bluuebunny/crossref_metadata_2025 huggingface dataset:
ATRIAL NATRIURETIC FACTOR IN HUMAN PATHOPHYSIOLOGY
Authors: Crozier Ian G. , Richards A. Mark , Nicholls M. Gary , Espiner Eric A. , Ikram Hamid , Yandle Tim G.
Published: June 2007

1. Evidence from numerous experiments incorporating central blood volume expansion and changes in sodium status supports atrial stretch as the prime determinant of ANF release.

2. Plasma ANF levels are the result of both secretion and clearance of the peptide. Clearance is altered by a number of factors, including changes in posture in normal man and is probably impaired in disease states with diminished renal and hepatic blood flow.

3. In normal subjects an inverse relationship exists between plasma ANF values and renin‐angiotensin‐aldosterone system activity. This relationship is lost and replaced by a positive association in heart failure, presumably reflecting the abnormal concurrence of increased atrial stretch and diminished renal perfusion in this condition. Plasma ANF values rise with increasing severity of heart failure and fall with effective treatment.

4. Plasma ANF values are elevated in hypertension and cardiac tachyarrhythmias possibly reflecting raised central venous and atrial pressures.

5. A variety of other disorders may be associated with abnormal plasma ANF values including cirrhosis and the syndrome of inappropriate ADH secretion.

6. Evidence from low‐dose infusions of ANF in normal volunteers suggests that the variations in plasma ANF seen in health and disease are sufficient to exert biological effects.

7. The advent of a specific antagonist is needed to provide further insight into the physiological and pathophysiological roles of ANF.
SPONTANEOUS OSCILLATIONS IN CYTOPLASMIC FREE CALCIUM CONCENTRATION IN VASCULAR SMOOTH MUSCLE: A POTENTIAL MECHANISM ASSOCIATED WITH MYOGENIC TONE
Authors: Bobik Alex , Weissberg Peter L. , Little Peter J.
Published: June 2007

1. The cytoplasmic free calcium concentration was monitored in primary rat aortic smooth muscle cells, grown in culture and serum‐deprived for 24–48 h, with the calcium sensitive fluoroprobe, Fura‐2.

2. In the absence of external stimuli, spontaneous increases in the cytoplasmic free calcium concentration were observed which averaged 60±11 nmol/l and lasted approximately 30s.

3. The calcium transients were in part dependent on intracellular calcium and were abolished when the temperature was lowered to 10°C.

4. It is concluded that vascular smooth muscle cells have an inherent ability to initiate spontaneous transient increases in cytoplasmic free calcium concentration via membrane calcium channels.
RESPONSE OF ATRIAL NATRIURETIC PEPTIDE TO ADRENALINE AND NORADRENALINE INFUSION IN MAN
Authors: Tunny Terry J. , Bachmann Anthony W. , Gordon Richard D.
Published: June 2007

1. Atrial natriuretic peptide (ANP) levels were significantly increased during both adrenaline and noradrenaline infusions, in the physiological range, in normal subjects and in patients with essential hypertension.

2. During adrenaline infusion significant increases in both circulating adrenaline and noradrenaline levels were observed. Mean arterial pressure was unaltered. Changes in heart rate were not significant.

3. During noradrenaline infusion, significant increases in circulating noradrenaline and mean arterial pressure were also observed. Heart rate and plasma adrenaline levels were unaltered.

4. Fluctuations in sympathetic nervous system activity may be involved in the regulation of ANP via adrenoceptor stimulated release of ANP. Other known regulators such as atrial stretch and increasing heart rate may modify this response.
EFFECTS OF INDOMETHACIN ON STEROID‐INDUCED CHANGES IN PRESSOR RESPONSIVENESS IN MAN
Authors: Whitworth Judith A. , Connell John M. C. , Gordon Deanna , Scoggins† Bruce A.
Published: June 2007

1. It has been shown previously that hydrocortisone (F) increases pressor responsiveness in normal subjects. The present study examined the role of vasodilator prostanoids in determining these changes.

2. Pressor responsiveness to angiotensin II (AII) (1–8 ng/kg per min) and phenylephrine (PE) (0.3–0.9 μg/kg per min) was examined in six normal men receiving: no treatment (day 1); 100 mg indomethacm p.o. (INDO) in three divided doses over 20 h (day 2); 200 mg F for 5 days, 50 mg 6 hourly p.o. (day 6); F plus 100 mg INDO (day 7).

3. Blood pressure, body weight and plasma glucose rose with F and plasma potassium fell. F alone produced significant increases in response to AII at 2 ng/kg per min, for systolic pressure (SBP), diastolic pressure (DBP) and mean arterial pressure (MAP), and at 1 ng/kg per min for DBP. The threshold for SBP, DBP and MAP rises with AII was decreased by F. Responses to PE following F were greater at 0.6 μg/kg per min for SBP, DBP and MAP and the threshold for all parameters fell.

4. INDO alone had no significant blood pressure or metabolic effects and no effect on the magnitude of the blood pressure rise with AII, but decreased the threshold dose for effects on MAP. INDO had no effect on the magnitude of the pressure rise with PE, but decreased the threshold dose for effects on SBP.

5. INDO did not modify responsiveness or threshold to AII following F. Responsiveness to PE was unchanged and threshold fell for SBP only during INDO.

6. These data do not suggest a major role for vasodilator prostanoids in modifying pressor responsiveness in F‐treated subjects.
ADRENAL TRANSITIONAL ZONE STEROIDS, 18‐OXO AND 18‐HYDROXYCORTISOL, USEFUL IN THE DIAGNOSIS OF PRIMARY ALDOSTERONISM, ARE ACTH‐DEPENDENT
Authors: Hamlet Stephen M. , Gordon Richard D. , Gomez‐Sanchez Celso E. , Tunny Terry J. , Klemm Shelley A.
Published: June 2007

1. The adrenal cortical ‘hybrid’ steroids 18‐oxocortisol (18‐OF) and 18‐hydroxy‐cortisol (18‐OHF) are elevated in patients with typical angiotensin‐unresponsive aldosterone‐producing adenoma (AII‐unresponsive APA) and fall to normal following surgical removal of the adrenal containing the tumour. Since 18‐OF was six times the upper limit of normal pre‐operatively, the tumour was the site of overproduction of hybrid steroids.

