bluuebunny/crossref_metadata_2025 huggingface dataset:
ENALAPRILAT RESTORES SENSITIVITY OF BAROREFLEX CONTROL OF RENAL AND TOTAL NORADRENALINE SPILLOVER IN HEART FAILURE RABBIT
Authors: Noshiro Takao , Way Diana , Miura Yukio , McCrath Barry P.
Published: June 2007

1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex‐mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin‐induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions.

2. Six saline‐treated (N group) and 11 doxorubicin‐treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group).

3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)‐renal noradrenaline (NA) spillover and MAP‐total NA spillover curves did not change during enalaprilat infusion.

4. After 6 weeks, the C group showed blunted MAP‐renal NA spillover and MAP‐total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP‐renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP‐total NA curve: from 1.61 to 3.59 ng/min per mmHg).

5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin‐angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.
METABOLIC STUDIES OF URIDINE IN RATS WITH DOCA‐SALT HYPERTENSION AND ON HIGH SODIUM DIET
Authors: Hasnain Quloobul , Macdonald Graham
Published: June 2007

1. The steady‐state metabolic clearance and calculated secretion rate of the pyrimidine nucleoside uridine were studied by equilibrium infusion in normal rats, rats on a high sodium diet, rats made hypertensive by subcutaneous injection of deoxycorticosterone acetate (DOCA), unilateral nephrectomy and high sodium drinking fluid, and two control groups of rats for the hypertensive group.

2. Basal plasma uridine concentration in DOCA‐salt hypertension rats was found to be significantly reduced to 3.99 ± 0.31 pmol/L (mean ± s.e.m.) compared with control rats (11.98 ±1.64 μmol/L). Metabolic clearance (MCR) in DOCA‐salt hypertensive rats was significantly raised (200.54±10.77 mL/kg per min) compared with control rats (65.17 ± 1.99 mL/kg per min). No difference was found in plasma uridine concentration and MCR among the other two control groups and high sodium diet rats. Calculated secretion rate was unchanged in all animals. No significant differences were found between different groups of rats in blood pressure responses to uridine.

3. The raised metabolic clearance and reduced plasma uridine concentration in DOCA‐salt hypertension may be consistent with increased intracellular transport and phosphorylation of uridine to the physiologically active compound uridine monophosphate (UMP) which would lead to arteriolar constriction, hypertension and natriuresis. The results contrast with those in humans with extracellular fluid (ECF) expansion from endstage renal failure and rats with one‐kidney, one‐clip (1K1C) hypertension but are not due to the pharmacological effects of deoxycorticosterone. The difference may be due to the haemodynamic consequences of reduced renal perfusion pressure or reduced renal mass compared with DOCA‐salt model.
THE INTRARENAL SITE OF CALCITONIN GENE‐RELATED PEPTIDE DEGRADATION IN THE ISOLATED PERFUSED RAT KIDNEY
Authors: Rubinstein C. , Fletcher D. R. , Shulkes A.
Published: June 2007

1. Calcitonin gene‐related peptide (CGRP) is a potent vaso‐active 37 amino acid peptide, typically elevated in plasma from patients with medullary thyroid cancer (MTC), but undetectable in the plasma of normal subjects.

2. The kidney is a major site for the clearance of exogenously infused CGRP but the intrarenal site of this clearance is unknown. Extra‐organ clearance is also significant for CGRP, and whereas the site and mechanism of this degradation remain uncertain, the vasculature has been postulated as the most likely site.

3. The isolated perfused rat kidney (IPRK) was studied to (i) localize the intrarenal site of CGRP clearance and (ii) determine the contribution of the renal vasculature to the clearance of CGRP. The half‐life of CGRP in the filtering IPRK was 63.9 ± 4.5 min, whereas blocking of filtration by elevation of the perfusate osmolarity abolished the degradation. This suggests that (i) renal CGRP degradation occurs after glomerular filtration with intratubular metabolism and (ii) that there is no active CGRP degradation in the (glomerular) capillary endothelium.

4. These results do not support the theory that renal vascular endothelium plays a major active role in CGRP degradation.
HAEMODYNAMIC AND HUMORAL CONSEQUENCES OF CHRONIC INFUSION OF VASOPRESSIN IN CONSCIOUS RATS
Authors: Tsuchihashi Takuya , Takata Yutaka , Nakao Yae , Tominaga Mitsuhiro , Takishita Shuichi , Kobayashi Kazuo , Abe Isao , Fujishima Masatoshi
Published: June 2007

1. To determine the long‐term haemodynamic and humoral effects of arginine vasopressin (AVP), a chronic intravenous infusion of AVP was performed in conscious Wistar normotensive rats.

2. AVP (1, 10, 50 or 100 ng/h) or saline as a vehicle control was infused continuously into the right jugular vein at a rate of 1 μL/h using an osmotic minipump for 7 days.

3. As a result, significant elevations of systolic blood pressure were observed in association with increases in plasma AVP concentration. Significant decreases in heart rate were observed during infusion of 100 ng/h of AVP. Mean arterial pressures measured directly on the sixth day of infusion were significantly higher in the rats given 50 ng/h (125 ± 3 mmHg) or 100 ng/h (125 ± 2 mmHg) compared with control rats (117 ± 2 mmHg). Intravenous injection of the V1 antagonist, d(CH2)5Tyr(Me)AVP, significantly reduced the elevated mean arterial pressure induced by 50 or 100 ng/h of AVP (—7 ± 4 and—11 ± 2 mmHg, respectively). Plasma renin and norepinephrine concentrations were not affected by AVP infusion, while plasma epinephrine concentration was lower in the rats given 100 ng/h of AVP. Intravenous infusion of AVP did not alter bodyweight, serum electrolytes or osmolality.

4. These results suggest that AVP has a long‐term pressor effect which is attributable to its vasoconstrictor action in conscious rats.
THE INHIBITORY EFFECT OF SA3443, A NOVEL CYCLIC DISULFIDE COMPOUND, ON ALPHA‐NAPHTHYL ISOTHIOCYANATE‐INDUCED INTRAHEPATIC CHOLESTASIS IN RATS
Authors: Tanaka M. , Nakata K. , Mita S.
Published: June 2007

1. We investigated the effect of SA3443, a novel cyclic disulfide compound, on alpha‐naphthyl isothiocyanate (ANIT)‐induced intrahepatic cholestasis in rats.

