bluuebunny/crossref_metadata_2025 huggingface dataset:
THE EFFECT OF HYPERTENSIVE EPISODES AND CARDIAC HYPERTROPHY ON THE CANINE CARDIAC BAROREFLEX
Authors: Kingwell Bronwyn A. , Krause Lisa , Julius Stevo
Published: June 2007

1. Left ventricular (LV) hypertrophy has been implicated in the reduction of baroreflex sensitivity present in hypertension. The aim of the current study was to investigate the mean arterial pressure‐heart rate reflex (MAP‐HR) in a model which induced left ventricular hypertrophy but no sustained blood pressure elevation.

2. Five mongrel dogs were exposed to transient blood pressure elevation of between 20 and 30 mmHg, through hindlimb compression using a pneumatic pressure suit, for 7 h per day, 6 days per week for 6 weeks. Resting blood pressure was not altered by the 6 week hindlimb compression intervention.

3. Echocardiographically determined LV mass (mean ± s.e.m.) was 116.0 ± 7.4 g prior to hindlimb compression (baseline) and elevated to 125.4 ± 8.1 g (P= 0.003) after 6 weeks of compression. A reduction in the early (E) to late (A) transmitral diastolic flow ratio (E/A) from 1.80 ± 0.06 at baseline to 1.54 ± 0.09 (P = 0.037) after the 6 week intervention suggested that cardiac compliance was reduced.

4. The maximum gain of the MAP‐HR reflex, studied using the ‘steady‐state’ drug technique, when blood pressure was normal, showed a trend for reduction from 3.85 ± 0.43 beats/min per mmHg at baseline to 3.10 ± 0.45 beats/min per mmHg (P= 0.067) after 6 weeks of compression. This gain reduction became significant after β‐adrenoceptor blockade with propranolol (3.13 ± 0.55 vs 2.32 ± 0.25 beats/min per mmHg; P= 0.039). Covariant analysis showed a significant inverse correlation between LV mass and maximum gain (r= 0.96; P<0.001) during the 6 week compression period.

5. The MAP‐HR reflex changes in this model mimic those present in hypertension and implicate cardiac hypertrophy as one possible mediator.
HYPOTHESIS: CYTOTOXIC LYMPHOCYTE GRANULE SERINE PROTEASES ACTIVATE TARGET CELL ENDONUCLEASES TO TRIGGER APOPTOSIS
Authors: Smyth Mark J. , Browne Kylie A. , Thia Kevin Y. T. , Apostolidis Vicki A. , Kershaw Michael H. , Trapani Joseph A.
Published: June 2007

Upon interaction with target cells, cytotoxic T lymphocytes and natural killer cells vectorially secrete highly specialized cytoplasmic granules containing perforin and a family of serine proteases (granzymes). This granule exocytosis mechanism of cytolysis is of patho‐physiological importance, and usually results in target cell DNA fragmentation. Neither perforin nor granzymes possess inherent nuclease activity, but in combination they can induce target cell apoptosis. Perforin forms transmembrane pores in the target cell, thereby enabling granzymes to access target cell substrates. The target cell substrates of granzymes are unknown, but granzyme A binding and cleavage of the nuclear shuttle protein nucleolin in target cells demonstrates that granzymes may act on nuclear substrates. Furthermore, the presence of granzyme B and other granzyme activities in the nucleus of cytotoxic lymphocytes indicates that granzymes can be transported from the cytoplasm to the nucleus.

It is hypothesized that perforin enables effector granzymes to enter the target cell cytoplasm and following their transport into the nucleus, granzymes cleave specific target cell nuclear proteins to activate autolytic endonucleases that fragment DNA. In cytotoxic effectors, these nuclear substrates are normally protected from granzymes by endogenous inhibitors.
AUGMENTATION OF ANGIOTENSIN II RELEASE FROM ISOLATED MESENTERIC ARTERIES OF WISTAR‐KYOTO AND SPONTANEOUSLY HYPERTENSIVE RATS FOLLOWING NEPHRECTOMY
Authors: Shi Shang‐Jin , Rakugi Hiromi , Higashimori Koichi , Higaki Jitsuo , Mikami Hiroshi , Ogihara Toshio
Published: June 2007

1. We previously reported that angiotensin II release from the mesenteric arteries of Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR) increased in a time‐dependent manner as a result of the isolation of the arteries and perfusion. This phenomenon appeared to be due to the withdrawal of circulating angiotensin II (AII).

2. The purpose of the present study was to test the hypothesis that vascular AII generation may be negatively regulated by circulating AII in WKY and SHR, and to clarify the role of this vascular angiotensin II in the sustained hypertension of SHR following nephrectomy.

3. The mesenteric arteries from kidney‐intact and nephrectomized WKY and SHR were perfused and the amount of AII released into the perfusate was measured. The effects of the angiotensin converting enzyme inhibitor, captopril, and the effects of supplementation of renal renin and circulating angiotensins to nephrectomized rats, by blood exchange between kidney‐intact and nephrectomized rats, on AII release were examined to clarify the pathway of vascular AII generation after nephrectomy.

4. Nephrectomy caused augmentation of vascular AII release both in WKY and SHR in spite of the abolishment of circulating renin. Captopril reduced this enhanced release of AII, but blood exchange did not affect it. There was no significant difference in these responses between WKY and SHR.

5. These results suggest that WKY and SHR have in common a potent pathway for production of vascular AII in response to the withdrawal of circulating AII, although this pathway is not responsible for the sustained hypertension of SHR after nephrectomy. The precise pathophysiological role of this pathway remains to be elucidated.
CONTROL OF CORONARY BLOOD FLOW BY ENDOTHELIAL RELEASE OF NITRIC OXIDE
Authors: Losano G. , Pagliaro P. , Gattullo Donatella , Marsh N. A.
Published: June 2007

1. Nitric oxide (NO) is released from vascular endothelium following conversion of l‐arginine to l‐citrulline by calcium‐calmodulin‐dependent ‘constitutive’ NO‐synthase.

2. Nitric oxide release occurs under basal conditions, in response to chemical stimuli (acetylcholine, bradykinin, thrombin, prostacyclin, serotonin, etc.) and in response to changes in shear stress (effects of blood velocity on vascular endothelium).

