPONTANEOUSLY AND RENAL HYPERTENSIVE RATS
Authors: Ishii R. , Naruse T. , Tagawa T. , Ishida T. , Namba K.
Published: June 2007

1. Antihypertensive effects of a new transdermal delivery system for clonidine (clonidine tape; M‐50417) were investigated in spontaneously hypertensive rats (SHR), 2‐kidney, 1‐clip renal hypertensive rats (RHR) and deoxycorticosterone acetate/salt (DOCA/Salt) hypertensive rats.

2. M‐5041T (0.5–4.5 mg/kg) elicited long‐lasting hypotensive effects and bradycardia in a dose‐dependent manner during 24 h patching in three hypertensive models compared with oral clonidine (100 μg/kg).

3. The most hypotensive effect of M‐5041T was observed in DOCA/salt hypertensive rats.

4. Co‐administration of M‐5041T with either trichloromethiazide (1 mg/kg, orally) or nifedipine (3 mg/kg, orally) at each dose without hypotensive effects per se induced significant hypotension in SHR.

5. Repeated administrations of M‐5041T (1.5 mg/kg per day) for a consecutive 7 days produced significant hypotensive effects at postpatching 6 h, and recovered a postpatching 24 h in SHR.

6. Repetitive M‐5041T administrations displayed no tolerance on the hypotensive effects and were devoid of any withdrawal syndrome.

7. These findings suggest that M‐5041T may serve as an efficiently useful antihypertensive transdermal delivery system in humans.
NORADRENERGIC HYPERINNERVATION IN THE CAVAL VEIN OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Tabei Ryo , Kondo Mari , Terada Miho , Miyazaki Tatsuhiko , Watanabe Yukihiko , Shimizu Daisaburou , Yamamoto Ichirou
Published: June 2007

1. The distribution of fluorescent noradrenergic (NA) nerve fibres in the caval vein, which originate from the coeliac ganglion, was examined by glyoxylic acid method in stroke‐prone spontaneously hypertensive rats (SHRSP) aged 10, 30, 60, 90 and 180 days. The results were compared with those in age‐matched normotensive Wistar Kyoto (WKY) rats.

2. The distribution pattern of NA nerve fibres in the caval vein in both strains changed from a meshwork pattern at 10 days of age to a wavelike line arrangement after 30 days of age.

3. The densities of NA fibres of the caval veins in SHRSP were significantly higher (P < 0.01, Student's t‐test, 6 d.f.) than those of WKY at all ages examined. The difference in NA fibre density between SHRSP and WKY showed double peaks at 10 and 90 days of age.

4. The present study suggests that hyperinnervation of the caval vein based on the hyperfunction of the coeliac ganglion is an important factor in the development of hypertension and also may participate in increasing cardiac output because the heart of SHR causes marked hypertrophy from 90 days of age.
NORADRENERGIC HYPERINNERVATION IN THE HEART OF STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Kondo Mari , Terada Miho , Fujiwara Takashi , Arita Norimasa , Yano Akemi , Tabei Ryo
Published: June 2007

1. Noradrenergic (NA) nerve fibre distribution was investigated in the epicardium and myocardium of the heart in stroke‐prone spontaneously hypertensive rats (SHRSP) and was compared to that in normotensive Wistar‐Kyoto (WKY) rats. Fluorescent NA nerve fibres in the left and right epicardium of both strains aged 10, 30, 60, 90 and 180 days, and in the myocardium of left and right ventricles and the ventricular septum of both strains aged 30, 90 and 180 days were examined by the glyoxylic acid method. The distribution densities of NA nerve fibres were measured by quantitative image analysis.

2. The distribution pattern of NA nerve fibres in the epicardium of both strains showed a constant meshwork pattern throughout the entire examination period.

3. In the myocardium, NA nerve fibres were distributed irregularly between myocytes of both strains in all ages examined.

4. The densities of NA nerve fibres in the epicardium of SHRSP were significantly higher (P < 0.01 and 0.05; Student's t‐test, 6 d.f.) than those of WKY at all ages examined except left epicardium at 90 days of age.

5. The densities in the right myocardium in 30 and 90 day old SHRSP were significantly higher (P < 0.05; Student's t‐test, 6 d.f.) than those of WKY.