2. SA3443 given orally at doses of 100 or 300 mg/kg, three times at 4h intervals, dosedependently suppressed the elevation of serum total bilirubin, alkaline phosphatase activity and transaminase activities induced by administration of ANIT (80 mg/kg) 3 h before the second dosages of SA3443.

3. SA3443 also significantly inhibited the reduction of bile flow in the ANIT‐treated rats.

4. These findings indicated that SA3443 had a markedly inhibitory effect on ANIT‐induced intrahepatic cholestasis in rats.
USE OF A COMPUTERIZED POSTURAL SWAY MEASUREMENT SYSTEM FOR ASSESSING WORKERS EXPOSED TO MANGANESE
Authors: Chia S. E. , Goh J. , Lee G. , Foo S. C. , Gan S. L. , Bose K. , Jeyaratnam J.
Published: June 2007

1. Computerized postural sway measurement systems have been used recently in human physiology and pharmacology for determining postural stability, but their applicability for the assessment of the effects of exposure to neurotoxic agents is lacking.

2. We have examined the feasibility of using a computerized postural sway measurement system to assess the postural sway parameters of manganese exposed workers compared with a control group.

3. Sway parameter data were collected using a kislter multicomponent measuring platform (Type 9281B) connected to vicon motion analysis system for 13 exposed and 16 control subjects.

4. Significant differences in several of the sway parameters (Px, Py—mean distance (mm), from the centre of the platform along the X‐axis [anterior‐posterior movement] and Y‐axis [lateral movement], respectively) between the exposed and control groups were observed even after adjustment for possible confounders. Computerized postural sway measurement system may be a useful method of assessing workers exposed to neurotoxic agents affecting posture.
RELEASE OF A SUBSTANCE FROM THE HUMAN PLACENTA HAVING DIGOXIN‐LIKE IMMUNOREACTIVITY
Authors: Grande A. Di , Boura A. L. A. , Read M. A. , Malatino L. S. , Walters W. A. W.
Published: June 2007

1. The human placental lobule, perfused with a constant flow (5 mL/min) of Krebs’ solution after delivery at term, released into the fetal perfusate a digoxin‐like substance, as measured by a fluorescence polarization immunoassay.

2. Initially the venous concentration was 360 ± 66.7 pmol/ L digoxin equivalents. This level did not change significantly during fetal vasoconstriction induced by prostaglandin F2α infusion and persisted for the duration of the experiment (1.5–2h).

3. Infusion into the fetal circulation of Fab fragments of sheep antibodies to digoxin caused vasodilatation, indicated by a fall in perfusion pressure.

4. Thus a digoxin‐like immunoreactive substance, previously reported to be present in the placenta, is released into the fetal circulation and may play a role in placental control of fetal vascular tone.
Foreword
Authors: Anderson Warwick P.
Published: June 2007

AUSTRALIAN PHYSIOLOGICAL AND PHARMACOLOGICAL SOCIETY ANNUAL GENERAL MEETING FEBRUARY 1994
CARDIAC BAROREFLEXES AND HYPERTENSION
Authors: Head Geoffrey A.
Published: June 2007

1. The role of cardiac reflexes in baroreflex control mechanisms and the changes that occur in chronic hypertension is reviewed. The rapid resetting properties of the arterial baroreceptors ensures its role in short‐term rather than long‐term control of blood pressure.

2. In hypertensive humans and animals, the baroreceptor‐heart rate reflex has diminished sensitivity due mainly to reduced maximum capacity of the cardiac vagal component rather than a change to the sympathetic.

3. The development of this vagal deficit in spontaneously hypertensive rats (SHR) coincides with the onset of cardiac hypertrophy rather than vascular hypertrophy. A combination of chronic perindopril treatment regimens in young and older SHR showed that the vagal deficit was better correlated with the degree of cardiac hypertrophy than with other variables such as blood pressure, hypertension or indices of vascular hypertrophy. Similar results have been shown for renovascular hypertension in rats.

4. The bradycardia produced by electrical stimulation of the vagus in urethane anaesthetized young SHR was enhanced compared to Wistar‐Kyoto rats (WKY) while responses observed in adult SHR and WKY were similar, suggesting that the vagal deficit in hypertensive rats is not due to a defect in the efferent arm of the baroreflex.

5. The association of the vagal deficit with cardiac hypertrophy, but not with the vagal efferent pathways, suggests an important role for cardiac afferents in hypertension in mediating the baroreflex deficit.

6. A diminished baroreflex and also a reduced heart rate variability is an independent risk factor for sudden death following myocardial infarction. Thus, antihypertensive therapy, which more effectively reduces cardiac hypertrophy, should have a desirable effect on baroreceptor reflexes and therefore in reducing blood pressure variability.
ION CHANNEL MODULATORS AS POTENTIAL POSITIVE INOTROPIC COMPOUNDS FOR TREATMENT OF HEART FAILURE
Authors: Doggrell Sheila , Hoey Andrew , Brown Lindsay
Published: June 2007

1. Current positive inotropy therapy of heart failure is associated with major problems: digoxin and the phosphodiesterase inhibitors can cause life‐threatening toxicity while β‐adrenoceptor agonists become less effective inotropic compounds as heart failure progresses. A new approach to positive inotropy is ion channel modulation.

2. An increased influx of Na+ during the cardiac action potential, as measured with DPI 201–106 and BDF 9148 which increase the probability of the open state of the Na+ channel, will increase force of contraction.

3. Activation of L‐type Ca2+ channels with Bay K 8644 will increase influx of Ca2+ and increase the force of contraction. However the Ca2+ channel activators developed to date have little potential for the treatment of heart failure as they are vasoconstrictors.

4. Blocking cardiac K+ channels is a possible mechanism of positive inotropy. Terikalant inhibits the inward rectifying K+ channel, tedisamil inhibits the transient outward K+ channel and dofetilide is one of the newly developed inhibitors of the slow delayed outward rectifying K+ channel. All these drugs prolong the cardiac action potential to increase Ca2+ entry and force of contraction.