3. Analogues of l‐arginine inhibit NO and are widely used to study the effects of NO on the cardiovascular system: in intact animals, these inhibitors cause vasoconstriction, leading to an increase in arterial blood pressure (ABP) and bradycardia.

4. Bradycardia induced by NO inhibitors is due, in part, to baroreceptor activity following the increase in ABP and in part to a direct effect on the sino‐atrial node.

5. In the intact animals and isolated perfused heart, NO inhibitors cause coronary vasoconstriction and hence a reduction in basal coronary flow. This effect, however, is not seen in isolated coronary vessels.

6. From experiments in which ABP did not change, NO does not appear to have an important role in regulating coronary vasomotor tone under basal conditions.

7. Nitric oxide appears to be involved in the duration of reactive hyperaemia following coronary vascular occlusion but is not involved to any significant extent in the peak amplitude of hyperaemia.

8. Responses to vasodilator stimuli which do not involve NO in the initiation of the vasodilation may be prolonged by the effect of increased blood flow (shear stress) which releases NO and potentiates hyperaemia.
FISH PROTEIN‐RICH DIET ATTENUATES HYPERTENSION INDUCED BY DIETARY Ng‐NITRO‐L‐ARGININE IN NORMOTENSIVE WISTAR‐KYOTO RATS
Authors: Jr O. G. Gutierrez , Ikeda K. , Nara Y. , Deguan G. U. , Yamori Y.
Published: June 2007

1. Dietary 0.023%NG‐nitro‐L‐arginine (L‐NNA), an inhibitor of nitric oxide synthesis, induced hypertension in normotensive Wistar‐Kyoto rats (WKY). This hypertension was significantly attenuated in WKY given a fish protein‐rich diet.

2. The supplement of 2% L‐arginine given in a standard diet or a diet containing 3% taurine for drinking did not significantly affect the development of hypertension induced by L‐NNA in WKY.

3. WKY which received the standard diet mixed with 10% urea and 0.023% L‐NNA had significantly attenuated hypertension compared with WKY receiving the standard diet mixed with 10% kaolin and 0.023% L‐NNA.

4. These results suggest that the attenuation of hypertension in L‐NNA‐treated WKY rats given a fish protein rich diet may be partly caused by urea, a metabolic end‐product of protein.
SIMILARITY OF BLOOD PRESSURE FOR EACH GENOTYPE OF THE INSERTION/DELETION POLYMORPHISM OF THE DIPEPTIDYL CARBOXYPEPTIDASE‐1 GENE IN DIFFERENT AGE GROUPS OF PATIENTS WITH SEVERE, FAMILIAL ESSENTIAL HYPERTENSION
Authors: Morris Brian J. , Zee Robert Y. L.
Published: June 2007

1. The association of alleles of an insertion/deletion polymorphism (I/D) of the dipeptidyl carboxypeptidase‐1 gene with hypertension is controversial. If a particular allele makes a major contribution to blood pressure, then hypertensives homozygous for this allele could be expected to have higher high blood pressure than those homozygous for the alternate allele.

2. The present study examined this hypothesis by comparing pretreatment blood pressures of hypertensives who had been genotyped for the I/D polymorphism. Blood pressures for different age groups (< 50, 50–59 and ≥60 years) were also examined for each genotype. In addition, several other parameters were examined.

3. Systolic blood pressures were found to be 167 ± 3, 167 ± 3 and 170 ± 6 mmHg (mean ± s.e.) for the genotypes II, ID and DD, respectively. Diastolic blood pressures were 113 ± 4, 111 ± 2 and 111 ± 4, for the respective genotypes. One‐way anova showed that the respective blood pressure values did not differ significantly across genotypes. Blood pressures for different age groups of hypertensives were also similar.

4. In addition, body mass index, mean age and sex did not differ between genotypes, either for the group as a whole or for the different age groups.

5. In conclusion, the present study could find no evidence to support a genetic association between the I/D polymorphism of DCP1 and blood pressure in a group with severe, familial hypertension living in Sydney.
MECHANISMS OF THE PRESSOR RESPONSE TO INTRAVENOUS THYROTROPIN‐RELEASING HORMONE IN THE RAT
Authors: Evequoz D. , Burnier M. , Niederberger M. , Brunner H. R. , Nussberger J. , Waeber B.
Published: June 2007

1. The purpose of this study was to examine the contribution of the sympatho‐adrenomedullary system to the blood pressure response to an intravenous bolus of thyrotropin‐releasing hormone (TRH) in conscious medullectomized and sham‐operated rats.

2. The peak pressor effect of 0.5 mg TRH was significantly increased in rats having no adrenal medulla (+ 24.2 ± 1.6 mmHg, mean ± s.e.m., P<0.01) as compared to sham‐operated animals (+12.2 ± 3.0 mmHg).

3. Blockade of alpha‐adrenergic receptors with phentolamine abolished the pressor effect of TRH in control rats (+ 2.1 ± 1.9 mmHg) but did not attenuate the blood pressure response of medullectomized rats (+ 21.5 ± 4.7 mmHg). In contrast, beta‐blockade with propranolol blunted the blood pressure responsiveness of rats subjected to adrenal medullectomy (+ 12.4 ± 2.6 mmHg) but did not modify the effect of TRH in sham‐operated controls (+ 10.9 ± 2.9 mmHg).

4. The direct in vitro effect of TRH on isolated mesenteric rat arteries was also evaluated. TRH did not induce contractions of isolated arteries.

5. These results suggest that in rats with intact adrenals, the pressor effect of intravenous TRH is mediated primarily by a stimulation of alpha‐adrenergic receptors. Adrenal medullectomy appears to enhance the blood pressure response to intravenous TRH. Activation of cardiac beta‐adrenocep‐tors seems to contribute to the blood pressure increasing effect of intravenous TRH in medullectomized animals.
DEVELOPMENTALLY REGULATED TRANSFORMING GROWTH FACTOR‐β1 ACTION ON VASCULAR SMOOTH MUSCLE GROWTH IN THE SHR
Authors: Saltis John , Agrotis Alex , Kanellakis Peter , Bobik Alex
Published: June 2007

1. This study examined the effects of transforming growth factor‐β11 (TGF‐β1) on platelet‐derived growth factor‐BB (PDGF‐BB)‐stimulated proliferation of vascular smooth muscle cells (VSMC) isolated from aortic tissue of I, 4 and 12 week old spontaneously hypertensive rats (SHR).