6. NA hyperinnervation in the epicardium and the myocardium of SHRSP may be assumed to be caused by the hyperfunction of the stellate ganglia which innervate the heart and may give rise to hypertrophy of the heart in SHRSP by a trophic effect of NA nerve fibre.
AGE‐RELATED CHANGES IN CEREBRAL AND PERIPHERAL MONOAMINE CONTENTS IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Uchida T. , Nishimura Y. , Suzuki A.
Published: June 2007

1. We examined monoamine contents in various regions of the brain and catecholamine contents in the heart and the adrenal gland of stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar‐Kyoto (WKY) rats aged 1.5, 3 and 6 months.

2. The noradrenaline (NA) content and the 5‐hydroxytryptamine (5‐HT) content in the brainstem were larger in 1.5 month old SHRSP than in the age‐matched WKY. In addition, at age 6 months the brainstem 5‐HT content was higher in SHRSP than in WKY.

3. The NA and 5‐HT contents in basal ganglia, thalamus, hypothalamus, septum and anterior and lateral cerebral cortex showed no significant difference between SHRSP and WKY at any age.

4. The dopamine (DA) contents in all brain regions examined did not differ between WKY and SHRSP at any age.

5. The NA contents in left and right ventricles were larger in 3 month old SHRSP than in the age‐matched WKY, but were lower in 6 month old SHRSP than in the age‐matched WKY. The cardiac DA contents did not differ between the two rat strains of any age.

6. The adrenal NA and adrenaline (A) contents in 6 month old SHRSP were significantly larger than those in the corresponding WKY.

7. These findings suggest that the increased NA and 5‐HT contents in the brainstem may be related to the onset of hypertension, and that the altered cardiac NA contents and adrenal NA and A contents change as a result of the onset or persistence of hypertension.
ROLE OF RENAL DOPAMINERGIC ACTIVITY ON RENAL SODIUM‐WATER METABOLISM IN CONGESTIVE HEART FAILURE
Authors: Hayashi Manabu , Shimamoto Kazuaki , Tsuchihashi Kazufumi , Ishiguro Toshiya , Torii Taka‐aki , Sawai Niroh , Mukai Hiroya , Iimura Osamu
Published: June 2007

1. The role of the renal dopaminergic system in water‐sodium metabolism in heart failure remains unclear.

2. In this study, the urinary free dopamine excretion (uDA), delivery of l‐dopa X creatinine clearance (Cer)), and the production of dopamine in the kidney [uDA/(plasma l‐dopa x Cer)] were investigated in patients with congestive herat failure (n= 30) and in normal controls (n = 12). In both groups, endogenous Ccr, urinary excretion of sodium (UNaV), fractional excretion of sodium (FENa), plasma noradrenaline concentration (pNA) and plasma l‐dopa and dopamine production in the kidney showed successively lower values in congestive heart failure with progression in NYHA functional class.

4. UNaV (r = 0.48, P < 0.05) and Cer (r = 0.539, P < 0.01) positively correlated with uDA. Linear correlations were found between left ventricular ejection fraction and uDA (r = 0.574, P < 0.01), pNA)r = ‐0.495, P < 0.01) or plasma l‐dopa (r = 0.423, P < 0.05).

5. From these findings, it was suggested that (i) uDA was clearly suppressed in patients with CHF, and (ii) the possible mechanisms of its suppression might be due to decrease of delivery of l‐dopa into the proximal tubulles and suppressed production of dopamine from l‐dopa in the kidney.
PROLONGED SYSTEMIC AND REGIONAL HAEMODYNAMIC EFFECTS OF INTRACEREBROVENTRICULAR ANGIOTENSIN II IN CONSCIOUS SHEEP
Authors: May Clive N.
Published: June 2007

1. 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

1. 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.
MOLECULAR COGS IN MACHINA CARNIS
Authors: Stephenson D George
Published: June 2007

1. This review explores the complexity of skeletal muscle function mainly from the perspective of work performed by the author over the past two decades.
SPARSE DRUG CONCENTRATION DATA ANALYSIS USING A POPULATION APPROACH: A VALUABLE TOOL IN CLINICAL PHARMACOLOGY
Authors: McLachlan Andrew J.
Published: June 2007

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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

1. 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 Papers

Cardiovascular protection by ginsenosides and their nitric oxide releasing action X Chen

Probing excitation‐contraction coupling in trachealis smooth muscle with the mycotoxin cyclopiazonic acid D Amoako, Y Quian, C‐Y Kwan and J‐P Bourreau

Antihypertensive effects of DL‐tetrahydropalmatine: An active principle isolated from Corydalis MT Lin, FY Chueh, MT Hsieh and CF Chen

A family of novel actin‐inhibiting marine toxins S‐Y Saito and H Karaki

In 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 Cheng

Tetrandrine 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

1. 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

1. 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

1. 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

1. 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).