5. Thus drugs which increase Na+ influx or block K+ channels represent exciting possibilities for positive inotropy and the potential of these compounds for the treatment of heart failure needs to be fully evaluated.
SODIUM LOADS ENHANCE THE NATRIURETIC RESPONSES TO ATRIAL NATRIURETIC PEPTIDE AND NEUTRAL ENDOPEPTIDASE INHIBITORS IN CONSCIOUS CYNOMOLGUS MONKEYS
Authors: Seymour Andrea A. , Asaad Magdi M. , Abboa‐Offei Benoni , Smith Patricia L. , Rogers W. Lynn
Published: June 2007

1. The effects of sodium supplements on the renal responses to human atrial natriuretic peptide (hANP 99–126) and to the selective inhibitors of neutral endopeptidase 3.4.24.11 (NEP) SQ 28 603 and candoxatrilat were determined in conscious monkeys.

2. When the monkeys’ diet was changed from 0.55% sodium to 1.1% sodium, the natriuretic response to 100 μmol/kg intravenous of SQ 28603 increased from 665 ± 64 to 1015 ± 224 μEq/3h. An acute oral load of 25 mEq sodium significantly increased the natriuresis stimulated by 300 pmol/kg, P.o., of SQ 28603 from 700 ± 332 μEq/3h in normal monkeys to 2437 ± 841 μEq/3h. Therefore, the non‐human primate model was appropriate for investigating the effects of sodium loads on the urinary ANP and cGMP responses to exogenous ANP in the presence and absence of NEP inhibitors.

3. Graded intravenous infusions of saline increased basal urine volume and excretion of sodium and ANP. Salt supplements enhanced the diuretic, natriuretic and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys treated with vehicle or 10 μmol/kg intravenous of candoxatrilat. The sodium and ANP excretions stimulated by hANP 99–126 were positively correlated with each other and with the calculated intravenous sodium load in the presence or absence of candoxatrilat.

4. SQ 28 603 and candoxatrilat (0.3 to 10 μmol/kg intravenous) each produced significant, dose‐related potentiation of the natriuretic, cGMP and ANP responses to 0.3 nmol/kg intravenous of hANP 99–126 in monkeys receiving 5 mL/kg + 0.2 mL/min saline. In addition, the highest dose of SQ 28 603 produced significant depressor activity.

5. In conclusion, the increased natriuretic activity of hANP 99–126 in sodium loaded monkeys was mediated, in part, by increased ANP delivery to the guanylate cyclase linked ANP receptors in the distal renal tubules.
THE EFFECTS OF CENTRAL ADMINISTRATION OF ω‐CONOTOXIN GVIA ON CARDIOVASCULAR PARAMETERS AND AUTONOMIC REFLEXES IN CONSCIOUS RABBITS
Authors: Whorlow Sarah L. , Angus James A. , Wright Christine E.
Published: June 2007

1. The effects of central administration of ω‐conotoxin GVIA (ω‐CTX), an N‐type calcium channel blocker, were examined in conscious rabbits implanted with lateral intracerebroventricular (i.c.v.) cannulae.

2. Experiments were performed over 4 consecutive days. On day 1, the baroreceptor heart rate (induced by glyceryl trinitrate and phenylephrine) and Bezold‐Jarisch like (elicited by serotonin) reflexes were measured before (0 h) and 2 h after central administration of ω‐CTX (3 or 30 pmol/ kg, i.c.v.) or vehicle. On days 2–4, resting parameters and reflexes were again monitored but no further ω‐CTX was administered.

3. No change in heart rate (HR) was observed in any rabbit treatment group during the experimental period. In the vehicle (n= 6) and ω‐CTX 3 pmol/kg (n = 6) groups, small falls in mean arterial pressure (MAP) of 6 ± 2 and 10 ± 3 mmHg, respectively, occurred between 0 and 24 h; MAP then remained stable. Baroreceptor‐heart rate reflex curve parameters did not change in either of these groups during the 4 day period.

4. Following administration of w‐CTX 30 pmol/kg (n = 7), MAP decreased progressively and by 48 h had fallen by 19 ± 4 mmHg. Also at 48 h, a 20% decrease in HR range of the baroreceptor‐heart rate reflex curve was seen without any change in the lower HR plateau from the 0 h control. This indicates that there was an attenuation of the sympathetically mediated upper component of the curve while the vagally mediated component was unaffected.

5. The Bezold‐Jarisch like reflex‐induced bradycardia, mediated by the efferent vagus nerve, was unaffected by i.c.v. administration of vehicle or either dose of ω‐CTX.

6. Therefore, central administration of ω‐CTX resulted in a slowly developing hypotensive response consistent with a sympatholytic action while vagally mediated reflexes were unaffected.
HIGH FISH OIL DIET INCREASES OXIDATIVE STRESS POTENTIAL IN MAMMARY GLAND OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Mehta R. S. , Gunnett C. A. , Harris S. R. , Bunce O. R. , Hartle D. K.
Published: June 2007

1. The purpose of this study was to determine whether high ω‐3 (19% menhaden oil, 1% corn oil) or high ω‐6 (20% corn oil) fatty acid diets would decrease expression of hypertension in the female spontaneously hypertensive rat (SHR), promote tumourigenesis in the rat 7,12‐dimethyl‐benz[a]anthracene (DMBA) model of mammary cancer or increase the susceptibility of the mammary gland to lipid peroxidation. A group of rats on a 5% corn oil diet served as the low fat control group.

2. We found that the high ω‐3 and high ω‐6 fatty acid diets did not significantly decrease mean arterial pressure. Marked differences occurred between the effects of ω‐3 and ω‐6 high fatty acid diets on baseline oxidation, auto‐oxidation and iron‐ascorbate catalyzed oxidation. The ω‐3 diet showed 675% increase in basal oxidation, a 2624% increase in auto‐oxidation and a 4244% increase in iron‐ascorbate catalyzed oxidation compared to the ω‐6 diet in mammary tissue homogenates. Although all rats were given 5 mg DMBA (i.g.), no mammary tumours were observed in any of the dietary groups.

