bluuebunny/crossref_metadata_2025 huggingface dataset:
ACTH HYPERTENSION IN THE RAT: ROLE OF KIDNEY AND GONADS
Authors: Whitworth J. A. , Hewitson T. D.
Published: June 2007

1. Adrenocorticotrophin (ACTH) administration produces an adrenally dependent rise in blood pressure in rats.

2. The haemodynamic and metabolic effects of ACTH were examined in nephrectomized, 5/6 nephrectomized and orchidectomized male Sprague‐Dawley rats and sham operated controls.

3. Reduction in renal mass did not increase the blood pressure rise produced by ACTH.

4. Gonadectomy did not reduce the blood pressure rise produced by ACTH, which was slightly higher in castrated animals.
INFLUENCE OF BETA‐BLOCKADE ON CIRCULATING PLASMA LEVELS OF 3‐METHOXY‐4‐HYDROXY PHENYLETHYLENE GLYCOL (MHPG) DURING EXERCISE IN MODERATE HYPERTENSION
Authors: Drici Milou D. , Roux Michel , Candito Mirande , Rimailho Alain , Morand Philippe , Lapalus P.
Published: June 2007

1. The effect of exercise testing and β‐blockade on plasma norepinephrine (PNE), and secretion of its metabolite 3‐methoxy‐4‐hydroxyphenylethylene glycol (MHPG), was assessed in 28 mild‐to‐moderate hypertensives before and after the administration of dilevalol, a new β‐blocker with β2‐agonism.

2. This double blind, placebo‐controlled study consisted of two successive submaximal exercise tests before and after the administration of a single oral dose of dilevalol (200 mg, 400 mg or 600 mg). Plasma norepinephrine levels were determined at rest, at 100 watts step of exercise and at maximal effort (Emax).

3. During the control test, mean PNE levels increased from 1.73±0.52 nmol/L (resting value) to 8.01 ± 4.01 nmol/L at Emax (P<0.01) as MHPG levels increased from 11.18 ± 1.33 nmol/L (rest) to 17.50 ± 1.15 nmol/ L (Emax, P<0.01). After dilevalol, PNE increased significantly as compared to controls (P<0.05), from 2.32 ± 0.99 to 12.42 ± 5.97 nmol/L (P<0.01). PNE and MHPG levels were correlated, both at rest and during exercise. PNE levels after β‐blockade were linearly related to the dose of β‐blocker administered. MHPG levels were unaltered by the administration of dilevalol, both before and after exercise.

4. The increase in MHPG that occurs during bicycle exercise is largely generated from an increase in central nervous system noradrenergic activity. While dilevalol increases the peripheral sympathetic nervous system, both at rest and during exercise (which is reflected by increases in PNE levels) the drug does not alter resting central nervous system noradrenergic activity nor amplify the increase in central noradrenergic activity that occurs during exercise.
TONIC CONTROL OF SUBRETROFACIAL VASOMOTOR NEURONS IN THE ROSTRAL VENTROLATERAL MEDULLA
Authors: Dampney R. A. L. , Sasaki S.
Published: June 2007

1. Vasomotor pressor neurons in the subretrofacial nucleus of the rostral ventrolateral medulla receive afferent inputs from different sources that utilize different neurotransmitters. This paper briefly reviews recent studies on the role of inputs releasing: (i) GABA, and (ii) angiotensin II (AII) in the subretrofacial nucleus.

2. There are two types of tonic GABAergic inhibitory inputs: one arises from peripheral baroreceptors, while the second is independent of peripheral baroreceptors.

3. Blockade of receptors for AII elicits a decrease in blood pressure and sympathetic vasomotor activity, indicating that subretrofacial neurons are also tonically excited by AII. It is likely that the AII is released from nerve terminals in the subretrofacial nucleus, but the origin of the pathway is unknown.
EFFECTS OF ADRENALINE AND NORADRENALINE ON CLEARANCE OF TRIACYLGLYCEROL‐RICH LIPOPROTEINS FROM PLASMA: STUDIES WITH CHYLOMICRON‐LIKE LIPID EMULSIONS IN RATS
Authors: Mackintosh Veronica , Redgrave Trevor G.
Published: June 2007

1. Adrenaline was infused intravenously in rats during the clearance from plasma of an injected lipid emulsion designed to model chylomicrons and the triacylglycerol‐rich plasma lipoproteins. The clearance rates of emulsion radiolabelled triolein (TO) and cholesteryl oleate (CO) were both increased, suggesting that hydrolysis of lipoprotein triglycerides and clearance of remnants from plasma were increased. The distribution of radiolabels in tissues showed more TO in skeletal and cardiac muscle after adrenaline, while more CO was found in liver compared with controls. Lesser amounts of both labels were found in the spleens of treated rats.

2. In a similar experiment with noradrenaline, the clearance rate of emulsion CO was decreased. The removal of CO was retarded more than that of emulsion TO, which was not significantly affected, and CO label recovered in liver was significantly decreased, suggesting that the removal of remnants from plasma was slowed after noradrenaline. In experiments in which noradrenaline was infused continuously for 1 week the clearances of emulsion CO and TO were both reduced.

3. Our findings suggest possible connections between plasma catecholamines and the development of arteriosclerosis, in view of the atherogenicity of remnants of the triacylglycerol‐rich plasma lipoproteins. Yet to be established is whether the linkage we have found between lipoprotein clearance, adrenaline and noradrenaline contributes to the atherogenic effects of chronic stress and for the protective effects of exercise.
NATRIURETIC EFFECT OF TMB‐8 IN ANAESTHETIZED DOGS
Authors: Takahara Akira , Ogasawara Aichi , Suzuki‐Kusaba Mizue , Hisa Hiroaki , Satoh Susumu
Published: June 2007

1. Effects of 8‐(N,N‐diethylamino)octyl‐3,4,5‐trimethoxybenzoate hydrochloride (TMB‐8), an inhibitor of intracellular calcium release, on renal function were examined in anaesthetized dogs.

2. Intrarenal arterial infusion of TMB‐8 (0.03 and 0.1 mg/kg per min) increased urine flow rate, urinary sodium excretion and fractional excretion of sodium without affecting blood pressure, renal blood flow or glomerular filtration rate.

