bluuebunny/crossref_metadata_2025 huggingface dataset:
NITRERGIC TRANSMISSION: NITRIC OXIDE AS A MEDIATOR OF NON‐ADRENERGIC, NON‐CHOLINERGIC NEURO‐EFFECTOR TRANSMISSION
Authors: Rand M. J.
Published: June 2007

1. The possibility that transmission at some non‐adrenergic, non‐cholinergic (NANC) neuro‐effector junctions is mediated by nitric oxide (NO) arose from the discoveries that NO mediated the effects of nitrovasodilator drugs and that endothelium‐derived relaxing factor (EDRF) was NO or a NO‐yielding substance.

2. NO donated by nitrovasodilator drugs or formed by endothelial cells activates soluble guanylate cyclase in smooth muscle and the consequent increase in cyclic guanosine monophosphate (cGMP) results in relaxation. The relaxations produced by stimulation of some NANC nerves are also due to a rise in cGMP.

3. The biosynthesis of NO by oxidation of a terminal guanidino nitrogen of l‐arginine is inhibited by some NG‐substituted analogues of l‐arginine. These substances block EDRF formation by NO synthase and endothelium‐dependent vasodilatation, and the blockade is overcome by l‐arginine

4. NANC relaxations in some tissues are blocked by NG‐substituted analogues of l‐arginine and restored by l‐arginine. Other agents that affect endothelium‐dependent vasodilator responses produce corresponding changes in responses to stimulation of these NANC nerves. Such observations indicate that transmission is mediated by NO: we have termed this mode of transmission nitrergic.

5. There is evidence for nitrergic innervation of smooth muscle in the gastrointestinal tract, genitourinary system, trachea and some blood vessels (penile and cerebral arteries).

6. The recognition of a mediator role for NO in neurotransmission calls for reconsideration of previously accepted generalizations about mechanisms of transmission.

7. Studies on nitrergic transmission will provide new insights into physiological control mechanisms and pathophysiological processes and may lead to new therapeutic developments.
ATRIAL AND BRAIN NATRIURETIC PEPTIDES: SECRETION DURING EXERCISE IN PATIENTS WITH ESSENTIAL HYPERTENSION AND MODULATION BY ACUTE ANGIOTENSIN‐CONVERTING ENZYME INHIBITION
Authors: Kohno Masakazu , Horio Takeshi , Yokokawa Koji , Murakawa Koh‐ichi , Yasunari Kenichi , Kurihara Naotsugu , Takeda Tadanao
Published: June 2007

1. This study examined whether brain and atrial natriuretic peptides (BNP, ANP) are secreted together through the coronary sinus from the heart, and whether plasma concentrations of BNP and ANP were affected by ergometric exercise in patients with essential hypertension. The effect of temocapril, a potent angiotensin‐converting enzyme (ACE) inhibitior, on plasma concentrations of these peptides was also examined.

2. The plasma concentrations of immunoreactive (ir) BNP and ir‐ANP in the coronary sinus in seven patients with ischaemic heart disease during cardiac catheterization were far greater than values with plasma obtained at the same time from the femoral artery.

3. The plasma concentrations of ir‐BNP and ir‐ANP increased with exercise and were correlated with each other. Temocapril reduced the blood pressure and slightly (but significantly) decreased the levels of both peptides at rest and during exercise.

4. The results suggested that BNP and ANP were secreted together through the coronary sinus from the heart. The secretion was increased by exercise and suppressed by acute ACE inhibition. The increase in these peptides during exercise may reflect a compensatory mechanism against further elevation of blood pressure.
REGULATION OF PROXIMAL TUBULE FUNCTION BY ANGIOTENSIN
Authors: Harris Peter J.
Published: June 2007

1. Independent of its effects on renal haemodynamics and glomerular filtration, angiotensin II (All) has direct actions on the proximal tubule involving transepithelial Na+, H+, HCO3‐, and water reabsorption, ammoniagenesis, gluconeogenesis and renal growth.

2. The effects of AH on water and electrolyte transport are biphasic and dose‐dependent, such that low concentrations (10‐12–10‐9 mol/L) stimulate reabsorption whereas high concentrations (10‐7‐10‐6 mol/L) inhibit reabsorption. Similar dose‐response relations have been obtained for luminal and peritubular addition of AIL

3. The cellular responses to All are mediated via an AT‐1 receptor coupled via G‐regulatory proteins to several parallel signal transduction pathways. Low doses inhibit the basolateral adenylate cyclase, lower intracellular cAMP and withdraw the inhibitory effect of protein kinase A on the luminal Na/H exchanger. Stimulation of this exchanger may also occur due to All‐receptor activation of phospholipase C to release diacyl glycerol, or by local transduction in the brush‐border membrane involving phospholipase A2.

4. Inhibition of proximal fluid reabsorption is associated with increased intracellular Ca2+ released from intracellular stores, or entering via voltage‐sensitive channels in response to the release of inositol‐l,4,5,‐trisphosphate, or following Ca2+ channel opening induced by the arachidonic acid metabolite 5,6,‐epoxy‐eicosatrienoic acid.

5. The stimulatory actions of peritubular All on proximal transport are inhibited by physiological concentrations of atrial natriuretic factor (ANF) and by parathyroid hormone (PTH).

6. It is concluded that intrarenal All acts to maintain optimal matching of fluid reabsorption and filtered load in response to changes in sodium balance, as well as to promote acidification of the urine during acidosis and perhaps to potentiate tubular growth following renal injury.
SODIUM AND NORADRENALINE IN CEREBROSPINAL FLUID AND BLOOD IN SALT‐SENSITIVE AND NON‐SALT‐SENSITIVE ESSENTIAL HYPERTENSION
Authors: Kawano Yuhei , Yoshida Kaoru , Kawamura Minoru , Yoshimi Hiroki , Ashida Terunao , Abe Hitoshi , Imanishi Masahito , Kimura Genjiro , Kojima Shunichi , Kuramochi Morio , Omae Teruo
Published: June 2007

1. The effects of dietary sodium on blood pressure and levels of sodium, other electrolytes and noradrenaline (NA) in the cerebrospinal fluid (CSF) and blood of 15 patients with essential hypertension were studied. The CSF and blood sampling was carried out after 7 days of a high salt intake (16–18 g/day) and after 7 days of a low salt intake (1–3 g/day).

