bluuebunny/crossref_metadata_2025 huggingface dataset:
A COMPARISON OF THE EFFECTS OF SODIUM THIOCYANATE AND DANTROLENE SODIUM ON A MAMMALIAN ISOLATED SKELETAL MUSCLE
Authors: MOULDS R.F.W.
Published: July 2012

A combination of electrical and pharmacological stimulation has been used to compare the effects of sodium thiocyanate and dantrolene sodium on the excitation‐contraction coupling (ECC) mechanism of the mouse soleus muscle.

Thiocyanate prolonged the ‘active state’ after electrical stimulation and increased the response to 8 mm caffeine and 80 mm KCl. Dantrolene had an opposite effect to thiocyanate on all the indices studied.

It is concluded that the mechanism of action of dantrolene is by inhibition of the release of the calcium ions involved in the ECC mechanism, probably at the level of the transverse tubules.
THE EFFECTS OF GLUCAGON, SECRETIN, PANCREOZYMIN AND PENTAGASTRIN ON THE HEPATIC ARTERIAL VASCULAR BED OF THE DOG
Authors: RICHARDSON P.D.I. , WITHRINGTON P.G.
Published: July 2012

The sympathetically‐innervated arterial vascular bed of the dog's liver was perfused from a femoral artery. Arterial blood flow and perfusion pressure were monitored continuously and the hepatic arterial vascular resistance (HAVR) calculated from these measurements.

Commercial preparations of secretin, pancreozymin, glucagon and pentagastrin were administered by intra‐arterial (i.a.) injection and infusion.

Secretin and pancreozymin by injection caused dose‐dependent hepatic arterial vasodilatation, and on a molar basis were both more potent than glucagon or pentagastrin.

Intra‐arterial infusions of secretin and pancreozymin caused hepatic arterial vasodilatation at calculated blood concentrations close to those measured under physiological conditions by other investigators. The vasodilatation was of the same duration as that of the hormone infusions.

Pentagastrin by i.a. injection caused dose‐dependent hepatic arterial vasodilatation; by i.a. infusion, vasodilatation occurred but there was marked ‘escape’ from the effects during the continued infusion.

As reported previously, glucagon by injection caused dose‐dependent hepatic arterial vasodilatation of long duration; by infusion, glucagon caused vasodilatation that persisted after the cessation of the infusion.

Glucagon infused i.a., inhibited the vasoconstrictor effects of i.a. noradrenaline, over the same range of infusions that caused hepatic arterial vasodilatation.

Secretin or pancreozymin did not antagonize the effects of noradrenaline on the hepatic arterial vascular bed at any doses used.

Pentagastrin did not antagonize the vasoconstrictor effect of noradrenaline whether hepatic arterial vasodilatation resulted from the pentagastrin infusion, or not.

These results are discussed with respect to the possible control of the hepatic arterial vascular bed by gastrointestinal hormones.
EFFECT OF ANTI‐THYROID AGENTS, METHIMAZOLE AND PROPYLTHIOURACIL, ON BRAIN NORADRENALINE CONTENT
Authors: HASHIZUME Y. , YAMAKI T. , HIDAKA H.
Published: July 2012

Methimazole (1‐methyl‐2‐mercaptoimidazole, MMI) and propylthiouracil (6‐propyl‐2‐thiouracil, PTU) which are used in the therapy of hyperthyroidism were found to reduce brain noradrenaline (NA) content. Endogenous NA levels in rat brain were reduced from 1 to 6 h after intraperitoneal injection of MMI by doses in excess of 25 mg/kg and by PTU at a dose of 50 mg/kg. However, endogenous NA in the rat heart was only slightly reduced after 50 mg/kg of MMI, and was not affected by PTU (50 mg/kg).

Both MMI and PTU effectively inhibited the in vivo conversion of [3H]‐dopamine into [3H]‐noradrenaline ([3H]‐NA) in the brain of rats after a single intraperitoneal injection of doses above 10 mg/kg (MMI) and 25 mg/kg (PTU). This inhibition by MMI and PTU was dose‐dependent over the range of 10 mg/kg to 50 mg/kg, was highest after 2–3 h and continued for at least 6 h after their injection. The conversion rates returned to normal after 24 hours.