3. The results suggest that TMB‐8 inhibits tubular sodium reabsorption to induce natriuresis.
A CONTROLLED STUDY OF THE EFFECTS OF AEROBIC EXERCISE ON ANTIHYPERTENSIVE DRUG REQUIREMENTS OF ESSENTIAL HYPERTENSIVE PATIENTS IN THE GENERAL PRACTICE SETTING
Authors: Allen D. H. G. , Puddey I. B. , Morton A. R. , Beilin L. J.
Published: June 2007

1. To investigate the effect of an exercise training programme on antihypertensive drug requirements, 19 sedentary subjects (14 men and five women) with mild essential hypertension (systolic blood pressure greater than 140 mmHg but less than 180 mmHg), aged 29–55 years, were randomly assigned to 16 weeks of moderate intensity exercise or light intensity exercise (control), and titrated on antihypertensive drug therapy (captopril and hydrochlorothiazide) until resting systolic blood pressure (sitting) of less than 140 mmHg was achieved.

2. The moderate exercise group (n= 11) followed a graded walk‐jog programme to >60% age‐predicted maximum heart rate (HRmax), attending 45 min sessions, three times each week. The light exercise group (n= 8) followed a programme of flexibility (stretching exercises) and walking to <60% age‐predicted HRmax, attending 45 min sessions, three times each week.

3. There was no difference between treatment groups for the level of reduction in both resting systolic and diastolic blood pressure over the 16 weeks (15.64 ± 10.6/12.81 ± 9.97 mmHg in the moderate intensity group and 15.31 ± 10.9/7.7 ± 7.1 mmHg in the light intensity group). The change in 24 h ambulatory blood pressure profile was also similar in both treatment groups. The final antihypertensive drug requirements to achieve these changes in blood pressure was not significantly different between the two treatment groups. This was despite a significant improvement in submaximal exercise performance in the moderate intensity exercise group (P < 0.001).

4. We conclude that in these mildly hypertensive subjects, a 16 week aerobic exercise programme did not decrease antihypertensive drug requirements. Captopril therapy did not influence submaximal exercise performance or prevent a training effect from regular aerobic exercise.
HISTAMINE‐INDUCED CALCIUM OSCILLATIONS IN HUMAN VASCULAR SMOOTH MUSCLE: TEMPORAL SEQUENCE AND SPATIAL ORGANIZATION IN SINGLE CELLS
Authors: Neylon Craig B. , Mason William T. , Irvine Robin F.
Published: June 2007

1. Video imaging of single, fura2‐loaded vascular smooth muscle cells was used to examine the spatial and temporal alterations in calcium, Ca2+, in response to low levels of vasoconstrictor stimuli.

2. Histamine (0.5 μmol/L) produced repetitive oscillations in Ca2+, which appeared to show some variation in amplitude and frequency between cells.

3. Individual oscillations consisted of an initial increase in Ca2+ in a localized region followed by a wave‐like propagation of this region of elevated Ca2+ throughout the rest of the cell cytoplasm.

4. It is suggested that the subcellular spatial organization of Ca2+ that was observed during a Ca2+ oscillation allows a population of cells to operate in unison. Thus, oscillatory fluctuations in Ca2+ may contribute to myogenic tone.
L‐TYPE CALCIUM CHANNELS AND CRH‐MEDIATED ACTH AND CORTISOL RELEASE IN HUMANS
Authors: Hockings Gregory I. , Grice Jeffrey E. , Walters Margaret M. , Jackson Richard V.
Published: June 2007

1. The effect of pretreatment with nifedipine on naloxone‐stimulated corticotrophin‐releasing hormone (CRH)‐induced adrenocorticotrophin (ACTH) release in humans was investigated. The mean peak plasma ACTH and cortisol levels and the mean peak change in cortisol levels from basal were significantly lower in the nifedipine/naloxone test than in the naloxone alone test. The integrated areas under the ACTH‐time and cortisol‐time curves were reduced by 33 and 49%, respectively, in the nifedipine/naloxone test compared with the naloxone alone test. These results correlate well with published in vitro studies.

2. Acute administration of oral nifedipine partially inhibited naloxone‐stimulated ACTH and cortisol release, probably by blockade of plasma membrane voltage‐dependent L‐type calcium channels normally activated following binding of CRH to pituitary corticotroph receptors.

3. Naloxone‐induced CRH release may replace insulin hypoglycaemia testing of pituitary ACTH reserve in humans.
MULTIPLE GROWTH ABNORMALITIES IN VASCULAR SMOOTH MUSCLE FROM SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Saltis John , Little Peter , Bobik Alex
Published: June 2007

1. In tissue culture the growth characteristics of aortic smooth muscle cells isolated from spontaneously hypertensive rats (SHR) were compared with those of normotensive Wistar‐Kyoto (WKY) rats.

2. Aortic smooth muscle cells from SHR exhibit enhanced proliferation when grown in the presence of low (1%) and moderate (5%) concentrations of fetal calf serum.

3. Cell quiescence in cultures of smooth muscle from SHR becomes apparent at cell densities approximately 20% higher than in cultures from WKY rats.

4. These different growth characteristics of smooth muscle between the two strains of rats may contribute to the early pre‐hypertensive development of vascular hypertrophy in the SHR.
CULTURING RAT NEONATAL MYOCYTES CAUSES CHANGES IN THE PHOSPHATIDYLINOSITOL TURNOVER PATHWAY
Authors: Woodcock Elizabeth A. , Fullerton Meryl , Land Sarah , Kuraja Ivana J.
Published: June 2007

1. Cultured neonatal myocytes are commonly used as a model system for the study of cardiac phosphatidylinositol (PI) turnover.

2. In neonatal myocytes stimulation with noradrenaline causes the release of the Ca2+‐releasing compound inositol‐1,4,5‐trisphosphate and the generation of the Ca2+‐regulatory compound inositol‐1,3,4,5‐tetrakisphosphate.

3. Addition of noradrenaline to intact, neonatal rat hearts stimulates the release of inositol‐1,4,5‐trisphosphate, but not inositol‐1,3,4,5‐tetrakisphosphate.