2. Blood pressure and sodium concentrations in CSF and serum were significantly higher in the high salt period than the low salt period (CSF Na+ concentration: 147.7 ± 0.4 mmol/L vs 145.3 ± 0.5 mmol/L; P < 0.001). Levels of CSF pressure and potassium or calcium concentrations were not different between the two periods. Plasma NA and plasma renin activity (PRA) were lower and CSF NA levels tended to be lower in the high salt period.

3. The levels and the changes in sodium and NA in CSF were not significantly different between the salt‐sensitive (n= 8) and the non‐salt‐sensitive (n= 7) subjects, but the changes in plasma NA and PRA were smaller in the salt‐sensitive subjects.

4. These results indicate that the sympathetic nervous system is less suppressed in salt‐sensitive subjects during high salt intake. This may be due to altered neural responsiveness to sodium loading rather than being greater increases in sodium concentration in the central nervous system.
SAMPLE SIZE REQUIREMENTS FOR CLINICAL TRIALS OF ISOLATED SYSTOLIC HYPERTENSION
Authors: Silagy C. A. , McNeil J. J. , McGrath B. P.
Published: June 2007

1. This study investigated components of blood pressure variability in elderly subjects with isolated systolic hypertension (ISH) using both ambulatory blood pressure monitoring (ABPM) and casual clinic blood pressure measurement. These were then used to determine sample size requirements for clinical trials of different designs.

2. Eleven elderly subjects not receiving antihypertensive medication were seen on four occasions at weekly intervals. On each occasion blood pressure was measured in the clinic and then for 24 h using a non‐invasive ABPM device. Nested analysis of variance was used to calculate the ‘between subject’ and ‘between subject within occasion’ components of blood pressure variability.

3. Increasing the number of readings or occasions where measurement was performed in a parallel group trial only reduced the variability substantially when the number of subjects involved was less than 50. Use of a cross‐over design substantially reduced the sample size required.

4. ABPM appears most useful as a strategy for reducing sample size in parallel group trials in ISH involving small numbers of subjects measured on one occasion.
CONCURRENCE OF PRIMARY ALDOSTERONISM AND RENAL ARTERY STENOSIS
Authors: Stokes Gordon S. , Monaghan Judith C. , Roche James , Grunstein Harry , Gordon Richard D.
Published: June 2007

1. An unusual clinical case is described in which renal artery stenosis (RAS) was found to coexist with adrenocortical hyperplasia, resulting in hypertension.

2. Partial relief of the hypertension was achieved by correction of RAS, and then further relief by extirpation of one adrenal gland affected by unilateral hyperplasia, in interventions 8 months apart.

3. Biochemical features typical of primary hyperaldosteronism were observed both before and after RAS repair but were not present after unilateral adrenalectomy.

4. The association of these two lesions could have occurred by chance, through genetic linkage, or by progression from RAS to tertiary aldosteronism.
FAMILIAL HYPERALDOSTERONISM TYPE II: FIVE FAMILIES WITH A NEW VARIETY OF PRIMARY ALDOSTERONISM
Authors: Stowasser Michael , Gordon Richard D. , Tunny Terry J. , Klemm Shelley A. , Finn Wendy L. , Krek Anton L.
Published: June 2007

1. Thirteen patients from five families had Familial Hyperaldosteronism Type II (FH‐II), a new variety of familial primary aldosteronism not suppressible with dexamethasone that often involves adrenocortical adenoma formation.

2. Five patients had solitary aldosterone‐producing adenomas, three had bilateral autonomous overproduction of aldosterone, and in five the subtype is yet to be determined.

3. Comparing FH‐II patients with 88 patients with primary aldosteronism of other causes revealed no differences in mean age at presentation or at onset of hypertension, sex incidence, lowest recorded serum potassium, plasma aldosterone, plasma renin activity or adenoma size.

4. Analysis of DNA in peripheral blood of patients with FH‐II, their affected and unaffected relatives, and in removed tumours is in progress in order to determine the underlying genetic defect(s) in FH‐II, perhaps an abnormality in the P‐450aldo gene (CYP11B2).

5. It is recommended that hypertensive relatives of patients with primary aldosteronism should have measurements of the aldosterone/renin ratio.
EFFECT OF ENALAPRIL ON BODY SODIUM AND HANDLING OF A SODIUM CHLORIDE LOAD IN HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: Ledingham J. M. , Simpson F. O.
Published: June 2007

1. The effect of enalapril on handling of an Na load and on body Na during 96 h of zero Na intake was measured in hypertensive rats (GH and SHR) and their normotensive controls (N and WKY) by a whole body counting method.

2. Enalapril treatment led to a greater fall in body Na in the first 24 h after the Na load (as expected from the known effect of ACE inhibition on aldosterone production) and thus to a slightly faster excretion of an amount equivalent to the load.

3. Enalapril‐treated rats were unable to maintain body Na on a zero Na intake. This was also expected from the known effect on aldosterone production, though other mechanisms are not excluded. The effect was more marked in the SHR and WKY than in GH and N but there was no significant difference in this effect between the hypertensives and their respective control strains.
ISOLATION OF ADULT CARDIOMYOCYTES INITIATES A RETURN OF INOSITOL TRISPHOSPHATE PHOSPHORYLATING ACTIVITY
Authors: Woodcock Elizabeth A. , Anderson Karen
Published: June 2007

1. We have previously reported that the addition of noradrenaline to [3H]‐inositol‐labelled adult rat atria or isolated perfused hearts caused the release of inositol‐1,4,5‐trisphosphate, which was metabolized by dephosphorylation to inositol‐4‐monophosphate. Inositol‐l,3,4,5‐tetrakisphosphate and its dephosphorylation products were not detected.