3. We conclude that: (i) high polyunsaturated fatty acid diets do not decrease blood pressure in the female SHR; (ii) high fish oil diet markedly increases oxidative potential in the mammary gland; and (iii) the female SHR is resistant to DMBA‐induced tumourigenesis.
GENETICS OF PRIMARY ALDOSTERONISM
Authors: Gordon Richard D. , Klemm Shelley A. , Tunny Terry J. , Stowasser Michael
Published: June 2007

1. In 1991 we described a familial variety of primary hyperaldosteronism which was not glucocorticoid‐suppressible and was associated with adenoma formation, and called it familial hyperaldosteronism type II (FH‐II) in order to distinguish it from the glucocorticoid‐suppressible variety described in 1966, familial hyperaldosteronism type I (FH‐I).

2. In 1992 the genetic basis of FH‐I was clarified by description of a hybrid gene.

3. Primary aldosteronism due to bilateral adrenocortical hyperplasia or to aldosterone‐producing tumour can be part of the multiple endocrine neoplasia type I syndrome (MEN I), in which loss of heterozygosity has been described on chromosome 11q13. Loss of heterozygosity at the MEN I locus was found in five of 26 aldosterone‐producing tumours from our series (by Japanese collaborators). These included two with adrenal cancer and two with FH‐II.

4. We recently described an association of aldosterone responsiveness of aldosterone‐producing adenomas with renin gene restriction fragment length polymorphisms, suggesting a possible role for renin genotype and intra‐adrenal renin gene expression in the development and biochemical expression of some aldosterone‐producing tumours.

5. We found abnormal karyotypes in 13 of 32 benign aldosterone‐producing adenomas.
P‐GLYCOPROTEIN EXPRESSION IN CLASSICAL MULTI‐DRUG RESISTANT LEUKAEMIA CELLS DOES NOT CORRELATE WITH ENHANCED CHLORIDE CHANNEL ACTIVITY
Authors: Wang Xueyong , Wall Dominic M. , Parkin John D. , Zalcberg John R. , Kemm Robert E.
Published: June 2007

1. P‐glycoprotein (Pgp) is an ATP‐dependent drug efflux pump responsible for classical multi‐drug resistance (MDR).

2. Pgp is part of a supergene family of membrane transport proteins that includes the cystic fibrosis gene product.

3. Transfection of cells with the MDRl gene has been previously shown to generate volume‐regulated chloride channel activity in association with Pgp expression.

4. We have used whole‐cell patch clamping to examine the drug‐sensitive T lymphoblastic cell line CEM‐CCRF and its classical MDR derivative CEM/VLB100. The results suggest that expression of Pgp is not associated with increased chloride channel activity in this multi‐drug resistant cell line.

5. We were unable to confirm previously reported results in MDRl transfected cell lines that suggested that Pgp was associated with the presence of volume‐regulated chloride channels.
RAT AORTIC SMOOTH MUSCLE CELLS EXPRESSING CHARYBDOTOXIN‐SENSITIVE POTASSIUM CHANNELS EXHIBIT ENHANCED PROLIFERATIVE RESPONSES
Authors: Neylon Craig B. , Avdonin Pavel V. , Larsen Michelle A. , Bobik Alex
Published: June 2007

1. The relationship between the expression of potassium (K+) channels and the growth properties of cultured vascular smooth muscle cells was examined.

2. Two groups of cells having different proliferative rates were cultured from the Wistar‐Kyoto rat aorta. One group of cells, derived from early passages (3–3, proliferated with a cell doubling time of 2.41 days. A second group of cells, derived from late passages (> 12), proliferated at a higher rate (cell doubling time, 0.61 days).

3. Exposure of the early passaged cells to endothelin‐1 (0.1 pmol/L) induced membrane depolarization. In contrast, exposure of the late passage cells to endothelin‐1 (0.1 pmol/L) evoked a rapid hyperpolarization. The hyperpolarization in the late passage cells was blocked by charybdotoxin (20 nmol/L), an inhibitor of the large‐conductance Calcium (Ca)‐activated K+ channel.

4. The authors conclude that rapidly proliferating vascular smooth muscle cells express enhanced activity of Ca‐activated K+ channels causing marked alterations in the electrical properties of the cells. It is therefore suggested that the reported increase in Ca‐activated K+ channel activity in the aortae of hypertensive rats is likely to be associated with the increased proliferative ability of the vascular smooth muscle cells.
BLOOD PRESSURE AND LIFESPAN FOLLOWING BRIEF ACE INHIBITOR TREATMENT IN YOUNG SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Harrap Stephen B. , Mirakian Christine , Datodi Shari R. , Lever Anthony F.
Published: June 2007

1. Brief treatment with angiotensin‐converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a reduction in blood pressure that persists into maturity. The lifetime effects of such treatment have not been studied.

2. Nineteen male SHR were treated with either water (n= 9) or perindopril (3 mg/ kg per day) (n = 10) by daily gavage between 6 and 10 weeks of age and systolic blood pressure and bodyweight were measured each month until all animals died in old age.

3. Following treatment the systolic blood pressure of SHR treated with perindopril remained consistently lower than control SHR until about 82 weeks of age. After this age the blood pressure of control SHR fell spontaneously so that smaller differences were observed between the two groups in the last 4 months of the study.

4. Rats that received perindopril lived on average 1 month longer than control rats, but this difference was not statistically significant.

5. Thus, brief ACE inhibition in early life in SHR ameliorated the hypertension throughout life.
EFFECTS OF HOE 140 ON SYSTEMIC DEPRESSOR RESPONSES TO BRADYKININ AND MESENTERIC VASCULAR REACTIVITY IN VIVO IN PREGNANT WISTAR‐KYOTO RATS
Authors: Chu Z. M. , Beilin L. J.
Published: June 2007

1. To examine possible changes in vascular reactivity to exogenous bradykinin (BK) and the possible role of endogenous BK in reduced mesenteric vascular reactivity in pregnant rats. The authors studied the effects of Hoe 140 on systemic depressor responses to BK and on mesenteric vascular reactivity in in situ blood‐perfused mesenteric resistance vessels of 18–20 day pregnant and age‐matched non‐pregnant Wistar‐Kyoto rats (WKY).

