bluuebunny/crossref_metadata_2025 huggingface dataset:
CALCIUM METABOLISM IN ELDERLY HYPERTENSIVE PATIENTS: POSSIBLE PARTICIPATION OF EXAGGERATED SODIUM, CALCIUM AND PHOSPHATE EXCRETION
Authors: Imaoka M. , Morimoto S. , Kitano S. , Fukuo F. , Ogihara T.
Published: June 2007

1. Renal handling of electrolytes, including calcium (Ca), in response to physiological saline infusion (20 mL/kg, i.v., for 2 h) as well as basal circulating levels of Ca‐regulating hormones were compared in 27 hypertensive elderly females (mean age 80±9 years), in 44 normotensive elderly females (79±9 years) and in 19 young normotensive females (23±4 years).

2. The hypertensive elderly females showed excessive increase in urine volume and urinary excretions of sodium (Na), Ca and inorganic phosphate (P) in response to saline infusion, associated with slight but significant decrease in circulating levels of Na and ionized Ca compared with those in the other groups. These hypertensive elderly patients also showed characteristic features both in circulating blood pressure and Ca regulating factors; they showed significantly low levels of plasma renin activity and aldosterone concentration, significantly high plasma levels of atrial natriuretic peptide and noradrenalin, compared with those in young controls and normotensive elderly females.

3. Moreover they showed significant increase in basal serum levels of parathyroid hormone and 1,25‐dihydroxyvitamin D, and significant decrease in basal serum levels of calcitonin, 25‐hydroxy‐vitamin D and 24,25‐dihydroxyvitamin D, compared with those in the other groups.

4. These results suggest that the exaggerated natriuresis associated with excessive loss of Ca and P in urine may participate in the abnormality of Ca metabolism in low‐renin hypertensive elderly patients.
CORONARY VASCULAR RESPONSE TO ENDOTHELIN IN ISOLATED PERFUSED HEARTS OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Takeshita Hiroshi , Nishikibe Masaru , Yano Mitsuo , Ikemoto Fumihiko
Published: June 2007

1. The coronary vasoconstrictive response to endothelin (ET‐1) was evaluated using the isolated perfused hearts of 15 week old spontaneously hypertensive rats (SHR) and age‐matched Wistar‐Kyoto rats (WKY). Endothelin produced marked increases in perfusion pressure (PP) in both SHR and WKY. The effects of ET‐1 were more potent than those of acetylcholine, vasopressin and angiotensin II. The vascular response to ET‐1, expressed as the increase in PP, was greater in SHR than in WKY.

2. Nicardipine (10−8 mol/L) shifted the concentration–PP response curve for ET‐1 to the right. The extent of the rightward shift was greater in SHR than in WKY. Additionally in SHR, Bay K‐8644 elicited a dose‐dependent increase in PP, the effect being more potent than that in WKY.

3. The increased response of the coronary vasculature to ET‐1 was observed after 15 weeks of age but not at 6 weeks, indicating that enhancement of the response develops with ageing in SHR.

4. Enhancement of the vascular response to ET‐1 in SHR was prevented by chronic (10 weeks) treatment with enalapril (10 mg/kg per day), but not by hydralazine (30 mg/kg per day).

5. These results indicate that the coronary vascular response to ET‐1 increases with age in SHR. The mechanism of the enhanced response may involve the activation of dihydropyridine‐sensitive Ca2+ channels, however, this type of mechanism may also be modulated at least in part by the renin–angiotensin system.
GOVERNMENT INITIATIVES IN THE DEVELOPMENT OF A PHARMACEUTICAL INDUSTRY IN AUSTRALIA
Authors: Hirst Christine A.
Published: June 2007

Government policy recognizes that the purchasing power of the government, through the Pharmaceutical Benefits Scheme, has suppressed prices and returns to the pharmaceutical industry in Australia, and that research, development and export activities have been low. The factor (f) scheme is designed to provide some pricing relief to those companies willing and able to undertake particular industry development activities. This scheme, together with the other changes implemented by the government, will result in the restructuring and development of the pharmaceutical industry in Australia.
SYMBIOTIC RELATIONSHIP BETWEEN A RESEARCH INSTITUTE AND A PHARMACEUTICAL COMPANY: THE BAKER INSTITUTE/GLAXO AUSTRALIA STORY
Authors: Angus James A.
Published: June 2007

1. The Baker Medical Research Institute is a non‐profit, charitable institution to advance knowledge and solve problems in the area of cardiovascular medicine. This allows scientists to collaborate within a critical mass and be flexible in their approach to research.

2. The Institute has interactions with the pharmaceutical industry at three levels: (i) contract research on a specific molecule; (ii) clinical trials; and (iii) collaborative basic research agreements.

3. The Glaxo Australia‐Baker Medical Research Institute Agreement is for curiosity driven research in specified areas of vascular pharmacology of interest to Glaxo Group Research.

4. The relationship between universities, research institutes and the pharmaceutical industry is discussed in terms of the starting point for drug development.

5. The enormous cost (US$100 million), lead time (10 years) and uncertainty of a successful profitable drug are compelling reasons why an independent pharmaceutical company is unlikely to succeed in Australia today.
ENDOTHELIN‐3‐INDUCED MICROVASCULAR INCOMPETENCE AND MITOCHONDRIAL DAMAGE IN RAT MYOCARDIUM
Authors: Maxwell Linda , Pratt Katherine , Gavin John
Published: June 2007

1. To determine the possible role of an endothelin in the development of postischaemic microvascular incompetence, isolated buffer‐perfused rat hearts were perfused with endothelin‐3 (ET‐3) in phosphate buffer.

2. ET‐3 produced a reduction in coronary flow rate, heart rate and arrhythmia. There was a marked reduction in the density of competent capillaries, and the myocytes showed vacuolation and mitochondrial damage in regions where microvascular incompetence was most severe.