4. These findings show that the isolation and culture of the neonatal myocyte causes changes in the PI turnover pathway so that it becomes similar to that described in other cell types and different from that in intact myocardial tissue.

5. The neonatal myocyte is not a useful model for the study of cardiac PI turnover.
A LOCUS ON THE LONG ARM OF CHROMOSOME 1 AS A POSSIBLE CAUSE OF ESSENTIAL HYPERTENSION
Authors: Griffiths Lyn R. , Zee Robert Y. L. , Ying Li‐Hua , Morris Brian J.
Published: June 2007

1. None of the genes responsible for essential hypertension has been identified. Recent work in genetically hypertensive rats has shown linkage of blood pressure with alleles of the renin gene. Since the renin gene is a member of a conserved synteny group that in humans spans chromosome 1q21.3–32.3 and includes the gene for antithrombin III (AT3), we used linkage studies to examine the relationship between alleles of AT3 and hypertension in a family having 10 affected members.

2. From the lod score obtained at a recombination fraction of zero the odds for linkage of AT3 and hypertension in this family were calculated as 6:1 in favour of linkage. This result provides grounds for further examination of the possible role of the 1q23 locus in the aetiology of essential hypertension.
ENHANCED VASOCONSTRICTION BY SEROTONIN IN RABBIT CAROTID ARTERIES WITH ATHEROMA‐LIKE LESIONS IN VIVO
Authors: Sobey Christopher G. , Dusting Gregory J. , Woodman Owen L.
Published: June 2007

1. In a new animal model which mimics the cellular events of early human atherosclerosis, atheroma‐like lesions were produced by positioning a hollow silastic collar around the common carotid arteries of rabbits. The functional significance of these arterial lesions on blood flow responses to vasoactive agents was then studied in anaesthetized rabbits in vivo.

2. After 1 week of lesion development, resting blood flow was lower in atherosclerotic (cuffed) carotid arteries compared with the contralateral, sham‐operated control arteries.

3. Intra‐carotid injection of serotonin (0.01–1 μg) produced dose‐dependent increases in blood flow in control arteries, but produced either smaller increases or decreases in flow in cuffed arteries. Serotonin caused complete vasospasm (zero blood flow) in one of six rabbits.

4. Acetylcholine (0.0001–0.01 μg, intra‐carotid) produced smaller increases in blood flow in cuffed arteries compared with controls.

5. These data support the proposal that morphological and functional alterations in large arteries in the early stages of atherogenesis play an important role in determining blood flow in vivo. The increased vascular reactivity to serotonin which accompanies development of the lesions might contribute to vasospasm.
CHLORIDE ION INGESTED WITH SODIUM AFFECTS THE DEVELOPMENT OF CEREBRAL LESIONS IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Ikeda K. , Nara Y. , Yamori Y.
Published: June 2007

1. To determine the effect of chloride ion on the development of hypertension and the incidence of cerebral lesions in stroke‐prone spontaneously hypertensive rats (SHRSP), groups of 10 rats were administered chronically with either 171 mmol/L sodium chloride or equimolar sodium provided as sodium citrate in the drinking water from the age of 12 weeks.

2. The life span was significantly extended in SHRSP given sodium citrate (336 ± 28 vs 246 ± 26 days, mean ± s.e.m., P<0.05) but their development of hypertension was not different from SHRSP given sodium chloride.

3. In order to determine the role of calcium homeostasis, calcium in urine was collected. Urinary calcium in SHRSP given sodium citrate was significantly decreased (1.0 ± 0.12 vs 1.8 ± 0.18 mg/ 24 h urine, P<0.05).

4. If the normal life span is 320 ± 35 days, this suggests that chloride ion ingested with sodium accelerates the development of cerebrovascular diseases, and that increased urinary calcium excretion may be related to this adverse chloride effect on the development of hypertension in SHRSP.
EFFECT OF RESERPINE ON CATECHOLAMINE CONTENTS AND MET‐ENKEPHALIN AND β‐ENDORPHIN LEVELS IN THE HYPOTHALAMUS AND THE PITUITARY
Authors: Tang Fai
Published: June 2007

1. The effects of reserpine treatment on the contents of catecholamines and opioid peptides have been studied in the rat hypothalamus and pituitary.

2. Hypothalamic and pituitary catecholamines were drastically depleted following acute reserpine treatment.

3. Reserpine treatment also resulted in a significant decrease in immunoactive met‐enkephalin content in both the hypothalamus (25%) and the anterior lobe (50%), but not in the neurointermediate lobe of the pituitary.

4. No changes were observed in immunoactive β‐endorphin levels.

5. These findings suggest that the met‐enkephalin contents in the hypothalamus and the anterior pituitary may be under catecholaminergic control.

6. The lack of effect of acute reserpine treatment on immunoactive β‐endorphin contents might be due to the opposing effects of adrenergic and dopaminergic mechanisms.
METABOLIC BASIS OF CATECHOLAMINE‐INDUCED WATER TRANSPORT IN EVERTED GUT SACS OF MOUSE
Authors: Mary P. L. , Rao J. Prakasa
Published: June 2007

1. Catecholamine‐induced water transport was measured using an everted gut sac technique. Adrenaline, noradrenaline and isoprenaline induce dose‐dependent increases in water transport by the proximal intestinal sacs. Use of selective adrenergic agents revealed the possible involvement of α1‐ and β2‐receptors in mediation of catecholamine stimulation of water transport in this segment.

2. Inhibition of glycolysis reduced the effect mediated through α1‐receptors, while the inhibition of oxidative phosphorylation blocked the β2‐receptor mediated increase in water transport.

3. Basal transport of water was also significantly reduced by inhibition of glycolysis but was significantly elevated by blockage of oxidative phosphorylation.