2. Mean intra‐arterial blood pressure (MBP) of pregnant rats was lower than non‐pregnant controls. Basal mesenteric perfusion pressure (BPP) was slightly, but not significantly, reduced in the pregnant group. Neither MBP nor BPP was significantly influenced by Hoe 140 (1 mg/kg. s.c.)

3. Systemic depressor responses to BK (1–30 μg/kg, i.v.) were significantly increased in pregnant rats at 1 and 3 μg/kg. Hoe 140 completely abolished systemic depressor responses to BK in either pregnant or non‐pregnant animals.

4. Mesenteric vascular responses to regional administration of noradrenaline, electrical stimulation of sympathetic nerve and angiotensin II were overall decreased in pregnant compared with non‐pregnant groups, but those responses were not significantly affected by Hoe 140 in either groups.

5. The results suggested that although systemic depressor responses to exogenous BK were increased, endogenous BK does not contribute to decreased mesenteric vascular reactivity in vivo in pregnant WKY.
REPERFUSION FOLLOWING MYOCARDIAL ISCHAEMIA ENHANCES INOSITOL PHOSPHATE RELEASE IN THE ISOLATED PERFUSED RAT HEART
Authors: Anderson K. E. , Dart A. M. , Woodcock E. A.
Published: June 2007

1. Global myocariial ischaemia (MI) for periods greater tan 5 min caused an inhibition of phosphatidylinositol specific phospholipase C (PtdIns‐PLC) activity.

2. Two min reperfusion following a 20 min MI period, a time point associated with reperfusion‐induced arrhythmias, resulted in an activation of PtdIns‐PLC activity, dependent on endogenous noradrenaline and mediated via al‐adrenoceptors.

3. This 2 min reperfusion response, in contrast to healthy myocardium, resulted in: (i) enhanced PtdIns‐PLC activity; (ii) increased sensitivity to endogenous noradrenaline; (iii) rapid increases in inositol(1,4,5)trisphosphate (Ins(1,4,5)P3); and (iv) PLC hydrolysis primarily of PtdIns(4,5)P2, such that the majority of InsP isomers derive from Ins(1,4,5)P3.

4. Together, these data suggest a functional role for Ins(1,4,5)P3 under postischaemic reperfusion conditions, and provide a possible link between al‐adrenoceptor stimulation of the PtdIns turnover pathway and reperfusion injury.
HAEMODYNAMIC, RENAL AND HORMONAL RESPONSES TO ENALKIREN IN FOUR PATIENTS WITH POST‐SURGICAL OLIGURIA
Authors: Jackson B. , Liu G. , Perich R. B. , Paxton D. , McNicols L. , Gutteridge G. , Johnston C. I.
Published: June 2007

1. The haemodynamic and hormonal responses of four patients with acute post‐surgical oliguria (urine output <0.5 mL/kg perh) were measured in response to the renin inhibitor enalkiren. Enalkiren was infused at 0.01 up to 0.1 mg/kg perh for up to 4h.

2. Enalkiren infusion was associated with a progressive fall in blood pressure, clinically significant in three of the four patients. Systemic vascular resistance fell in proportion to blood pressure fall. Cardiac output and pulse rate remained unchanged. Effective renal plasma flow rose in all four cases (236 ± 19 to 327± 38). There was no change in urine flow rate, or urinary sodium excretion.

3. Plasma renin activity (ng angiotensin I/mL perh) fell from 1.9 ± 0.5 to 0.02 ± 0.01 (P<0.04), plasma angiotensin II (pg/mL) fell from 104 ± 93 to 7.7 ± 1.5, and plasma aldosterone (ng/dL) fell from 32 ± 8 to 21 ± 9 (P= 0.03) at the highest infusion dose.

4. Enalkiren inhibited plasma renin activity with reduced plasma angiotensin II and aldosterone concentrations. This was associated with vasodilation, reduced blood pressure and maintained cardiac output. There was no beneficial effect on renal function in these patients with post‐surgical oliguria.
EFFECT OF SEX‐RELATED CHANGES IN BLOOD PRESSURE AT ENTRY TO THE MRC TRIAL ON PREDICTION OF CARDIOVASCULAR RISK
Authors: Millar J. A. , Lever A. F.
Published: June 2007

1. Using the MRC trial placebo group as the data source, we examined relationships between cardiovascular risk, gender, and blood pressure (BP) at screening, on entry to the trial, and after 3 months of follow up.

2. Blood pressure on entry to the trial (162/98 mmHg) was significantly higher than at the second screening (154/95 mmHg) visit and at 3 months (144/91 mmHg). The entry BP was higher, and the changes from screening to entry and from entry to 3 months were greater in females. Females had a low cardiovascular risk, but because of the greater changes of BP at entry they were over‐represented at the top of the entry BP distribution, whereas males were over‐represented at the bottom. The result of these effects was that the relationship between cardiovascular risk and entry BP was shifted to the right and was flatter than the corresponding curves measured at screening or after 3 months of follow up.

3. In consequence, the severity of hypertension in the trial population was overestimated from measurement of BP at entry, and the capacity of trial entry BP to predict cardiovascular risk was weakened.

4. BP on entry to the MRC Trial was affected by a pressor effect that diminished the value of BP as a cardiovascular risk factor because it differentially affected sub‐populations by gender.
COMPARATIVE HAEMODYNAMIC EFFECTS OF VERAPAMIL, FLECAINIDE, AMIODARONE AND SOTALOL IN THE CONSCIOUS RABBIT
Authors: Twidale N. , Roberts‐Thomson P. , McRitchie R. J. , Chalmers J. P.
Published: June 2007

1. The effect of intravenous boluses of verapamil (0.15 mg/kg), flecainide (2 mg/kg), amiodarone (5 mg/kg), and sotalol (l.5 mg/kg) on mean arterial pressure, heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), and peak rate of change of left ventricular pressure (LV dP/dt) were assessed in the conscious rabbit.

2. All four drugs had negative inotropic effects: verapamil reduced peak LV dP/dt by 19±4% (mean±s.e.m.; P<0.01), flecainide by 27 ± 9% (P<0.001), amiodarone by 11 ± 2% (P<0.01) and sotalol by 13 ± 3% (P<0.01).