3. These results indicate that ET‐3 can substantially reduce microvascular perfusion in the heart and can also cause damage to the myocyte.
MECHANISM AND PREVENTION OF CHRONIC COLONIC INFLAMMATION WITH TRINITROBENZENE SULFONIC ACID IN RATS
Authors: Hoshino Hiroshi , Sugiyama Satoru , Ohara Atsushi , Goto Hidemi , Tsukamoto Yoshihisa , Ozawa Takayuki
Published: June 2007

1. The role of prostanoids in experimental colitis with trinitrobenzene sulfonic acid (TNBS) in rats was investigated. The effects of cyclosporine A (CsA) on the development of experimental colitis were also examined.

2. Five kinds of prostanoids were detected in rat colonic tissue by high performance liquid chromatography. These were 6‐keto‐prostaglandin (PG) F1α, PGF2α, PGE2, PGD2 and thromboxane B2.

3. In TNBS‐induced experimental colitis, all prostanoid concentrations except PGD2 increased, although the time courses differed from each other.

4. Medication with indomethacin markedly reduced prostanoid concentrations in TNBS‐induced colitis. However, indomethacin did not show any effect on damage scores.

5. Cyclosporine A reduced damage scores 14 days after TNBS treatment, and the protective effects were observed, whereas CsA did not affect colonic tissue prostanoid concentrations.

6. Prostanoids might be produced secondarily in the genesis of TNBS‐induced colitis, although they may attenuate the inflammatory response. It was also suggested that CsA was likely to have therapeutic effects on experimental colitis by inhibiting the immune reaction with TNBS, which induced the chronic inflammation.
THE ROLE OF THE RENAL NERVES IN RENIN SYNTHESIS
Authors: Zhang Yanling , Morgan Trefor , Read Gullvig
Published: June 2007

1. Renin synthesis and secretion were studied in Balb/ c mice with a denervated left kidney.

2. Denervation inhibited renin secretion.

3. Denervation reduced the renal renin content.

4. Denervation reduced renal renin mRNA.

5. Renal denervation inhibits renin secretion by blocking the synthetic system prior to mRNA formation.
ACTIVATION OF NORADRENERGIC AND NITRERGIC MECHANISMS IN THE RAT ANOCOCCYGEUS MUSCLE BY NICOTINE
Authors: Rand M. J. , Li C. G.
Published: June 2007

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1. Nicotine (10 μmol/L) produced rapidly developing but transient contractions of anococcygeus muscle isolated from rats. The magnitude of the response varied considerably between preparations. Tachyphylaxis occurred, such that no response was elicited by the same or a larger concentration in the continued presence of 10 μmol/L nicotine.

2. Contractions produced by nicotine were not affected by atropine, but were abolished by Hexamethonium and the α‐adrenoceptor antagonists prazosin and phentolamine. Contractions were absent in the anococcygeus muscles of rats pretreated with reserpine.

3. The (α‐adrenoceptor agonist UK 14304, or guanethidine, raised the tone of the anococcygeus muscle, and converted responses to field stimulation and nicotine to relaxations. Nicotine‐induced relaxations were more pronounced in the presence of UK14304 than guanethidine.

4. Relaxations produced by nicotine (1–18 μmol/L) were transient, and tachyphylaxis occurred. When precautions were taken to avoid tachyphylaxis, concentration‐response curves could be constructed. The relaxations elicited by nicotine were abolished or greatly reduced by hexamethonium, tetrodotoxin or ω‐conotoxin GVIA.

5. The nitric oxide synthase inhibitor l‐NG‐nitroarginine methyl ester (90 μmol/L) enhanced contractile responses to field stimulation and nicotine, and markedly reduced relaxations elicited by field stimulation and nicotine in the presence of UK14304. These relaxations were restored by l‐arginine (270 μmol/L).

6. The results suggest that nicotine acts on nicotinic receptors of noradrenergic and nitrergic nerve terminals in the rat anococcygeus muscle, resulting in the release of noradrenaline and nitric oxide respectively.
PROPOFOL ANAESTHESIA IN MALIGNANT HYPERPYREXIA SUSCEPTIBLE SWINE
Authors: Foster P. S. , Hopkinson K. C. , Denborough M. A.
Published: June 2007

1. Malignant hyperpyrexia (MH) is an inherited muscle abnormality that presents clinically as a syndrome of life‐threatening complications during general anaesthesia.

2. Propofol is a new sedative hypnotic used for the induction and maintenance of anaesthesia.

3. Propofol did not induce MH in five susceptible pigs. Propofol did not induce contracture in isolated MH susceptible muscle but did modify halothane, caffeine and KCl contractures.
RENAL HANDLING OF ENDOGENOUS LITHIUM IN EXPERIMENTAL DIABETES MELLITUS IN THE RAT
Authors: Pollock Carol A. , Field Michael J.
Published: June 2007

1. The usefulness of determining the renal handling of endogenous lithium as a marker of proximal tubular sodium reabsorption was assessed in streptozotocin induced diabetes mellitus in the Sprague‐Dawley rat.

2. The clearance and fractional excretion of lithium were determined before and following the development of diabetes mellitus, and compared with measurements of proximal tubular reabsorption made directly using micropuncture techniques. Endogenous lithium was measured in order to avoid the toxic tubular effects of exogenously administered lithium salts.

3. Although a trend existed for a reduction in the fractional excretion of lithium in diabetic animals (1.8±0.3 vs 2.4±0.5%; P > 0.20), this did not reach statistical significance and did not accurately reflect the change in directly measured tubular Na reabsorption.

4. The decrease in proximal tubular Na reabsorption demonstrated in diabetic animals treated with phlorizin was not significantly reflected in the fractional lithium excretion, although again a corresponding trend was evident (1.9 ± 0.8 vs 0.6 ± 0.2%; P > 0.10.