2. In 1 week old SHR, TGF‐βl inhibited by about 60% VSMC proliferation stimulated by PDGF‐BB; this inhibitory action of TGF‐β1 was absent in VSMC isolated from 4 week old, prehypertensive SHR. In contrast, TGF‐β1 potentiated by about 125% the mitogenic activity of PDGF‐BB in VSMC cultures from adult SHR.

3. Age‐dependent alterations in the action of TGF‐β1 suggests an important role for TGF‐β1 in the development of vascular hypertrophy from adolescence onwards in the SHR.
EFFECT OF FLUMAZENIL ON BASAL AND NALOXONE‐STIMULATED ACTH AND CORTISOL RELEASE IN HUMANS
Authors: Torpy David J. , Jackson Richard V. , Grice Jeffrey E. , Hockings Gregory I. , Crosbie Georgina V. , Walters Margaret M.
Published: June 2007

1. Endogenous benzodiazepine receptor ligands are thought to influence the human hypo‐thalamic‐pituitary‐adrenal (HPA) axis and naloxone, a known stimulator of adrenocorticotropic hormone (ACTH) release, is thought to act via release of hypothalamic corticotropin‐releasing hormone.

2. The aim of the present study was to assess the influence of endogenous benzodiazepine‐receptor ligands by administering flumazenil (Ro 15–1788), a benzodiazepine antagonist, and measuring ACTH and cortisol release, both basal and during naloxone‐stimulation.

3. Nine normal volunteers in a placebo‐controlled double‐blind design were studied. Flumazenil (0.5 mg, i.v. bolus) was given 2 min before naloxone (125 μg/kg bodyweight, i.v. bolus) immunoreactive‐adrenocorticotropic hormone (IR‐ACTH) and cortisol levels were measured at frequent intervals from 60 min before to 120 min after naloxone injection.

4. Flumazenil had no effect on ACTH and cortisol release when given alone; flumazenil area under the ACTH/time curve (pmol/L.min) = ‐36.5 ± 63.5 compared with placebo = ‐ 53.5± 31.8, flumazenil area under the cortisol/time curve (nmol/L.min x 10−3) = ‐ 2.4 ± 2.4 compared with placebo ‐ 0.56 ± 1.4. Flumazenil did not change the ACTH and cortisol release achieved with naloxone; naloxone area under the ACTH/time curve (pmol/L. min) = 327.8 ± 61.7 compared with flumazenil/naloxone = 366.3 ± 88.1, naloxone area under the cortisol/time curve (nmol/L.minX 10−3) = 12.2 ± 3.4 compared with naloxone/flumazenil = 10.5±2.1.

5. The authors conclude that flumazenil does not modify basal or stimulated ACTH and cortisol release in healthy humans. This would suggest that endogenous benzodiazepine‐like ligands and the benzodiazepine/gamma‐aminobutyric acid receptor complex do not tonically influence the hypothalamic‐pituitary‐adrenal axis.
EFFECT OF TEMOCAPRIL ON HAEMODYNAMIC AND HUMORAL RESPONSES TO EXERCISE IN PATIENTS WITH MILD ESSENTIAL HYPERTENSION
Authors: Arita Mikio , Ueno Yuji , Nakamura Chigusa , Akitsu Toshio , Nakamura Yoshinari , Wanaka Yoshio , Nishio Ichiro , Masuyama Yoshiaki
Published: June 2007

1. This study was carried out to evaluate the effect of temocapril on haemodynamic and humoral responses to exercise in nine patients with mild essential hypertension (WHO stages I and II).

2. After a 4‐week placebo period, temocapril was administered at a dose of 1.0 mg once daily for 2–4 weeks. Graded submaximal bicycle ergometer exercise was performed before and after temocapril treatment, and the changes in arterial blood pressure, heart rate, cardiac output (CO), and systemic vascular resistance (SVR) were evaluated. In addition, the plasma norepinephrine (NE) level was determined both at rest and peak exercise before and after temocapril treatment.

3. Both the systolic and diastolic blood pressure were reduced at rest and during exercise by temocapril treatment. No significant change in the resting heart rate and CO was observed, and the exercise‐induced increase of these parameters was also not affected by temocapril. In contrast, the resting SVR was significantly decreased by temocapril, although the exercise SVR was similar during both temocapril and placebo treatment.

4. Although there was no significant change in the plasma NE level with temocapril treatment, the exercise‐induced increase of plasma NE was significantly suppressed by temocapril.

5. These results indicate that temocapril reduces the blood pressure without causing any significant changes in the heart rate and CO at rest, and that it does not produce any changes in the haemodynamic response to exercise.
RENIN AND ANGIOTENSIN‐CONVERTING ENZYME GENOTYPES IN PATIENTS WITH ESSENTIAL HYPERTENSION AND LEFT VENTRICULAR HYPERTROPHY
Authors: West M. J. , Summers K. M. , Burstow D. J. , Wong K. K. , Huggard P. R.
Published: June 2007

1. The associations between left ventricular hypertrophy (LVH) and specific alleles of the renin and angiotensin‐converting enzyme (ACE) genes were studied in patients with essential hypertension and normal blood pressure.

2. LVH was present in 42% of those with essential hypertension (n= 72) and 17% of those with normal blood pressure (n= 44).

3. The frequency of each renin allele was the same in hypertensive and in normotensive patients. Renin allele frequencies were also the same for those with LVH and those with normal cardiac mass. When only hypertensives were considered, renin alleles were in the same proportion for the groups with and without LVH. Similarly, ACE alleles were not associated with essential hypertension nor with elevated cardiac mass.

4. We conclude that, in this population, variations in the renin or ACE genes do not contribute significantly to the development of LVH or to essential hypertension.
INTERACTION BETWEEN EPIDERMAL GROWTH FACTOR AND ARGININE VASOPRESSIN IN RENAL MEDULLARY MEMBRANES
Authors: Grant S. L. , Phillips P. A. , Gow C. B.
Published: June 2007

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin‐induced water reabsorption.