3. The drugs had different effects on CO as a result of differences in their actions on peripheral blood vessels: verapamil and amiodarone produced, respectively, a 12 ± 4% (P<0.03) and 16 ± 6% (P<0.01) increase in CO associated with a substantial vasodilatory effect (TPR reduced 15 ± 7%[P<0.05] and 20 ± 5% [P<0.01], respectively). Flecainide caused only a small (6 ± 1%; P<0.01) increase in CO and sotalol had no effect on either CO or TPR.

4. Bolus intravenous injections of verapamil, flecainide and amiodarone produced an increase in HR, while sotalol reduced HR by 10 ± 2% (P<0.01). The increase in HR and cardiac output seen with verapamil, flecainide and amiodarone was in part secondary to reflex increase in sympathetic tone and these changes were abolished after total cardiac autonomic blockade.

5. The modest reduction in cardiac performance associated with sotalol was abolished by cardiac autonomic blockade, suggesting that the predominant effect of sotalol on contractility was mediated through its β‐adrenoceptor blocking effect.
RENIN GENE POLYMORPHISM ASSOCIATED WITH ALDOSTERONE RESPONSIVENESS TO THE RENINANGIOTENSIN SYSTEM IN PATIENTS WITH ALDOSTERONE‐PRODUCING ADENOMAS
Authors: Ballantine Donna M. , Klemm Shelley A. , Tunny Terry J. , Stowasser Michael , Gordon Richard D.
Published: June 2007

1. Aldosterone levels in patients with unilateral aldosterone‐producing adenomas may be responsive or unresponsive to the renin‐angiotensin system, with the former often previously misdiagnosed as bilateral adrenal hyperplasia.

2. In tumours from patients in the responsive subgroup, renin mRNA is expressed in greater amounts than in tumours from patients in the unresponsive subgroup, or in normal adrenals.

3. We compared the frequency of four renin gene polymorphisms in peripheral blood DNA from the two subgroups and found significant associations between BglI, TaqI and HinfI restriction fragment length polymorphisms (RFLP) and aldosterone responsiveness.

4. Allelic variation in the constitutive renin gene was associated with a specific cause of hypertension.
REMODELLING OF RESISTANCE ARTERIES BY TREATMENT WITH ENALAPRIL IN THE NEW ZEALAND GENETICALLY HYPERTENSIVE RAT
Authors: Ledingham J. M. , Phelan E. L. , Cross M. , Laverty R. , Millar J. A.
Published: June 2007

1. New Zealand genetically hypertensive (GH) rats were treated with enalapril from the age of 4 to 10 weeks and the effects of treatment on the structure of mesenteric resistance arteries (MR A) was measured by use of stereological analysis of stained sections and by myograph techniques.

2. Tail‐cuff blood pressure (BP) was measured weekly and intra‐arterial BP recorded just before MRA were either fixed by perfusion or mounted on a myograph.

3. Stereological techniques (Cavalieri and optical dissector) were used to determine media and lumen volume, fraction of smooth muscle (SM) within the media and SM cell density. For MRA mounted on the myograph, lumen diameter, media thickness, active tension and active pressure were recorded.

4. BP was significantly (P<0.0001) lowered by enalapril throughout the experiment. Intra‐arterial BP and left ventricular (LV) mass were also significantly lower in the enalapril treated GH rats (P<0.0001).

5. Stereological measurements showed that enalapril treatment significantly (P<0.0001 reduced media volume by 50%, doubled lumen volume (P<0.0001)), reduced the fraction of SM in the media (P<0.04), and had no effect on the number of SM cell layers or on SM cell density.

6. Myograph measurements showed a decrease in the ratio media thickness/lumen diameter which was accompanied by a decrease in maximum active tension and pressure development.

7. In the GH rat early treatment with enalapril causes a true loss of medial tissue that is not simply due to rearrangement of existing media around an enlarged lumen.

8. The reduction in media without changes in SM cell density or in the number of layers of SM cells supports the suggestion that angiotensin‐converting enzyme (ACEI) have an effect on cell matrix.
DIFFERENTIAL REGULATION OF UTERINE AND GLOMERULAR ANGIOTENSIN II RECEPTORS IN NORMAL AND HYPERTENSIVE PREGNANCY IN THE RAT
Authors: Yang Y. , Macdonald G. J. , Duggan K. A.
Published: June 2007

1. In the non‐pregnant state uterine and glomerular angiotensin II (AII) receptors have been shown to regulate in a similar fashion. This study sought to determine whether such parallel regulation occurred during pregnancy. We also investigated the role of plasma AII in these changes.

2. These studies were performed in Wistar‐Kyoto (WKY) and spontaneously hypertensive rats (SHR). The SHR has increased receptor number, increased sensitivity to infused AII and decreased plasma volume compared to the WKY. These features are also seen in pregnancy induced hypertension (PIH).

3. Age matched female WKY and SHR were exposed to an appropriate breeder and sacrificed on day 14 of gestation. Plasma AII was measured by radio‐immunoassay. Uterine and glomerular receptor binding was determined by saturation analysis using 125I(Sar1,Ileu8)AII. Data were analysed using the program ligand.

4. Uterine and glomerular AII receptors showed different patterns of regulation during pregnancy. The uterine AII receptor affinity decreased significantly in both strains at 14 days of gestation and receptor number also decreased significantly in WKY. In contrast, glomerular AII receptor affinity did not change significantly in either strain. Receptor numbers in the glomeruli increased significantly compared to their respective non‐pregnant controls.

5. We conclude that the uterine and glomerular AII receptors do not regulate in a parallel fashion in pregnancy. Plasma AII concentration does not appear to be involved in the regulation of either uterine and glomerular receptor expression in pregnancy.
INOSITOL‐1,4,5‐TRISPHOSPHATE [INS(1,4,5)P3] AND INS(1,4,5)P3 RECEPTOR CONCENTRATIONS IN HEART TISSUES
Authors: Fitzgerald Melinda , Anderson Karen E. , Woodcock Elizabeth A.
Published: June 2007

1. The isolation and culture of neonatal cardiomyocytes causes changes in the metabolism of inositol(1,4,5) trisphosphate (Ins(1,4,5)P3) from primarily dephosphorylation in the intact tissue to a combination of phosphorylation and dephosphorylation in the cultured cells (Woodcock et al. 1992).