5. In summary, the significant alterations in tubular Na handling in diabetes mellitus, previously demonstrated directly using micropuncture techniques, are not reflected in the renal handling of endogenous lithium. This indirect method is inadequate to assess proximal tubular Na transport in experimental diabetes mellitus.
FAILURE OF THE NITROUS OXIDE TISSUE EQUILIBRATION METHOD FOR THE DETERMINATION OF BRAIN AND MYOCARDIAL BLOOD FLOW UNDER CONTROLLED CONDITIONS
Authors: Reid Michael A. , Runciman William B. , McLean Colin F. , Mather Laurence E.
Published: June 2007

1. Two adult merino ewes were prepared with intravascular cannule for sampling aortic root blood, sagittal sinus blood and coronary sinus blood.

2. One week after preparation the animals were anaesthetized then ventilated with a gas mixture containing 10% nitrous oxide (N2O) for 60 min. Serial measurements of brain and myocardial blood flow were made using the N2O tissue equilibration method of Kety and Schmidt.

3. N2O failed to achieve matching arteriovenous blood concentration equality and saturation of the relevant tissues. Valid use of the Kety‐Schmidt method, therefore, could not be confirmed.

4. Because of the failure of the arteriovenous equilibration, serially determined brain and myocardial blood flows were found to decrease with time.

5. The use of this method in circumstances where tissue saturation with the indicator gas cannot be ascertained is arbitrary.
POTASSIUM CHANNEL ACTIVATION IMPROVES BLOOD FLOW PATTERN OF CONSCIOUS RATS IN CUTANEOUS MICROCIRCULATION
Authors: Hertel RolfF.
Published: June 2007

1. A dose‐dependent mean arterial blood pressure reduction (tailcuff method) to an intravenously administered potassium channel activator (22 or 24 μg/ kg bw) was found in conscious rats.

2. Intravital microscopic analysis of skin microcirculation in conscious rats was performed with respect to erythrocyte flow velocity and diameters of capillaries. There was a dose‐dependent increase of erythrocyte flow velocity; diameters of capillaries were dilated following a dosage of 6 and 12 Mg/kg bw, but constricted following a dosage of 24 μg/kg bw.

3. Frequency distributions of velocity ranges in capillaries under observation (real time video recordings) proved that the increase of microvascular perfusion is manifested by a shift of maximal values to increasing velocity ranges.

4. It is concluded that potassium channel activation plays an important role in the local regulation of perfusion on the peripheral circulation.
INACCURACY OF ELECTRONIC SPHYGMOMANOMETERS
Authors: Mann Stewart
Published: June 2007

1. Eight electronic sphygmomanometers were purchased locally and evaluated for clinical accuracy during blood pressure recording on volunteer patients.

2. Direct comparisons of systolic and diastolic pressure were made in seven devices using a Y‐tube connection to a mercury sphygmomanometer, simultaneous measurements being made by a trained observer on 16–18 subjects.

3. Indirect comparisons were made for all eight devices by comparing the average values obtained from all measurements made on each subject by the device with the average value from mercury sphygmomanometric readings made over the same time period.

4. Results were analysed by measuring the mean and standard deviation of the differences between device readings and mercury readings. Published criteria were used to grade the devices.

5. The most accurate machine was the Omron HEM‐719K, which used the cuff as a sound sensor and had an internal microphone. The least accurate was the Omron HEM‐812F, which used a finger‐cuff method. The other devices (all oscillometric) ranged from fair to poor in performance accuracy.
EVIDENCE FOR PRESYNAPTIC β‐ADRENOCEPTOR STIMULATION 24 HOURS AFTER A 6 HOUR ADRENALINE INFUSION
Authors: Bachmann Anthony W. , Gordon Richard D. , Ballantine Donna M.
Published: June 2007

SUMMARYM

1. The effects of 6 h infusions of adrenaline (INF‐A) and dextrose (INF‐D) were compared in nine normal subjects.

2. A significant increase in systolic blood pressure was observed during INF‐A compared with INF‐D and, 24 h after infusion, diastolic blood pressure was higher after INF‐A than after INF‐D.

3. Heart rate (HR) was significantly higher during INF‐A than during INF‐D.

4. As expected, plasma ADR increased significantly during INF‐A but, unexpectedly, remained elevated 60 min post infusion compared with INF‐D. Levels during activity the next morning were somewhat higher after INF‐A, but not significantly different from INF‐D.

5. Plasma NA increased transiently during INF‐A and decreased during INF‐D. Urinary NA was significantly higher during INF‐A than during INF‐D, and insignificantly higher during overnight recumbency, consistent with enhanced noradrenergic transmission.
PROSTAGLANDINS AND SYSTOLIC BLOOD PRESSURE, BUT NOT ANGIOTENSIN II, INDEPENDENTLY AFFECT ATRIAL NATRIURETIC PEPTIDE LEVELS IN MAN
Authors: Klemm Shelley A. , Gordon Richard D. , Tunny Terry J. , Finn Wendy L. , Hornych Antonin
Published: June 2007

1. Two hours after a single dose of indomethacin (INDO), plasma renin activity (PRA) and atrial natriuretic peptide (ANP) levels decreased, which is consistent with an effect of lowering prostaglandins (PG).

2. After 48 h of INDO, PRA remained low but ANP had increased, which is consistent with the known effect of prostaglandin inhibitors to cause sodium retention, with a resulting volume expansion.

3. Infusions of angiotensin II (All), which raises diastolic blood pressure (BP) 20 mmHg or more, consistently raised ANP levels. The ANP response to All infusion was reduced 48 h after INDO, which is consistent with an important role for PG in All‐stimulated ANP release.

4. After PG were blocked with INDO, the stimulating effect of All on ANP at doses that increased diastolic BP less than 20 mmHg was insignificant, whereas before INDO it was significant.

5. In dose‐response studies, INDO increased the systolic BP response but decreased the ANP response to All, which is consistent with a direct effect of PG on ANP that is independent of systolic BP.

6. Prostaglandins and BP are important in the ANP response to All infusion in normal subjects, but All itself appears to have little direct effect on ANP.
HAEMODYNAMIC CHANGES IN THE MONCADA MODEL OF ATHEROSCLEROSIS
Authors: Yong A. C. , Townley G. , Boyd G. W.
Published: June 2007

1. The application of a non‐constricting silastic cuff to the rabbit common carotid artery (CCA; n= 5) results in intimal thickening within 7 days.