2. The failure of angiotensin‐responsive APA to overproduce the hybrid steroids may be linked to their more ‘normal’ production of cortisol, which falls significantly on removal of the tumours.

3. Hybrid steroid levels were also normal in patients with idiopathic hyperplasia of the adrenals (IHA) and in low renin essential hypertension.

4. In All‐responsive APA, glucocorticoid‐suppressible hyperaldosteronism (GSH) and IHA, the hybrid steroids showed brisk responses to stimulation by ACTH and suppression by dexamethasone of endogenous ACTH.

5. Long‐term suppression by dexamethasone of hybrid steroids in GSH is consistent with ACTH dependence, rather than angiotensin dependence.

6. Studies of the regulation of hybrid steroid secretion in various categories of hypertension will further define the biosynthetic distinctiveness which is already useful diagnostically.
THREE Alu REPEATED SEQUENCES ASSOCIATED WITH A HUMAN GLANDULAR KALLIKREIN GENE
Authors: Schedlich Lynette J. , Morris Brian J.
Published: June 2007

1. Recently the complete primary structure of a human glandular kallikrein gene, hGK‐1, was reported. The present paper presents further structural information.

2. Associated with the gene were three Alu repeated sequences: one in the second intron and two approximately 0.4 kb and 1.2 kb upstream.

3. The 5′ non‐coding and 5′ flanking DNA was highly homologous to that in the mouse genes.

4. Different polyadenylation signals are used in different human kallikrein genes.
HIGH SALT DIET DECREASES LONGEVITY IN THE SPONTANEOUSLY HYPERTENSIVE RAT
Authors: Di Nicolantonio R. , Silvapulle M. J. , Spargo S. , Morgan T. O.
Published: June 2007

1. Blood pressure, body weight and mortality rate were examined in female spontaneously hypertensive rats (SHR) of the Okamoto strain maintained on a lifelong high (5% NaCl w/w) or low (0.1% NaCl w/w) salt diet.

2. A high salt diet increased mortality and decreased body weight in SHR, but failed to significantly alter blood pressure up to 24 months of age.

3. Hence, a low salt diet does not appear to be a long‐term risk factor and may protect the SHR from cardiovascular accidents.
THE EFFECT OF DIETARY FISH OIL AND LONG‐TERM SALT LOADING ON BLOOD PRESSURE AND EICOSANOID METABOLISM IN SPONTANEOUSLY HYPERTENSIVE RATS
Authors: Croft K. D. , Beilin L. J. , Codde J. , Vandongen R.
Published: June 2007

1. Dietary suppression of prostanoid synthesis with fish oils has had little effect on blood pressure in models of experimental hypertension in rats. However, a pressor effect of dietary fish oils was observed in spontaneously hypertensive rats (SHR) subject to 1 week of salt loading.

2. Animals were allocated to semisynthetic diets containing either 10% by weight Max EPA fish oil or a control diet of coconut oil, and studied after receiving 1.5% saline for 4 weeks.

3. Within the first week of salt loading, SHR‐fed fish oil showed an increase in blood pressure (mean = 9 mmHg) relative to controls. This effect was transient, and after the first week of salt loading there was little difference in blood pressure between the two dietary groups.

4. Following dietary treatment there were substantial changes in plasma fatty acid composition with a 48% decrease in arachidonic acid content of fish oil‐fed rats compared with control animals. Rats on the fish oil diet showed a threefold decrease in serum thromboxane generation. Prostacyclin production by incubated segments of aorta was reduced by more than 50% compared with the coconut oil‐fed control group.

5. SHR on the fish oil diet showed increased urine volume and sodium excretion, presumably due to increased fluid and salt intake.

6. This study shows that dietary suppression of prostacyclin synthesis is associated with only a minor effect on blood pressure in long‐term salt loading of SHR.
AN ANALYSIS OF THE HAEMODYNAMIC EFFECTS OF TOLBUTAMIDE IN CONSCIOUS DOGS
Authors: Lee King C. , Wilson Randall A. , Randall David C. , Altiere Ralph J. , Kiritsy‐Roy Judith A.
Published: June 2007

1. In conscious chronically instrumented dogs, tolbutamide (5–45 mg/kg) induced significant dose‐related increases in mean arterial pressure and left ventricular enddiastolic pressure.

2. Cardiac output was descreased while heart rate, d(LVP)/dt, and regional myocardial performance at the left ventricle were not significantly affected. Computed total peripheral resistance was increased.

3. Pretreatment with the a‐antagonist phentolamine (1–1.5 mg/kg) abolished the pressor response. Furthermore, the pressor response to norepinephrine (0.1 μg/kg) was enhanced by pretreatment with tolbutamide (45 mg/kg).

4. In an isolated tissue preparation using ring segments of canine femoral arteries, neither tolbutamide nor its major hepatic metabolites (carboxytolbutamide, p‐toluenesulfonamide and p‐toluenesulfonylurea) caused any smooth muscle contraction. However, pretreatment of these tissues with 10–4, 10–3, or 10–2 mol/l tolbutamide potentiated the contractile response to norepinephrine by up to 19% and to phenylephrine by up to 8%.

5. It was concluded that the pressor effect of tolbutamide arises by potentiating the a‐adrenoceptor mediated vasoconstrictor action of circulating endogenous catecholamines.
DIHYDROCYCLOSPORIN D IN SHEEP: HAEMODYNAMIC AND RENAL EFFECTS
Authors: Tresham J. J. , Whitworth J. A. , de Lima J. J. G. , McDougall J. G. , Scoggins B. A.
Published: June 2007

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1. This study was designed to test the haemodynamic and renal effects in sheep of dihydrocyclosporin D (dCyD), an immunosuppressant agent derived from the fungus Tolypocladium inflatum Gams.

2. dCyD was infused for 5 days at 12 mg/kg per day. Mean arterial pressure (MAP) was elevated after 24 h, but thereafter returned to control levels. Heart rate was significantly elevated throughout the infusion and was still high 24 h postinfusion. Cardiac output rose after 5 days, but total peripheral resistance was unchanged during the infusion.

3. Glomerular filtration rate, renal blood flow and effective renal plasma flow remained unchanged, although urine sodium excretion rose for the first 48 h.