4. Suppression or stimulation of glycolysis was paralleled by similar changes in lactic acid release from the gut wall.

5. It is concluded that the energy for the catecholamine‐induced water transport is contributed by glycolysis and oxidative phosphorylation coupled to α1‐ and β2‐receptors, respectively. Under basal conditions water transport is mainly dependent on glycolysis in the segment of intestine examined.
KETOCONAZOLE AND PLASMA AND URINE STEROID LEVELS IN CUSHING'S DISEASE
Authors: Mortimer Robin H. , Cannell Graeme R. , Thew Caroline M. , Galligan John P.
Published: June 2007

1. Plasma and urine steroid and plasma ACTH levels were measured for 2 weeks in eight subjects (six female, two male) with Cushing's disease with each given 200 mg ketoconazole orally four times daily.

2. Treatment was associated with major falls in excretion of free cortisol and the cortisol metabolites tetrahydrocortisol, 5α‐tetrahydrocortisol and tetrahydrocortisone.

3. Plasma cortisol and ACTH levels did not change significantly.

4. Excretion of the androgen metabolites, androsterone, 11β‐hydroxyandrosterone and aetiocholanolone was also reduced but there was no significant fall in plasma testosterone. Plasma levels of progesterone, 17α‐hydroxyprogesterone and 11β‐deoxycortisol and excretion of pregnanediol, pregnanetriol and tetrahydrodeoxycortisol rose with treatment.

5. Analysis of steroid precursor/product ratios indicated that ketoconazole significantly inhibited 11β‐hydroxylase and 17,20‐lyase but not 17α‐hydroxylase in these patients with Cushing's disease.
INTRACELLULAR pH AND SODIUM‐PROTON EXCHANGE ACTIVITY OF LYMPHOCYTES IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Di‐yuan Li , Kobayashi Ayame , Nara Yasuo , Ikeda Katsumi , Mori Chuzo , Yamori Yukio
Published: June 2007

1. At the age of 20 weeks, intracellular pH (pHi) of circulating lymphocytes suspended in HCO3−‐free NaCl media was not significantly different between stroke‐prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar‐Kyoto rats (WKY).

2. The initial recovery rate of pHi in lymphocytes tended to be greater in SHRSP than in WKY after the addition of 60 mmol/L or 120 mmol/L of NaCl, but there was no statistically significant difference.

3. The H+ equivalent efflux rate, which was a true reflection of Na+‐H+ activity, was significantly greater in SHRSP than in WKY (P<0.05). The difference in H+ equivalent efflux rate was not due to the difference in cellular buffering power between the two groups (P>0.05). An increased Na+‐H+ exchange activity may play a partial role in the pathogenesis of hypertension.
COMPARISON OF VASOPRESSOR EFFECTS OF NITRO ARGININE IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS AND WISTAR‐KYOTO RATS
Authors: Kobayashi Yuta , Ikeda Katsumi , Kakizoe Eiichi , Shinozuka Kazumasa , Nara Yasuo , Yamori Yukio , Hattori Keisuke
Published: June 2007

1. NG‐nitro‐L‐arginine (NO2Arg) is a guanidine nitro arginine derivative and an inhibitor of endothelium‐dependent vascular relaxation. Significant rise of the systolic blood pressure was observed after 1 week administration of NO2Arg in food (0.023% in weight, about 2.8 mg of NO2Arg/rat per day) in female rats of stroke‐prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar‐Kyoto rats (WKY). The rises were not different between SHRSP (21 mmHg) and WKY (23 mmHg).

2. In ring preparations of the thoracic aorta of NO2Arg‐administered rats of both strains, relaxation by acetylcholine decreased markedly compared with those of the control rats (to 43–44%). On the contrary, glyceryltrinitrate‐induced relaxation was slightly but significantly increased in the aorta of WKY after NO2Arg administration and the same tendency was observed in SHRSP.

3. The rise of blood pressure and the decrease of acetylcholine‐induced relaxation suggested that NO2Arg inhibited the endothelium‐dependent relaxation not only in WKY but also in SHRSP. The relaxation of the thoracic aorta preparation of SHRSP by acetylcholine was much less (ca 38%) than that of WKY; however, that of SHRSP by glyceryltrinitrate was slightly less (ca 74%), indicating that endothelium‐dependent relaxation declined in vascular preparation of SHRSP.

4. The present results suggest that endothelium‐dependent relaxation has some contribution on blood pressure regulation in the hypertensive state, although a decline of endothelium‐dependent relaxation is evident in vascular preparation of SHRSP compared with WKY.
POTENTIATION BY ALDOSTERONE OF VASOPRESSIN‐INDUCED CALCIUM KINETICS IN VASCULAR SMOOTH MUSCLE CELLS
Authors: Okada Koji , Ishikawa San‐e , Saito Toshikazu
Published: June 2007

1. The present study was undertaken to examine the effect of aldosterone on arginine vaso‐pressin (AVP)‐induced Ca2+ kinetics in cultured rat vascular smooth muscle cells (VSMC). The pre‐incubation of cells with 1 X 10−6 mol/L aldosterone for 24 h did not affect the basal cytosolic free Ca2+ ([Ca2+]i) but enhanced the AVP‐induced mobilization of [Ca2+]i (1 X 10−8 mol/L AVP; 287 vs 401, 1 X 10−6 mol/L AVP; 430 vs 714 nmol/L).

2. The pre‐incubation of cells with 1 X 10−7 mol/L aldosterone for 24 h did not show this enhancing effect on the AVP‐induced mobilization of [Ca2+]i. Without the preincubation, aldosterone did not change the basal [Ca2+]i or the AVP‐induced mobilization of [Ca2+]i. This enhancement was still observed in the Ca2+‐free solution containing 0.1 mmol/L EGTA (1 X 10−8 mol/L AVP; 169 vs 341 nmol/L).

3. The enhancement by aldosterone of the AVP‐mobilized [Ca2+]i was completely blocked by the simultaneous administration of 1 X 10−4 mol/L spironolactone (1 X 10−8 mol/L AVP; 258 vs 265 nmol/L). The treatment with aldosterone also stimulated the AVP‐produced [45Ca2+] efflux during a 3 min period (1 X 10−8 mol/L AVP; 32 vs 49, 1 X 10−6 mol/L AVP; 50 vs 58% released from the resting intracellular [45Ca2+]‐contents).