2. Ultrasonography showed kinking of the CCA at the cuff edges, as well as a 13% arterial narrowing (P < 0.02) within the cuffed segment, both at days 1 and 7. Correspondingly, the time averaged diastolic Doppler velocity (TAV) was 68.8 ± 12.8% higher (P < 0.025) in the cuffed region in comparison with that 1 cm proximal (P 1 cm) on day 1, and 54.2 ± 11.5% higher at day 7(P < 0.05). TAV values along control silastic strips were not significantly changed.

3. There was a significant increase (P < 0.025) in intimal area within the cuffed region (0.098 ±0.024 mm3) compared with both the proximal control (0.014 ±0.001 mm3) and with that over control silastic strips (0.021 ±0.004 mm3, P < 0.01).

4. Medial area within the cuff (0.433 ±0.017 mm3) was decreased (P < 0.005) compared with P 1 cm control (0.602 ±0.069 mm3).

5. There was gross peri‐arteritic thickening involving the adventitia along the non‐constricted cuffed segment. Importantly, it was also noted alongside the control silastic strip.

6. Kinking of the CCA and associated vasoconstriction cause changes in blood flow velocity along even a non‐constricting cuff, and this may explain the intimal thickening previously noted in this experimental model. The peri‐arteritic changes, on the other hand, appear to be a reaction to the silastic itself.
RENAL VASOCONSTRICTION IS MODULATED BY NITRIC OXIDE
Authors: Reid Julianne J. , Rand Michael J.
Published: June 2007

1. The effect of the nitric oxide synthesis inhibitor, NG‐nitro‐L‐arginine (NOLA), has been examined on vascular reactivity in the rat isolated perfused kidney.

2. NOLA (10 jμmol/L) had no effect on basal perfusion pressure, but significantly enhanced the vasoconstrictor responses to sympathetic nerve stimulation (1–16 Hz, 10 s) and noradrenaline (10–300 pmol). The enhancements were greater with the lower frequencies of stimulation and lower doses of noradrenaline.

3. The enhancing effect of 10 /μmol/L NOLA on vasoconstrictor responses to nerve stimulation was partially prevented by 100 μmol/L L‐arginine while 100 μmol/ L D‐arginine had no effect.

4. The results suggest that nitric oxide attenuates vasoconstrictor responses in the rat kidney, and provide evidence that nitric oxide has a physiological role in the modulation of vascular reactivity.
LONG‐TERM ANGIOTENSIN II ANTAGONISM IN SPONTANEOUSLY HYPERTENSIVE RATS: EFFECTS ON BLOOD PRESSURE AND CARDIOVASCULAR AMPLIFIERS
Authors: Oddie Catherine J. , Dilley Rodney J. , Bobik Alex
Published: June 2007

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR).

2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities.

3. Part of the hypotensive effect induced by long‐term treatment with losartan persisted for a long time after the withdrawal of treatment.

4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.
DIFFERENTIAL REGULATION BY TRANSFORMING GROWTH FACTOR‐β1 OF PLATELET‐DERIVED GROWTH FACTOR‐ STIMULATED PROLIFERATION OF VASCULAR SMOOTH MUSCLE CELLS FROM SHR AND WKY RATS
Authors: Saltis John , Agrotis Alex , Bobik Alex
Published: June 2007

1. This study has examined and compared the time‐course of action of transforming growth factor‐β1 (TGF‐β1) on platelet‐derived growth factor‐BB‐stimulated proliferation of vascular smooth muscle cells isolated from normotensive Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).

2. Transforming growth factor‐β1 inhibited vascular smooth muscle cell proliferation stimulated by platelet‐derived growth factor‐BB in WKY rats by approximately 60–75%.

3. In contrast, transforming growth factor‐β1 potentiated an 8–35% growth factor action on cell proliferation in the SHR.

4. Defects in transforming growth factor‐β1 action may be part of the molecular mechanism responsible for the development of vascular hypertrophy in the SHR.
Platelet‐activating factor in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome
Authors: Matsumoto Kohei , Taki Fumio , Kondoh Yasuhiro , Taniguchi Hiroyuki , Takagi Kenzo
Published: June 2007

1. To clarify the role of platelet‐activating factor (PAF) in the development of adult respiratory distress syndrome (ARDS), we performed bronchoalveolar lavage (BAL) in 19 patients with ARDS and examined cell populations, albumin concentrations and PAF levels. PAF levels were measured by a newly developed radioimmunoassay.

2. In the BAL fluid of ARDS patients, neutrophil percentages and albumin concentrations markedly increased compared with control subjects.

3. PAF was detected in 14 of 19 patients with ARDS, whereas it did not exist in the control subjects.

4. Furthermore, we investigated the priming effect of recombinant human tumour necrosis factor‐α (TNFα), which is known to be one of the most important mediators in the development of ARDS, on PAF production induced by the calcium ionophore in neutrophils.

5. Pre‐incubation with TNFα dose‐dependently increased both extracellular and intracellular PAF production in neutrophils.

6. These results suggest that PAF might play an important role in the development of ARDS.
INTERACTION OF THE NON‐STEROIDAL ANTIINFLAMMATORY DRUG FLUFENAMIC ACID WITH GASTRIC ACID SECRETION AND H+/K+ ‐ATPase
Authors: Beil W. , Greite C. , Sewing K‐F.
Published: June 2007

1. The effects of the non‐steroidal anti‐inflammatory drug (NSAID) flufenamic acid on H+production in isolated and enriched guinea‐pig parietal cells and on H+/K+‐ATPase activity in ion‐tight inside‐out membrane vesicles from pig gastric mucosa were studied.

2. At low concentrations (0.1 and 1.0 μmol/L), flufenamic acid increased the secretory response of parietal cells to dibutyryl cyclic AMP (dbcAMP). At higher concentrations (10 and 100 μmol/L) it progressively inhibited basal and dbcAMP‐stimulated acid production.