2. The aim of this study was to determine any interaction between epidermal growth factor and the V1 (vascular) and/or V2 (antidiuretic) arginine vasopressin receptor subtypes.

3. Radioligand binding displacement assays demonstrated that although arginine vasopressin related peptides displaced both radioligands from renal medullary membranes at low concentrations epidermal growth factor displaced neither.

4. Arginine vasopressin V2 receptor second messenger cyclic adenosine monophosphate (CAMP) production was inhibited by epidermal growth factor (IC50 2 ± 10−7 mol/L) as was sodium fluoride cAMP production but only at much higher concentrations.

5. Therefore the diuretic effect of epidermal growth factor is not via direct antagonism of arginine vasopressin receptors but seems mediated via inhibition of the V2 second messenger system.
PROCEEDINGS OF THE HBPRCA DIFFERENTIAL EFFECT OF RENAL WRAP HYPERTEN SION ON AORTIC SMOOTH MUSCLE POLYPLOIDY IN THE RAT AND RABBIT
Authors: Black M. Jane , Campbell Julie H. , Campbell Gordon R.
Published: June 2007

1. The incidence of aortic smooth muscle cell polyploidy was investigated in rabbits and rats with renal wrap induced (cellophane perinephritic) chronic hypertension.

2. Bilateral renal cellophane wrapping was performed in young adult animals. Blood pressure was measured intra‐arterially in the rabbits twice during the experimental period and tail‐cuff blood pressure measured twice weekly in the rats. At 8 weeks post‐surgery the incidence of aortic smooth muscle cell polyploidy was determined in enzymatically isolated cells by flow cytometric DNA analysis.

3. Systolic blood pressure was significantly increased in the bilateral renal wrapped rabbits and rats compared to the shams, such that at 8 weeks post‐surgery, systolic blood pressure was 139 ± 2 mmHg and 84±2 mmHg, respectively, in the rabbits and 188±6 mmHg and 155±4 mmHg, respectively, in the rats.

4. The incidence of polyploid smooth muscle cells was significantly higher in the hypertensive renal wrapped rat compared to the sham (20.9±1.5% and 8.1±0.5%, respectively). However, the incidence of polyploid cells was low in the rabbit aortae with no significant difference in the incidence of aortic smooth muscle polyploidy in the hypertensive rabbit compared to the sham (2.6 ± 0.6% and 2.7 ± 0.6%, respectively).

5. This study demonstrates a species difference in the induction of polyploidy during the same model of experimental hypertension in aortic smooth muscle derived from the rabbit and rat.
MITOGENIC ACTIONS OF ENDOTHELIN‐1 AND EPIDERMAL GROWTH FACTOR IN CULTURED AIRWAY SMOOTH MUSCLE
Authors: Stewart Alastair G. , Grigoriadis George , Harris Trudi
Published: June 2007

1. Hyperplasia of airway smooth muscle contributes to the increase in bronchomotor responsiveness that characterizes asthma. We have investigated the mitogenic potential of endothelin‐1 (ET‐1) and epidermal growth factor (EGF) in guinea‐pig cultured airway smooth muscle and the relationship of these actions to tyrosine phosphorylation and increases in intracellular calcium (Ca2+i).

2. ET‐1 stimulated DNA and protein synthesis and also increased cell number, but these mitogenic actions were small compared with those of EGF.

3. ET‐1 and EGF increased the level of tyrosine phophorylation of a range of proteins with apparent molecular weights between 80 and 100 kDa and also increased phosphorylation of a single protein of 33 kDa.

4. Ca2+i levels were increased by both ET‐1 and EGF. However, concentrations of EGF three orders of magnitude higher than those having mitogenic actions or increasing protein tyrosine phosphorylation were required. ET‐1 was a more potent stimulant of increases in intracellular calcium than of mitogenesis.

5. We conclude that elevation of Ca2+i is unlikely to be an important signal for the mitogenic action of EGF. It is suggested that stimulants at the EGF receptor (EGF and transforming growth factor a) may play a role in the airway smooth muscle hyperplasia in asthma.
DIFFERENTIAL BLOCKADE OF THE RENAL VASOCONSTRICTOR AND DIURETIC RESPONSES TO ENDOTHELIN‐1 BY ENDOTHELIN ANTAGONIST
Authors: Kamphuis C. , Yates N. A. , McDougall J. G.
Published: June 2007

1. The effect of cyclo(d‐Trp‐d‐Asp—Pro‐d‐Val—Leu) (or BQ123), a selective ETa receptor antagonist, on the vasoconstrictor and diuretic responses elicited by endothelin‐1 (ET‐1) was examined in conscious sheep with chronic indwelling renal arterial cannulae.

2. Using low dose close renal arterial infusion, ET‐1 has potent effects on the kidney causing a marked decrease in effective renal plasma flow and an increase in urine output and free water clearance in the normally hydrated animal.

3. The vasoconstrictor response to renal arterial infusion of ET‐1 at 5 μg/h was blunted by renal arterial infusion of the ETA receptor selective antagonist, BQ123 (400 μg/h).

4. In contrast, the effect of ET‐1 on urine production and free water clearance was not affected by this dose of BQ123.

5. The differential effect of BQ123 on renal blood flow and urine production suggests that these effects of endothelin on the kidney are mediated through different receptor mechanisms.
A NEW RESTRICTION FRAGMENT LENGTH POLYMORPHISM IN THE FIRST INTRON OF THE SPONTANEOUSLY HYPERTENSIVE RAT RENIN GENE
Authors: Wang D. Z‐M. , Wilks A. , Morgan T. O. , Nicolantonio R. Di
Published: June 2007

1. Amplification of the entire first intron of the renin gene of spontaneously hypertensive rat (SHR), Wistar‐Kyoto (WKY) and Sprague‐Dawley rats (SD) followed by Bgl II digestion uncovered a new deletion (∼50 bp) which exists upstream of the SHR renin gene first intron tandem repeat element.

2. The SHR tandem repeat element was 600 bp shorter than that in the WKY while the WKY tandem repeat element was 280 bp shorter than that in the SD.

