bluuebunny/crossref_metadata_2025 huggingface dataset:
RECEPTORS AND STEROID‐DEPENDENT HYPERTENSION
Authors: Coghlan John P. , Reid Amanda F. , Spence Campbell D. , Scoggins Bruce A. , Whitworth Judith A.
Published: June 2007

1. Repeated observations indicate that ACTH administration causes hypertension.

2. Development of hypertension requires 17α‐hydroxyprogesterone and 17α, 20α‐dihydroxy‐4‐pregnene‐3‐one to be present in association with other steroids.

3. The hypertensinogenic activity of corticosteroids is distinct from their glucocorticoid and mineralocorticoid effects.

4. The location of central and peripheral receptors for this hypertensinogenic activity is not clear.

5. The physiological mechanisms that mediate the response are unknown, though a number of potential mediating effects has been demonstrated.

6. The overall importance of unusual steroids and steroid actions in human essential hypertension still requires elucidation.
VOLUNTARY BLOOD PRESSURE CONTROL USING CONTINUOUS SYSTOLIC BLOOD PRESSURE BIOFEEDBACK
Authors: Cejnar M. , Hunyor S. N. , Liggins G. W. , Bartrop R.
Published: June 2007

1. Ability to alter blood pressure (BP) acutely with continuous systolic (SBP) BP biofeedback was assessed in volunteers using a new non‐invasive finger BP monitor.

2. Reliability of finger BP measurement was demonstrated in six hypertensive subjects (21–60 years), by beat‐to‐beat comparison with brachial intra‐arterial BP over 90 min. Wide variation of BP was achieved by physiological manoeuvres. Mean error of finger BP was ‐3.0/‐2.2 mmHg with intra‐subject s.d. of 7.2/5.4 mmHg.

3. Thirteen normotensives (21–51 years) were paid to undergo 30 trials of SBP biofeedback in six sessions over 3 weeks. The SBP trend was displayed on a monitor with appropriately ‘shaped’ targets; each trial consisted of BP‐raising and ‐lowering periods of 45 and 90 s respectively with intervening 45 s baselines.

4. Nine subjects raised BP, on analysis of the last 10 trials, by an average of 18.8 mmHg while five of the 13 successfully lowered BP by an average of 10.0 mmHg. BP lowering was best achieved by diminishing respiratory rate and depth, and muscular relaxation.

5. Demonstration of large BP reductions in five of 13 normotensives using strategies applicable to longer training sessions warrants further investigations in hypertensive subjects, focusing on mediating mechanisms and transfer of effect beyond the laboratory.
INHIBITION OF SEROTONIN‐INDUCED ACTH RELEASE IN MAN BY CLONIDINE
Authors: Jackson R. V. , Grice J. E. , Jackson A. J. , Vella R. D. , Armour M. B.
Published: June 2007

1. Clonidine, an α2‐adrenergic agonist, is thought to inhibit noradrenergic neuronal activity (NNA) in the central nervous system (CNS) by a presynaptic α2‐receptor mechanism. Central NNA is thought to be the primary monoaminergic stimulus to pituitary ACTH release. Fenfluramine, a serotonin releasing agent and uptake inhibitor, causes ACTH release in normal man.

2. The present study investigated the effect of clonidine on fenfluramine‐induced ACTH release in six normal volunteers. Four protocols were used: 1.5 mg/kg body weight oral fenfluramine; 4.3 μg/kg body weight oral clonidine; oral clonidine + oral fenfluramine 1 h later; placebo clonidine. Plasma ACTH and cortisol were measured at intervals for 5 h after clonidine and for 4 h after fenfluramine.

3. The mean plasma ACTH and cortisol levels and the mean maximal changes in these levels were significantly lower during the clonidine + fenfluramine test than during fenfluramine alone. Plasma ACTH and cortisol levels were not lowered significantly more by clonidine than by placebo.

4. In conclusion, clonidine blocked the ACTH‐releasing activity of fenfluramine in normal humans. This inhibition of active ACTH release may result from clonidine blockade of fenfluramine‐induced activation of central NNA. Clonidine alone was no more effective than placebo in lowering plasma ACTH and cortisol.
ATTENUATED RENAL RESPONSE TO ATRIAL NATRIURETIC PEPTIDE INFUSION IN RATS WITH HEART FAILURE
Authors: Kohzuki Masahiro , Hodsman G. Peter , Harrison Richard W. , Johnston Colin I.
Published: June 2007

1. The natriuretic and diuretic effects of three atrial natriuretic peptide (ANP) infusion rates were examined in rats 4 weeks after myocardial infarction induced by left coronary artery ligation.

2. The natriuretic and diuretic effects of ANP were observed in controls and rats with infarction, but the effects were significantly attenuated in the latter.

3. Rats with chronic left heart failure were less sensitive to the renal effects of ANP compared with controls.

4. Impaired sodium and water excretion in chronic heart failure may be due partly to an attenuated renal response to ANP.
SERUM LIPIDS IN INSULIN‐DEPENDENT DIABETICS ARE MARKEDLY ALTERED BY DIETARY FISH OILS
Authors: Mori Trevor A. , Vandongen Robert , Masarei John R. L. , Dunbar Diana , Stanton Kim G.
Published: June 2007

1. The effect of dietary fish oil supplementation on serum lipids was examined in normolipidaemic insulin‐dependent male diabetics and healthy controls. Fish oil was given as Max eicosapentaenoic acid (EPA), 15 g daily (equivalent to 2.7 g/day of EPA) for 3 weeks.

2. There was a substantial increase in EPA but a depletion of arachidonic acid content of platelet phospholipids.

3. Diabetics showed a rise in total cholesterol, attributable to increases in low density and high density lipoprotein (LDL and HDL) cholesterol. The rise in HDL cholesterol was largely due to an increase in its HDL2 subclass. Similar changes were found in the healthy men although these were not as marked. A decrease in triglycerides was observed in both diabetics and normal controls.