4. Infusion of the castor oil‐based vehicle for cyclosporin, Cremaphore EL, for 5 days in four sheep did not produce any sustained changes in any of the parameters measured.
THE EFFECT OF TRIFLUOPERAZINE ON BRONCHIAL RESPONSIVENESS IN ASTHMA
Authors: Bowden J. J. , Latimer K. M. , Crockett A. J. , Ruffin R. E.
Published: June 2007

1. The protective effects of oral trifluoperazine (TFP) (7mg) against standardized methacholine and histamine inhalation tests (MIT and HIT) were examined 2 and 22 h post‐treatment in eight stable asthmatics using a randomized double‐blind protocol.

2. A preliminary study tested whether a preceding MIT influenced the result of a subsequent HIT.

3. The mean baseline forced expiratory volumes in 1 s (FEV1) were similar prior to placebo and TFP. The mean FEV1 values 2 h after ingestion of placebo or TFP were not different from the baseline values.

4. TFP did not alter bronchial responsiveness to inhaled methacholine or histamine 2 h postingestion, but at 22 h the PC20 methacholine was greater than placebo, while PC20 histamine did not change. This change in methacholine responsiveness was not clinically significant.

5. There was a correlation between geometric mean provocative concentration of histamine to cause 20% fall in FEV (PC20H) for HIT performed in isolation ('separate day') and for HIT performed after MIT (‘same day’).

6. The effect of inhaled TFP (10 mg/ml, nebulized for 5 min) was examined single‐blind and placebo‐controlled in a separate group of six stable asthmatics.

7. Inhaled TFP had a bronchoconstrictor effect in all six asthmatics. The mean fall in FEV1 was 36.4% after inhaled TFP and 2.1% after saline.

8. In the asthmatics studied, ingested TFP exhibited a weak anticholinergic effect 22 h pest‐treatment, but a brisk spontaneously self reverting bronchoconstrictor response was invariably seen when TFP was inhaled.
CALMODULIN‐ANTAGONIST DRUGS AND PORCINE MALIGNANT HYPERPYREXIA
Authors: Collins S. P. , White M. D. , Denborough M. A.
Published: June 2007

1. Landrace swine were identified as malignant hyperpyrexia susceptible (MHS) or control by the contracture responses of gracilis muscle fibre bundles to 3% halothane, 2 mmol/l caffeine and 80 mmol/l KCI. The effects of calmodulin‐antagonist drugs on the contractile behaviour of control and MHS preparations were investigated in vitro.

2. Calmodulin‐antagonists at micromolar concentrations induced contracture in both control and MHS muscle. Pretreatment of MHS muscle with calmodulin‐antagonist drugs potentiated its response to halothane and caffeine.

3. These results suggest that calmodulin‐antagonist drugs cause an increase in myoplasmic Ca2+ concentration in both control and MHS muscle.
CARDIOVASCULAR RESPONSE TO EMOTIONAL STRESS AND SPONTANEOUS BLOOD PRESSURE VARIABILITY IN GENETICALLY HYPERTENSIVE RATS OF THE LYON STRAIN
Authors: Julien C. , Cerutti C. , Kandza P. , Barres C. , Su D. , Vincent M. , Sassard J.
Published: June 2007

1. Intra‐aortic blood pressure (BP) was continuously recorded in freely moving genetically hypertensive (LH), normotensive (LN) and low BP (LL) rats of the Lyon strains under basal conditions and during aversive stimulation (a jet of air for 20 min). Rats were studied when 5 and 14 weeks old.

2. The 24 h standard deviation (i.e., variability) of diastolic BP was significantly greater in LH rats of both ages than in LN and LL control rats.

3. In response to the stressor, LH rats showed larger increases in BP than age‐matched controls.

4. The BP variability was related to the BP responses to stress in the whole series of rats.

5. It is concluded that the spontaneous BP variability and the BP responses to an experimental stressor rely upon a common regulatory mechanism in rats and that an increased lability of diastolic BP is a primary characteristic of Lyon hypertensive rats.
CALMODULIN‐INDEPENDENT STIMULATION OF RENIN RELEASE BY EXPOSURE OF RAT KIDNEY CORTICAL SLICES TO CALCIUM
Authors: Matsumura Y. , Koyama Y. , Shinyama H. , Uriu T. , Ichihara T. , Morimoto S.
Published: June 2007

1. Effects of calcium‐interacting agents on the calcium‐induced stimulation of renin release from kidney cortical slices pretreated with calcium‐free medium were examined.

2. The exposure of calcium to the slices pretreated with calcium‐free medium enhanced the release of renin, followed by a decreased response in the release. The amount of lactate dehydrogenase released from the slices did not correlate with that of renin.

3. High potassium depolarization significantly potentiated the decreased response of renin release, with no influence on the stimulation of the release by exposure to calcium.

4. The decrease in renin release was attenuated by calcium‐interacting agents, such as nifedipine, TMB‐8 and W‐7, but these agents were without effect on the stimulation of the release by exposure to calcium.

5. Thus, the calcium‐calmodulin system apparently is not involved in the increased response of renin release following exposure to calcium.
COMPARISON OF THE ACTIVITY OF CIRCULAR AND LONGITUDINAL MYOMETRIUM FROM PREGNANT RATS: CO‐ORDINATION BETWEEN MUSCLE LAYERS
Authors: Tomiyasu B. A. , Chen C. J. , Marshall J. M.
Published: June 2007

1. Contractions and electrical activity were recorded from isolated segments of longitudinal (L) and circular (C) myometrium from rats on gestation days 16–17 and 21 before and during parturition.

2. The segments were arranged so that the activity of the two layers could be monitored simultaneously and independently.

3. Out of the 15 preparations from days 16–17, 13 showed no co‐ordination of activity between the layers. In the other two preparations a large contraction of C occasionally initiated a contraction of L. Surgical separation of the layers disrupted the co‐ordination and L then developed its independent rhythm.

4. On day 21 before delivery, eight of 10 preparations exhibited 1:1 co‐ordination of activity between the two layers, but C did not consistently pace L. The pacing shifted from one layer to the other several times during an experiment.

5. During parturition there was a 1:1 co‐ordination of activity in all 10 preparations examined. In nine of these L initiated the activity of the C. Surgical separation of the layers disrupted the co‐ordination and C developed its independent rhythm. In one the pacing shifted from one layer to the other several times during the experiment.