3. Flufenamic acid (10 μmol/L) increased K+ (0.5–10.0 mmol/L) and K+ (0.5–1.0 mmol/L) plus gramicidin‐stimulated ATPase activity in gastric membrane vesicles. The Km value for K+ (1.6 and 1.0 mmol/L in the absence and presence of gramicidin, respectively) was decreased to 0.8 and 0.5 mmol/L, respectively. At higher concentrations (≥ 50 μmol/L), flufenamic acid inhibited K+ plus gramicidin‐stimulated ATPase activity (inhibited concentration at 50% [IC50] = 186 μmol/L) and reduced the proton concentration (IC50= 50 μmol/L).

4. It is concluded that flufenamic acid‐induced enhancement of dibutyryl cyclic AMP‐stimulated H+ production in the parietal cell reflects the stimulation of H+/K+‐ATPase. We suggest that activation of the enzyme involves increased affinity of K+ towards the K+‐binding site of the enzyme and/ or increased KC1 permeability at the vesicle membrane. The inhibitory action of the drug on H+production in parietal cells results from a detergent and/or protonophoric‐like action at the apical parietal cell membrane, and from inhibition of H+/K+‐ATPase activity.
PLASMA ADENOSINE CONCENTRATIONS ARE ELEVATED IN CONSCIOUS SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Yamada K. , Goto A. , Ishii M. , Yoshioka M. , Matsuoka H. , Sugimoto T.
Published: June 2007

1. Plasma levels of adenosine were measured in unrestrained, conscious spontaneously hypertensive rats (SHR) to examine the potential role of adenosine, a naturally occurring substance with profound cardiovascular actions, in cardiovascular regulation in these genetically hypertensive rats.

2. We employed a specific and sensitive assay for adenosine based on fluorescent determination of adenine compounds by high performance liquid chromatography.

3. Plasma adenosine concentrations were significantly higher in 13 week old SHR with hypertension than in Wistar‐Kyoto rats (0.165±0.022 vs 0.096±0.008 μmol/L; P < 0.05).

4. These observations indicate that plasma adenosine levels are increased in conscious SHR with established hypertension, and also suggest that adenosine may be at least partly involved in the pathophysiology of high blood pressure in SHR.
INTRACORONARY PGE2 AND VERATRINE INHIBITS RENIN RELEASE IN CONSCIOUS DOGS VIA CHEMOSENSITIVE VENTRICULAR AFFERENTS
Authors: Gorman A. J. , Chen J‐S. , Foster S. , Snyder R. G. , Lams S. G.
Published: June 2007

1. Prostaglandins (PG) and veratrum alkaloids stimulate ventricular sensory receptors with non‐myelinated vagal afferents and mediate inhibitory circulatory responses.

2. The present study in conscious instrumented dogs was carried out to determine the effects of intracoronary artery infusions of veratrine (Ver‐IC) and PGE2 (PGE2‐IC) on plasma renin activity (PRA).

3. A 15‐20 mmHg decrease in arterial pressure was produced during Ver‐IC (0.2–0.8 μg/kg per min) and PGE2‐IC (10‐50 ng/kg per min), but there was no change in PRA or heart rate.

4. In contrast, significant increases in PRA (+ 3.51 ± 0.37 ng angiotensin 1/mL per h; P < 0.01) and heart rate (+ 38.5 ± 6.2 beats/min; P < 0.001) were elicited in response to a 15–20 mmHg decrease in arterial pressure produced by intravenous infusions of nitroprusside.

5. Pharmacological blockade of afferent fibres in the pericoronary region of the left main coronary artery during Ver‐IC resulted in significant hypotension‐induced increases in PRA (P < 0.001) and heart rate (P < 0.001), thus removing the inhibitory influence of chemosensitive ventricular afferents.

6. Therefore, intracoronary veratrum alkaloids and prostaglandins inhibit hypotension‐induced increases in PRA and heart rate in the conscious dog. This is mediated by chemosensitive receptors located in the left ventricular myocardium along with afferent nerves in the pericoronary region and cervical vagi.
A DEVELOPMENTAL GENETIC MECHANISM INVOLVING ANGIOTENSIN IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Harrap Stephen B.
Published: June 2007

1. Certain genes drive the blood pressure of young spontaneously hypertensive rats (SHR) to stable hypertensive levels in adulthood.

2. Relatively brief blockade of the renin‐angiotensin system in young SHR can reset the track of SHR pressure to a lower level for the life of the animal. This effect appears to be a characteristic of the SHR strain.

3. It is proposed that the expression of a particular SHR hypertensive gene depends on angiotensin and is limited to young animals. This hypothesis explains some of the phenotypic abnormalities observed in young SHR and the decremental long‐term blood pressure effects following ACE inhibitor treatment.

4. The identity of the gene is unclear, but information from biochemical, physiological and pharmacological studies may direct attention to distinct candidate genes within specific chromosomal regions of interest.

5. Understanding these genetic mechanisms may have important implications for future preventive strategies.
DIABETIC RENAL MICROVASCULAR DISEASE: THE ROLE OF HYPERTENSION AND ACE INHIBITORS
Authors: Cooper Mark E. , Rumble Jonathan R. , Gin Trevor , Lim‐Joon Troy
Published: June 2007

1. It has been suggested that hypertension may be an important determinant of the rate of progression of diabetic microangiopathy.

2. Renal microvascular disease as assessed by urinary albumin excretion and glomerular ultra‐structure was evaluated in a model in which streptozotocin diabetes was induced in spontaneously hypertensive rats (SHR).

3. Diabetes was associated with increases in urinary albumin excretion, and hypertension resulted in a further increase in albuminuria.

4. Various antihypertensive regimens were administered to diabetic SHR, with the angiotensin‐converting enzyme inhibitor perindopril and triple therapy (hydralazine, reserpine and hydrochlorothiazide) being more effective than the calcium antagonist (lacidipine) in retarding the increase in albuminuria in diabetic SHR.