4. Generally, diabetics showed greater changes in lipid concentrations which may suggest an altered metabolic response to w3 fatty acids. Therefore, the possible detrimental effect of the rise in total cholesterol and LDL cholesterol following fish oil administration may be offset by the increase in the protective HDL2 subclass.
VASCULAR SMOOTH MUSCLE POLYPLOIDY IN THE DEVELOPMENT AND REGRESSION OF HYPERTENSION
Authors: Black M. J. , Adams M. A. , Bobik A. , Campbell J. H. , Campbell G. R.
Published: June 2007

1. Two groups of spontaneously hypertensive rats (SHR) were treated with enalapril (25–30 mg/kg per day): Group I received treatment from 4 to 14 weeks of age to inhibit development of hypertension and Group R received the drug from 14 to 20 weeks of age to reverse established hypertension.

2. Systolic blood pressure, ploidy of aortic smooth muscle cells (flow cytometric DNA analysis) and aortic hypertrophy (medial cross‐sectional area) were determined at times both during and after enalapril treatment (up to 30 weeks).

3. Enalapril treatment normalized blood pressure to that of age‐matched Wistar‐Kyoto rats in both groups. Blood pressure rose again following cessation of treatment.

4. In untreated SHR the incidence of polyploid cells increased concomitantly with increasing pressure throughout the time studied, whereas in Group I the incidence remained low. In Group R, the incidence of polyploidy directly paralleled both the decrease (normalization) and the rise in blood pressure following cessation of treatment.

5. Hence, the incidence of vascular smooth muscle cell polyploidy is not simply a result of growth of the vessel with increasing age of the SHR, but parallels inhibition, reversal, and redevelopment of hypertension.
RENIN RESPONSE TO GRADED HAEMORRHAGE IN CONSCIOUS RATS
Authors: Roarty Timothy P. , Raff Hershel
Published: June 2007

1. A haemorrhage volume/plasma renin activity (PRA) response relationship was established for five levels of acute haemorrhage ranging from 1.5 to 15 ml/kg in conscious rats. In addition, the effects of chronic indomethacin and/or acute propranolol administration on the PRA response to 5 and 10 ml/kg haemorrhage was assessed.

2. Mean arterial pressure decreased in a haemorrhage volume dependent manner which was not significantly altered by indomethacin and/or propranolol.

3. Haemorrhage volumes of 1.5 and 3.0 ml/kg did not significantly alter PRA. At haemorrhage volumes of 5.0 ml/kg and higher, PRA increased in a volume‐dependent manner. Propranolol decreased basal PRA levels but had little effect on the response to haemorrhage. Indomethacin had no effect on basal PRA, but attenuated the response to haemorrhage somewhat. When propranolol and indomethacin were combined, the PRA response to haemorrhage was significantly attenuated.

4. The conscious cannulated rat model exhibits predictable and reproducible renin responses to haemorrhage and is an excellent model for studying the control of renin secretion.
INHIBITION OF VASODILATATION BY METHYLENE BLUE IN LARGE AND SMALL ARTERIES OF THE DOG HINDLIMB IN VIVO
Authors: Sobey C. G. , Woodman O. L. , Dusting G. J.
Published: June 2007

b

1. Injection of acetylcholine (ACh, 0.0005–2 μg/kg) or glyceryl trinitrate (GTN, 0.01–20 μg/kg) into the femoral artery increased femoral artery diameter, femoral blood flow and heart rate, and reduced femoral vascular resistance and systemic arterial blood pressure in anaesthetized dogs. The intravenous (i.v.) injection of ACh (2 μg/kg) produced a small decrease in systemic arterial pressure and an increase in heart rate, but did not dilate the hindlimb vessels.

2. Methylene blue, a guanylate cyclase inhibitor, continuously infused into the femoral artery (10 mg/min), attenuated the increase in femoral artery diameter and femoral blood flow, and the decrease in femoral vascular resistance produced by intra‐arterial injections of both ACh and GTN.

3. In addition, methylene blue potentiated the decrease in systemic arterial pressure produced by ACh (injected directly into the femoral artery or i.v.), but did not affect the depressor response to GTN. This selective potentiation of ACh‐induced hypotension was not affected by autonomic ganglion blockade with hexamethonium (25 mg/kg, i.v.).

4. These results suggest that both ACh‐and GTN‐induced vasodilatation in vivo occurs through a mechanism involving guanylate cyclase activation in large arteries and resistance vessels in the dog hindlimb. Methylene blue inhibited the local vasodilator actions of ACh in the femoral vasculature despite potentiating the systemic depressor response to that agent.
ACTION OF MEFLOQUINE ON AGONIST‐INDUCED CONTRACTIONS OF THE GUINEA‐PIG ISOLATED ILEUM
Authors: Go M. L. , Lee H. S.
Published: June 2007

b

1. Responses of the guinea‐pig isolated ileum to cumulative concentrations of acetylcholine (ACh), histamine (H), and prostaglandin E2 (PGE2) were obtained in the presence or absence of mefloquine or quinine.

2. The effects of increasing the external calcium concentration and the presence of a low concentration (1.8 nmol/l) of PGE2 on the mefloquine‐and quinine‐induced inhibition of the ACh cumulative dose‐response curves were also investigated.

3. Mefloquine (1–10 μmol/l) and quinine (50–100 μmol/l) both caused a dose‐dependent non‐parallel right shift of the log concentration‐response curve of every agonist. Mefloquine is a more potent inhibitor of PGE2‐induced responses whereas quinine inhibited all three agonist‐induced responses to the same extent.

4. Increasing the external calcium concentration enhanced the inhibitory effects of both drugs on ACh‐induced responses. Pre‐incubation with 1.8 nmol/l PGE2 had a similar effect.

5. The actions of mefloquine on ACh‐and H‐induced contractions are non‐specific, like other antimalarials, but its greater inhibitory action on PGE2 may involve a more complex effect.
ENDOTHELIUM‐DEPENDENT INHIBITION OF SYMPATHETIC VASOCONSTRICTION BY FRUSEMIDE ADMINISTRATION TO RATS
Authors: Gerkens J. F. , Armsworth S. J. , Dosen P. J. , Smith A. J.
Published: June 2007

1. Segments of the tail artery of the rat were cannulated at both ends and mounted in an organ bath filled with Krebs solution.

2. Using an extracorporeal circuit, blood was pumped at a constant 2 ml/min from the carotid artery of anaesthetized rats to perfuse the segment of tail artery, and returned to the donor rat via the jugular vein.