The results suggest that the reduction of brain NA by these drugs is, at least in part, due to the inhibition of brain dopamine β‐hydroxylase.
CAN BARIUM SUPPORT THE RELEASE OF ACETYLCHOLINE BY NERVE IMPULSES?
Authors: SILINSKY E. M.
Published: July 2012

Conventional electrophysiological techniques were used to study the effects of Ba on the release of acetylcholine (ACh) from frog motor nerve terminals. Equimolar substitution of Ba for Ca eliminated end‐plate potentials (e.p.ps) without a corresponding decline in the amplitude of the nerve terminal action potential. Miniature end‐plate potentials (m.e.p.ps) were readily detectable in Ba solutions despite a depolarized muscle membrane. Studies on the e.p.p in curarized preparations bathed with different concentrations of Ca and Ba suggest that Ba may compete with Ca in the process by which depolarization of the nerve terminal leads to the release of ACh. Repetitive nerve stimulation at 1 Hz in Ba solutions caused 5–20 fold increases in m.e.p.p frequencies (7 experiments). Stimulation of Ba‐bathed preparations at 10 Hz elevated m.e.p.p frequencies to very high levels that could not be measured accurately (»100/s). It is suggested that the asynchronous discharge of m.e.p.ps produced by repetitive nerve stimulation is the electrophysiological correlate of the evoked ACh outflow in Ba solutions detected previously by bioassay of the perfusion fluid.
THE INTERACTION OF SOME BIS‐ARYLHYDROXYSULPHONIC ACIDS WITH A SITE OF KNOWN STRUCTURE IN HUMAN HAEMOGLOBIN
Authors: BROWN F.F. , GOODFORD P.J.
Published: July 2012

1 Two bis‐arylhydroxysulphonic acids were previously designed to interact with the known molecular configuration of the 2,3‐diphosphoglycerate (DPG) receptor‐site of human haemoglobin. These compounds liberate oxygen from the haemoglobin similarly to DPG.

2 Solutions of haemoglobin have now been observed under physiological conditions by nuclear magnetic resonance (n.m.r.) in the presence of DPG and of the compounds.

3 Two peaks in the n.m.r. spectrum of haemoglobin are shifted when DPG is added to the solution.

4 The same two peaks in the spectrum are affected by the compounds.

5 The observations are compatible with the predicted interaction between the compounds and the haemoglobin receptor site.
SOME OBSERVATIONS ON THE MECHANISM OF BENZODIAZEPINE‐BARBITURATE INTERACTIONS IN THE MOUSE
Authors: CHAMBERS D.M. , JEFFERSON G.C.
Published: July 2012

1 The prolongation of pentobarbitone sleeping times by five benzodiazepines, administered by prior intraperitoneal injection, was measured in mice. The pentobarbitone was injected either intraperitoneally or intracerebroventricularly. For each benzodiazepine, the prolongation was dose‐related and differences in potency between benzodiazepines were not marked.

2 The percentage prolongation of sleeping times produced by most of the benzodiazepines was greater when the pentobarbitone was given intracerebroventricularly and was explained by a preferential addition of CNS depressant effects associated with this route.

3 To test whether the action of intraperitoneally administered pentobarbitone had been influenced by a metabolic component, the effects of nitrazepam on drug metabolism, measured by changes in plasma phenazone levels in the mouse, were studied. Nitrazepam (32 mg/kg, i.p.) produced a 23% reduction in the rate of phenazone metabolism.

4 Nitrazepam was also shown to have produced a transient fall in body temperature. Calculations based on Q10 values suggested that this hypothermia accounted, at most, for half the metabolic change measured.
DRUGS ALTERING INSULIN SECRETION: EFFECTS ON PLASMA AND BRAIN CONCENTRATIONS OF AROMATIC AMINO ACIDS AND ON BRAIN 5‐HYDROXYTRYPTAMINE TURNOVER
Authors: CURZON G. , FERNANDO J.C.R.
Published: July 2012

1 An investigation was made into the effects of drugs which alter insulin secretion on the concentrations of tryptophan and other aromatic amino acids in plasma and brain and on 5‐hydroxytryptamine (5‐HT) and 5‐hydroxyindoleacetic acid (5‐HIAA) in train. Drugs used were streptozotocin, propranolol, tolbutamide and phentolamine.

2 Tolbutamide and phentolamine increased the plasma insulin concentrations by 100% and 300% respectively but with little effect on the brain/plasma ratios for the aromatic amino acids. Previously propranolol was found to decrease plasma insulin by 50% without altering the above ratios. The ratios were decreased by streptozotocin but only when plasma insulin fell by more than 50%.