4. The present results indicate that aldosterone enhances the vascular action of AVP mediated through the stimulation of Ca2+ kinetics which may be dependent on the changes in the cellular signal transduction systems.
CARDIOVASCULAR SENSITIVITY CHANGES TO EICOSANOIDS IN RATS WITH EXPERIMENTALLY INDUCED DIABETES MELLITUS
Authors: Hodgson Wayne C. , Sikorski Bogdan W. , King Roger G.
Published: June 2007

This paper attempts to provide a short review of the evidence for:

1. Increased platelet production of thromboxane A2 and reduced vascular production of prostacyclin in the human and also animal models of diabetes.

2. Reduced depressor responsiveness to arachidonic acid of anaesthetized alloxan‐ and streptozotocin‐induced diabetic rats.

3. Enhanced constrictor responsiveness to arachidonic acid in blood‐perfused hindquarters of alloxan‐induced diabetic rats.

4. Potentiation by the thromboxane A2‐mimetic, U46619, of constrictor responses to 5‐hydroxy‐tryptamine in Krebs'‐perfused hindquarters and kidneys of both control and alloxan‐induced diabetic rats.

5. Alterations during diabetes in production of, and responsiveness to, eicosanoids may contribute to the cardiovascular changes which occur in this disease.
THE EVOLUTION OF HYPERTENSIVE THERAPY
Authors: Robson R. D.
Published: June 2007

1. During the past 30 years many antihypertensive agents, acting at differing levels on the mechanisms controlling arterial blood pressure, have been introduced.

2. Whereas the usefulness of early drugs was limited by side effects, the discovery of successive classes of agents has resulted in the gradual introduction of drugs causing fewer adverse effects with consequent improvements in patient compliance.

3. The recent appearance of angiotensin II antagonists and potassium channel openers, together with increased knowledge of the roles played by atrial natriuretic factor and endothelial cell‐derived autacoids in control of vascular tone, hold prospects for still further improvements in therapy.
GABAa AGONISTS AS TARGETS FOR DRUG DEVELOPMENT
Authors: Johnston Graham A. R.
Published: June 2007

1. Agents with selective actions on bicuculline‐sensitive GABAa receptors have been developed by systematically restricting the conformational mobility of the GABA molecule.

2. THIP, a bicyclic isoxazole that represents GABA held in a relatively rigid and partially extended conformation, is an analgesic of potency comparable to that of morphine. THIP represents a lead compound for a novel series of analgesics acting independently of Naloxone‐sensitive opiate systems.

3. ZAPA, a conformationally‐restricted analogue of GABA containing an isothiouronium moiety, is a selective agonist for low affinity GABAa receptors and is a lead compound for the development of a novel series of anthelmintics.

4. (+)‐TACP, a cyclopentane analogue of GABA, may activate a different subclass of GABAa receptors from THIP.

5. Pharmacological, molecular modelling and molecular biological studies provide evidence for a heterogeneity of GABAa receptors which might be exploited for drug development.
ARACHIDONIC ACID METABOLISM IN NICOTINE‐TREATED RATS AND NICOTINE‐INCUBATED RABBIT AORTIC SMOOTH MUSCLE CELLS
Authors: Hui S‐C. G. , Wang Z. , Zhang H. , Ogle C. W.
Published: June 2007

1. The changes in plasma levels of thromboxane‐B2 (TXB2) and 6‐keto‐prostaglandin‐F1α(6‐keto‐PGF1α) were examined in rats given 5, 25, 50 or 100 μg/mL nicotine in drinking water for 10 days.

2. The effect of nicotine on prostacyclin (PGI2) synthesis from endogenous arachidonic acid by cultured rabbit aortic smooth muscle cells was also studied.

3. Plasma levels of TXB2 were increased dose‐dependently by treatment for 10 days with nicotine.

4. 6‐Keto‐PGF1α values were lowered dose‐dependently, both in the plasma of nicotine‐treated rats and in rabbit aortic smooth muscle cells incubated with the alkaloid.

5. The results suggest that endogenous synthesis of thromboxane‐A2 and PGI2, as reflected by TXB2 and 6‐keto‐PGF1α levels, respectively, is influenced by nicotine treatment. These findings may be related to cardiovascular diseases associated with cigarette smoking, but further studies are needed.
BRADYCARDIA DURING REVERSIBLE HYPOVOLAEMIC SHOCK: ASSOCIATED NEURAL REFLEX MECHANISMS AND CLINICAL IMPLICATIONS
Authors: Secher Niels H. , Jacobsen John , Friedman Daniel B. , Matzen Steen
Published: June 2007

1. Heart rate response to reversible central hypovolaemia can be divided into three stages. In the first stage (corresponding to a reduction of the blood volume by approximately 15%) a modest increase in heart rate (<100 beats/min) and total peripheral resistance compensate for the blood loss, and a near normal arterial blood pressure prevails (preshock). During the second stage, a reduction of the central blood volume by approximately 30% results in a decrease in heart rate, total peripheral resistance and blood pressure due to activation of unmyelinated vagal afferents (C‐fibres) from the left ventricle. In the third stage, blood pressure falls further as haemorrhage continues and tachycardia (> 120 beats/ min) is manifest. This stage may proceed into irreversible shock with death from cardiac arrest probably related to the formation of free oxygen radicals.

2. Recognition of the vasodepressor–cardioinhibitory reaction to a reduced circulating blood volume is important and suggests the need for immediate treatment with volume expansion in critically ill patients.
ARTERIAL BAROREFLEX CONTROL OF HEART PERIOD IS NOT RELATED TO BLOOD PRESSURE VARIABILITY IN CONSCIOUS HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: Su Ding‐Feng , Cerutti Catherine , Barrès Christian , Julien Claude , Vincent Madeleine , Paultre Christian , Sassard Jèan
Published: June 2007

1. The short‐term (within 30 min periods) and the long‐term (among 30 min periods) variabilities, expressed as variation coefficients, of blood pressure (BP) and heart period (HP) were studied using a computer analysis of BP recordings in freely moving genetically hypertensive (LH), normotensive (LN) and low BP (LL) rats of Lyon strains at ages 5, 9, 21 and 40 weeks. The baroreflex control of HP was estimated with the slope of the linear relationship between systolic BP (SBP) and HP (SBP‐HP slope) computed after phenylephrine and nitroglycerin injections.