3. Peri‐arterial electrical stimulation of the ex vivo blood perfused tail artery at 5 Hz produced vasoconstriction and an increase in perfusion pressure.

4. The intravenous administration of frusemide 5 mg/kg to the donor rat resulted in an inhibition of the vasoconstrictor responses of the perfused tail artery segment. Diuresis‐induced losses of volume and frusemide were prevented by a urinary bladder‐venous shunt.

5. Removal of the endothelium from the tail artery segment, by perfusion with dry gas for 4 min, prevented the vasoconstrictor‐inhibitory effect of frusemide administration. Removal of the endothelium was confirmed histologically and by the absence of a vasodilator response to acetylcholine.

6. On the basis of these and previous results it is concluded that parenteral frusemide administration releases an unidentified but non‐prostanoid hormone from the kidney which produces an endothelium‐dependent inhibition of sympathetic vascoconstriction.
EFFECT OF DIABETES MELLITUS ON SALIVARY PARACETAMOL ELIMINATION
Authors: Adithan C. , Danda D. , Swaminathan R. P. , Indhiresan J. , Shashindran C. H. , Bapna J. S. , Chandrasekar S.
Published: June 2007

1. Salivary elimination of paracetamol was studied in nine type I and ten type II diabetics. Ten healthy volunteers served as a control group.

2. A significant increase in the elimination half‐life (t1/2) and apparent volume of distribution was observed in type I diabetics compared with controls. Clearance rate (CL) was not significantly altered.

3. In type II diabetics paracetamol elimination t1/2 was significantly increased with a corresponding decrease in CL. Apparent volume of distribution of the drug was not significantly different.

4. Paracetamol elimination t1/2 had significant correlation with fasting blood sugar values.
BOOK REVIEWS
Authors: CHRISTOPHIDIS NICHOLAS
Published: June 2007

Self‐Assessment in Clinical Pharmacology. By Henry L. Elliott, MD, MRCP, John L. Reid, MD, FRCP, Peter C. Rubin, MD, MRCP and Brian Whiting, MD, FRCP. Pages viii + 154, 14 cm ± 21 cm. Blackwell Scientific Publications: Oxford, 1987. Price $24.00.

IVAN. Living with Parkinson's Disease. By Ivan Vaughan. Pages 224. Macmillan, London, 1988. $12.95.
CONTROL OF GLOMERULOSA CELL FUNCTION BY ANGIOTENSIN II: TRANSDUCTION BY G‐PROTEINS AND INOSITOL POLYPHOSPHATES*
Authors: Catt Kevin J. , Balla Tamas , Baukal Albert J. , Hausdorff William P. , Aguilera Greti
Published: June 2007

1. The receptor‐activated mechanisms that mediate the steroidogenic actions of angiotensin II (AII) have been characterized in rat and bovine adrenal glomerulosa cells. In rat adrenal cells, the AII receptor is coupled to a guanine nucleotide inhibitory protein which reduces adenylate cyclase activity and cyclic AMP production. However, receptor‐mediated stimulation of aldosterone production by AII is exerted through a separate pertussis‐insensitive nucleotide regulatory protein that subserves coupling of activated receptors to phospholipase C.

2. In AII‐stimulated glomerulosa cells, hydrolysis of phosphatidylinositol (4,5)‐bisphosphate (PIP2) by phospholipase C yields diacylglycerol and inositol 1,4,5‐trisphosphate (Ins‐P3), which act as second messengers by activating calcium‐calmodulin and calcium‐phospholipid dependent protein kinase pathways. Ins‐1,4,5‐P3 is a potent stimulus of intracellular calcium mobilization, and is promptly inactivated by two major routes of metabolism. Direct degradation of Ins‐1,4,5‐P3 by a 5‐phosphatase gives inositol 1,4‐bisphosphate which in turn is metabolized to inositol‐4‐monophosphate. The latter product can be derived only from higher inositol phosphates, and thus serves as a specific marker of polyphosphoinositide breakdown in agonist‐stimulated cells. In contrast, inositol‐1‐phosphate is largely derived from phosphatidylinositol hydrolysis, which is not increased during the initial phase of AII action.

3. Ins‐1,4,5‐P3 formed in AII‐stimulated glomerulosa cells is also phosphorylated by a calcium‐calmodulin dependent 3‐kinase to form inositol 1,3,4,5‐tetrakisphosphate (Ins‐P4), which is rapidly dephosphorylated to the biologically inactive Ins‐1,4,5‐P3 isomer, Ins‐1,3,4‐trisphosphate. The latter metabolite, like Ins‐1,4,5‐P3, is both degraded to lower phosphates (Ins‐3,4, P2 and Ins‐1,3‐P2) and phosphorylated to form a new tetrakisphosphate isomer (Ins‐1,3,4,6‐P4). Ins‐1,4,5‐P3 formed during AII action is bound with high affinity to specific intracellular receptors through which InsP3 causes calcium mobilization during the initiation of cellular responses to AII and other calcium‐dependent ligands.
EFFECT OF DIETARY FISH OILS ON THE FORMATION OF LEUKOTRIENE B4 AND B5, THROMBOXANE AND PLATELET ACTIVATING FACTOR BY RAT LEUKOCYTES
Authors: Croft Kevin D. , Codde James P. , Barden Anne , Vandongen Robert , Beilin Lawrence J.
Published: June 2007

1. This study investigates the effect of dietary eicosapentaenoic acid (EPA), in the form of ‘Max EPA’ fish oil, on leukotriene B4 (LTB4) production in ionophore‐stimulated rat leukocytes. Male Wistar rats (200–250 g) were fed for 3 weeks on a synthetic chow supplemented with either 10% by weight Max EPA oil or a coconut oil/safflower oil mixture.

2. The EPA‐rich diet significantly increased the EPA content of leukocyte phospholipids and decreased the arachidonic acid level by 35% (P < 0.001) compared with the control diet.

3. The concentration of leukotrienes in the ionophore (A23187) stimulated leukocytes was measured by reverse‐phase HPLC using prostaglandin B2 as the internal standard. The EPA‐supplemented diet caused a 50% decrease in LTB4 production (P < 0.001) and a concomitant increase in the formation of the biologically less active LTB5 compared with the control diet. The amount of LTB4 and LTB5 produced by stimulated leukocytes closely resembled the changes in arachidonic acid and EPA content of leukocyte phospholipids.