3 Phentolamine and propranolol did not alter the brain/plasma ratios for the aromatic amino acids in streptozotocin‐treated rats.

4 The results suggest that only large changes of insulin secretion e.g. those associated with food intake or aminophylline injection are likely to alter appreciably the brain/plasma ratios for the aromatic amino acids.

5 Tolbutamide displaced tryptophan from its binding to plasma albumin and increased brain 5‐HIAA probably by inhibiting 5‐HIAA efflux from brain. The other drugs did not alter brain 5‐HT or 5‐HIAA concentrations.
SOME OBSERVATIONS ON THE ANORECTIC ACTIVITY OF PROSTAGLANDIN F2α
Authors: DOGGETT N.S. , JAWAHARLAL K.
Published: July 2012

1 Intracerebroventricular injection of prostanglandin F2α (10‐40 μg) decreases food intake in a dose‐dependent manner in rats trained to consume their daily total food intake in a 2 h period.

2 This anorexia is also observed in satiated rats, which had ad libitum access to food.

3 The anorectic activity of prostaglandin F2α is not modified by changes in the internal environment of the body after food intake, such as increased blood glucose and insulin levels and decreased fatty acid levels, or by the presence or absence of food in the stomach, as is evident from the anorectic activity of prostaglandin F2α in partially satiated rats.

4 The anorexia is not due to pain or irritative properties of prostaglandin F2α since induction of comparable pain with 3% acetic acid does not affect food intake in rats deprived of food for 22 hours.

5 Anorectic doses of prostaglandin F2α when injected intraperitoneally cause hypothermia.

6 The results suggest that the inhibitory activity of prostaglandin F2α on food intake is at both peripheral and central sites.

7 Prostaglandin F2α‐induced anorexia is associated with the behavioural tranquillization that is seen after the ingestion of food.
THE EFFECT OF CLOPROSTENOL ON HUMAN LUTEAL STEROID AND PROSTAGLANDIN SECRETION in vitro
Authors: McDOUGALL A.N. , WALKER FELICITY M. MAULE , WATSON J.
Published: July 2012

1 Human luteal tissue slices from days 18, 21 and 25 of the menstrual cycle were superfused in vitro with Medium 199 alone or containing cloprostenol (1 μg/ml). Concentrations of progesterone, oestradiol‐17β and prostaglandins F2α and E2 were determined in the superfusate samples.

2 Secretion of steroids and prostaglandins was maintained at an approximately constant level throughout the experiments (21 h in one case) when the tissue was perfused with M199 alone.

3 Superfusion with cloprostenol (1 μg/ml) resulted in an initial depression of progesterone and oestradiol‐17β but this was not maintained, levels returning to control values or showing an increase, while superfusion with cloprostenol continued. Cloprostenol is not therefore considered to be luteolytic at this dose and under these conditions for human luteal tissue in vitro.

4 Superfusion with cloprostenol (1 μg/ml) also resulted in a large stimulation of secretion of endogenous prostaglandin F2α following a short lag phase. This stimulation was possibly due to the initial depression of progesterone secretion. A short‐lived stimulation of prostaglandin E2 secretion was also observed.

5 The significance of the increase in prostaglandin E2 secretion and the interrelationships between the various changes observed with cloprostenol are difficult to interpret.
EFFECTS OF ATENOLOL ON REGIONAL MYOCARDIAL BLOOD FLOW AND ST SEGMENT ELEVATION IN THE CANINE MYOCARDIUM
Authors: BERDEAUX A. , BOISSIER J.R. , GIUDICELLI J.F.
Published: July 2012

1 The effects of atenolol on regional myocardial blood flow (RMBF) and on ST segment elevation were studied both in normal and ischaemic regions of the myocardium in dogs. Some of the experiments were performed with cardiac pacing or after bilateral stellectomy.

2 In the absence of cardiac pacing, atenolol (1 mg/kg, i.v.) induced a marked reduction in heart rate and contractile force and a decrease in RMBF, which was of the same magnitude in normal and ischaemic areas. There was no modification in the endo/epi flow ratio. ST segment elevation in ischaemic areas was significantly reduced.

3 Bilateral stellectomy induced similar effects to those of atenolol. Atenolol after bilateral stellectomy exhibited no additional effects.