2. In the current study, the addition of noradrenaline to [3H]‐inositol‐labelled adult rat cardiomyocytes caused the release of inositol‐1,4,5‐trisphosphate, which was metabolized in part by phosphorylation to inositol‐l,3,4,5‐tetrakisphosphate.

3. These results demonstrate that the isolation and culture of rat adult cardiomyocytes initiates enhanced generation of inositol‐1,3,4,5‐tetrakisphosphate. This change would be expected to enhance the calcium response of the cells to stimulation of α1‐adrenoceptors.
INFLUENCE OF WORKLOAD ON THE ANTIHYPERTENSIVE EFFECT OF EXERCISE
Authors: Matsusaki Motonori , Ikeda Masaharu , Tashiro Eiichiro , Koga Manabu , Miura Shin‐ichiro , Ideishi Munehito , Tanaka Hiroaki , Shindo Munehiro , Arakawa Kikuo
Published: June 2007

b

1. The relation between workload and the antihypertensive effect of exercise therapy in hypertensive patients, and the mechanism of that effect, were investigated.

2. Twenty‐six patients participated in the study and were randomly assigned to 10 weeks of either low or high workload exercise. In the low workload group, 16 mild hypertensive patients were treated with bicycle ergometer exercise at approximately 50% of their maximum oxygen consumption (V̇O2max) for 60 min three times a week for 10 weeks. In the high workload group, 10 mild hypertensive patients exercised on the same schedule, but at approximately 75% of V̇O2max.

3. After 10 weeks of exercise, the low workload group had significantly lower systolic (9 mmHg), mean (6 mmHg) and diastolic (6 mmHg) blood pressures. In the high workload group, decreases in systolic (3 mmHg), mean (4 mmHg) and diastolic (5 mmHg) blood pressure were not statistically significant.

4. In the low workload group, changes in haemodynamic and humoral variables were not significant, except for a reduction in plasma norepinephrine at week 7. Cardiac index and plasma norepinephrine tended to decrease. In the high workload group, plasma norepinephrine and the renin‐angiotensin system were transiently stimulated after 4 weeks of exercise. Stroke volume significantly increased (+26.4%) after 10 weeks of high workload exercise.

5. Based on these results and better patient compliance with the exercise programme in the low workload group than in the high workload group, low workload exercise therapy was recommended to mild hypertensive patients.
THE EFFECT OF GRADED HAEMORRHAGE ON ERYTHROPOIETIN PRODUCTION IN THE IMMATURE OVINE FOETUS
Authors: Moritz Karen M. , Wintour Marelyn
Published: June 2007

1. Basal and haemorrhage‐stimulated erythropoietin (Epo) and ACTH levels were measured in the chronically cannulated immature ovine foetus (< 125 days) by radio immunoassay (RIA).

2. Basal erythropoietin levels were found to be higher than those previously reported in the late gestation (> 130 days) ovine foetus, but were lower than those observed in the neonatal lamb.

3. In control foetuses (Protocol 1) the small degree of haemorrhage associated with the sampling procedure increased the plasma Epo values from 11.4 ± 3.0 (n= 5) mU/mL to 23.8±4.3 mU/mL at 24 h (mean ± s.e.m.). There was a significant monotonic increase with time (F= 16.4; d.f. 1,19; P= 0.001). An initial haemorrhage of approximately 10% blood volume (Protocol 2) increased plasma Epo values from 7.3±2.3 to 24.2 ± 7.1 mU/mL(n= 3).

4. Haemorrhage of 20% fetal blood volume (Protocol 3) produced an increase in plasma Epo from 9.3±1.7 to 54.7 ± 15.5 mU/mL at 6 hand to 57.6 ± 7.3 mU/mLat24 h n= 5). By repeated measures ANOVA, the effect of the 20% haemorrhage was significant when compared with the control group (F= 7.32, d.f. 2, 16, P= 0.006). There was a significantly greater decrease in haematocrit (F= 6.7, d.f. 2, 20, P= 0.004) and haemoglobin (F= 5.0, d.f. 2, 20, P= 0.013) in animals of Protocol 3 than in those of Protocol 1.

5. Fetal blood gases and plasma adrenocorticotropic hormone (ACTH) did not alter with haemorrhage, indicating the tolerance of the foetus to this degree of haemorrhage.
INHIBITION OF NITRIC OXIDE SYNTHASE SPECIFICALLY ENHANCES ADRENERGIC VASOCONSTRICTION IN RABBITS
Authors: Du Z‐Y. , Dusting G. J. , Woodman O. L.
Published: June 2007

1. The effect of inhibition of nitric oxide biosynthesis using N‐nitro‐l‐arginine (NOLA) was examined in conscious rabbits and rabbit isolated aortae.

2. In autonomically blocked conscious rabbits intravenous infusion of NOLA (15 mg/kg) significantly increased arterial pressure and hindlimb vascular resistance but did not affect heart rate. Depressor and hindlimb vasodilator responses to acetylcholine (3–12 μg/kg per min) were significantly attenuated in the presence of NOLA. In contrast, NOLA significantly enhanced responses to intravenous infusion of glyceryl trinitrate (10–40 Mg/kg per min) in vivo.

3. Infusion of noradrenaline (1–4 μg/kg per min) or the release of neuronal noradrenaline in response to the infusion of tyramine (80–320 Mg/kg per min) increased arterial pressure and hindlimb vascular resistance in autonomically blocked conscious rabbits. After the administration of NOLA, the vasoconstrictor responses to both noradrenaline and tyramine were significantly enhanced.

4. In isolated rabbit aortae, NOLA (10 μmol/L) significantly impaired relaxant responses to acetylcholine but did not affect responses to glyceryl trinitrate. NOLA enhanced contractile responses to the adrenoceptor agonists noradrenaline and phenylephrine but did not affect the contractile responses to the thromboxane‐mimetic U46619.