2. Short‐term variability of BP increased between 5 and 9 weeks of age and then remained stable. Hypertension was accompanied by an increase in both short‐and long‐term variabilities of diastolic BP in adult rats.

3. A sharp increase in SBP‐HP slope was observed between 5 and 9 weeks of age in LN rats. SBP‐HP slope of LH rats increased slightly up to 21 weeks but remained lower than that of normotensive controls.

4. The weak inverse correlation existing between SBP‐HP slope and BP variability appeared to be mediated by the BP level. In addition, atropine which is known to abolish almost completely the SBP‐HP slope, did not increase BP variability. It is concluded that SBP‐HP slope is not linearly associated with BP variability in conscious rats.
RELATIONSHIP BETWEEN ATP RESYNTHESIS AND CALCIUM ACCUMULATION IN THE REPERFUSED RAT HEART
Authors: Hasin Y. , Kneen M. M. , Craik D. J. , Nayler W. G.
Published: June 2007

1. The postulate that the composition of solutions used to reperfuse ischaemic hearts may modulate their ability to synthesize high‐energy compounds was tested in isolated rat hearts subjected to 30 min normothermic ischaemia and then reperfused with either Krebs'‐Henseleit buffer (K‐H) for 20 min (control reperfusion, CR), or a ‘myocardial protective solution’ (MPS) for 5 min, followed by 15 min K‐H (modified reperfusion, MR). The ‘myocardial protective solution’ was designed to protect against damage caused by sodium and calcium accumulation and by free radicals. Metabolic precursors were also included to promote and support adenosine triphosphate (ATP) resynthesis during reperfusion under both aerobic and hypoxic conditions.

2. 31P nuclear magnetic resonance (NMR) was used to measure tissue ATP and creatine phosphate (CP), and atomic absorption spectrometry was used to measure Ca++. Early during CR, ATP recovered to 28% of the pre‐ischaemic value, but fell to 5.5% with continued perfusion. Similarly, CP recovered to 45.5% of the pre‐ischaemic level during early CR but fell to 25.5% with continued perfusion.

3. Better maintenance of ATP was seen during MR with oxygenated MPS (O2‐MR), the final ATP remaining at 16.9% of the pre‐ischaemic level. During O2‐MR, CP recovered to 43.55 of the pre‐ischaemic level but was not maintained and fell to a final level of 29.5%.

4. During MR with O2‐free MPS (non‐O2‐MR), there was no reperfusion‐associated fall in ATP or CP, with the levels maintained at 26.6% and 34.55, respectively.

5. During 5 min CR, tissue Ca++ was elevated but this did not happen during 5 min reperfusion with O2‐MR or non‐O2‐MR. After 20 min reperfusion there was no significant difference in Ca2+between the groups (CR 16.56±1.33; O2‐MR 13.48±1.2; non‐O2‐MR 15.97±2.4 μmol/g dry weight). When reperfused with O2‐free histidine‐containing MPS, tissue Ca1+ increased substantially without any change in ATP (26.2 ± 1.65% at 20 min).

6. Thus reperfusion injury, assessed by a secondary reduction in ATP, can be limited by the initial use of appropriately designed reperfusion ‘cocktails', and Ca++ overload is not the primary factor limiting ATP regeneration.
ANTAGONISM BY ENDOTHELIN OF CENTRALLY MEDIATED CARDIOVASCULAR EFFECTS OF POTASSIUM IN ANAESTHETIZED RATS
Authors: Shah Jui , Jandhyala Bhagavan S.
Published: June 2007

1. We have previously demonstrated that cerebroventricular administration of potassium chloride (KCI) solutions produces dose‐dependent reductions in blood pressure and heart rate in anaesthetized rats and that these effects are significantly attenuated by ouabain, a selective inhibitor of the Na+‐pump. These observations suggest an important relationship between Na+, K+‐ATPase activity in the central nervous system (CNS) and neural mechanisms involved in the regulation of cardiovascular function.

2. Since endothelin‐1 (ET‐1) has been shown to affect various ion transport mechanisms, including the Na+‐pump, the present studies were conducted to evaluate whether this peptide would antagonize central effects of KCI.

3. The present studies demonstrate that cumulative doses of ET‐1 (0.8–3.2 pmol, intracerebrolateral ventricular administration, i.c.v.) produced significant attenuation of hypotension and bradycardia produced by i.c.v. injections of KCI (0.75 μmol/5 μL, i.c.v.); in a separate series, a single high dose of ET‐1 (4.0 pmol, i.c.v.) significantly reduced cardiovascular responses to various doses of KCI (0.375, 0.75, 1.25 μmol/5μL, i.c.v.).

4. These studies suggest that endothelin may be involved in the regulation of arterial pressure since it is present in CNS and possesses a ouabain‐like effect. However, it is not conclusive that ET‐1 inhibits neuronal Na+‐pump, since alternative mechanisms can also account for the efficacy of the peptide to antagonize central effects of potassium chloride.
REPETITIVE ELECTRICAL ACTIVITY OF THE MUSCLE MEMBRANE INDUCED IN CHLORIDE‐FREE MEDIUM
Authors: Nánási P. P. , Dankó M.
Published: June 2007

1. Superficial fibres of frog skeletal muscle were electrically stimulated in Ringer solution where the chloride content had been replaced by various weakly permeant anions. Changes of the membrane potential were recorded at three different time scales. The complex response was initiated by a volley of fast repetitive action potentials (10–20 ms cycle length) superimposed on the ascending phase of a transient depolarization to ‐ 35 mV. The transient depolarization was followed by a membrane potential oscillation (0.3–0.6 s cycle length). The parameters of the volley and membrane potential oscillation were not greatly affected by the substituent anion.

2. The transient depolarization was fully abolished by tetrodotoxin (3 μmol/L), but left unaffected by nifedipine (5 μmol/L), or by the replacement of extracellular Ca for Ni or Co. Tetraethylammonium (20–40 mmol/L) increased the duration and amplitude of the transient depolarization. The shape of transient depolarization was uniform in a given fibre, in spite of its marked variability under different experimental conditions.