6. In all cases where co‐ordination between the layers was observed it was myogenic and apparently related to the spread of action potentials between the two muscles.
ARRHYTHMOGENIC EFFECT OF FORSKOLIN IN THE ISOLATED PERFUSED RAT HEART: INFLUENCE OF NIFEDIPINE REDUCTION OF EXTERNAL CALCIUM
Authors: Huang X. D. , Wong T. M.
Published: June 2007

1. This study investigated first the effects of forskolin on cardiac rhythm, and second the roles of calcium in cardiac arrhythmogenesis by cAMP.

2. Two series of experiments were performed. In the first series, forskolin was administered into the isolated perfused rat heart. In the second series, forskolin administration was preceded by administration of nifedipine, a calcium channel blocker, or infusion of a low concentration calcium solution. In both experiments, the myocardial cAMP level and electrocardiogram were determined.

3. It was found that forskolin increased cAMP level as well as inducing arrhythmia. Pretreatment with nifedipine or a reduction of external calcium, that either maintained or further enhancd the forskolin‐induced increase in the cAMP level, abolished the forskolin‐induced arrhythmia.

4. The results of the present study support the hypothesis that myocardial cAMP mediates cardiac arrhythmia, and provide evidence that calcium is essential in arrhythmia mediated by cAMP.
ADRENOCORTICAL STEROID REQUIREMENTS FOR INITIATION OF ACTH‐DEPENDENT HYPERTENSION IN SHEEP
Authors: Spence Campbell D. , Coghlan John P. , Denton Derek A. , Mills Eric H. , Whitworth Judith A. , Scoggins Bruce A.
Published: June 2007

1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11‐deoxycortisol (S), 17α‐hydroxyprogesterone (17αOHP) and 17α, 20α‐dihydroxy‐4‐pregnane‐3‐one (17α20αOHP), at rates equivalent to their production during adrenocorticotrophic hormone (ACTH) treatment, reproduced the pressor and metabolic responses to ACTH administration in sheep.

2. This study examined which of these adrenocortical steroids were necessary for the initiation of the hypertension produced by these steroids in sheep.

3. Infusion of F, ALDO, 17αOHP and 17α20αOHP together, increased MAP by 19 mmHg, similar to both complete steroid cocktail (+25 mmHg) or ACTH administration (+ 21 mmHg). Infusion of F, 17αOHP and 17α20αOHP increased MAP by +7 mmHg. Infusion of ALDO, 17αOHP and 17α20αOHP had no effect on MAP. Thus F and ALDO were essential for the pressor effects of the steroid infusion.

4. To determine the role of glucocorticoid activity in the MAP rise, prednisolone, a non‐pressor glucocorticoid, was substituted for cortisol. Combined prednisolone, ALDO, 17αOHP and 17α20αOHP infusion did not raise blood pressure. This suggested that the mineralocorticoid component rather than glucocorticoid component of cortisol's activity was involved in the pressor response.

5. Aldosterone (7 μg/h) was substituted for cortisol, giving a total of 10 μg/h aldosterone. High dose ALDO (10 μg/h), 17αOHP and 17α20αOHP infusion raised blood pressure by 18 mmHg. Thus, the essential role of cortisol appeared to be due to its occupancy of mineralocorticoid receptors, rather than glucocorticoid receptors.

6. Given that ACTH produces a transient initial increase in aldosterone secretion of up to 10 μg/h, it appears that aldosterone and not cortisol is essential for the pressor effects of ACTH.

7. Hypertension resulting from the combined steroid infusion in the sheep appears to be produced by a mechanism which involves a complex interaction between ALDO, F, 17αOHP and 17α20αOHP. Therefore, the putative ‘hypertensinogenic’ receptor may be multivalent with binding sites for F, ALDO and 17α20αOHP, or is a site of single interactive receptors for these steroids and that F exerts its permissive action by occupying the same site as ALDO on the hypertensinogenic receptors.
MATERNOFETAL TRANSFER OF PHENYTOIN, p‐HYDROXY‐PHENYTOIN AND p‐HYDROXY‐PHENYTOIN‐GLUCURONIDE IN THE PERFUSED HUMAN PLACENTA
Authors: Dickinson R. G. , Fowler D. W. , Kluck R. M.
Published: June 2007

1. Transplacental transfer of the anti‐epileptic agent phenytoin (PHT), its phase I metabolite, p‐hydroxy‐phenytoin (p‐OH‐PHT), and its phase II conjugate p‐OH‐PHT‐glucuronide, was studied in term placental lobules perfused single pass in both maternal and fetal circuits.

2. Ratios of clearance of PHT, p‐OH‐PHT and p‐OH‐PHT‐glucuronide to clearance of antipyrine were 1.08 ± 0.03, 0.52 ± 0.02 and 0.12 ± 0.01 (mean and s.e.m.), respectively.

3. Transfer was positively correlated with lipophilicity as measured by the apparent partition coefficient determined between octanol and pH 7.4 buffer.
INHIBITION OF SYMPATHETIC NEUROTRANSMISSION BY THE OPIOID δ‐RECEPTOR AGONIST DAMA IN THE PITHED RAT
Authors: Wong‐Dusting Helen , Rand Michael J.
Published: June 2007

1. The effects of [d‐Ala2, Met5]enkephalinamide (DAMA), an analogue of [Met5]‐enkephalin that acts selectively on opioid receptors of the 8‐subtype, were studied on pressor responses elicited by sympathetic stimulation in pithed rats.

2. Intravenous injections of bolus doses of 0.1 mg/kg and 0.3 mg/kg of DAMA did not affect either the basal blood pressure or pressor responses to noradrenaline.

3. Pressor responses elicited either by electrical stimulation of the spinal sympathetic outflow or by stimulation of sympathetic ganglion cells with the muscarinic agonist McN‐A‐343 were reduced by DAMA.

4. Naloxone (1 mg/kg + 0.5 mg/kg per h) had no significant effect on the basal blood pressure or on pressor responses to spinal sympathetic stimulation, but antagonised the inhibitory effect of DAMA.

5. These results indicate that activation of opioid 8‐receptors on sympathetic vasomotor nerve terminals can inhibit noradrenergic neurotransmission.
STUDIES ON THE BIPHASIC RELAXANT CURVE OF GLYCERYLTRINITRATE IN RAT AORTA: ROLE OF GTN METABOLITES
Authors: Malta Errol
Published: June 2007

1. The present study has examined the possibility that one or more metabolites of glyceryltrinitrate (GTN) (i.e. glyceryl‐1,2‐ and ‐1,3‐dinitrate and glyceryl‐1‐ and ‐2‐mononitrate) may be responsible for the second phase of the biphasic relaxant curve to GTN in phenylephrine‐contracted rings of rat aorta.