5. These data indicate that in autonomically blocked conscious rabbits, NOLA causes systemic vasoconstriction, impairs dilator responses to acetylcholine and enhances dilator responses to glyceryl trinitrate. In addition, NOLA enhances constrictor responses to both exogenous and neuronally‐released noradrenaline. These results suggest that nitric oxide is important in the regulation of normal vascular tone and in the modulation of vascular responses to vasodilator and vasoconstrictor agents.
NERVE GROWTH FACTOR mRNA CONTENT PARALLELS ALTERED SYMPATHETIC INNERVATION IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Falckh Patrick H. , Harkin Louise A. , Head Richard J.
Published: June 2007

1. In order to explore the mechanisms responsible for the hypernoradrenergic innervation of the vasculature in the spontaneously hypertensive rat (SHR) the tissue content of nerve growth factor messenger ribonucleic acid (NGFmRNA) was examined.

2. The concentration of NGFmRNA was markedly elevated in mesenteric veins obtained from SHR when compared with the contents of NGFmRNA in veins from Wistar Kyoto rats (WKY).

3. The NGFmRNA content of kidneys was greater in SHR when compared with the levels present in WKY rats for 10‐ and 43‐day‐old animals.

4. In contrast to the pattern observed for veins and kidneys, the NGFmRNA content of SHR hearts was smaller than those present in hearts from WKY rats for 2, 10 and 43‐day‐old animals.

5. The results demonstrate that tissues with enhanced innervation (the kidney and mesenteric vasculature) in SHR are associated with an enhanced expression of NGFmRNA. In contrast, the heart, which does not display an enhanced sympathetic innervation in the SHR, does not have an increased expression of NGFmRNA.

6. It is suggested that in the SHR there is a tight relationship between hypernoradrenergic innervation in the vasculature and gene expression for NGFmRNA.
l‐ARGININE INFUSION INDUCES HYPOTENSION AND DIURESIS/NATRIURESIS WITH CONCOMITANT INCREASED URINARY EXCRETION OF NITRITE/NITRATE AND CYCLIC GMP IN HUMANS
Authors: Kanno Kazuo , Hirata Yukio , Emori Toshiaki , Ohta Kazuki , Eguchi Satoru , Imai Taihei , Marumo Fumiaki
Published: June 2007

1. The vascular endothelium produces endothelium‐derived relaxing factor (EDRF) or nitric oxide (NO), which exerts vasodilation through cyclic guanosine monophosphate (cGMP) as a second messenger. To determine whether EDRF has any vasodilating and natriuretic action in man, the present study examined the effects of l‐arginine (l‐Arg), a substrate for NO, on the responses of mean blood pressure (MBP) and heart rate (HR); plasma concentrations of cGMP, atrial natriuretic factor (ANF) and nitrite/nitrate (NOx); urinary excretion of sodium, cGMP and NOx; and urinary flow in eight normal male subjects. These parameters were compared with those following saline infusion in the same subjects. Clearance of para‐aminohippuric acid (PAH) and inulin was studied in five normal subjects.

2. Infusion of l‐Arg (30 g) caused a significant fall in MBP (–8 mmHg) with a concomitant rise in HR (10 beats/min), while saline infusion had no effects on these parameters.

3. Neither l‐Arg nor saline infusion caused appreciable changes in plasma concentrations of ANF or NOx. Plasma cGMP concentrations increased significantly during (1.7‐fold) and after (1.9‐fold) l‐Arg infusion, but only slightly (1.3‐fold) during saline infusion.

4. Urine flow increased more remarkably following l‐Arg infusion than that following saline infusion. Remarkable increases in urinary excretion of sodium and fractional excretion of sodium were observed after l‐Arg infusion compared with those after saline infusion. Natriuresis was associated with enhanced urinary excretion of cGMP and Nox. Urinary NOx excretion showed positive correlations with urinary flow (r= 0.69, P < 0.001) and with urinary cGMP excretion (r= 0.60, P < 0.01). PAH clearance showed significant increase by l‐Arg infusion, while no significant change of inulin clearance was observed.

5. These date suggest that infusion of l‐Arg causes hypotension and diuresis/natriuresis associated with increase in renal plasma flow, possibly via the formation of endogenous EDRF in man.
REMODELLING OF THE VASCULAR SYSTEM IN RESPONSE TO HYPERTENSION AND DRUG THERAPY
Authors: Levy B. I. , Safar M. E.
Published: June 2007

1. Arterial remodelling is an important mechanism in the pathophysiology of hypertension and its complications, being involved in the decrease of vascular reserve, the autoregulation of cerebral blood flow and the development of atherosclerosis. There is now evidence that, in addition to several other growth factors, vasoactive peptides such as angiotensin II may act as vascular smooth muscle growth‐promoting substances. Based on these data, the effects of perindopril, a potent and long‐lasting angiotensin‐converting enzyme (ACE) inhibitor, on structural and mechanical properties of the arterial wall have been studied in animal models of hypertension. Perindopril completely reversed the aortic medial hypertrophy and arterial stiffening observed in renovascular hypertensive rats and in spontaneously hypertensive rats. The effect of perindopril was consistent with the potent inhibition of vascular ACE, and emphasized the potential role of angiotensin II as a vascular growth modulator. Whether the time constant of remodelling is similar or not in the heart and large vessels remains an important question that requires further investigation.
ENHANCED CONTRACTION TO NORADRENALINE, SEROTONIN AND NERVE STIMULATION BUT NORMAL ENDOTHELIUM‐DERIVED RELAXING FACTOR RESPONSE IN SKIN SMALL ARTERIES IN HUMAN PRIMARY HYPERTENSION
Authors: Angus J. A. , Jennings G. L. , Sudhir K.
Published: June 2007

1. We measured the reactivity of 2 mm long ring segments of human resistance arteries dissected from gluteal skin biopsies and mounted on wires in a Mulvany‐Halpern myograph for recording isometric force. Arteries were taken from eight normotensive (N) volunteers (average age 46 years, blood pressure 126/82 mmHg) and eight untreated hypertensives (H; average age 48 years, blood pressure 149/101 mmHg).