3. Single outward current pulses applied in chloride‐free solution containing tetraethylammonium (20–40 mmol/L) evoked prolonged depolarizations to positive membrane potentials accompanied by increases in the specific membrane conductance. This slow response, which was also frequently observed in the absence of TEA, was mediated by Ca ions, as it was insensitive to tetrodotoxin (3 μmol/L) but abolished by nifedipine (10 4mUmol/L).

4. Two populations of the muscle fibres were observed during the slow response. Some fibres repolarized completely, while others failed to produce complete repolarization but formed a plateau between ‐ 20 and ‐ 30 mV, lasting for several minutes. When the external K concentration was abruptly increased to 5 or 10 mmol/L during the plateau of the slow response, repolarization and increase in membrane conductance were observed.

5. In muscle fibres, having osmotically disrupted T‐system, the duration of transient depolarization was in the range of minutes, in contrast to the range of seconds observed in intact fibres. The volley was preserved in glycerol treated fibres, however, the baseline of discharges was close to the resting potential and the rate of depolarization of the baseline was significantly less in glycerol treated than in intact fibres.

6. These results are consistent with the existence of a second stable membrane potential level in skeletal muscle between ‐ 40 and ‐ 30 mV. The depolarization and repolarization during the membrane potential oscillation and transient depolarization can be regarded as a partial or full transition, respectively, between these two stable membrane potential levels, possibly due to the conductance changes of the inward rectifier K channels. It seems likely that the various types of repetitive activity are also linked to these conductance changes indicating that they are endogenous properties of the skeletal muscle membrane.
BLOOD SERUM BIOCHEMICAL CHANGES IN PHYSICALLY CONDITIONED AND UNCONDITIONED SUBJECTS DURING BED REST AND CHRONIC HYPERHYDRATION
Authors: Zorbas Yan G. , Naexu Konstantin A. , Federenko Youri F.
Published: June 2007

1. It has been suggested that prolonged exposure to a rigorous bed rest regimen (hypokinesia) may induce greater serum carbohydrate and electrolyte changes in physically conditioned than unconditional subjects and that chronic hyperhydration may normalize or attenuate the development of these biochemical alterations in physically conditioned subjects.

2. Serum carbohydrate and electrolyte changes were determined in 18 physically healthy male volunteers aged 19–24 years during 30 days of a rigorous bed rest regimen. The subjects were divided into three equal groups. The first g oup consisted of six unconditioned subjects with V̇o2 max of 44 mL/kg bodyweight/min, the second group consisted of six conditioned subjects with V̇o2 max of 69 mL/ kg bodyweight/ min and the third group consisted of six conditioned subjects with V̇o2 max of 69 mL/kg body weight/min who consumed daily an additional amount of 26 mL water/kg bodyweight and 0.10 mg sodium chloride/kg bodyweight.

3. For the simulation of the hypokinetic effect all volunteers were kept under a rigorous bed rest regimen for 30 days. During the pre hypokinetic period of 15 days and during the bed rest period of 30 days the concentrations of cortsol, aldosterone, testosterone, tri‐idothyronine (T3), thyroxine (total; T4), glucose, potassium, sodium and chloride were determined in blood serum of volunteers.

4. During the bed rest period of 30 days serum carbohydrate and electrolyte changes were more pronounced in physically conditioned than unconditioned hypokinetic subjects. In physically conditioned hyperhydrated subjects serum carbohydrate and electrolyte changes were less pronounced than in physically conditioned and unconditioned hypokinetic subjects.

5. It was concluded that exposure to a rigorous bed rest regimen over a prolonged period of time induced significantly more changes in serum carbohydrate and electrolyte concentrations in physically conditioned than in unconditioned subjects and that chronic hyperhydration may be used to normalize or stabilize all serum biochemical changes in physically conditioned subjects during prolonged exposure to a rigorous bed rest regimen.
FISH OIL FEEDING SELECTIVELY ATTENUATES CONTRACTILE RESPONSES TO NORADRENALINE AND ELECTRICAL STIMULATION IN THE PERFUSED MESENTERIC RESISTANCE VESSELS OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Chu Z. M. , Yin K. , Beilin L. J.
Published: June 2007

1. The mechanism of the antihypertensive effects of n‐3 fatty acids were examined in spontaneously hypertensive rats (SHR) by feeding ‘Max EPA’ fish oil or hydrogenated coconut oil and determining the responses of perfused mesenteric resistance vessels to various contractile agents and peri‐arterial nerve stimulation.

2. Fish oil feeding for 4 weeks caused a decrease in the responses to exogenous noradrenaline and electrical nerve stimulations but had no significant effect on vasopressin and KC1 (80 mmol/L) induced contractions.

3. These results provide direct evidence for specific attenuation of vascular responses to sympatho‐adrenal stimulation in resistance vessels following fish oil feeding and may account for the antihypertensive effects seen in humans and in some forms of hypertension in rats.
ISOLATION AND CHARACTERIZATION OF THE RAT LIVER AVP RECEPTOR USING [125I][d(CH2)5′SARCOSINE7]AVP1
Authors: Trinder Deborah , Kelly Janice M. , Fernley Ross , Mooser Vincent , Phillips Paddy A. , Johnston Colin I.
Published: June 2007

1. A vasopressin (AVP) binding protein was purified from rat liver membranes by an improved method using [125I][d(CH2)5′Sarcosine7]AVP, a selective Vi AVP radioligand and a combination of CHAPS solubilization, gel filtration, lectin affinity and FPLC ion exchange chromatography.

2. The purified protein exhibited a maximum binding activity of 2480 pmol/ mg protein with a KD of 4.5 nmol/ L, which corresponds to a purification of approximately 26 700‐fold. The molecular weight of this protein was 70 000 Da.

3. The binding of [125I][d(CH2)5′Sarcosine7]AVP to the solubilized membranes was dependent on the protein concentration, and was inhibited by the unlabelled peptides [d(CH2)5′Sarcosine7]AVP, AVP, and to a lesser degree by peptides with high V2 receptor affinity, such as 1‐desamino‐D‐AVP and [d(CH2)5′D‐Ileu2‐Ileu4]AVP.