2. The IC50 values for the two phases of the GTN curve were 0.1 μmol/L and 12 μmol/L with the initial phase eliciting 60% of the total relaxation response. The curves for glyceryl‐1,2‐ and ‐1,3‐dinitrate were monophasic with IC50 values of 248 μmol/L and 110 μmol/L, respectively. The mononitrate metabolites elicited relaxant effects at concentrations ≥ 1 mmol/L.

3. The induction of tolerance to GTN or pretreatment with oxyhaemoglobin (5 μmol/L) resulted in a monophasic GTN curve with IC50 values of 16 μmol/L and 18 μmol/L respectively suggesting selective abolition of responses to low concentrations of GTN with little effect on responses to high concentrations of GTN. The relaxant effects of the ‐1,2‐ and ‐1,3‐ dinitrates, like that to GTN, were essentially unaltered by GTN tolerance or oxyhaemoglobin.

4. Thus while the relaxant effects of the dinitrate metabolites possess similar properties to that of the second phase of relaxation to GTN, a role for these metabolites is unlikely since their IC50 values are 9–20‐fold greater than that for the second phase of relaxation to GTN. Whether these differences are due to the 8–10‐fold lower lipophilicity of the dinitrates as compared with the parent compound requires further study.
SYNERGISTIC POTENTIATION BY CAPTOPRIL AND PROPRANOLOL OF BRADYKININ‐INDUCED BRONCHOCONSTRICTION IN THE GUINEA‐PIG
Authors: Lau W. A. K. , Rechtman M. P. , Boura A. L. A. , King R. G.
Published: June 2007

1. Captopril (30 or 100 μg/kg intravenous (i.v.)) in anaesthetized artificially ventilated guinea‐pigs potentiated bronchoconstrictor responses to bradykinin, but not those to histamine or the thromboxane A2‐mimetic U46619.

2. Propranolol (5 mg/kg, i.v.) potentiated bradykinin‐induced bronchoconstriction. The potentiated responses were further augmented by captopril.

3. The captopril‐potentiated responses to bradykinin were inhibited during cyclo‐oxygenase inhibition with indomethacin. Bronchoconstrictor responses to bradykinin, but not those to histamine or U46619, were reduced after thromboxane synthase inhibition with dazoxiben. The thromboxane A2 antagonist AH23848 inhibited bronchoconstrictor responses to bradykinin, arachidonic acid or U46619 whereas it did not affect those to histamine.

4. A kininase I inhibitor dl‐2‐mercaptomethyl‐3‐guanidinoethyl thiopropanoic acid caused no change in bronchoconstriction caused by bradykinin and did not alter the potentiated responses occurring after captopril.

5. Thus, confirmation has been obtained that bradykinin causes bronchoconstriction in the guinea‐pig indirectly, by release of eicosanoids. Thromboxane A2 is likely to be the major eicosanoid released, since the bronchoconstrictor effect of bradykinin was blocked by indomethacin, dazoxiben and AH23848. The intensity of the bronchoconstriction appears dependent on sympathetic influences mediated by β‐adrenoceptors. Kininase I, in contrast to kininase II apparently has little role in terminating the effects of bradykinin in the lung.
EFFECTS OF ADENOSINE ANTAGONISM AND β‐BLOCKADE DURING LOW‐FLOW ISCHAEMIA IN RAT HEART
Authors: Headrick J. P. , Willis R. J.
Published: June 2007

1. The effects of adenosine antagonism (8‐phenyltheophylline) and β‐blockade (1‐propranolol) were examined during low‐flow ischaemia (0.5 mL/min per g for 20 min) in rat heart.

2. Myocardial adenosine release, heart rate, and left ventricular developed pressure were monitored to determine whether endogenous adenosine affected ischaemic function directly, and/or via interaction with endogenous catecholamines.

3. Adenosine release increased more than 10‐fold during low‐flow ischaemia. Release displayed a phasic pattern, with maximal release occurring at 10 min. Ischaemia produced bradycardia (—180 beats/min) which was reduced by 8‐phenyltheophylline infusion (P < 0.001, n= 10). Adenosine antagonism also significantly increased left ventricular developed pressure in the initial 5 min of ischaemia (P < 0.001, n= 10).

4. β‐blockade alone was without effect in ischaemic hearts, however, β‐blockade significantly reduced the initial increases in heart rate and developed pressure observed during infusion of 8‐phenyltheophylline (P < 0.001, n= 10). The effect of β‐blockade was transient, occurring in the initial 5–6 min of ischaemia.

5. The data indicate that endogenous adenosine directly mediates > 30% of the bradycardia associated with low‐flow ischaemia, and that endogenous adenosine inhibits the release and/or the effects of endogenous catecholamines produced during the initial 5–6 min of ischaemia.
RENAL INTERACTION OF ATRIAL NATRIURETIC PEPTIDE WITH ANGIOTENSIN II: GLOMERULAR AND TUBULAR EFFECTS
Authors: Rakugi Hiromi , Ogihara Toshio , Nakamaru Mitsuaki , Saito Hiroshi , Shima Junko , Sakaguchi Katsuhiko , Kumabara Yuichi
Published: June 2007

1. The possible interactions between the renal effects of atrial natriuretic peptide (ANP) and angiotensin II (All) were studied in normal sodium‐replete human subjects. Recent investigations have suggested that ANP inhibits the pressor and volume‐retaining effects of activation of the renin‐angiotensin system. Thus, ANP may attenuate the effects of All on renal haemodynamics or tubular transport.

2. ANP (0.1 μg/kg per min, 60 min) was intravenously infused into eight normal human subjects with and without pretreatment with enalapril (20 mg, per oral), an inhibitor of the converting enzyme, and during infusion of All (10 mg/kg per min).