2. In small diameter arteries (internal diameter < 500/μm), the cumulative concentration‐response curves to noradrenaline, serotonin and angiotensin II had a greater maximum by 72, 300 and 69%, respectively, in vessels from hypertensive patients than in those from normal volunteers. Nerve stimulation also caused a greater maximum contraction in hypertensive vessels (by 352%).

3. Arteries from H and N patients contracted submaximally by the thromboxane mimetic U46619 were similarly sensitive to the endothelium‐dependent relaxing factor (EDRF) acetylcholine, indicating no difference in EDRF release or sensitivity.

4. Morphological measurements of the ratio of wall thickness to lumen radius of the wire‐mounted vessels showed no significant difference between H and N vessels.

5. In larger arteries (internal diameter > 500 μm), no response to acetylcholine was noted in either H or N arteries. The sensitivity to serotonin and angiotensin II was similar between these arteries but the EC50 to noradrenaline was less in H than in N arteries (ΔEC50= 0.61 ‐log mol/L).

6. Subcutaneous resistance arteries with an internal diameter less than 500 μm from hypertensive patients show enhanced contractility to noradrenaline, serotonin and nerve stimulation despite a lack of detectable medial hypertrophy. These changes may be confined to the medium small arteries acting as pharmacological amplifiers in the circulation. We could not demonstrate a significant defect in neuronal uptake nor in endothelium‐derived relaxing factor in arteries from patients with essential hypertension.
COMPARISON OF THE PHARMACOKINETICS AND PHARMACODYNAMICS OF PERINDOPRIL, CILAZAPRIL AND ENALAPRIL
Authors: Louis W. J. , Conway E. L. , Krum H. , Workman B. , Drummer O. H. , Lam W. , Phillips P. , Howes L. G. , Jackson B.
Published: June 2007

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose).

2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h.

3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin‐converting enzyme (ACE) activity in both acute and steady state studies.

4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat > cilazaprilat > enalaprilat.

5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.
ANGIOTENSIN‐CONVERTING ENZYME INHIBITION AS FIRST‐LINE TREATMENT FOR HYPERTENSION
Authors: Thurston Herbert
Published: June 2007

1. Perindopril (4 mg) was compared with atenolol (50 mg), captopril (25 mg b. d.) or a diuretic (hydrochlorothiazide 50 mg and amiloride 5 mg) in three studies involving a total of 503 hypertensive patients with a diastolic blood pressure (DBP) of 95–125 mmHg.

2. A 4 week single‐blind placebo period preceded 12 weeks of active treatment. Dose titration was at weeks 4 and 8 if supine DBP >90 mmHg. The dose was doubled and if necessary a diuretic was added in the atenolol or captopril comparisons, and atenolol was added in the diuretic study.

3. The fall in supine blood pressure (BP) was 27/17 mmHg with perindopril and 21/16 mmHg for atenolol. Monotherapy controlled 55% of patients on perindopril and 48% on atenolol, increasing to 78% and 58% with the addition of hydrochlorothiazide, respectively. Captopril caused a BP fall of 19/12 mmHg compared with 27/18 mmHg for perindopril, with 49% of both groups being controlled on monotherapy.

4. Diuretic addition produced a greater antihypertensive effect with perindopril (75%) compared with 57% for captopril in achieving control. Perindopril caused a comparable fall in supine BP to the diuretic combination 27/19 mmHg and 31/18 mmHg, but the fall in erect systolic BP was significantly greater for the diuretic. At 3 months, 85% of the diuretic group and 78% of the perindopril group achieved the target BP.

5. A multicentre trial of 856 patients treated with perindopril (690 patients treated for 1 year or more) has shown that BP control is maintained in the long term with a low incidence of side‐effects (7.9%) causing withdrawal from treatment. These studies demonstrate that perindopril compares favourably with standard first‐line therapy for mild to moderate hypertension.
THE EFFECT OF SOME α2‐ADRENOCEPTOR AGONISTS AND ANTAGONISTS ON GASTROINTESTINAL TRANSIT IN MICE: INFLUENCE OF MORPHINE, CASTOR OIL AND GLUCOSE
Authors: Ali B. H. , Bashir A. A.
Published: June 2007

1. The effects of graded doses of the α2‐adrenoceptor agonists clonidine, tizanidine and BHT‐920, and the α2‐adrenoceptor antagonists yohimbine and idazoxan, on gastrointestinal transit were investigated in mice using the charcoal meal test.

2. The agonists produced significant and dose‐dependent decreases in gastrointestinal transit, and the antagonists produced the opposite effect. In affecting the gastrointestinal transit, clonidine (1 mg/kg) was as effective as tizanidine (12 mg/kg) and BHT‐920 (40 mg/kg), while yohimbine (2 mg/kg) was as effective as idazoxan (1 mg/kg).

3. Morphine (2, 4 and 8 mg/kg) significantly inhibited gastrointestinal transit. This effect was significantly reversed by the co‐administration of yohimbine (2 mg/kg) and idazoxan (1 mg/kg).

4. The acute administration of glucose (5.04 g/kg, i.p.) potentiated the inhibition of gastrointestinal transit produced by clonidine (1 mg/kg) and BHT‐920 (40 mg/kg). Glucose treatment, however, had no significant effect on the increase in gastrointestinal transit induced by yohimbine (2 mg/kg) or idazoxan (1 mg/kg).

5. Castor oil (0.25 mL/mouse, orally) induced diarrhoea in saline‐treated animals within about 45 min. Clonidine (1 mg/kg), tizanidine (12 mg/kg) and BHT‐920 (40 mg/kg) delayed the occurrence of diarrhoea to 2.1, 1.2 and 1.4 h, respectively.
EFFECTS OF ANAESTHESIA ON THE REMOVAL FROM PLASMA OF INTRAVENOUSLY INJECTED CHYLOMICRON‐LIKE LIPID EMULSIONS IN RATS AND MICE
Authors: Mortimer Bok‐Cheng , Umeda Yoh , Elsegood Caryn L. , Redgrave Trevor G.
Published: June 2007

1. In order to find an anaesthesia with minimum perturbation to the metabolism of chylomicrons, the effects of seven different anaesthetic agents on clearance from plasma of chylomicron‐like emulsions were compared.