4. Thromboxane B2 (TxB2) production in stimulated leukocytes from the EPA‐fed animals was also decreased compared with the control group.

5. Although the formation of platelet activating factor by stimulated leukocytes was not altered by dietary treatment, the ability of an EPA‐rich diet to decrease LTB4 and TxB2 production suggests that these diets may attenuate leukocyte activity and have useful anti‐inflammatory effects.
INHIBITION BY COCAINE OF NORADRENALINE RELEASE FROM SYMPATHETIC NERVES IN THE RABBIT EAR ARTERY
Authors: Parker D. A. S. , de la Lande I. S.
Published: June 2007

SUMMARY

1. Effects of cocaine on release of noradrenaline (NA) from sympathetic nerves were studied in the isolated perfused central artery of the rabbit ear. Indices of release were the vasoconstrictor response to nerve stimulation and stimulation‐induced overflow of radioactivity after the nerves had been loaded with [3H]‐NA. The overflow studies were carried out on phenoxybenzamine‐treated arteries to eliminate the effect of cocaine on neuronal uptake.

2. Cocaine enhanced the constrictor responses of the artery to stimulation in concentrations of 3 and 30 μmol/l, but in higher concentrations (tested up to 300 μmol/l) the enhancement declined and was replaced by inhibition. Responses to extraluminal NA remained enhanced throughout the concentration range (tested up to 150 μmol/l).

3. In contrast, cocaine depressed the overflow of radioactivity, the effect being detectable in a concentration of 3 μmol/l (a decrease of 15%); the decrease was 40% at the highest concentration tested (90 μmol/l).

4. It is suggested that when assessed in terms of the vasoconstrictor response, inhibition of transmitter release by cocaine is masked by inhibition of neuronal uptake except in high concentrations of cocaine.
EFFECT OF SHORT COURSE CHEMOTHERAPY ON SALIVARY PARACETAMOL ELIMINATION
Authors: Madhusudanarao K. , Bapna J. S. , Adithan C. , Ray K. , Venkatadri N. , Kamatchi G. Lenin , Seetharaman M. L. , Bahadur P.
Published: June 2007

SUMMARY

1. Salivary elimination of paracetamol was studied in six male pulmonary tuberculosis patients on short course chemotherapy.

2. Peak paracetamol concentration showed a steady decrease at the end of first week and continued until the end of the study.

3. The elimination half‐life of paracetamol decreased 5 weeks after the therapy with a corresponding increase in the clearance rate.

4. Adjustment of dosage of drugs that are metabolized by the microsomal enzymes may be required in patients on anti‐tubercular drug regimen in which rifampicin is included.
α1‐ AND α2‐ADRENOCEPTORS OF THE CIRCULAR MYOMETRIUM FROM THE DIOESTROUS GUINEA‐PIG
Authors: Haynes John , Pennefather Jocelyn N.
Published: June 2007

1. In order to investigate the nature of the α‐adrenoceptors mediating contraction of circular myomctrium from dioestrous guinea‐pigs, the effects of several adrenoceptor antagonists upon log concentration curves to noradrenaline and phenylephrine have been examined.

2. In the presence of ICI 118,551 and nisoxetine both phenylephrine and noradrenaline produced concentration‐dependent contractures of circular myometrium from virgin dioestrous guinea‐pigs. Noradrenaline was the more potent and produced larger maximal contractions. Indomethacin (1 μmol/l) decreased the maximum effects of phenylephrine but not those of noradrenaline. Xylazine produced indomelhacin‐sensitive contractions which were not dose‐related and which never exceeded 40% of those evoked by noradrenaline. Responses to xylazine and to noradrenaline, but not those to phenylephrine, were reduced in a low calcium solution.

3. Prazosin produced competitive antagonism of the effects of phenylephrine upon preparations of circular myometrium from virgin and parous dioestrous animals; pA2 values were both 8.1. Phentolamine also competitively antagonized the effects of phenylephrine (virgin animals, pA2= 7.7).

4. Both prazosin and phentolamine antagonized the effects of noradrenaline upon preparations from virgin dioestrous animals, however, Schild plot analysis did not indicate a simple bimolecular interaction between agonist and receptors. In the presence of prazosin the α2‐adrenoceptor antagonist idazoxan produced dose‐dependent parallel shifts in the positions of the log concentration‐response curves to noradrenaline; the pA2 was 7.7. In the presence of idazoxan or of indomethacin prazosin competitively antagonized the effects of noradrenaline; the pA2 values were 8.5 and 8.2 respectively.

5. The present findings indicate that the effects of noradrenaline upon the contractility of the circular myometrium of dioestrous guinea‐pigs may result from activation of both α1‐ and α2‐adrenoceptors.
RENAL EFFECTS OF ATRIAL NATRIURETIC FACTOR (99–126) IN POTASSIUM LOADED SHEEP
Authors: Yates N. A. , Coghlan J. P. , Scoggins B. A. , McDougall J. G.
Published: June 2007

1. The renal response to renal arterial infusion of synthetic atrial natriuretic factor (ANF 99–126) was examined in conscious sheep following dietary K loading, and compared with the response in normal sheep.

2. Renal arterial infusion of ANF in K loaded sheep increased the excretion of Na and Ca, but did not affect the excretion of K.

3. The natriuretic effect of ANF was attenuated in K loaded animals, possibly as a consequence of the reduction in Na status which is associated with K loading.
CV 6209 IS A NON‐COMPETITIVE ANTAGONIST OF PLATELET‐ACTIVATING FACTOR RECEPTORS ON GUINEA‐PIG RESIDENT PERITONEAL MACROPHAGES
Authors: Stewart Alastair G.
Published: June 2007

1. The characteristics of antagonism of platelet‐activating factor (Paf) receptors by the phospholipid Paf analogue, CV 6209, were studied in rabbit platelets and polymorphonuclear leucocytes (PMN) and in guinea‐pig macrophages.

2. Paf‐induced aggregation of PMN or platelets was antagonized in a competitive and specific manner by CV 6209 with no detectable difference between the pA2 values (approximately 9.5).