3. ANP infusion alone caused increases in the urine volume (from 96 ± 23 to 229 ± 44 mL/h, P < 0.05) and urinary sodium excretion (from 11.5 ± 1.6 to 20.9 ± 4.2 mEq/h, P < 0.05). These changes were accompanied by an increase in the glomerular filtration rate (from 127 ± 9 to 158 ± 9 mL/min, P < 0.05). ANP infusion after enalapril administration lowered the mean blood pressure (from 76 ± 2 to 71 ± 3 mmHg, P < 0.05) to a level similar to that observed during ANP infusion alone (from 84 ± 2 to 74 ± 2 mmHg, P < 0.01), but did not result in a significant diuresis (from 139 ± 23 to 174 ± 51 mL/h) or natriuresis (from 19.7 ± 2.5 to 14.3 ± 3.4 mEq/h, P < 0.05). This combined treatment with a converting enzyme inhibitor and ANP reduced both the glomerular filtration rate (160 ± 9 to 141 ± 10 mL/min) and the renal plasma flow (from 775 ± 49 to 570 ± 45 mL/min, P < 0.01).

4. The antinatriuretic effects of exogenous All were reversed by superimposed ANP infusion (urinary sodium excretion: from 4.8 ± 1.0 to 24.3 ± 5.2 mEq/h, P < 0.01). Under these conditions, the glomerular filtration rate increased (from 114 ± 6 to 156 ± 7 mL/min, P < 0.05) to levels similar to those observed with ANP infusion alone. In addition the increased tubular sodium reabsorption induced by All was inhibited by concomitant ANP infusion (fractional proximal tubular sodium reabsorption: from 90.7 ± 3.5 to 80.3 ± 16.6%, P < 0.05, fractional post‐proximal tubular sodium reabsorption: from 91.5 ± 9.8 to 87.6 ± 8.8%, P < 0.05).

5. These results suggest that ANP interacts with endogenous All particularly in the glomerulus, to cause a diuresis and natriuresis, and also suggest that ANP inhibits All‐induced tubular sodium reabsorption.
DOPAMINE RECEPTOR BLOCKING ACTION OF A DIBENZOTHIEPIN DERIVATIVE ISOFLOXYTHEPIN IN RATS
Authors: Yamada K. , Matsuo N. , Nagashima M. , Kumagai M. , Furukawa T.
Published: June 2007

1. Subcutaneous injection of isofloxythepin or haloperidol inhibited exploratory behaviour, methamphetamine (3 mg/kg)‐induced hyperactivity and bromocriptine (15 mg/kg)‐induced yawning, and also elicited catalepsy.

2. Isofloxythepin and haloperidol increased concentrations of dihydroxyphenyl‐acetic acid in the striatum and elevated serum prolactin levels.

3. The results suggest that isofloxythepin, as well as haloperidol, blocks the action of the dopamine D2‐receptors in the striatum, nucleus accumbens and pituitary.
EVIDENCE THAT INCREASES IN CIRCULATING CATECHOLAMINES OF ADRENAL ORIGIN ARE NOT INVOLVED IN PRESSOR RESPONSE TO BILATERAL CAROTID OCCLUSION IN ANAESTHETIZED DOGS
Authors: Brassard Martine , Yamaguchi Nobuharu
Published: June 2007

1. We studied whether or not circulating catecholamines of adrenal origin play a major role in cardiovascular responses evoked by bilateral carotid artery occlusion (3 min) in anaesthetized dogs.

2. In the control group, the following parameters increased significantly (P < 0.05) during bilateral carotid occlusion: aortic systolic pressure, heart rate, net adrenal catecholamine output, net renal noradrenaline output, and plasma catecholamine concentrations in aortic blood. Similar responses were obtained during the second occlusion performed approximately 25 min after the first occlusion.

3. After functional adrenalectomy (ADRX: diversion of adrenal venous blood flow), the increase in aortic adrenaline concentration observed during bilateral carotid occlusion was abolished. The increase in aortic noradrenaline concentration during the occlusion was significantly attenuated by approximately 60% (P < 0.01) after ADRX.

4. The increase in net renal noradrenaline output during bilateral carotid occlusion after ADRX was not different from that observed before ADRX. Similarly, the response of aortic systolic pressure and heart rate during the occlusion was unaffected by ADRX. Furthermore, the increase in net adrenal catecholamine output during the occlusion was not affected by ADRX itself.

5. From these results, we conclude that the increase in circulating catecholamines of adrenal origin during bilateral carotid occlusion is not a major determinant for the increases in aortic pressure and heart rate. The results suggest that these cardiovascular responses during the occlusion are mediated principally by neuronal noradrenaline released from peripheral sympathetic nerve terminals.
INHIBITION OF VASOCONSTRICTION BY PLATELET ACTIVATING FACTOR IN THE IN SITU BLOOD PERFUSED RAT MESENTERY
Authors: Gerkens John F.
Published: June 2007

1. Perfusion pressure was measured in the in situ mesentery of anaesthetized rats perfused with blood at a constant 2 mL/min.

2. Increases in perfusion pressure were produced by mesenteric peri‐arterial nerve stimulation at 10 Hz for 5 s at 2 min intervals and by bolus intra‐arterial injections of the vasoconstrictors noradrenaline, angiotensin II and 5‐hydroxytryptamine.

3. The intra‐arterial infusion of platelet‐activating factor (PAF) to produce a blood concentration of 3 × 10−10 mol/L inhibited all responses to a similar extent. Intra‐arterial prazosin (1–5 × 10−9 mol/L), however, preferentially reduced responses to nerve stimulation and noradrenaline.

4. PAF at concentrations from 3 × 10−11 to 10−9 mol/L produced increasing inhibition of vasoconstrictor responses to nerve stimulation. The dose‐response to PAF was shifted to the right by the concomitant intra‐arterial infusion of the PAF antagonist SRI 63–441.

5. PAF at very low concentrations in vivo inhibits mesenteric vasoconstriction, produced by sympathetic nerve stimulation or various agonists, by a PAF‐receptor mediated vasodilatation of the mesenteric vasculature.
CHARACTERIZATION OF SINGLE HEART CELL CONTRACTILITY BY RAPID IMAGING
Authors: Delbridge Leanne M. , Harris Peter J. , Morgan Trefor O.
Published: June 2007

1. A rapid imaging technique with temporal resolution of about 1 ms was employed to describe cell‐length changes during the isotonic contraction cycle of adult rat ventricular myocytes at 22°C.

2. Parameters of cell contraction and relaxation were defined and values obtained under control conditions and after treatment with 5 μmol/L verapamil.