2. Avertin, urethane, fentanyl, and a ketamine/xylazine mixture all slowed the removal from plasma of emulsion triolein and cholesteryl oleate. The steroid anaesthetic althesin slowed the clearance of emulsion cholesteryl oleate without affecting the removal from plasma of emulsion triolein. Nembutal when injected intravenously at a hypnotic dose did not affect the clearance of emulsion triolein or cholesteryl oleate, whereas at the anaesthetic dose, nembutal slowed the clearance rate of both labelled lipids.

3. Except for althesin, which did not affect the plasma clearance of triolein, fractional clearance rates of emulsion triolein and cholesteryl oleate calculated from blood samples taken during 12 min after injection were significantly slower in the anaesthetized groups compared with controls. However, with avertin, althesin, nembutal and ketamine/xylazine, amounts of radiolabelled triolein and cholesteryl oleate remaining in plasma 25 and 30 min after injection were comparable with the control. Radioactive lipids in plasma remained much higher in rats treated with urethane and fentanyl‐fluanisonium even 30 min after injection.

4. Avertin was simple to administer and produced a suitable depth of anaesthesia for minor surgery, tail vein injections and blood sampling, whereas althesin and the ketamine/xylazine mixture required supplementary doses to maintain anaesthesia towards the end of the experiment. We concluded that anaesthesia is best avoided for studies of chylomicron clearance. Avertin is the preferred agent if anaesthesia must be used, for example in newborn rats or in mice.
EFFECTS OF VERAPAMIL AND DILTIAZEM ON DOPAMINE RELEASE IN THE CENTRAL NERVOUS SYSTEM OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Tsuda Kazushi , Tsuda Seiko , Goldstein Menek , Masuyama Yoshiaki
Published: June 2007

1. The purpose of the present study was to investigate the effects of Ca2+‐antagonists (verapamil and diltiazem) on dopamine release in the central nervous system in hypertension.

2. Striatal slices obtained from spontaneously hypertensive rats (SHR) and Wistar‐Kyoto (WKY) rats were prelabelled with [3H]‐dopamine, and superfused with Krebs‐Ringer solution in vitro. The slices were stimulated electrically at a frequency of 1 Hz.

3. Stimulation‐evoked release of [3H]‐dopamine from striatal slices was significantly decreased in SHR compared with WKY rats.

4. Exposure of slices to verapamil and diltiazem significantly increased the stimulation‐evoked [3H]‐dopamine release. The facilitatory effects of the Ca2+‐antagonists on dopamine release were significantly greater in SHR than in WKY rats.

5. Because central nervous system dopaminergic mechanisms appear to be depressor, the results suggest that the pronounced effects of verapamil and diltiazem on dopamine release in SHR might be involved in the central hypotensive mechanisms of the Ca2+‐antagonists.
EFFECTS OF NAFTIDROFURYL ON ISOLATED PERFUSED KIDNEYS OF SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Zhang B. L. , Liu K. L. , Sacquet J. , Wiernsperger N. , Benzoni D. , Sassard J.
Published: June 2007

1. Experiments were designed to determine the effects of low concentrations (5–500 nmol/L) of naftidrofuryl, a 5‐hydroxytryptamine (5‐HT) antagonist, on renal functions and prostanoid synthesis responses to noradrenaline (NA) and 5‐HT. Isolated kidneys of 8 week old male spontaneously hypertensive rats were perfused at a constant flow rate in a single‐pass system.

2. In baseline conditions, naftidrofuryl did not modify the renal vascular resistance and the glomerular filtration rate (GFR), although it elicited a significant but not dose‐dependent increase in the venous excretion of 6‐keto‐prostaglandin (PG) F1α and thromboxane (Tx)B2, the stable end‐products of PGI2 and TxA2, respectively.

3. NA increased renal vascular resistance and GFR in a dose‐dependent manner and enhanced the venous excretion of 6‐keto‐PGF1α and TxB2. Naftidrofuryl significantly attenuated the effects of NA on renal vascular resistance, abolished those on GFR and enhanced, at the highest concentration (500 nmol/L) only, those on 6‐keto‐PGF1α excretion.

4. 5‐HT increased renal vascular resistance but not GFR. It did not change the sodium excretion and the release of 6‐keto‐PGF1α and TxB2. Naftidrofuryl blunted the RVR response to 5‐HT without change in the prostanoid release. The inhibitory action of naftidrofuryl was not modified by indomethacin which, by itself, prevented the vasoconstrictor response to 5‐HT.

5. It is concluded that, in isolated perfused kidneys of SHR, naftidrofuryl inhibits the contractile response to 5‐HT and NA; this effect is not dependent upon changes in synthesis of PGI2 or TxA2 and the vasoconstrictor effect of 5‐HT involves the release of a cyclooxygenase metabolite that differs from TXA2.
EFFECTS OF HIGH SALT INTAKE ON CONTROL OF HINDLIMB VASCULAR RESISTANCE BY ARTERIAL BROREFLEX AND VAGAL AFFERENTS IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Hoka Sumio , Takeshita Akira , Yamamoto Kunihiko , Ito Naoya
Published: June 2007

1. This study aimed to examine whether a high salt diet alters control of vascular resistance by arterial baroreflex and vagal afferents in spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY).

2. SHR and WKY aged 8 weeks were fed either high (8%) or normal salt (0.4%) diet for 4 weeks. Arterial baroreflex control of hindlimb vascular resistance was assessed by examining reflex‐induced vasodilation and vasoconstriction in response to phenylephrine and nitroprusside, respectively, in the constant‐flow perfused hindlimb of urethane‐anesthetized rats.