3. Since elements regulating gene expression are known to exist in the first intron of other genes, this new restriction fragment length polymorphism (RFLP) might play a role in the reported overexpression of the SHR renin gene independent of changes in the length of the tandem repeat element.
THE EFFECT OF ADRENALECTOMY ON WATER PERMEABILITY IN RAT PAPILLARY COLLECTING DUCT
Authors: Ray C. , Carney S. , Gillies A.
Published: June 2007

1. Chronic adrenal insufficiency impairs maximal urine concentration, probably in part due to reduced medullary tonicity but also possibly by inhibition of distal nephron water transport. This latter defect has been demonstrated in rabbit but not in rat.

2. Since the time between adrenalectomy and experiment was different in rabbit and rat studies, diffusional water permeability was evaluated in the papillary collecting duct in the absence and presence of submaximal (20 μU/mL) and supramaximal (200 μU/mL) arginine vasopressin (AVP) in adrenalectomized rats at 7, 14 and 21 days.

3. Experimentation 7 days after adrenalectomy failed to demonstrate significantly altered basal or AVP‐induced water permeability which increased by 23 and 78% with submaximal and supramaximal concentrations, respectively. Submaximal AVP concentrations also induced a comparable change in water permeability in adrenalectomized rats at 14 days; however, 21 days after adrenalectomy, diffusional water permeability was not increased by 20 μU/mL AVP (3.31 ±.22 to 3.31 ±.24 μm/s). Nevertheless, the effect of a supramaximal AVP concentration (200 μU/mL) was not altered by adrenalectomy (4.54 ±.39 to 8.08 ±.96; P<0.01). Incubation of collecting ducts in aldosterone for 2 h did not reverse the inhibitory effect of chronic adrenalectomy on AVP‐stimulated water transport.

4. These studies suggest that mineralocorticoid withdrawal does impair the hydro‐osmotic action of AVP in the rat papillary collecting duct but that this effect takes between 14 and 21 days to occur.
THE INTERACTION BETWEEN ENALAPRILAT AND SELECTED α‐ADRENOCEPTOR ANTAGONISTS IN ISOLATED RAT TAIL ARTERIES
Authors: Marwood John F.
Published: June 2007

1. Isolated perfused rat tail artery preparations were used to investigate the effects of the angiotensin converting enzyme inhibitor enalaprilat on the actions of a series of α‐adrenoceptor antagonists. The agonist used was phenylephrine.

2. Enalaprilat (1 μmol/L) potentiated the competitive α1‐adrenoceptor antagonist actions of phentolamine (10–100 nmol/L) and yohimbine (0.3–3.0 μmol/L) as well as the non‐competitive antagonist action of phenoxybenzamine (50–100 pmol/L).

3. The competitive α1‐adrenoceptor antagonist action of prazosin (1–10 nmol/L) was not affected by enalaprilat.

4. For the competitive α1‐adrenoceptor antagonists, including prazosin, there appeared to be an inverse relationship between antagonist potency and the extent of potentiation by enalaprilat.

5. The results support the hypothesis and angiotensin II modulates vascular smooth muscle α1‐adrenoceptor function.
THE VASCULAR TISSUE ANGIOTENSIN I‐CONVERTING ENZYME ACTIVITY AND AORTIC ELASTIN CONTENT IN STROKE‐PRONE SPONTANEOUSLY HYPERTENSIVE RATS FED FISH DIET
Authors: Murakami Tetsuo , Soga Masahiko , Mitsunaga Toshio , Yoshizumi Hajime , Ito Hiroyuki
Published: June 2007

1. Stroke‐prone spontaneously hypertensive rats (SHRSP) were fed a diet with fish meal as the protein source (fish diet) during the progressive stage of hypertension, and its effects on the activity of angiotensin I‐converting enzyme (ACE) in serum and vascular tissues and on the aortic elastin content were studied. The effects of the antihypertensive drugs captopril and hydralazine were also studied.

2. Stroke‐prone spontaneously hypertensive rats fed the fish diet showed a distinctly lower level (P<0.05) of serum ACE activity than the control group fed a commercial stock chow.

3. ACE activity was enhanced in the SHRSP which was administered with captopril.

4. Serum ACE activity was similar in the SHRSP receiving the hydralazine treatment and the control group.

5. The thoracic aorta ACE activity was lowered more (P<0.05) in the fish diet group and the captopril‐treated group than in the control group. In the hydralazine‐treated group however, the activity was similar to the control group.

6. The ratio of aorta weight to bodyweight was significantly lower (P<0.05) in the fish diet group and the captopril‐treated group than in the control group, but there was no difference in the hydralazine group. Higher levels of aortic elastin were observed in the drug‐treated groups (P<0.05).

7. No differences were seen between the fish diet and captopril‐treated groups by electron‐microscopy.

8. The results suggest that suppression of hypertrophy and ameliorations of reduction in elasticity of the vascular wall in the SHRSP fed a fish diet were due to inhibition of vascular tissue ACE activity.
ANGIOTENSIN II RECEPTOR DENSITY IN BOVINE OVARIAN FOLLICLES RELATES TO TISSUE RENIN AND FOLLICULAR SIZE
Authors: Nielsen A. H. , Hagemann A. , Svenstrup B. , Nielsen J. , Poulsen K.
Published: June 2007

1. The purpose of this study was to investigate angiotensin II (AII) receptors in isolated bovine ovarian follicles and the relationship of their density to follicular concentrations of prorenin, active renin, oestradiol and progesterone.

2. Displacement of [125I]‐[Sar1‐Ile5‐Ile8]‐AII binding by the AII receptor antagonists PD 123319 and Losartan (DuP 753) confirmed that follicular AII receptors are of subtype 2 (AT2 receptor).

3. The dissociation constant (Kd) for [Ile5]‐AII (human AII) was 0.84 (range 0.51–1.47) nmol/ L. The receptor density varied between 90 and 5990 (mean 1640) fmol/ mg membrane protein.

4. The follicular AII receptor density correlated positively with follicular diameter (Spearman's rho= 0.518; P<0.003) and tissue weight (Spearman's rho= 0.636; P<0.0001), and negatively with the active renin concentration in the follicular wall (Spearman's rho=‐0.399; P<0.02). The AII receptor density did not correlate with the follicular fluid concentrations of prorenin, active renin, oestradiol (E2, progesterone (P4) or the E2/P4 ratio. The follicular fluid concentrations of prorenin correlated negatively with the E2/P4 ratio (Spearman's rho= ‐0.716; P<0.00001).