3. Over 15 min, verapamil dramatically reduced the maximum shortening attained. This was associated with delay in both excitation‐contraction coupling latency and the time at which maximum rate of shortening occurred. However, peak shortening was recorded earlier in the contraction cycle. Total cell‐cycle time was abbreviated under the influence of verapamil and maximum rates of shortening and lengthening were depressed in a similar manner.

4. The results highlight the value of improved temporal precision in describing myocyte contractility and validate the use of the parameters defined in the single‐cell model for the study of the mechanisms of action of cardiotonic agents.
NATRIURETIC AND HYPOTENSIVE EFFECTS OF BRAIN NATRIURETIC PEPTIDE IN ANAESTHETIZED DOCA‐SALT HYPERTENSIVE RATS
Authors: Kita Toshihiro , Kida Osamu , Kato Johji , Nakamura Shigeru , Eto Tanenao , Minamino Naoto , Kangawa Kenji , Matsuo Hisayuki , Tanaka Kenjiro
Published: June 2007

1. Both natriuretic and hypotensive effects of brain natriuretic peptide (BNP), a novel peptide identified in porcine brain, were investigated in anaesthetized DOCA‐salt rats and control rats.

2. An intravenous injection of two different doses (0.5 and 5.0 nmol/kg) of BNP produced a rapid and marked natriuresis and hypotension in DOCA‐salt rats.

3. In particular, significant differences of responsiveness were observed between DOCA‐salt and control rats when administered the lower dose of BNP.

4. It was suggested that DOCA‐salt rats might be relatively more susceptible to BNP.
EFFECT OF COLFORSIN ON HUMAN NEUTROPHIL SUPEROXIDE PRODUCTION AND INTRACELLULAR CALCIUM MOBILIZATION
Authors: Furui Hidehiko , Suzuki Kenji , Takagi Kenzo , Satake Tatsuo
Published: June 2007

1. The effects of dibutyryl cyclic AMP (cAMP), isoproterenol and colforsin (forskolin) were evaluated on respiratory burst in human polymorphonuclear neutrophils (PMN).

2. Dibutyryl cAMP showed a dose‐dependent inhibition of n‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP)‐induced superoxide production by human PMN.

3. Administration of isoproterenol induced a dose‐dependent inhibition of FMLP‐induced superoxide production by human PMN, and the inhibition was blocked by propranolol.

4. Administration of colforsin induced a dose‐dependent inhibition of FMLP‐induced superoxide production by human PMN, and the inhibition could not be blocked by propranolol.

5. Incubation with colforsin caused a significant increase in the cAMP level in human PMN.

6. Pretreatment with colforsin caused a dose‐dependent inhibition in the elevation of intracellular free calcium (monitored by fura‐2 fluorescence), which was observed in human PMN stimulated with FMLP.

7. These results suggest that cAMP is an inhibitory factor of superoxide production and intracellular calcium mobilization in human PMN stimulated with FMLP.
ENDOTHELIN RECEPTORS IN RAT ADRENAL GLAND VISUALIZED BY QUANTITATIVE AUTORADIOGRAPHY
Authors: Kohzuki Masahiro , Johnston Colin I. , Chai Siew Yeen , Casley David J. , Rogerson Fraser , Mendelsohn Frederick A. O.
Published: June 2007

1. The radioligand [125I]‐endothelin was used to map receptors for endothelin in rat adrenal gland using in vitro autoradiography and computerized densitometry.

2. In the adrenal, a high density of binding was found in the adrenal medulla (binding affinity constant 0.18 ± 0.11 × 109M−1) and zona glomerulosa (binding affinity constant 0.18 ± 0.07 × 109M−1). Binding was low to undetectable in the zona fasciculata and zona reticularis. Unrelated peptides did not displace endothelin.

3. These results provide evidence of endothelin receptor distribution in adrenal gland and suggest that endothelin might exert multiple actions in the adrenal gland on catecholamine and aldosterone biosynthesis and secretion.
REPRODUCIBILITY OF 24‐HOUR NON‐INVASIVE AMBULATORY BLOOD PRESSURE MONITORING USING THE SUNTECH ACCUTRACKER
Authors: Torre L. B. , Rouse I. L. , Beilin L. J.
Published: June 2007

1. The reproducibility of 24‐hour non‐invasive ambulatory blood pressure monitoring (ABPM) using the ‘Accutracker’ (AC) (Suntech Medical Instruments, NC) was determined to evaluate the AC's suitability for clinical trials investigating the effects of environmental determinants on blood pressure.

2. Six healthy males from the University Department of Medicine underwent 24 h ABPM on the same working day of the week on six occasions. Reproducibility of hourly mean systolic blood pressure (SBP) and diastolic blood pressure (DBP) was determined using analysis of variance.

3. No familiarization effect of measurement with the AC was detected.

4. When comparing four time periods (0000–0759 h, 0800–1259 h, 1300–1859 h and 1900–2359 h), reproducibility of SBP was highest during the afternoon (1300–1859 h) whereas reproducibility of DBP was highest during late morning (0800–1259 h).

5. Hourly mean SBP was significantly lower during late morning (0800–1259 h) than in the afternoon (1300–1859 h) or at night (1900–2359 h). Hourly mean SBP and DBP was significantly lower during sleep.

6. Based on a select sample of volunteers, the AC is suitable for clinical trials involving paired measurements, particularly between 0800 and 1900 h when only 10–15 subjects would provide 80% power to demonstrate a 5 mmHg difference in SBP and DBP significant at the 0.05 level.
NIFEDIPINE BLOCKS ACTH AND CORTISOL RELEASE IN MAN
Authors: Jackson Richard V. , Jackson A. Jane , Grice Jeffrey E. , Vella Rodney D.
Published: June 2007

1. The present study investigated the effect of prior administration of nifedipine on AVP‐induced ACTH release in seven normal volunteers. Three protocols were used: 20 mg oral nifedipine; 0.14 pressor units intramuscular (i.m.) per kg bodyweight aqueous AVP; oral nifedipine plus i.m. AVP 90 min later. Plasma ACTH and cortisol were measured at intervals for 2.5 h during each test.

2. The mean peak plasma ACTH and cortisol levels and the mean peak changes from basal in these levels were significantly lower in the nifedipine/AVP test than in the AVP alone test. The integrated area under the cortisol time curve was significantly lower for the nifedipine/AVP test than that for the AVP test alone. Nifedipine alone caused no changes in ACTH or cortisol.