5. Antihypertensive therapy appears to ameliorate the development of diabetic renal disease.
THE EFFECT OF HYPERTENSION AND ACE INHIBITION ON ARTERIAL STRUCTURE AND COMPLIANCE
Authors: Safar M. E. , Levy B. I.
Published: June 2007

1. Large artery dilatation may be produced by angiotensin‐converting enzyme inhibition in hypertensive subjects independently of blood pressure reduction. The resulting increase in arterial compliance may be due to both blood pressure reduction and to arterial smooth muscle relaxation.

2. In healthy volunteers and in hypertensive subjects, dosages producing large artery dilatation seem to be even higher than those causing arteriole dilatation with the resulting blood pressure reduction.

3. It may be important to consider such findings for the remodelling of the cardiovascular system produced by angiotensin‐converting enzyme inhibition.
CLINICAL EFFICACY OF PERINDOPRIL IN HYPERTENSION
Authors: Morgan Trefor , Anderson Adrianne
Published: June 2007

1. Perindopril's effectiveness in mild to moderate hypertension was evaluated in three studies.

2. Perindopril was more effective than sodium restriction in reducing blood pressure, and the effects were additive.

3. Perindopril was as effective as atenolol in reducing blood pressure, and was well tolerated.

4. Perindopril lowered blood pressure to the same extent as enalapril at peak drug levels but had a greater effect at the trough level of the drugs.

5. Perindopril is an effective antihypertensive agent with an acceptable side‐effect profile in people with hypertension.
DIABETIC RAT AORTA RESPONSIVENESS TO D600 AND NIFEDIPINE
Authors: Orie N. N. , Aloamaka C. P.
Published: June 2007

1. The responsiveness of aortic rings from 4 and 12 week streptozotocin‐induced diabetic rats to D600 (Gallopamil) and nifedipine was studied.

2. The sensitivity and responsiveness to D600 were significantly enhanced (P < 0.05; 5‐test, ANOVA; 9 d.f.) only in the 4 week diabetic preparations precontracted with noradrenaline.

3. Nifedipine‐induced relaxations were significantly enhanced (P < 0.05–0.01; t‐test, ANOVA; 8–12 d.f.) in all the diabetic (4 and 12 weeks) aortic preparations precontracted with both noradrenaline (10‐7 mol/L) and KCl (40 mmol/L) when compared with controls.

4. D600, unlike nifedipine, did not produce significant relaxation of diabetic aortic preparations precontracted with KCl (40 mmol/L) at both week 4 and 12 of the disease when compared with controls.

5. These results suggest that there is differential responsiveness of streptozotocin diabetic rat aorta to D600 and nifedipine.
ACUTE EFFECT OF PHYSIOLOGICAL CONCENTRATIONS OF VASOPRESSIN ON RAT RENAL FUNCTION
Authors: Carney Shane L. , Gillies Alastair H. B. , Ray Cheryl D.
Published: June 2007

1. The antidiuretic, pressor and electrolyte transport effects of arginine vasopressin (AVP) were simultaneously evaluated in the anaesthetized water diuretic rat. Increasing concentrations of AVP (7.5, 75 and 750 ng/kg bolus and per h), were used to produce plasma levels which approximate the physiological range (4.8 ± 2.4, 35.7 ± 12.5, 85.2 ± 16.1 pg/mL respectively).

2. Administration of a minimally effective antidiuretic dose (7.5 ng) increased mean urine osmolality (from 101 ± 7 to 312 ± 89 mosmol/kg) without altering mean arterial pressure (MAP), renal plasma flow (RPF) or glomerular filtration rate (GFR). A maximal antidiuretic dose of AVP (75 ng) increased mean urine osmolality to 2002 ± 109 mosmol/kg and was associated with significant mean increases in MAP (9 mmHg), RPF and GFR (25%) by 30–60 min. A further ten‐fold increase in AVP (750 ng) produced a greater increase in MAP (116 ± 6 to 134 ± 7 mmHg; P < 0.01) as well as increasing RPF and GFR by 35.5 and 38.9% respectively.

3. Increasing concentrations of AVP also progressively increased the fractional excretion of sodium, potassium and phosphate. However, fractional calcium and magnesium excretion was significantly decreased with maximal and supramaximal concentrations.

4. These studies support evidence that AVP is a pressor hormone in physiological concentrations in baroreceptor intact animals. Its role in renal electrolyte transport is unclear. Measured increases in RPF and GFR with the maximal and supramaximal AVP concentrations appear to be correlated with the increase in MAP.
SENSITIVITY OF PROPRANOLOL ELIMINATION TO HYPOXIA IN THE ISOLATED PERFUSED RAT LIVER PREPARATION
Authors: Elliott Susan L. , Morgan Denis J. , Angus Peter W. , Ghabrial Hany , Smallwood Richard A.
Published: June 2007

1. The relationship between the hepatic elimination of propranolol and hepatic oxygen delivery was examined in the single‐pass isolated perfused rat liver preparation. Varying rates of oxygen delivery were produced (1.35–8.10 μmol/min per g liver) by equilibrating the perfusate with O2/N2 mixtures.

2. In two experiments, in which the rate of oxygen delivery was increased or decreased within the hypoxic range (< 4–5 μmol/min per g liver) every 5 min for 120 min, propranolol clearance responded very rapidly in the same direction as the change in oxygen delivery.

3. In five experiments, propranolol clearance, measured at steady state during an initial 30 min normoxia phase and three subsequent 30 min hypoxia phases (oxygen delivery in the range 1.35–5.89 μmol/min per g liver), was linearly related to hepatic oxygen delivery and consumption (r= 0.92 ± 0.07).

4. These data, combined with those from six further experiments that used one normoxia phase followed by one hypoxia phase, showed that there was a threshold for oxygen delivery of about 6 μmol/min per g liver, below which propranolol clearance decreased with decreasing oxygenation.