5. The inverse relationship between AII receptor density and the high active renin concentrations in the follicular wall suggests an active regulated tissue renin‐angiotensin system. A high AII receptor density is a general feature of large bovine ovarian follicles.
GABA RECEPTORS: AS COMPLEX AS ABC?
Authors: Johnston Graham A. R.
Published: June 2007

1. Receptors for the inhibitory neurotransmitter GABA are currently classified pharmacologically into two major subtypes.

2. GABAa receptors are antagonized by the convulsant alkaloid bicuculline, and are insensitive to activation by the GABA analogue baclofen. GABAB receptors are insensitive to bicuculline and activated stereoselectively by baclofen.

3. There is increasing evidence for ‘novel’ GABA receptors that pharmacologically fall outside that defined by the GABAa/b classification.

4. GABA receptors insensitive to both baclofen and bicuculline have been described in the spinal cord, optic tectum, retina, cerebellum and hippocampus. In addition such novel GABA receptors may be widespread in insects and bacteria. These novel receptors have been given a variety of descriptions: GABAc, GABAnanb (non‐A, non‐B) and GABAρ (cloned from retina).

5. cis‐4‐Aminocrotonic acid (CACA), a structural analogue of GABA in a folded conformation, is considered to be a selective agonist of the putative GABAc receptors. Tritiated CACA binds to cerebellar membranes in a GABA‐sensitive, baclofen‐insensitive manner. It can be displaced only by relatively high concentrations of bicuculline.

6. Autoradiographic studies show pronounced differences in regional distribution between the binding of CACA, the GABAa agonist muscimol and the GABAb agonist baclofen.

7. Novel GABA receptors may represent important new pharmacological targets.
DIFFERENTIAL CONTROL OF VASCULAR TONE AND HEART RATE BY DIFFERENT AMINO ACID NEUROTRANSMITTERS IN THE ROSTRAL VENTROLATERAL MEDULLA OF THE RAT
Authors: Katahira K. , Mikami H. , Otsuka A. , Moriguchi A. , Kohara K. , Higashimori K. , Okuda N. , Nagano M. , Morishita R. , Ogihara T.
Published: June 2007

1. To test the hypothesis that a central mechanism may play a role in the minimal reflex tachycardia noted in response to peripheral converting enzyme inhibition, we compared the effects of intravenous (i.v.) ceronapril (CER) with nitroglycerin (NTG) on neurotransmitter release in the rostral ventrolateral medulla (RVLM), using an in vivo microdialysis method in pentobarbital anaesthetized rats.

2. CER (0.1 mg/kg, i.v.) caused a progressive decrease in glutamate (GLU) release (CER 65 ± 7%vs NTG 83 ± 3% of each baseline at 140 min, P<0.05) and attenuated the increase in glycine (GLY) release (CER 100 ± 8%vs NTG 122 ± 9%, P<0.05).

3. Prevention of blood pressure reduction due to i.v. CER by concomitant infusion of a subpressor dose of angiotensin II (AII) attenuated the progressive reduction of GLU release (87 ± 4%, P<0.05 compared with NTG group), whereas GLY release was not affected (106±5%, NS compared with NTG group).

4. Perfusion of GLU into this area at approximately physiological concentrations resulted in a sustained tachycardia with an attenuation of the depressor effect of i.v. CER and perfusion of GLY solely lowered blood pressure.

5. These results demonstrate that i.v. converting enzyme inhibitor reduces the release of GLU in the RVLM, which was specifically caused by reducing circulating AII, without any effect on GLY release, thus resulting in the reduction of blood pressure with minimal effect on the heart rate.
BLOCKADE BY INTRAVENOUS LOSARTAN OF AT1 ANGIOTENSIN II RECEPTORS IN RAT BRAIN, KIDNEY AND ADRENALS DEMONSTRATED BY IN VITRO AUTORADIOGRAPHY
Authors: Zhuo Jialong , Song Keifu , Abdelrahman Aly , Mendelsohn Frederick A. O.
Published: June 2007

1. The in vivo inhibition of angiotensin II (AII) receptor binding in the rat brain, kidney and adrenal was investigated after intravenous administration of the AT1‐selective AII receptor antagonist losartan.

2. Male Sprague‐Dawley rats were administered intravenously either vehicle, or losartan at doses of 1, 3 or 10 mg/kg. Plasma samples were collected and tissues removed at 1,2, 8 or 24 h after administration of the antagonist, The effects of losartan on AII receptor binding were assessed by quantitative in vitro autoradiography.

3. Losartan significantly increased plasma renin activity (PRA) by six‐fold and nine‐fold at doses of 1 and 10 mg/kg, respectively (P<0.05). Plasma losartan concentrations rose from 0.83 μg/mL at 1 mg/kg to 46.5 μg/mL at 10 mg/kg 1 h after administration of the drug. Plasma renin activity returned to control, whilst losartan was undetectable 24 h after injection of the antagonist.

4. In the brain, losartan produced a dose‐dependent inhibition of AII receptor binding to the brain structures which express exclusively, or predominantly, AT1 receptors both outside and within the blood brain barrier. By contrast, losartan did not affect binding to the nuclei which contain exclusively, or predominantly, AT2 receptors.

5. In the kidney, losartan blocked AII receptor binding to all anatomical sites in a dose‐dependent manner. The inhibition peaked at 1 h and persisted beyond 24 h despite the fact that PRA had returned to control, and losartan was not detectable in the circulation. In the adrenal gland, where AT1 and AT2 receptors occur in both the cortex and medulla, losartan caused partial inhibition at both regions.

6. These results indicate that losartan, administered intravenously at these doses, and/or its active metabolites, partially penetrate the blood brain barrier to selectively inhibit central AT1 receptors, and exert selective and prolonged blockade of AT1 receptors in peripheral target tissues.
POTASSIUM CHANNEL OPENERS AND OTHER REGULATORS OF KATP CHANNELS
Authors: Challinor‐Rogers Joanne L. , McPherson Grant A.
Published: June 2007

1. Interest in ATP‐sensitive K (Katp) channels first arose when it was shown that hypoglycaemic sulphonylureas, such as glibenclamide, closed these channels in pancreatic p‐cells to cause insulin release. The demonstration that certain smooth muscle relaxants (K channel openers) may exert their actions through opening a similar channel in vascular smooth muscle fuelled further investigation of these channels and their physiological role in a variety of tissue types, including various types of smooth muscle, cardiac and skeletal muscle and neural and endocrine organ function.