4 In dogs submitted to cardiac pacing, atenolol no longer decreased RMBF and ST segment elevation.

5 These results demonstrate that with atenolol, there is no correlation between bradycardia and the endo/epi flow ratio while there is one between bradycardia and reduction in ST segment elevation.
STUDIES ON THE CARDIOVASCULAR EFFECTS OF PINDOLOL IN DOCA/SALINE HYPERTENSIVE RATS
Authors: BUCKINGHAMM R.E. , HAMILTON C. , ROBSON D.
Published: July 2012

1 A hypotensive response to orally administered pindolol in conscious normotensive and deoxycorticosterone acetate (DOCA)/saline hypertensive rats (DS‐rats) is described. In DS‐rats, pindolol (10‐50 μg/kg) produced a dose‐dependent fall in blood pressure and elevation of resting heart rate.

2 The hypotensive response and tachycardia produced by oral pindolol (50 μg/kg) in DS‐rats were prevented by propranolol (5 mg/kg), suggesting that pindolol's effects are mediated by β‐adrenoceptor stimulation.

3 After mecamylamine (10 mg/kg), oral pindolol (50 μg/kg) produced a further fall in blood pressure in DS‐rats, suggesting that its hypotensive effects are probably mediated in the peripheral vasculature.

4 Pretreatment with oral pindolol (10 or 50 μg/kg) resulted in a reduction of neuronally‐induced tachycardia in pithed DS‐rats; neuronally‐evoked pressor effects were also antagonized by pindolol (50 μg/kg, orally).

5 Whereas pindolol, 50 μg/kg orally or intraperitoneally, produced a marked and progressive hypotensive response of rapid onset (20 min) in DS‐rats the same dose intravenously produced a smaller response of delayed onset (80 minutes).

6 In anaesthetized DS‐rats, an equivalent degree of cardiac β‐adrenoceptor blockade was produced by pretreatment with pindolol, 50 μg/kg orally (2 h previously) or intravenously (1 h previously).

7 After administration of pindolol, 2 mg/kg intravenously, to conscious DS‐rats, the tachycardia produced by intravenous isoprenaline, 3 μg/kg, was almost abolished for the first 60 min of the study, whereas a hypotensive response to pindolol was delayed in onset (100 minutes).

8 The hypotensive response and tachycardia produced by oral pindolol, 50 μg/kg, in DS‐rats were prevented by inhibition of metabolic enzyme activity by pretreatment with Proadifen (SKF 525‐A), 80 mg/kg.

9 The results suggest that pindolol's effects on blood pressure and heart rate in the conscious DS‐rat are mediated by a metabolite(s) acting by stimulation of peripheral β‐adrenoceptors.
FELINE ENDOTOXIN SHOCK: EFFECTS OF METHYLPREDNISOLONE ON KININOGEN‐DEPLETION, ON THE PULMONARY CIRCULATION AND ON SURVIVAL
Authors: AL‐KAISI NAHLA , PARRATT J.R. , SIDDIQUI H.H. , ZEITLIN I.J.
Published: July 2012

1 Escherichia coli endotoxin, administered intravenously in a dose of 2mg/kg to pentobarbitone‐anaesthetized, artificially ventilated cats resulted in pulmonary hypertension, systemic hypotension and an immediate (1‐2 min) 30‐40% reduction in plasma kininogen, an effect which probably indicates a release of plasma kinins.

2 Methylprednisolone (30 mg/kg), when administered 30 min before endotoxin, did not influence the endotoxin‐induced pulmonary hypertension or systemic hypotension but completely prevented the depletion of plasma kininogen.

3 In spontaneously breathing cats, methylprednisolone, administered 30 min after endotoxin, caused a rapid repletion of kininogen and prolonged survival (47% at 6 h compared to 10% in the endotoxinalone animals). Methylprednisolone did not appear to influence lactate production or the hyperventilation observed during the delayed endotoxin shock phase.

4 It is concluded that methylprednisolone does not prevent the release, by endotoxin, of a pulmonary vasoconstrictor prostaglandin, or its effects, but that perhaps by preventing kinin release it may reduce endotoxin‐induced capillary leakage.
REVERSAL OF PROSTAGLANDIN E2 EFFECT ON ADRENAL CATECHOLAMINE RELEASE AFTER HYPOPHYSECTOMY
Authors: BOONYAVIROJ PUNYA , FEUERSTEIN GIORA , GUTMAN YEHUDA
Published: July 2012

Prostaglandin E2 induced increased catecholamine release in vitro from adrenals of hypophysectomized rats, while in adrenals of intact rats catecholamine release was suppressed by prostaglandin E2.
EFFECTS OF ASPIRIN‐LIKE DRUGS ON CANINE GASTRIC MUCOSAL BLOOD FLOW AND ACID SECRETION
Authors: BENNETT A. , CURWAIN B.P.
Published: July 2012

1 The effects of aspirin, paracetamol and benorylate were studied on gastric mucosal blood flow (MBF) and acid secretion in canine denervated gastric pouches.