3. The specificity of CV 6209 (1–100 nmol/L) for Paf receptors in platelets and PMN was indicated by a lack of effect on A23187 (10 μmol/L) or fMLP (1 μmol/L) induced aggregation, respectively.

4. CV 6209 (1–100 nmol/L) was also a potent antagonist of Paf‐induced prostacyclin (PGI2) generation by guinea‐pig peritoneal macrophages. However, CV 6209 caused significant depression of the maximum response to Paf and a non‐parallel shift in the concentration‐response curve indicating a non‐competitive type antagonism.

5. PGI2 generation induced by the ionophore A23187 was unaffected by CV 6209 (up to 100 nmol/L) whereas basal PGI2 production by macrophages was reduced by lower concentrations (10–100 nmol/L). These observations are not consistent with a direct effect of CV 6209 on the enzymes involved in PGI2 synthesis but do suggest that endogenous Paf regulates basal PGI2 generation.

6. The non‐competitive antagonism of guinea‐pig macrophage Paf receptors gives further support to the contention that these receptors are distinct from those mediating aggregation of platelets and PMN,
MEASUREMENT OF NET SODIUM INTAKE BY THE OVINE FETUS WITH OESOPHAGEAL LIGATION
Authors: Lumbers Eugenie R. , Smith Francine G.
Published: June 2007

1. If the fetal sheep is in sodium balance, then the net intake of sodium is equal to the sum of the losses of sodium in fetal urine and lung liquid plus the rate of deposition of sodium with growth.

2. In seven fetal sheep with oesophageal ligation net sodium intake was 23.1 ± 2.8 (s.e.m.) μmol/min per kg; 11.8 ± 1,4 μmol/min per kg was excreted by the lungs and 8.7 ± 2.3 μmol/min per kg was excreted by the kidneys. The excretion of sodium by the lungs accounted for 52.8 ± 4.8% of the total amount of sodium; the excretion of sodium by the kidneys accounted for 34.9 ± 5.4% and the calculated variable, that is, sodium deposited due to growth was 12.3 ± 1.4%.

3. All but one fetus excreted more sodium from the lungs than from the kidneys. There was no relationship between the clearance of sodium by the lungs and net sodium intake but there was a direct relationship between renal sodium clearance and net sodium intake (r=0.92, P < 0.005). This suggests that fetal urinary sodium excretion is dependent upon net sodium intake by the fetus. This animal model shows that normally there must be sodium fluxes from allantoic and/or amniotic cavities to either the fetus or the ewe.
EFFECTS OF AUTONOMIC BLOCKADE ON THE HYPERTENSIVE RESPONSE OF THE FETUS TO HYPEROSMOLALITY
Authors: Kingsford Nicola M. , Lumbers Eugenie R.
Published: June 2007

1. Infusions of hyperosmotic mannitol to the ewe caused a rise in fetal arterial pressure in 17 chronically catheterized fetal sheep aged 120–140 days. The fetal heart slowed in 13 out of 17 of these fetuses. The rise in pressure occurred before there was any rise in fetal urinary osmolality.

2. In seven fetal sheep combined α‐ and β‐adrenoceptor and muscarinic blockade delayed the onset of the rise in blood pressure and no bradycardia was observed. It is concluded that the hypertension was due in part to increased activity of the sympatho‐adrenal system, and that any reflex bradycardia that occurred was mediated by the vagus.

3. In three other fetal sheep aged 125–131 days, the cardiovascular responses elicited by infusion of hyperosmotic mannitol to the ewe were not blocked by a specific vasopressin antagonist. Thus vasopressin could not be responsible for either the initial rise in pressure nor the delayed hypertensive response that was not blocked by α‐ and β‐adrenoceptor blockade.

4. Fetal blood volume was maintained even though the changes in plasma osmolality and electrolytes were indicative of a fall in blood volume. Thus changes that threaten maintenance of fetal blood volume seem to induce increased solute and water transport across the placenta or from the extracorporeal fluid compartments.
ROLE OF GABAERGIC SYSTEM IN PROLACTIN ANALGESIA
Authors: Ramaswamy S. , Suthakaran C. , Bapna J. S.
Published: June 2007

1. The role of the GABAergic system in the analgesic action of prolactin was investigated using a pharmacological approach.

2. THIP, a GABAmimetic, per se produced an analgesic effect and potentiated the analgesic effect of prolactin and morphine.

3. Bicuculline, in subconvulsive doses, per se did not alter the number of writhings, while it attenuated the analgesic effect of prolactin.

4. These results indicate a positive role for the GABAergic system in prolactin induced analgesia.

5. Since THIP resembles morphine and because prolactin possesses several other morphine‐like functions, it is possible that the role played by GABA may be an opioid‐related one.
MICROPUNCTURE COMPARISON OF NEPHRON FUNCTION DURING ACUTE AND CHRONIC ADH EXCESS IN THE RAT
Authors: Field Michael J. , Seow Francis , Lawrence James R.
Published: June 2007

1. The aim of this study was to compare the effect of acute versus chronic ADH administration on the handling of sodium, potassium and water by the nephron. Simultaneous clearance and free‐flow micropuncture experiments were performed on rats, infused with hypotonic Ringer solution, following either 1–3 h ('acute') or 10–12 days ('chronic') of continuous treatment with arginine vasopressin, 50 mU/h. A third group of animals receiving no exogenous ADH acted as controls.

2. Chronic ADH treatment led to more profound concentration of the urine and antidiuresis than acute treatment, due to enhanced extraction of water in the renal medulla.

3. Fractional sodium excretion during this protocol was increased after ‘acute’ but not ‘chronic’ ADH treatment. The acute natriuretic response was brought about principally along the length of the proximal tubule, probably due to volume expansion and increased arterial blood pressure.

4. Fractional excretion of potassium was also increased by ‘acute’ ADH, but this response was due to stimulation of potassium secretion in the late distal tubule.

5. It is concluded that acute and chronic exposure to ADH have different effects on nephron function, as a result of both direct and indirect actions.
INHIBITORY EFFECT OF OUABAIN AND ACETAZOLAMIDE ON SECRETIN‐STIMULATED PANCREATIC EXOCRINE SECRETION IN ANAESTHETIZED DOG
Authors: Iwatsuki K. , Horiuchi A. , Yonekura Y. , Chiba S.
Published: June 2007

1. The effects of ouabain and acetazolamide on the secretion of pancreatic juice stimulated by secretin in anaesthetized dogs were investigated.