2. The content of Ins(1,4,5)P3 was found to be higher in intact heart tissue than in the isolated neonatal cells (10.9 ± 1.3 and 0.5 ± 0.1 pmol/mg tissue, mean ± s.e.m., n= 4, P<0.002, respectively).

3. Despite this difference, Ins(1,4,5)P3 receptors in intact tissue and in isolated cells were not different in terms of affinity (8.0 ± 1.7 and 10.9 ± 1.6 nmol/L, n= 3, respectively) or concentration (143.3 ± 20.5 and 91.2 ± 16.0 fmol/mg protein, n = 3, respectively).

4. Thus, while there appears to be a relationship between the tissue content of Ins(1,4,5)P3 and its metabolism, no relationship to the properties of Ins(1,4,5)P3 receptors could be demonstrated.
THE INFLUENCE OF CAPTOPRIL AND NALOXONE ON THE VALSALVA MANOEUVRE AND SYSTOLIC TIME INTERVALS IN HEALTHY VOLUNTEERS
Authors: Richter J. P. , Sommers De K. , Snyman J. R.
Published: June 2007

1. The aim of the study was to ascertain whether the inhibition of the sympathetic nervous system by angiotensin‐converting enzyme (ACE) inhibitors is mediated by endogenous opioids. Naloxone was used to evaluate the effects of the latter on systolic time intervals (STI) and Valsalva manoeuvre‐induced blood pressure and heart rate changes.

2. Baseline recordings were done in 12 healthy male volunteers and repeated 2h after oral administration of 75 mg of captopril and again after naloxone 0.4 mg/kg was administered intravenously over 10 min.

3. After captopril there was a significant reduction in systolic (P<0.02) and mean blood pressure (P<0.04) without any changes in heart rate. Furthermore, captopril increased the Valsalva ratio (P<0.06) but did not influence inotropism as indicated by STI. Naloxone did not influence any of these findings.

4. The changes in the Valsalva ratio after captopril were mediated by an increase in the maximum bradycardia in nine of the 12 subjects.

5. The results indicate that endogenous opioids do not play a role in the putative sympatholytic effect of ACE inhibition.
SPONTANEOUS ENDOTHELIN PRODUCTION BY CIRCULATING MONONUCLEAR CELLS FROM PATIENTS WITH CHRONIC HEART FAILURE BUT NOT FROM NORMAL SUBJECTS
Authors: Krum Henry , Itescu Silviu
Published: June 2007

1. Plasma endothelin‐1 (ET‐1) levels are increased in chronic heart failure (CHF). Because chronic immunologic activation occurs in CHF and mononuclear cells (MNC) are capable of ET‐1 production, the possible contribution of circulating MNC to the increased plasma ET‐1 levels in CHF patients was investigated.

2. Unseparated MNC (107/mL) from eight CHF patients spontaneously produced ET‐1 (1.54 ± 0.37 pg/100 mL). After separation of MNC into monocytes (106/mL) and lymphocytes (107/mL) at ratios approximating those in the circulation, ET‐1 was spontaneously produced by CHF lymphocytes (0.81 ± 0.26 pg/100 mL), and after macrophage colony stimulating factor (MCSF) stimulation by CHF monocytes (0.56 ± 0.08 pg/100 mL). In contrast, there was neither spontaneous nor MCSF‐induced production of ET‐1 in six normal subjects.

3. It was concluded that heightened ET‐1 production by MNC may contribute to increased plasma levels in CHF patients. Because unseparated MNC produced greater ET‐1 than lymphocytes and monocytes separately, contact between these MNC subtypes may be necessary for maximal ET‐1 production.
RESPONSE TO UNILATERAL ADRENALECTOMY FOR ALDOSTERONE‐PRODUCING ADENOMA: EFFECT OF POTASSIUM LEVELS AND ANGIOTENSIN RESPONSIVENESS
Authors: Stowasser M. , Klemm S. A. , Tunny T. J. , Storie W. J. , Rutherford J. C. , Gordon R. D.
Published: June 2007

1. Normokalaemic primary aldosteronism (PA) masquerades as ‘essential hypertension', and 50% of patients with aldosterone‐producing adenoma (APA) are normokalaemic at presentation to this unit.

2. Angiotensin‐responsive (AII‐R) APA is as common as angiotensin‐unresponsive (AII‐U) APA, and requires adrenal venous sampling for differentiation from bilateral adrenal hyperplasia (BAH).

3. From 1981 to 1992, 55 patients with APA underwent unilateral adrenalectomy and were followed up for at least 12 months postoperatively. Hypertension was cured in 55% and improved in the remainder.

4. Cure rate was lower (P<0.001) in males (11/32, 34%) vs females (19/23, 83%), lower (P<0.005) in patients over 45 years of age (13/33, 39%) vs those 45 years or younger (17/22, 77%), lower (P<0.05) in AII‐R APA (11/28, 39%) vs AII‐U APA (19/27, 70%) and tended to be lower (not significant) in normokalaemic APA (7/17, 41%) vs hypokalaemic APA (23/38, 61%).

5. A higher proportion (P<0.001) of AII‐R APA patients were males (23/28, 82%) vs AII‐U APA (9/27, 33%), and a higher proportion were from the older age group (AII‐R APA 20/28, 71%vs AII‐U APA 13/27, 48%; P<0.05). Females with AII‐U APA who were hypokalaemic had a very high cure rate (16/17, 94%).

6. Since unilateral adrenalectomy cures or improves blood pressure in normokalaemic and AII‐R as well as in hypokalaemic and AII‐U patients, all hypertensives should be screened for PA, and AII‐R APA differentiated from BAH in proven PA.
AGE‐RELATED CHANGES IN NEUROPEPTIDE Y CONTENT IN BRAIN AND PERIPHERAL TISSUES OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Pavia Jillian M. , Morris Margaret J.
Published: June 2007

1. This study examined neuropeptide Y (NPY) concentrations in brain regions and peripheral tissues of young (3–4 months) and old (17–18 months) normotensive Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR).