5. This study shows that in the intact liver propranolol elimination is very sensitive to hepatic oxygen supply, with impairment in clearance occurring at the lower limit of what is considered normal hepatic oxygenation in the rat.
RENIN AND PRORENIN IN REPRODUCTIVE TISSUES DURING GESTATION IN PIGS AND CATTLE
Authors: Hagemann Arne , Dantzer Vibeke , Nielsen Arne H. , Poulsen Knud
Published: June 2007

1. High concentrations of prorenin and active renin were previously found in ovarian follicular fluid from cattle but not from pigs. In the present study female reproductive tissues and fluids from cattle and pigs during gestation were investigated to clarify a possible species difference in active renin and prorenin concentrations.

2. Very high concentrations of active renin but no prorenin were found in corpus luteum from both species.

3. Relatively low concentrations of active renin, in the same order as in maternal blood plasma, were found in myometrium, endometrium, placenta and fetal membranes from both species. Prorenin was undetectable in these tissues except for bovine myometrium and porcine endometrium in some animals.

4. The concentrations of active renin and prorenin in amnionic fluid from both species were below the maternal plasma values. In allantoic fluid the concentrations were higher than in amnionic fluid.

5. The plasma concentrations of active renin and prorenin did not change during gestation in pigs. This finding is in contrast to the observations in humans and does not support a systemic effect of prorenin during gestation.

6. The presence of renin in the reproductive tissues, especially the very high concentrations in the corpus luteum, indicates a local function of the renin‐angiotensin system during gestation.
ANALGESIC ACTIVITY OF CERTAIN FLAVONE DERIVATIVES: A STRUCTURE‐ACTIVITY STUDY
Authors: Thirugnanasambantham P. , Viswanathan S. , Ramaswamy S. , Krishnamurty V. , Mythirayee C. , Kameswaran L.
Published: June 2007

1. Flavone, its methoxy derivatives and flavanone were synthesized by standard methods and were tested for analgesic activity in mice by employing acetic acid writhing and tail flick methods.

2. All the tested compounds except flavanone exhibited significant dose‐dependent analgesic activity in both the assay models. Some of the compounds were found to involve opioid mechanisms in their analgesic effect.

3. A definite structure‐activity relationship was observed in the analgesic activity of flavone derivatives as well as in their mechanism of action.
A1‐and A2‐PURINOCEPTORS IN THE GUINEA‐PIG UTERUS
Authors: Haynes John M. , Pennefather Jocelyn N.
Published: June 2007

1. Radioligand binding and functional studies were undertaken to investigate the P1‐purinoceptors present in the separated myometrial layers and the endometrium of the guinea‐pig uterus.

2. In preparations of endometrium‐denuded circular myometrium, the A2‐selective agonists (2‐p‐(2‐carboxyethyl)phenethylamino‐5'‐N‐ethylcarboxamido‐adenosine (CGS 21680, 100 μmol/L) and N‐ethylcarboxamido adenosine (NECA, 1–10 μmol/L) inhibited contractile responses to phenylephrine. In preparations of endometrium‐intact circular myometrium, NECA (10 μmol/L) enhanced responses to phenylephrine. NECA did not modulate the spontaneous contractions of longitudinal myometrium.

3. Homogenate binding studies with circular myometrium, longitudinal myometrium and endometrium revealed saturable high affinity [3H]‐NECA binding sites. The mean maximal densities of binding sites (Bmax) were 2.08, 14.7 and 15.5 fmol/mg protein, and pKD (neg. log dissociation constant) values were 9.82, 9.19 and 7.44, respectively.

4. (R‐) and (S‐) ‐N6‐(2‐phenylisopropyl)adenosine (R‐ and S‐PIA) both competed for two [3H]‐NECA binding sites in preparations of circular myometrium. CGS 21680 competed for two [3H]‐NECA binding sites in preparations of endometrium and longitudinal myometrium. All other agonist competition was for one site only. The rank orders of potency of high affinity binding were S‐PIA ≥ R‐PIA ≥ CGS 21680 (circular myometrium), R‐PIA ≥ CGS 21680 ≥ S‐PIA (longitudinal myometrium) and CGS 21680 > > S‐PIA ≥ R‐PIA (endometrium).

5. In preparations of circular myometrium, longitudinal myometrium and endometrium the selective A1‐purinoceptor antagonist, 1,3‐dipropyl‐8‐(2‐amino‐4‐chloro)‐phenylxanthine (PACPX), competed for two [3H]‐NECA binding sites, the non‐selective antagonist 3,7‐dimethyl‐1‐propargylxanthine (DMPX), competed for one site only.

6. NECA increased cyclic adenosine monophosphate (CAMP) levels in preparations of both circular myometrium and endometrium.

7. These results indicate that P1‐purinoceptors of the A2‐subtype mediate the inhibitory effects of adenosine analogues on the phenylephrine‐induced contractions of the circular myometrium of the guinea‐pig, this effect is modified by the presence of the endometrium. There is no evidence that the [3H]‐NECA binding sites of the longitudinal myometrium correlate with functional P1‐purinoceptors in this tissue.
EFFECT OF BREATHING PATTERN ON BLOOD PRESSURE AND HEART RATE OSCILLATIONS IN HUMANS
Authors: Laude Dominique , Goldman Michael , Escourrou Pierre , Elghozi Jean‐Luc
Published: June 2007

1. The relationships of respiratory sinus arrhythmia (RS A) and respiratory changes in systolic blood pressure (SBP) to tidal volume (VT) and breathing frequency (BF), were quantified during voluntary control of VT and BF in healthy subjects.

2. Respiration was measured non‐invasively with a respiratory inductive plethysmograph, which was calibrated prior to each study while breathing through a pneumotachygraph. Finger arterial blood pressure was measured non‐invasively by the Finapres.

3. Heart rate (HR) increased during inspiration, with a nearly fixed time delay for most VT and BF approximating 0.9 s. The magnitude of RS A increased with increases in VT and with decreases in BF. SBP decreased during inspiration, with a time delay which increased as BF decreased, resulting in a phase delay approximating 160°. The magnitude of the inspiratory fall in SBP increased with increases in VT. Increased amplitudes of RSA and SBP variation occurred at the lowest BF, consistent with the possibility of interactions between respiratory‐related influences and those due to ‘slow waves’ of vasomotor tone.