3. Tonic influence of the cardiopulmonary vagal afferents was evaluated by examining the effects of vagotomy on hindlimb vascular resistance and on the gain of arterial baroreflex control of hindlimb vascular resistance.

4. The gain of the arterial baroreflex control of hindlimb vascular resistance in response to both phenylephrine and nitroprusside were not significantly different between SHR receiving high and normal salt diets, and between WKY receiving high and normal salt diets.

5. Vagotomy increased hindlimb vascular resistance in all four groups of rats. However the magnitude of the increase in hindlimb vascular resistance was less in SHR on a high salt diet than those in SHR on a normal salt diet but similar between the two groups of WKY. Vagotomy increased the slope of arterial baroreflex control of hindlimb vascular resistance in SHR receiving a normal salt diet and the two groups of WKY but not in SHR receiving a high salt diet.

6. These results suggest that a high salt diet attenuates the inhibitory influence of vagal afferents on the control of vascular resistance in SHR but not in WKY, while the arterial baroreflex control of vascular resistance is preserved during high salt diet in both SHR and WKY.
PREVENTIVE EFFECT OF A NEW CALCIUM ANTAGONIST, MONATEPIL, ON DRUG‐INDUCED ISCHAEMIC ELECTROCARDIOGRAPHIC CHANGES IN RATS
Authors: Yamamoto Taku , Nakatsuji Katsuyoshi , Hosoki Kanoo , Karasawa Tadahiko
Published: June 2007

1. The preventive effects of monatepil, a new calcium antagonist with α1‐adrenoceptor blocking activity, on ischaemic electrocardiographic changes in rat models of vasospastic angina were evaluated and compared with those of the existing calcium antagonists (diltiazem, verapamil, nicardipine and nifedipine).

2. In order to assess the contribution of the α1‐adrenoceptor blocking action of monatepil to its anti‐vasospastic action, the anti‐ST depression effect of prazosin, an α1‐adrenoceptor blocker, was also examined.

3. Monatepil given orally (3–30 mg/kg) inhibited vasopressin (0.2 IU/kg, i.v.)‐induced ST depression which is considered to indicate ischaemic electrocardiographic changes in a vasospastic angina. This effect of monatepil was more potent and long‐lasting than that of diltiazem, and was similar to that of verapamil and nicardipine. At a dose of 30 mg/kg, monatepil produced a significant inhibition, even at 7 h after administration.

4. Monatepil given intravenously (0.3 mg/kg) exerted a significant inhibitory effect on methacholine (16 μg/kg, intracoronary arterial administration; i.c.a.)‐induced ST elevation which seems to be caused by coronary vasospasm. This effect was more potent or equipotent to those of the existing calcium antagonists.

5. These results indicate that monatepil produces the preventive effect on the drug‐induced ischaemic electrocardiographic changes in rats and suggest that monatepil may have potential for the treatment of vasospastic angina.
BLOOD PRESSURE EFFECTS OF THROMBOXANE A2 BLOCKADE IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Boussairi El Habib , Sacquet Joëlle , Benzoni Daniel , Sassard Jean
Published: June 2007

1. The effects of CGS 22652, a thromboxane (Tx) A2 synthase inhibitor and TxA2 prostaglandin (PG) H2 receptor antagonist, on blood pressure (BP) were studied in conscious freely moving spontaneously hypertensive rats (SHR).

2. Three groups of 13 male SHR were subcutaneously infused from 5 to 11 weeks of age via osmotic minipumps with CGS 22652 at doses of 5 (SHRa) or 10 (SHRb) mg/ kg per 24 h or with the vehicle only (SHRc). A fourth group (SHRd, n= 13) was orally treated from 3 to 11 weeks of age with CGS 22652 (30 mg/kg) given by gavage once a day.

3. CGS 22652 dose‐dependently reduced the age‐related increase in systolic BP. The pressor response to noradrenaline (200 ng/kg, i.v.) but not to angiotensin I or II was slightly (P<0.05) diminished in 11 week old SHRb and SHRd compared to SHRc. Acute ganglionic blockade by trimethaphan (10 mg/kg, i.v.), as well as angiotensin converting enzyme inhibition by perindopril (2 mg/kg, i.v.) decreased BP to a similar extent in the four groups. After combined blockade of vasopressin receptors and of the autonomic nervous system and the administration of a direct vasodilator (hydralazine, 3 mg/kg, i.v.), the residual mean BP was identical in the four groups of rats.

4. Chronic treatment with CGS 22652 dose‐dependently antagonized the TxA2 PGH2 receptors but did not modify the TxA2 synthesis. The urinary sodium excretion did not differ between groups.

5. In conclusion, at the doses used, CGS 22652 given either orally or subcutaneously exhibited only TxA2/PGH2 receptor blocking properties in SHR. Chronic treatment modestly prevented the development of hypertension in SHR, probably through a decrease in the pressor effects of TxA2 and of noradrenaline.
THE EFFECTS OF PERTUSSIS TOXIN ON VASOCONSTRICTOR AND VASODILATOR AGENTS IN THE PITHED RAT MAY NOT BE AN INDICATOR OF G‐PROTEIN RECEPTOR COUPLING
Authors: Costa Mary , Majewski Henryk
Published: June 2007

1. In the present study, rats were treated with pertussis toxin (8.4 μg, i.v.) to determine whether pertussis toxin‐sensitive G‐proteins were linked to receptors that mediate effects in the cardiovascular system.

2. In the pithed rat the pressor responses to the α‐adrenoceptor agonists noradrenaline and (to a lesser extent) methoxamine were attenuated by pertussis toxin treatment; the tachycardia produced by noradrenaline was unaffected. The pressor response to serotonin was also attenuated by pertussis toxin treatment. These observations are consistent with known effects of pertussis toxin on these receptors.