2. The K channel openers have a variety of potential therapeutic applications, including disorders of smooth muscle hyperreactivity, such as hypertension, and a great deal of research has focused on this field. More recently, attention has turned to the cardiac actions of these compounds and this area is discussed in detail. One of the current problems is the lack of selectivity of Katp channel regulators. However, there have been a number of recent encouraging reports suggesting that, under certain pathophysiological conditions, the action of the K channel openers may be enhanced, conferring upon them some degree of selectivity.

3. A number of endogenous regulators of these channels have been identified, particularly in the category of endogenous openers of these channels. At present though, the physiological role of these channels and the endogenous regulators identified, is unclear.

4. It is evident that, although advances have been made, much work is still required to increase our understanding and ultimately to allow selective pharmacological manipulation of these channels to become a therapeutic reality.
EFFECT OF INCREASED MYOCARDIAL CYCLIC GMP INDUCED BY CYCLIC GMP‐PHOSPHODIESTERASE INHIBITION ON OXYGEN CONSUMPTION AND SUPPLY OF RABBIT HEARTS
Authors: Weiss Harvey R. , Rodriguez Elizabeth , Tse James , Scholz Peter M.
Published: June 2007

1. We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and areas of low O2 supply/consumption balance, using zaprinast, a selective cyclic GMP‐phosphodiesterase inhibitor.

2. The study was conducted in three groups (vehicle, 10−‐3 and 3×10−‐3 mol/L zaprinast) of anaesthetized open‐chest New Zealand white rabbits (n = 24). Coronary blood flow (radioactive microspheres), arterial and venous O2 saturation (microspectrophotometry), O2 consumption, cyclic GMP content (competitive binding) and cyclic GMP‐phosphodiesterase activity (conversion of 3H‐cyclic GMP to 3H‐GMP) were determined.

3. Agents were applied to a patch on the myocardial surface and did not cause significant haemodynamic changes, except for bradycardia in the vehicle and low dose group.

4. The total myocardial cyclic GMP‐phosphodiesterase activity was 148 ± 14 while the zaprinast (10 μmol/L) inhibitable activity averaged 63 ± 8 pmol/mg protein per min. Cyclic GMP content was increased with increasing doses of zaprinast (vehicle, 4.308 ± 0.349 pmol/g; low dose zaprinast, 4.803 ± 0.279 and high dose zaprinast, 7.938 ± 1.304 pmol/g).

5. Coronary blood flow was not different after treatment (198 ±11, 209 ± 10 and 153 ± 9 mL/min per 100 g for the vehicle, low and high dose zaprinast, respectively).

6. Under control conditions, 48% of the small veins had O2 saturations below 50%. With zaprinast, this value was reduced to 19% for the low and 24% for the high dose.

7. Average venous O2 saturation increased with zaprinast (49 ± 2%, 61 ± 3% and 59 ± 1%). Myocardial O2 consumption was decreased with increasing doses of zaprinast (15.0 ± 1.9, 11.2 ± 1.0 and 7.7 ± 0.7 mL O2/min per 100 g for the vehicle, low and high dose zaprinast, respectively.

8. Thus, increasing the myocardial level of cyclic GMP with zaprinast was correlated with reduced cardiac O2 consumption and a reduced number of veins with low O2 saturations.
EFFECTS OF CYCLIC NUCLEOTIDE PHOSPHODIESTERASE IV INHIBITOR, Ro20,1724, ON PANCREATIC EXOCRINE SECRETION IN DOG
Authors: Iwatsuki K. , Ren L‐M. , Chiba S.
Published: June 2007

1. The effects of the cyclic nucleotide phosphodiesterase (PDE) inhibitors, Ro20,1724, 3‐isobutyl‐1‐methylxanthine (IBMX), trifluoperazine (TFP) and amrinone on pancreatic exocrine secretion were investigated in anaesthetized dogs in comparison with those of secretin and cholecystokinin octapeptide (CCK‐8).

2. Ro20,1724 (1–30 nmol/kg), IBMX (3–30 nmol/kg), secretin (0.01–0.1 pmol/kg) or CCK‐8 (0.1–1 pmol/kg) injected i.a. elicited a dose‐dependent increase in the secretion of pancreatic juice, but TFP and amrinone (up to 1 μmol/ kg) did not.

3. The bicarbonate concentration in pancreatic juice was increased and the protein concentration was decreased by Ro20,1724, IBMX and secretin. Cholecystokinin octapeptide increased the protein concentration but did not alter the bicarbonate concentration.

4. Ro20,1724 and IBMX elicited more than the respective additive secretory response when added together with secretin, although the stimulatory effects of CCK‐8 with Ro20,1724 and IBMX were additive.

5. Ro20,1724 and IBMX increased cyclic AMP concentration but did not affect cyclic GMP concentration.

6. These results suggest that Ro20,1724 and IBMX have secretory properties on pancreatic exocrine glands of the dog, which may be mediated through an increase in cyclic AMP subsequent to inhibition of PDE activity. Furthermore, pancreatic PDE enzymes in the dog may be mainly type IV.
EVIDENCE FOR IMPAIRED ENDOTHELIUM DEPENDENT VASODILATION IN EXPERIMENTAL LEFT VENTRICULAR DYSFUNCTION
Authors: Kaye David M. , Jennings Garry , Angus James A.
Published: June 2007

1. The full range of vascular reactivity was investigated in the hindlimb circulation of conscious, autonomically blocked rabbits with experimental (adriamycin‐induced) cardiomyopathy.

2. Adriamycin treatment caused a significant reduction in left ventricular systolic function, as assessed by echocardiography (left ventricular fractional shortening, controls vs adriamycin treatment; 36.7 ± 1.7%vs 27.3 ± 2.6%, P<0.05).

3. Under pharmacological autonomic effector block, the range of the vasodilator response (resistance range, from resting to full vasodilatation) to acetylcholine was reduced by 41% (P<0.05) and by 37% for adenosine (P<0.05). Despite these changes the sensitivity (ED50) of the responses were unaltered.