4. In addition, an AVP anti‐idiotypic monoclonal antibody bound to both the partially purified and purified lectin affinity AVP binding protein in a concentration‐dependent manner. These results indicate that the purified protein displays similar characteristics to the liver membrane‐bound AVP V1 receptor.
MEASUREMENT AND IDENTIFICATION OF PRORENIN AND RENIN IN OVARIAN FOLLICULAR FLUID FROM CATTLE AND PIG
Authors: Hagemann Arne , Nielsen Arne Høj , Dantzer Vibeke , Avery Birthe , Poulsen Knud
Published: June 2007

1. In previous studies we have demonstrated and solved several methodological problems in relation to the measurement of prorenin by trypsin activation in rat, bovine, hog and horse plasma.

2. The aim of the present study was to develop a method for the measurement of prorenin in bovine and porcine ovarian follicular fluid.

3. Trypsin activation of follicular fluid generated angiotensin I immunoreactive material (AI IM) in both species.

4. The AI IM interfered with the renin assay, but could be completely removed by a cation exchange resin in a batch‐wise technique.

5. The enzymatic activity of trypsin‐activated prorenin and pre‐existing active renin was completely inhibited by a specific inhibitor of renin.

6. The reactions were optimized and an accurate measurement of prorenin in ovarian follicular fluid was developed.

7. The existence of prorenin and renin in bovine ovarian follicular fluid was established. Prorenin and renin in porcine ovarian follicular fluid was demonstrated for the first time.

8. The ratio between ovarian follicular fluid and plasma was 43 for prorenin and 19 for active renin in cattle. The same ratios in pigs were 1.3 and 0.4, respectively. These findings indicate a species difference with respect to the amount of prorenin or active renin present in ovarian follicular fluid.
INCREASE IN SERUM TOTAL ANGIOTENSIN‐CONVERTING ENZYME ACTIVITY WITH ENALAPRIL THERAPY IN HUMANS: A CONTROLLED TRIAL
Authors: Stokes Gordon S. , Monaghan Judith C. , Marwood John F. , Okoro E. Obi , Johnston Heather
Published: June 2007

1. In a controlled, randomized double‐blind trial, 15 patients with essential hypertension were treated with enalapril 5–20 mg/day, or doxazosin 1–8 mg/day, during a 7 week dose titration phase. This was followed by 7 weeks of combined treatment with doxazosin and enalapril.

2. Blood was taken after a 2 week placebo run‐in phase, and at 3 and 7 weeks in the single‐agent and combined treatment phases, for measurement of plasma renin activity (PRA), plasma angiotensin II (All), plasma aldosterone and serum free and total angiotensin‐converting enzyme (ACE) activities.

3. Doxazosin had no effect on serum free or total ACE activities.

4. Enalapril reduced serum free ACE activity and increased serum total ACE activity, which at 7 weeks was significantly greater than in patients receiving doxazosin.

5. In those patients who received enalapril, 10 mg/day for 3 weeks and then 20 mg/day for 4 weeks (n= 12), with or without doxazosin, mean serum total ACE activity increased by 51%. PRA was also increased in this group, but there were no changes in plasma AH or aldosterone concentrations.
POPULATION‐BASED SURVEY OF HUMAN SODIUM AND POTASSIUM EXCRETION
Authors: Beard T. C. , Eickhoff R. , Mejglo Z. A. , Jones M. , Bennett S. A. , Dwyer T.
Published: June 2007

1. During the 1989 National Heart Foundation Risk Factor Prevalence Survey a subsample in Hobart collected 24 h urine samples to measure electrolyte excretion.

2. The ranges were 30‐344 mmol/24 h for Na+ excretion (mean 160 mmol/24 h for men, 124 mmol/24 h for women), and 25‐119 mmol/24 h for K+ excretion (mean 77 mmol/24 h for men, 68 mmol/24 h for women).

3. As in other surveys, women excreted about 20–25% less Na+ and K+ than men, although there was no significant sex difference in the ratio of Na+/K+ excretion.

4. The recommended dietary intake (RDI) for Na+ and K+ was followed simultaneously by 19% of subjects, and 13% had a 24 h urinary Na+/K+ ratio ≤ 1.0.

5. Observance of the RDI limited the value of iodized salt for goitre prophylaxis.

6. Sodium excretion rates were outside the therapeutic range of thiazide diuretics in 22% of subjects.

7. Diet groups for long‐term prospective cohort studies to test the prophylactic value of avoiding salt could apparently be recruited from existing subsamples of the population.
EFFECTS OF ARGININOSUCCINIC ACID ON NITRIC OXIDE‐MEDIATED RELAXATIONS IN RAT AORTA AND ANOCOCCYGEUS MUSCLE
Authors: Rand M. J. , Li C. G.
Published: June 2007

1. Argininosuccinic acid (ASA), a naturally occurring NG derivative of arginine, and the nitric oxide synthase (NOS) inhibitor JVG‐nitro‐L‐arginine methyl ester (l‐NAME) were compared for their ability to reduce responses to nitric oxide (NO) derived from endothelial cells (aorta) and nitrergic nerves (anococcygeus muscle).

2. In isolated rings of rat aorta, endothelium‐dependent relaxation responses to acetylcholine were abolished by l‐NAME (0.1 mmol/L) and were reduced by ASA (0.1 and 0.3 mmol/L). Relaxations induced by sodium nitroprusside (SNP) were not affected by l‐NAME but were reduced by ASA.

3. In rat isolated anococcygeus muscles, relaxations elicited by nitrergic nerve stimulation at 1 Hz were abolished by l‐NAME (0.1 mmol/L) but were only slightly reduced by ASA (1 mmol/L). The effect of ASA was not sustained. l‐Arginine (1 mmol/L) prevented the effect of L‐NAME but not that of ASA. Neither ASA or l‐NAME inhibited SNP‐induced relaxation in the anococcygeus muscle.

4. The results suggest that ASA inhibits NOS but this does not totally account for its effects in reducing NO‐mediated relaxations produced by the endothelium‐dependent vasodilator acetylcholine in rat aortic rings and stimulation of nitrergic nerves in the rat anococcygeus muscle.