2. Intra‐arterial injection of ouabain (1–10 μg) and acetazolamide (1–10 mg) caused dose‐dependent decreases in the volume of pancreatic juice. When both drugs were added together, the inhibitory effects were significantly higher than for each drug alone.

3. The bicarbonate concentration in the pancreatic juice was decreased and the chloride concentration was increased by ouabain and acetazolamide, but sodium and protein concentrations were not modified.

4. The results suggest that the Na+K+‐ATPase and carbonic anhydrase activities play important roles in water and electrolyte secretion, and that ouabain and acetazolamide inhibit secretin‐stimulated pancreatic secretion by acting on different systems in the exocrine cells in dogs.
CARDIOVASCULAR ACTIONS OF HUMAN ENDOTHELIN IN CONSCIOUS SHEEP
Authors: Scoggins Bruce A. , Spence Campbell D. , Parkes David G. , McDonald Michele , Wade John D. , Coghlan John P.
Published: June 2007

1. Synthetic human endothelin was injected intravenously over the range 1.5–50 μg to examine its cardiovascular actions in conscious sheep.

2. Mean arterial pressure increased by 9–21 mmHg within 30–120s over the range 5–50 μg endothelin. The increase in blood pressure was associated with increased calculated total peripheral resistance and a fall in cardiac output and heart rate. Stroke volume was increased.

3. Injection of endothelin into ganglion blocked sheep produced vasoconstriction and an increased blood pressure response associated with an attenuation of the effects on cardiac output, heart rate and stroke volume.

4. This study suggests that endothelin produces potent arterial vasoconstriction and reflex mediated effects on the heart in conscious sheep.
POTENTIATION OF FENFLURAMINE‐INDUCED ACTH RELEASE IN MAN BY NALOXONE
Authors: Jackson Richard V. , Grice Jeffrey E. , Jackson A. Jane , Vella Rodney D.
Published: June 2007

1. This study set out to compare the effect of the combination of fenfluramine (Fen) and naloxone (Nal) on ACTH and cortisol release with each of these agents alone in six normal volunteers. Three protocols were used: 1.5 mg/kg bodyweight oral Fen; 125 μg/kg bodyweight i.v. Nal; oral Fen plus i.v. Nal 135 min later. Plasma ACTH and cortisol were measured at intervals of 285 min over each test.

2. The mean peak levels and mean peak changes from basal in plasma ACTH and cortisol were significantly greater in the combination test (Fen/Nal) than in either the Fen alone or the Nal alone tests. Fen and Nal given together cause a synergistic release of ACTH and cortisol as determined by the areas under the ACTH‐time and cortisol‐time curves for Fen/Nal compared to the sums of Fen alone plus Nal alone curves for ACTH and cortisol.

3. We conclude that Fen and Nal acting synergistically work through different and potentiating mechanisms at the hypothalamic, central nervous system and/or pituitary levels to cause ACTH release.
LEVELS OF ATRIAL NATRIURETIC PEPTIDE ARE NOT ALWAYS CONSISTENT WITH ATRIAL PRESSURE: IS THERE ALTERNATIVE REGULATION AS EVIDENCED IN GORDON'S AND BARTTER'S SYNDROMES?
Authors: Klemm Shelley A. , Gordon Richard D. , Tunny Terry J. , Hawkins Peter G. , Finn Wendy L. , Hamlet Stephen M. , Kewal Narendra K. , Purton Karen J.
Published: June 2007

1. In Bartter's syndrome, atrial pressures were low, consistent with volume contraction, while atrial natriuretic peptide (ANP) levels were unexpectedly elevated. Infusion of normal saline increased both right atrial pressure (RAP) and ANP levels, while administration of prostaglandin inhibitors raised RAP, probably due to volume expansion, but ANP levels fell paradoxically.

2. In Gordon's syndrome, atrial pressures were unexpectedly low or normal despite volume expansion, while ANP levels were normal. Pressor infusions of angiotensin II either raised right and left atrial pressures (LAP) without increasing ANP, or increased ANP without increasing atrial pressures.

3. In these two syndromes, atrial pressures and ANP levels were poorly correlated, leading to the proposal that other regulators of ANP may be important.
PHAEOCHROMOCYTOMAS SECRETING ADRENALINE BUT NOT NORADRENALINE DO NOT CAUSE HYPERTENSION AND REQUIRE PRECISE ADRENALINE MEASUREMENT FOR DIAGNOSIS
Authors: Bachmann Anthony W. , Hawkins Peter G. , Gordon Richard D.
Published: June 2007

1. Urinary noradrenaline (NA) and adrenaline (ADR) determinations are a more sensitive index than plasma measurements for the diagnosis of phaeochromocytoma (phaeo).

2. Even though urinary NA excretion serve as a sufficient single diagnostic test for the majority of phaeos, it is necessary to measure urinary ADR excretion if ADR‐only secreting phaeos are not to be missed, particularly in patients with multiple endocrine neoplasia (MEN) syndrome.

3. The clonidine suppression test confirmed all tumour diagnoses, and in this series was not responsible for any false negative or false positive results.
EFFECT OF ENALAPRIL ON HANDLING OF A SODIUM CHLORIDE LOAD BY GENETICALLY HYPERTENSIVE AND NORMOTENSIVE RATS
Authors: Ledingham Janet M. , Simpson F. O.
Published: June 2007

1. Enalapril was given in the drinking water (300 mg/L) for 4.5 days to normotensive (N) and genetically hypertensive (GH) rats on zero sodium intake. An intraperitoneal NaCl load was given 12 h after enalapril was started.

2. Enalapril did not increase the maximum rate of sodium excretion, but caused the rats to excrete more than the load in the first 24 h and then to have a slow fall in body sodium while on a sodium‐free diet.

3. In terms of the Strauss et al. (1958) concept of body sodium, enalapril appears to lower the basal level. However, in addition it causes a slow leak of sodium which becomes apparent when sodium intake is very low.
EFFECT OF Na+ PUMP SUPPRESSION ON REACTIVITY OF RAT TRACHEALIS TO COOLING
Authors: Chen W. Y.
Published: June 2007

1. This study tests the hypothesis that suppression of Na+ pump would increase the rate of tension development and the magnitude of contraction induced by cooling in airway smooth muscle.