4. The ED50 of constrictor responses to noradrenaline and angiotensin II were similarly unaltered, in conjunction with a non‐significant attenuation of the constrictor‐response range.

5. These results suggest that in this model of experimental left ventricular dysfunction, the capacity of the hindlimb circulation to respond to regionally infused endothelium dependent vasodilators is attenuated.
ANTISENSE OLIGONUCLEOTIDES: A NEW TOOL IN NEUROSCIENCE
Authors: Pilowsky Paul M. , Suzuki Satoshi , Minson Jane B.
Published: June 2007

1. Recent studies have shown that gene expression can be selectively attenuated by administration of short sequences of nucleotides (oligonucleotides) that are complementary to a portion of messenger RNA coding for a particular gene product.

2. This technique is known as ANTISENSE, because the oligonucleotides are complementary to the mRNA which has the same sequence as the SENSE strand of DNA.

3. In the present review we focus, after a brief discussion of gene expression and mechanisms of action of ANTISENSE, on the methodological aspects of ANTISENSE experiments in neuroscience. In particular, we address the advantages, disadvantages and controls for the ANTISENSE technique, as well as the choice, design, mode of delivery, dose and storage of ANTISENSE oligonucleotides.
INFLUENCE OF α1‐ADRENOCEPTOR ANTAGONISM OF KETANSERIN ON THE NATURE OF ITS 5‐HT2 RECEPTOR ANTAGONISM
Authors: Marwood John F.
Published: June 2007

1. In order to investigate α1‐adrenoceptor interactions with 5‐HT2 receptors, the effect of ketanserin (which antagonizes both types of the above receptors) on responses to 5‐hydroxytryptamine (5‐HT) and phenylephrine (PE) was measured in isolated perfused rat tail arteries.

2. Ketanserin was found to be a competitive antagonist at 5‐HT2 receptors (pA2= 9.19) and α1‐adrenoceptors (pA2= 7.52).

3. Ritanserin, an analogue of ketanserin with very weak α1‐adrenoceptor antagonist activity, was found to be a potent non‐competitive 5‐HT2 receptor antagonist.

4. In the presence of the potent α1‐adrenoceptor antagonist prazosin, ketanserin was a non‐competitive 5‐HT2 receptor antagonist.

5. Thus, for ketanserin to exhibit competitive 5‐HT2 receptor antagonism, its coexisting α1‐adrenoceptor antagonist property appears mandatory.
INVOLVEMENT OF TRANSFORMING GROWTH FACTOR‐β1 FOR PLATELETS‐INDUCED STIMULATION OF ENDOTHELIN‐1 PRODUCTION
Authors: Matsumura Yasuo , Murata Satoshi , Takada Kimi , Takaoka Masanori , Morimoto Shiro
Published: June 2007

1. Possible mechanisms by which platelets stimulate the production of endothelin‐1 (ET‐1) in vascular endothelial cells (EC) were investigated.

2. A supernatant of platelets stimulated the expression of prepro ET‐1 mRNA, followed by an increased secretion of ET‐1 from cultured EC. These responses were markedly enhanced by pretreatment of the platelets with thrombin, at a concentration which did not influence the ET‐1 production in EC. A platelet suspension, separated from cultured EC by a permeable nylon membrane, also markedly stimulated the ET‐1 secretion from EC.

3. Endothelin‐1 production enhanced by the platelet supernatant, with or without thrombin pretreatment, correlated with the active transforming growth factor‐β1 (TGF‐β1) concentrations in the supernatant. The supernatant‐induced increase in ET‐1 secretion from the EC was markedly suppressed by TGF‐β1 neutralizing antibody.

4. We tentatively conclude that platelets stimulate the endothelial ET‐1 production by releasing a bioactive diffusible substance, mainly TGF‐β1.
ACUTE TOXICITY OF BUPIVACAINE METABOLITES IN MICE
Authors: Bruguerolle B. , Attolini L. , Gantenbein M.
Published: June 2007

1. This study was designed to document the acute toxicity of two metabolites of bupivacaine, desbutylbupivacaine (2,6, desbutylbupivacaine; PPX) and pipecolic acid in mice. All the compounds were administered by the intraperitoneal (i.p.) route.

2. The mean convulsant activity was 100% for controls, 30, 100, 100, 100 and 90% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively, and 0% for the animals receiving pipecolic acid.

3. The acute induced mortality was 60% for bupivacaine control group (50 mg/kg/i.p.), 60, 30 and 0% for 800, 400 and 200 mg/kg of pipecolic acid, respectively, and 100, 90, 60, 80 and 10% for 400, 200, 150, 125 and 112.5 mg/kg i.p. of PPX, respectively.

4. The time to convulse was 158 ± 16 s for bupivacaine, 230 ± 30, 270 ± 24, 255 ± 21, 442 ± 84 and 418 ± 32 s for 200, 150, 125, 112.5 and 100 mg/kg i.p. of PPX, respectively; any pipecolic acid treated animal have convulsed.

5. In conclusion, the present study demonstrated that PPX is more toxic than expected since we found that its induced mortality was approximately three times that found for bupivacaine and its CNS toxicity was about two times that of bupivacaine.
A NEW MODEL FOR THE GENERATION OF SYMPATHETIC NERVE ACTIVITY
Authors: Malpas Simon C.
Published: June 2007

1. Sympathetic discharges from multifibre nerve recordings vary in their frequency of occurrence which displays both slow and fast rhythms and in their amplitude which reflects the number of activated fibres. It has been shown that the frequency of occurrence of these rhythms varies according to baroreceptor activity (via blood pressure and heart rate) while the number of activated fibres is independently affected by chemoreceptor activity.

2. A new model is proposed for the generation of sympathetic nerve activity by the central nervous system to account for these results. The upper layer of the model comprises two oscillators, a fast and a slow cycle frequency oscillator, with the balance and occurrence maintained by afferent inputs such as the baroreceptors.

3. It is hypothesized that two central oscillators impinge on a lower layer of the model influencing the number of activated fibres within each postganglionic sympathetic burst. This is independent of the frequency control and affected by separate afferent inputs such a chemoreceptors.