3. The vasodepressor responses to the muscarinic receptor agonist carbachol and to adenosine were reduced by pertussis toxin, suggesting that these events may have been mediated by pertussis toxin‐sensitive G‐proteins. However, the depressor responses to the β2‐adrenoceptor agonist salbutamol and to the receptor‐independent vasodilator drugs sodium nitroprusside and hydralazine were also reduced by pertussis toxin. These latter effects suggest that caution must be used in interpreting the effects of pertussis toxin since the mechanism of action of these drugs as elucidated in vitro is thought not to involve pertussis toxin‐sensitive G‐proteins.
IDENTIFICATION AND CHARACTERIZATION OF AN AMIDATING ENZYME IN OVINE HEART
Authors: Lew Rebecca A. , Smith A. Ian
Published: June 2007

1. Levels of peptidylglycine α‐amidating mono‐oxygenase (PAM) activity were examined in sheep and rat heart. This enzyme is responsible for α‐amidation of a large number of peptide hormones, a modification essential for the bioactivity of these peptides.

2. PAM activity was measured in membrane and soluble fractions of atrial and ventricular homogenates by monitoring the amidation of iodinated synthetic substrate ([125I]‐Ac‐Tyr‐Val‐Gly).

3. PAM activity in both species resided almost exclusively in the atria rather than the ventricles, and similar levels of activity were found in left and right atria. Membrane‐associated activity was 50‐to 100‐fold greater than soluble activity in the sheep, yet was only five‐ to 10‐fold greater in the rat, indicating a larger proportion of soluble enzyme in the rat atrium.

4. Similar apparent Km values were found for atrial membrane‐associated activity in both species (15.6 and 17.4 μmol/L for rat right and left atria, 16.7 and 15.6 μmol/L for sheep right and left atria); however, the maximum velocity (Vmax) levels were higher in the rat (40.5 and 43.9 pmol/μg per h vs 12.8 and 15.1 pmol/μg per h).

5. Because expression of many peptides and processing enzymes can be regulated by steroid hormones, the possible effects of chronic glucocorticoid administration (1 mg dexamethasone i.m. twice daily for 10 days) on PAM levels were tested in four sheep, with four sheep receiving saline only as controls. There was no discernible effect of dexamethasone on either the distribution or the kinetics of PAM activity in the sheep heart.

6. This study demonstrates the presence of high levels of predominantly membrane‐associated amidating activity in sheep atria, and the failure of glucocorticoid treatment to alter this activity. The presence of abundant atrial PAM activity suggests the production of an amidated peptide which has yet to be identified.
CORTISOL PRODUCTION BY ALDOSTERONE‐PRODUCING ADENOMASIN VITRO
Authors: Stowasser Michael , Tunny Terry J. , Klemm Shelley A. , Gordon Richard D.
Published: June 2007

1.In vitroshort‐term production of cortisol by dispersed tumour and non‐tumorous adrenal cortical cells was measured with and without added angiotensin II (AII) or adrenocorticotrophin (ACTH) in adrenals removed from five patients with primary aldosteronism.

2. Aldosterone‐producing adenomas (APA) were classified as angiotensin responsive (AII‐R) or angiotensin unresponsive (AII‐U) based on pre‐operative behaviourin vivo.

3. Cortisol was produced by both tumour and cortexin vitrowithout stimulation, and significantly more cortisol was generated by the cortex.

4. Addition of AII significantly increased cortisol production by both tumour and cortex to an equal extent.

5. Addition of ACTH also significantly increased cortisol production by both tumour and cortex, but tumours were more responsive than cortex. The response to ACTH exceeded the response to angiotensin in both tumour and cortex.

6. There was no obvious difference between AII‐R and AII‐U APA in terms of cortisol production.
DETECTION OF RENIN mRNA IN ALDOSTERONE‐PRODUCING ADENOMAS BY POLYMERASE CHAIN REACTION
Authors: Klemm Shelley , Pinet Florence , Rioual‐Caroff Nathalie , Tunny Terry , Corvol Pierre , Gordon Richard
Published: June 2007

1. Ribonucleic acid (RNA) was extracted from two normal human adrenal cortices and from five aldosterone‐producing adenomas (APA).

2. The five APA could be categorized, on the basis of in vivo aldosterone responsiveness to angiotensin infusion and upright posture, into two APA responsive to both stimuli, two responsive only to angiotensin infusion, and one unresponsive to either stimulus.

3. RNA was reverse transcribed and coamplified by polymerase chain reaction (PCR) with an internal standard of renin complementary DNA (cDNA) containing a 60 base pair insertion. Renin mRNA in the APA was compared with normal adrenals.

4. Renin mRNA was greater than normal in the two APA responsive to both stimuli and less than, or similar to normal, in the two APA responsive only to angiotensin infusion. Renin mRNA was also less than, or similar to normal, in the APA unresponsive to either stimulus.

5. These findings support a possible role for adrenal renin in the development and biochemical behaviour of angiotensin‐responsive APA.
ANGIOTENSIN‐RESPONSIVEALDOSTERONE‐PRODUCING ADENOMAS: POSTOPERATIVE DISAPPEARANCE OF ALDOSTERONE RESPONSE TO ANGIOTENSIN
Authors: Tunny Terry J. , Klemm Shelley A. , Stowasser Michael , Gordon Richard D.
Published: June 2007

1. Nineteen out of 47 patients (40%) with confirmed unilateral aldosterone‐producing adenoma (APA) were responsive to low‐dose angiotensin II infusion (AH‐R), as defined by an increase in plasma aldosterone concentration of >50% over basal at 2 ng/kg per min for 60 min.

2. Seven to ten days after unilateral adrenalectomy, aldosterone was no longer responsive to angiotensin infusion in AII‐R APA (100%, n = 17). Therefore, angiotensin responsiveness resides within the adenoma in AII‐R APA.

3. The upright posture test for the differentiation of adenoma from hyperplasia was unreliable for the AII‐R APA (26%), but generally reliable in the angiotensin‐unresponsive subtype, (AH‐U APA, 96%).

4. The reported predominance of females in APA was seen in AII‐U APA (68%), but was reversed in AII‐R APA (37%).