4. The present results are consistent with the conclusion that respiratory effects on SBP are caused by a mechanism other that simply changes in HR.
THE MARINE NATURAL PRODUCT 3,5‐DIBROMO‐2‐(2,4‐DIBROMO‐PHENOXY)PHENOL, INHIBITS CONTRACTILE ACTIVITY IN THE GUINEA‐PIG ILEUM
Authors: Bussau Lindsay J. , Beveridge Andrew A. , Nadeson Ray , Anderson Andrew P.
Published: June 2007

1. The tetrabrominated diphenyl ether 3,5‐dibromo‐2‐(2,4‐dibromophenoxy)phenol (BPE), a natural marine product isolated from a sponge, was tested for pharmacological activity in guinea‐pig ileum.

2. BPE (2 μmol/ L) decreased basal force and the frequency of spontaneous contractions of the ileum. It also significantly decreased contractions of the ileum induced by 5 mmol/L barium and to electrical stimulation at parameters which stimulated intrinsic nerves.

3. The slopes of concentration‐response curves to acetylcholine (ACh), histamine and 5‐hydroxytryptamine (5‐HT) were significantly reduced by BPE at concentrations of 2 μmol/L or greater.

4. BPE (2 μmol/L) did not affect calcium‐induced contractions of longitudinal muscle fibres from guinea‐pig ileum which were stripped of their cellular membrane. It (6 μmol/L) also had no effect on ATP levels in longitudinal muscle fibres.

5. BPE (2 μmol/L) reduced both phasic and tonic components of contractions induced by raising the extracellular concentration of K+ to 15, 30, 45 or 60 mmol/ L (in the presence of atropine, propranolol, phentolamine and desensitization to 5‐HT to inhibit the effects of nerve transmitter release).

6. BPE (2 μmol/L) reduced carbachol‐induced contractions of ileum pre‐incubated in 1 μmol/L felodipine, a blocker of l‐type voltage‐operated calcium channels (VOCC).

7. BPE dose dependently (0.6–6 μmol/L) reduced contractions induced by Ca2+ in both K+ depolarized ileum and in tissue exposed to carbachol (10 μmol/L) in the presence of felodipine (0.1 μmol/L).

8. These results suggest that BPE affects intracellular messenger systems controlling cytosolic calcium and/or blocks entry of calcium into the cell through both VOCC and receptor‐operated channels (ROC).
INHIBITORY EFFECT OF OCTOPAMINE ON THE RELEASE OF ENDOGENOUS ACETYLCHOLINE FROM ISOLATED MYENTERIC SYNAPTOSOMES OF GUINEA‐PIG
Authors: Chang Shu‐Shi , Cheng Juei‐Tang
Published: June 2007

1. The effect of octopamine on the release of endogenous acetylcholine (ACh) from isolated ileal synaptosomal preparations of guinea‐pigs was examined using high pressure liquid chromatography with electrochemical detection. Release of ACh was induced by substance P or by depolarization with high potassium (50 mmol/ L) in medium containing atropine, propranolol and naloxone.

2. Octopamine produced a dose‐dependent inhibition of substance P‐induced ACh release. A simiiar inhibitory action of octopamine was found in the samples depolarized by high potassium as a reference.

3. The action of octopamine was not reversed by the dopamine receptor antagonists either for the DA‐2 subtype, domperidone, or for the DA‐1 subtype, SCH23390, or by haloperidol. However, idazoxan and yohimbine antagonized this octopamine‐induced inhibition at concentrations sufficient to abolish the action of clonidine.

4. Failure of guanethidine or nomifensine to inhibit octopamine ruled out mediation by noradrenergic neurotransmitters.

5. Octopamine decreased the influx of [45Ca] stimulated by substance P into synaptosomal preparations and this was reversed by idazoxan or yohimbine at concentrations sufficient to block the action of clonidine.

6. Pertussis toxin abolished the inhibitory action of octopamine at a dose high enough to block the action of clonidine.

7. These results indicate that octopamine suppresses the influx of calcium ions into cholinergic nerve terminals of ileal synaptosomes of guinea‐pigs via an activation of α2‐adrenoceptors coupled with a pertussis toxin‐sensitive GTP‐binding protein which results in a decrease of ACh release.
PERFUSION PRESSURE AND TRANSMURAL FLOW DISTRIBUTION IN THE LEFT VENTRICLES OF ISOLATED RAT HEARTS
Authors: Walland A. , Weihs H. , Mutschler E.
Published: June 2007

1. The influence of perfusion pressure on flow distribution in the left ventricular wall was investigated with a newly developed microsphere method in Langendorff preparations of the rat heart.

2. Microspheres with a diameter of 10 μm stained with the fluorescent dye yellow‐green were infused into the perfusion medium. The hearts were then relaxed with a calcium‐chelator, fixed with formaldehyde and cut transversally with a freezing microtome. Photographs were taken of the 52 μm slices with a fluorescence photomacroscope. The ventricular wall was subdivided into four zones, evaluated planimetrically and the beads were counted for calculation of microsphere density.

3. Perfusion of groups of hearts, paced at 5 Hz, with Tyrode's solution at pressures of 30, 50, 80 or 120 cmH2O for 30 min revealed an increase of left ventricular pressure amplitude, coronary flow, myocardial oxygen consumption and flow redistribution towards the endocardium of the left ventricular wall with increasing perfusion pressure.

4. The quotient of the sphere densities in the inner endocardium over that in the outer epicardium, however, was already maximal at a pressure of 80 cmH2O and amounted to 1.59 ± 0.15. This quotient was only 0.52 ± 0.11 at a perfusion pressure of 30 cmH2O, thus indicating massive change in flow distribution upon hypoperfusion.

5. These results indicate that transmural left ventricular flow redistribution in response to hypoperfusion in the isolated rat heart is similar to that in hearts of much larger species.