2. Neuropeptide Y‐like immunoreactivity (NPY‐LI) was determined in kidney, adrenal, heart ventricles, atria and four brain regions, cerebral cortex, hypothalamus, ventrolateral medulla (VLM) and dorsomedial medulla containing the nucleus tractus solitarius (NTS), by radio‐immunoassay following acid extraction.

3. Significant age‐related increases in organ weights were observed in atria, ventricle and kidney of both WKY and SHR (P<0.01). In order to take into account tissue hypertrophy, NPY‐LI data were analysed as pmol/g tissue as well as total pmol/tissue.

4. At each age, similar NPY‐LI concentrations were observed in WKY and SHR in all brain regions. A significant age‐induced decrease in NPY‐LI concentration and total NPY content was found in the hypothalamus of both WKY and SHR (P<0.01).

5. In the cardiac ventricle, decreases were observed in NPY‐LI concentration with ageing, and in SHR relative to WKY; however, no differences were observed in total NPY‐LI content. A significant age‐related increase in adrenal NPY‐LI concentration was observed. No age‐ or strain‐related alterations in atrial or renal NPY‐LI were detected, with the exception of an increase in total kidney NPY‐LI in WKY with ageing.

6. Thus in the periphery, few changes in NPY‐LI were observed with genetic hypertension or with ageing. A significant reduction in hypothalamic NPY‐LI concentration occurred with age in both normotensive and hypertensive rats. Thus the previously reported age‐related reduction in NPY‐LI in the hypothalamus, an area where the peptide influences neuro‐endocrine responses and food and water ingestion, is not affected by hypertension.
ROLE OF CALCIUM‐ACTIVATED POTASSIUM CHANNELS IN THE RELAXATION OF TRACHEAL SMOOTH MUSCLES BY FORSKOLIN
Authors: Hiramatsu Tetsuo , Kume Hiroaki , Kotlikoff Michael I. , Takagi Kenzo
Published: June 2007

1. The role of calcium‐activated potassium (KCa) channels in bronchodilation produced by a direct adenylyl cyclase activator, forskolin, was investigated. The involvement of intracellular cyclic AMP (cAMP) in the process was also examined.

2. The isometric tension records from guinea‐pig tracheal smooth muscles indicated that application of charybdotoxin (ChTX), a selective inhibitor of large conductance KCa channels, led to a suppression of the relaxant effect of forskolin in the precontracted tissue by carbachol (CCh). However, the inhibitory action by ChTX had a much greater effect on the relaxation caused by isoproterenol than by forskolin.

3. In contrast to the effect of ChTX, glybenclamide, a cromakalim‐sensitive K+ channel inhibitor and apamin, a small conductance KCa channel blocker, had no effects on the bronchodilation produced by forskolin.

4. The effects of forskolin and nifedipine on tone produced by high K+ was compared. Concentration‐inhibition curves in guinea‐pig trachealis precontracted by 20 mmol/L K+ solution were similar for forskolin and nifedipine. Conversely, relaxation by forskolin was significantly diminished when tissues were contracted with 40 mmol/ L K+ solution, whereas nifedipine relaxations were unaffected.

5. A single channel record from a cell‐attached patch in a porcine tracheal myocyte demonstrated that forskolin stimulates reversibly KCa channels without affecting the unitary amplitude.

6. The results are consistent with forskolin‐induced relaxation occurring at least in part through the opening of ChTX‐sensitive KCa channels, by means of a cAMP‐dependent channel modulation. The lesser effect of ChTX on forskolin compared with isoproterenol‐induced relaxations suggests a tighter coupling between relaxation and channel opening by β‐adrenergic receptor stimulation, and is consistent with cAMP‐independent mechanisms of receptor‐channel coupling.
INCREASE IN HAEMATOCRIT IN BORDERLINE HYPERTENSIVE MEN
Authors: Siebers R. W. L. , Carter J. M. , Maling T. J. B.
Published: June 2007

1. Haematologic parameters were measured in untreated borderline hypertensive (BHT) men, and weight and age matched with normotensive men to determine whether previously described increased haematocrit (Hct) in established hypertension is evident in borderline hypertension.

2. Haematocrit was significantly increased in BHT men (mean 0.46, s.d. 0.032) compared with normotensive men (mean 0.43, s.d. 0.014) and correlated significantly with mean arterial pressure in this group (r = 0.67, P= 0.036) independent of weight.

3. The correlation of blood pressure with Hct in BHT men supports the concept that increased Hct may contribute to increased blood viscosity and thus to raised arterial pressure.
COMPARATIVE STUDY ON α1‐ADRENOCEPTOR ANTAGONIST BINDING IN HUMAN PROSTATE AND AORTA
Authors: Yamada Shizuo , Suzuki Mayumi , Tanaka Chiaki , Mori Ryutaro , Kimura Ryohei , Inagaki Osamu , Honda Kazuo , Asano Masaharu , Takenaka Toichi , Kawabe Kazuki
Published: June 2007

1. Specific binding of [3H]‐prazosin in prostatic and aortic membranes of humans was saturable and of high affinity (prostate: apparent dissociation constant, Kd= 0.35 ± 0.03 nmol/L; aorta: Kd= 0.26 ± 0.03 nmol/L). The density of [3H]‐prazosin binding sites (Bmax) for prostate and aorta was 546 ± 31 and 61.6 ± 1.6 fmol/mg protein, respectively.

2. Prazosin, YM617, naftopidil and urapidil competed with [3H]‐prazosin for the binding sites in a dose‐dependent manner in the prostate and aorta of humans. The binding affinities of these antagonists in both tissues were compared, based on the inhibition constant, Ki. Both prazosin and urapidil showed similar affinity to [3H]‐prazosin binding sites in human tissue, whereas YM617 and naftopidil showed approximately a 12 and two times higher affinity, respectively, to α1‐adrenoceptor sites of prostate than aorta.

3. The chloroethylclonidine treatment reduced partially the Bmax values for specific [3H]‐prazosin binding in the prostate and aorta of humans with little effect on the Kd values.

4. These data suggest that YM617 is a relatively selective antagonist of human prostatic α1‐adrenoceptors.