2. Rat tracheal preparations were incubated in ouabain for 8 h and tested hourly for their response. In a representative specimen the rate of tension development increased from the control value of 0.7 mg/s to 5.5 mg/s after 7 h of incubation in ouabain concentration of 4 × 10−4 mol/L; likewise, the magnitude of contraction increased from the control value of 80 mg to 550 mg.

3. Using ouabain concentrations between 9 × 10−5mol/Land6 × 10−3mol/L, the rate of tension development and the magnitude of contraction first increased in a dose‐dependent manner up to 8 × 10−4 mol/L, then declined with higher doses but the responses were still greater than the control values at all concentrations.

4. After 3 h incubation in ouabain at 8 × 10−4 mol/L, the mean rate of tension development and the mean magnitude of contraction increased to 647% and 578% of the control value, respectively.

5. These results indicate that depression of Na+ pump results in hypersensitivity and hyper‐reactivity of the airway smooth muscle to cooling.
DOES PERIPHERAL COLLATERALIZATION ALSO CAUSE COLLATERALIZATION IN THE CANINE HEART?
Authors: Hengy Ben , Watanabe Noriyasu , Williams Arthur G. , Downey H. Fred
Published: June 2007

1. Experiments were conducted in chronically prepared dogs to determine if gradual obstruction of the proximal femoral arteries would also cause collateralization in the coronary circulation.

2. Peripheral coronary pressure was measured before and after peripheral collateralization as an index of coronary collateral function. Coronary collateral blood flow was measured with radioactive microspheres after peripheral collateralization.

3. Peripheral coronary pressure was not significantly altered by peripheral collateralization. Coronary collateral blood flow measured after peripheral collateralization was similar to that reported in non‐collateralized hearts.

4. Results indicated that the mechanism(s) reponsible for peripheral collateralization do not act systemically, at least not on the coronary circulation.
RENAL EFFECTS OF ATRIAL NATRIURETIC FACTOR (99–126) IN WATER‐DEPRIVED SHEEP
Authors: Yates N. A. , Coghlan J. P. , Scoggins B. A. , McDougall J. G.
Published: June 2007

1. The renal response to renal arterial infusion of synthetic human atrial natriuretic factor (ANF) (99–126) at 50 μg/h was examined in conscious sheep dehydrated by 48 h water deprivation and was compared with the response of normally hydrated animals.

2. Renal arterial infusion of ANF produced increases in the excretion of Na, K, Ca and urine in both dehydrated and normally hydrated animals, although the effect was significantly blunted in dehydrated animals compared with normally hydrated animals.

3. The attenuation of renal effects of ANF in dehydrated animals is probably due to the negative sodium and/or fluid balance of the dehydrated animals.
EFFECTS OF RESERPINE PRETREATMENT ON NEUROEFFECTOR TRANSMISSION IN THE VAS DEFERENS
Authors: Cunnanc T. C. , Manchanda R.
Published: June 2007

1. The effects of reserpine pretreatment on neurotransmission in the guinea‐pig vas deferens have been re‐examined with a view to study the role of noradrenaline (NA) in mediating postjunctional electrical responses and, in particular, excitatory junction potentials (EJP).

2. Reserpine (5 mg/kg, i.p.) caused almost total depletion (below detection levels) of the NA content of the vas deferens. However, spontaneous and evoked excitatory junction potentials (SEJP, EJP) and currents (SEJC, EJC) could still be recorded in NA‐depleted tissues. The amplitude distribution of SEJC in control and reserpinized tissues was similar.

3. Facilitation of EJP and EJC was markedly slowed in reserpinized tissues, EJP taking 50–60 pulses to facilitate fully. However the amplitudes of fully facilitated EJP were comparable to EJP recorded in control tissues.

4. EJPs in reserpinized vasa deferentia were unaffected by the NA synthesis inhibitor, α‐methyl tyrosine, but were abolished in the presence of the stable ATP analogue α,β‐methylene ATP which desensitizes postjunctional P2‐purinoceptors.

5. Local application of ATP, but not NA, mimicked the EJP. These results indicate that EJP are mediated by a non‐noradrenergic neurotransmitter, possibly ATP.
DOES SUPPRESSION OF RESPONSIVENESS TO β‐ADRENOCEPTOR ACTIVATION EXPLAIN THE ENHANCEMENT OF VASOCONSTRICTOR RESPONSES BY α2‐ADRENOCEPTOR AGONISTS?
Authors: Rand M. J. , Xiao X.‐H. , Rajanayagam S. , Story D. F.
Published: June 2007

1. The α2‐adrenoceptor agonist TL99, in concentrations that had no other observable effect, enhanced constrictor responses to phenylephrine in perfused segments of the rat tail artery.

2. Vasoconstrictor responses to phenylephrine were also enhanced by propranolol (0.3 μmol/L).

3. Vasoconstrictor responses to phenylephrine in the presence of propranolol were further enhanced by TL99 (10 nmol/L).

4. The enhancement of vasoconstrictor responses by α2‐adrenoceptor agonists is not due to the removal of a counteracting vasodilator component produced by activation of p‐adrenoceptors.
EFFECT OF HAEM ON CYTOCHROME P‐450 SYNTHESIS
Authors: May Brian K. , Hansen Antony J.
Published: June 2007

1. The expression of the phenobarbital‐inducible cytochrome P‐450 mRNA species (P‐450 IIB1 and IIB2) were investigated in different tissues of rats following treatment with 2‐allyl‐2‐isopropylacetamide.

2. The mRNAs were detected as a single 2.1 kb mRNA species by Northern blot analysis. These mRNAs were readily detected in liver, lung and kidney but were not detected in testis, brain or erythroid tissue.

3. When rats were administered 2‐allyl‐2‐isopropylacetamide, cytochrome P‐450 levels were elevated specifically in the liver and kidney but remained undetectable in testis, brain and erythroid spleen. Thus these cytochrome P‐450 mRNAs are expressed and induced by drug in a tissue‐specific fashion. Levels of mRNA for 5‐aminolaevu‐ linate synthase, the rate controlling enzyme of haem biosynthesis, were also induced by drug in a similar tissue‐specific fashion.