3. Acute administration of oral nifedipine caused an inhibition of AVP‐stimulated ACTH and cortisol release in normal humans. This effect may be due to blockade of plasma membrane calcium channels normally activated during AVP stimulation of pituitary corticotrophs.
UNEXPECTED INCIDENCE OF LOW BLOOD PRESSURE 2 YEARS AFTER UNILATERAL ADRENALECTOMY FOR PRIMARY ALDOSTERONISM
Authors: Gordon Richard D. , Hawkins Peter G. , Hamlet Stephen M. , Tunny Terry J. , Klemm Shelley A. , Backmann Anthony W. , Finn Wendy L.
Published: June 2007

1. Serial observations of blood pressure after unilateral adrenalectomy for aldosterone‐producing adenoma revealed an incidence of hypotension (systolic BP < fifth percentile for age‐ and sex‐matched normal population) of 27% at 2 years, more than 5 times that predicted.

2. Serial observations of volume regulatory hormones showed significantly raised mean levels of plasma renin activity consistent with hypovolaemia. Significantly reduced mean aldosterone levels despite significantly raised mean plasma renin activity levels may reflect reduced responsiveness of the remaining adrenal.

3. Reduction of significantly elevated preoperative ANP levels to significantly reduced levels postoperatively is also in keeping with postoperative hypovolaemia.

4. A 50% reduction in plasma adrenaline after unilateral adrenalectomy might contribute to reduced noradrenergic activity (prejunctional β‐receptor) and reduced blood pressure, but plasma noradrenaline did not fall significantly postoperatively.

5. Postoperative levels of renin, aldosterone, adrenaline and noradrenaline were not significantly different between those who did, and those who did not, become hypotensive.
MAGNESIUM SUPPLEMENTATION IN MILD HYPERTENSIVE PATIENTS ON A MODERATELY LOW SODIUM DIET
Authors: Nowson C. A. , Morgan T. O.
Published: June 2007

1. The effect of oral magnesium supplementation was assessed in a group of untreated, mild hypertensive subjects who were following a moderately low sodium diet (baseline urinary sodium 86 ± 6 mmol/day).

2. Thirteen patients were allocated placebo and 12 were allocated magnesium aspartate (10 mmol/day) in a double blind fashion for 8 weeks.

3. There was no fall in blood pressure with magnesium supplementation and no significant difference in blood pressure between groups at the end of the study.

4. In the magnesium group there was an increase in urinary magnesium (4.4 ± 0.6 to 6.1 ± 1 mmol/day P < 0.001), and urinary calcium (4.3 ± 0.7 to 5.5 ± 0.9 mmol/day P < 0.01). There was no change in plasma or red cell magnesium or plasma renin activity with supplementation.

5. Magnesium supplementation does not appear to have an additive hypotensive effect in mild hypertensive subjects on a reduced sodium intake.
AN IN VITRO STUDY OF INTERACTIONS BETWEEN DOXAZOSIN AND ENALAPRILAT AT VASCULAR α1‐ADRENOCEPTORS
Authors: Tierney Garth , Marwood John , Stokes Gordon
Published: June 2007

1. Isolated perfused male Sprague‐Dawley rat tail artery segments were used to investigate interactions between the α‐1‐adrenoceptor antagonist, doxazosin, and the angiotensin converting enzyme (ACE) inhibitor, enalaprilat, using phenylephrine (PE) as the α1‐adrenoceptor agonist.

2. In concentrations of up to 10–5 mol/L, enalaprilat had no effect on arterial responses to PE.

3. Doxazosin produced a concentration‐dependent competitive α1‐adrenoceptor antagonism, yielding a mean pA2 value of 8.72.

4. In the continuous presence of 10−6 mol/L enalaprilat, doxazosin with a pA2 value of 9.10 was a 2.4‐fold more potent α1‐adrenoceptor antagonist than in the absence of enalaprilat.

5. These results are interpreted to indicate that endogenously produced angiotensin II can modulate the activity of α1‐adrenoceptors in vascular smooth muscle.
INHIBITION OF TRANSMITTER RELEASE FROM SYMPATHETIC NERVE ENDINGS BY ω‐CONOTOXIN
Authors: Brock J. A. , Cunnane T. C. , Evans R. J. , Ziogas J.
Published: June 2007

1. The effects of the calcium channel blocker, ω‐conotoxin, on sympathetic neuroeffector function in the guinea‐pig vas deferens have been investigated using a combination of mechanical and electrophysiological recording techniques.

2. Diphasic contractions evoked by electrical field stimulation were irreversibly abolished by ω‐conotoxin (10–100 nmol/L).

3. Electrically evoked excitatory junction potentials and currents were irreversibly blocked by ω‐conotoxin (10–100 nmol/L). Spontaneous excitatory junction potentials and currents were unaffected by this treatment.

4. ω‐Conotoxin did not block impulse propagation in the nerve terminals. However, in three of four experiments ω‐conotoxin caused a decrease in the size of the nerve terminal impulse.

5. These findings support the suggestion the co‐conotoxin acts prejunctionally to inhibit sympathetic neuroeffector by interfering with depolarization‐secretion coupling.
DILATATION OF THE RIGHT ATRIUM STIMULATES PHOSPHATIDYLINOSITOL TURNOVER
Authors: von Harsdorf Rüdiger , Lang Rudolph E. , Woodcock Elizabeth A.
Published: June 2007

1. Dilatation of the rat right atria caused a stimulation of the phosphatidylinositol turnover pathway as measured by an increase in the accumulation of inositol phosphates in isolated, perfused hearts.

2. In right atria, increases were detected after 1 min dilatation and maximal increases were observed after 10 min. Dilatation for 10 min caused an increase in inositol monophosphate inositol bisphosphate and inositol trisphosphate from 23.3 ± 0.9, 15.4 ± 0.4, and 9.5 ± 0.3 (mean and s.e.m., n= 7 ct/min per mg tissue) to 74.6 ± 2.3, 20.2 ± 1.3 and 13.6 ± 1.5 (n= 8), respectively (P < 0.01 for all inositol phosphates.)

3. These results show that the myocardium can respond to dilatation by an activation of the phosphatidylinositol turnover pathway.