4. The proposal that haem is required for the transcription of cytochrome P‐450 IIB1/IIB2 and other cytochrome P‐450 genes was investigated in rat liver using succinylacetone, a specific inhibitor of the haem biosynthetic pathway.

5. While 2‐allyl‐2‐isopropylacetamide induced levels of cytochrome P‐450 IIB1/IIB2 mRNAs, succinylacetone administration did not affect this induction. However, succinylacetone substantially elevated both basal and drug‐induced levels of mRNA for 5‐aminolaevulinate synthase.

6. Since 5‐aminolaevulinate synthase mRNA synthesis is inhibited by the end‐product haem, the results show that lowered haem levels do not affect cytochrome P‐450 gene transcription. The work does not provide evidence for the suggestion that haem is required for cytochrome P‐450 gene transcription.
CHARACTERIZATION AND REGULATION OF RAT LIVER UDP GLUCURONOSYLTRANSFERASES
Authors: Mackenzie P. I. , Chowdhury N. Roy , Chowdhury J. Roy
Published: June 2007

1. The use of DNA recombinant techniques to study UDP glucuronosyltrans‐ferases is reviewed.

2. The cloning and sequencing of the cDNAs to five forms of UDP glucuronosyl‐transferase demonstrated that these proteins are encoded by a superfamily of genes.

3. The substrate specificities of four isozymes have been analysed by expression of their corresponding cDNAs in cell culture.

4. Analysis of liver mRNA levels using radiolabelled DNA probes demonstrated that one isozyme, UDPGTr‐2, is elevated by phenobarbital whereas a second isozyme, 4‐nitrophenol GT is elevated by 3‐methylcholanthrene. The levels of other isozymes are unaffected by these two prototypic inducers of drug metabolizing enzymes.

5. The level of 4‐nitrophenol GT mRNA is elevated 10–15‐fold in hyperplastic nodules in livers of rats treated with 2‐acetylaminofluorene. Similar increases were not observed for mRNAs encoding other forms of UDP glucuronosyltransferase.
DOPAMINE RECEPTORS: CLASSIFICATION, PROPERTIES AND DRUG DEVELOPMENT
Authors: Beart Philip M.
Published: June 2007

1. The pharmacology, biochemistry and structure‐activity relationships pertinent to the Dl and D2 subtypes of dopamine receptors are reviewed.

2. Recent advances in receptor purification and our understanding of the secondary messenger systems involved are presented.

3. Dl and D2 receptors of central nervous, endocrine and peripheral systems are identical.
THE CLASSIFICATION OF 5‐HYDROXYTRYPTAMINE RECEPTORS
Authors: Mylecharane Ewan J.
Published: June 2007

1. The current classification of receptors for 5‐hydroxytryptamine (5‐HT) is based on functional studies, and encompasses three main receptor types.

2. 5‐HT1‐like receptors mediate inhibition of release of various neurotransmitters from central and peripheral sites, smooth muscle contraction and relaxation (and release of endothelium‐derived relaxing factor), tachycardia, a variety of behavioural actions (for example, forepaw treading, hypothermia, hyperphagia, drug discriminative stimulus properties, nociceptive pathway modulation, and anxiolytic, anti‐aggressive and prosexual effects), and central neuronal excitatory and inhibitory activity. Selective antagonists for this receptor are not yet available, but the 5‐HT2 receptor antagonists methysergide and methiothepin have appreciable affinity for 5‐HT1‐like receptors, and 5‐carboxamidotryptamine is a selective agonist.

3. 5‐HT2 receptors mediate smooth muscle contraction, platelet aggregation, increased capillary permeability, some behavioural syndromes (for example, head twitch and wet‐dog shakes) and drug discriminative stimulus properties, central neuroexcitatory effects, and some neuroendocrine functions. Ketanserin and cypro‐heptadine are selective antagonists.

4. 5‐HT3 receptors mediate peripheral afferent and efferent neuroexcitatory actions, anxiogenic effects, and modulation of cytotoxic drug‐induced emesis, gastric emptying, and dopamine‐related mesolimbic hyperactivity. Selective antagonists include cocaine, MDL 72222 and ICS 205–930; 2‐methyl‐5‐HT is a selective agonist.
FUNCTION, CHARACTERIZATION AND AUTORADIOGRAPHIC LOCALIZATION AND QUANTITATION OF β‐ADRENOCEPTORS IN CARDIAC TISSUES
Authors: Molenaar Peter , Russell Fraser D. , Shimada Tatsuo , Summers Roger J.
Published: June 2007

1. This paper demonstrates the use of organ bath, radioligand binding and autoradiography to detect β1‐ and β2‐adrenoceptors in human and guinea‐pig cardiac tissues.

2. In organ bath experiments, non‐selective and β1‐ and β2‐adrenoceptor selective agonists produced concentration‐dependent inotropic responses in human right atrial appendage. Both subtypes mediate inotropic responses. In guinea‐pig right atria chronotropic responses were mediated predominantly through β1‐adrenoceptors.

3. Receptor binding studies using (—)[125I]‐cyanopindolol (CYP) and β1‐ and β2‐adrenoceptor selective antagonists showed that β2‐adrenoceptors comprised 25% of the total population of β‐adrenoceptors in guinea‐pig right atria. In human right atria the proportion is higher (40%).

4. Quantitative autoradiography was used to determine the location and densities of β1‐ and β2‐adrenoceptors in guinea‐pig heart. Both β2‐ and β2‐adrenoceptors were distributed on myocardium. The atrioventricular conducting system had a higher density of β2‐adrenoceptors compared with myocardium.
OPIATE RECEPTORS: LIGANDS AND METHODS OF STUDY
Authors: Olley Jean E.
Published: June 2007

1. An introduction to the current knowledge of the μ‐, k‐ and δ‐opioid receptors will be given.

2. The many problems associated with opiate ligands with respect to selectivity, potency, slow receptor kinetics, instability and poor access to the central nervous system will be discussed.

3. Current systems for analysis of the receptor profile of opiate ligand activity will be given.

4. The properties of opioid ligands will be discussed in the context of the identified problems.