2 Aspirin 20 mM in the unstimulated pouch had no effect; pentagastrin‐stimulated acid output, but not MBF, was reduced. Aspirin buffered to pH 6 was ineffective.

3 Aspirin 3‐50 mg/kg reaching the pentagastrin‐stimulated pouch through the blood, increased acid secretion and MBF, but the MBF: secretion ratio was variably affected.

4 Paracetamol (10 or 20 mg/kg i.v., or 20 mM in the pouch) or benorylate (280 mg/kg orally) mainly had little effect.

5 Circular muscle strips from dog arteries were contracted by prostaglandins E2, F1α or F2α, and often slightly by indomethacin, but prostaglandin E1 produced variable effects.

6 These results do not favour the view that aspirin causes gastric bleeding in dogs by breakdown of blood vessels due to ischaemia following mucosal vasoconstriction.
AN INVESTIGATION OF THE SEX DIFFERENCE IN THE DIURETIC RESPONSE TO ETHACRYNIC ACID IN MICE
Authors: COOLING M.J. , SIM M.F.
Published: July 2012

1 Female mice of the Hough/Porton and Tuck/TO strains were found to be more sensitive than male mice to the diuretic effects of oral and intravenous doses of ethacrynic acid.

2 The sensitivity of Hough/Porton male mice to ethacrynic acid was increased after pretreatment with stilboestrol and the sensitivity of female Hough/Porton mice decreased after pretreatment with testosterone.

3 There were no significant sex differences in the diuretic response to frusemide, acetazolamide, aminophylline, bendrofluazide, and Su 15049A although a small, but significant, increase in the sensitivity of male Tuck/TO mice to triamterene was noted.

4 The sex difference in diuretic response to ethacrynic acid may be related to an effect of sex hormone balance on its metabolism or on the sensitivity of its renal receptor.
ENZYMATIC HISTAMINE DEGRADATION BY HUMAN SKIN
Authors: FRANCIS D. , GREAVES M.W. , YAMAMOTO S.
Published: July 2012

1 Degradation of histamine by homogenized human skin in vitro, in the presence of the cofactor S‐adenosyl methionine, indicates the presence of the histamine metabolizing enzyme histamine‐N‐methyl transferase in human skin. Under the experimental conditions described, no significant histamine degradation by diamine oxidase was observed.

2 The enzyme activity is temperature‐sensitive with an optimum at 37°C. The enzyme is stable in intact excised skin at −20°C, but unstable in homogenized skin at this temperature.

3 Little or no enzyme activity is present in mid‐ or deep dermis, but the distribution of the enzyme between superficial papillary dermis and epidermis is uncertain.

4 The presence of a potent histamine degrading mechanism raises the possibility that histamine‐N‐methyl transferase activity may be an important modulating factor in histamine‐mediated skin disorders
THE EFFECT OF DIURETICS ON THE FAECAL EXCRETION OF WATER AND ELECTROLYTES IN HORSES
Authors: ALEXANDER F.
Published: July 2012

1 The effect on plasma, urinary and faecal electrolytes of frusemide and hydrochlorthiazide was measured in ponies, mean weight 180 kg.

2 The rapid loss in urine of large quantities of sodium had only a small effect on plasma sodium concentration.

3 Faecal sodium excretion was increased substantially after the administration of frusemide.

4 Frusemide increased faecal potassium during the 48 h following administration and faecal water in the 24/48 h period. It also produced a hypopotassaemia.

5 Hydrochlorthiazide increased faecal chloride during the 24 h after administration.

6 Frusemide increased the intestinal transit time of both liquid (polyethylene glycol) and particulate (Cr2O3) markers.
RENAL BLOOD FLOW AUTOREGULATION AND RENAL VENOUS PROSTAGLANDINS IN THE PUMP‐PERFUSED CANINE KIDNEY (In situ)
Authors: DIGHE K.K. , HALL JANET C. , SMITH G.W. , UNGAR A.
Published: July 2012

Renal autoregulation of blood flow was re‐examined in the pump‐perfused canine kidney and concentrations of prostaglandins E and F in the renal venous plasma were measured by radioimmunoassay.

At low perfusion pressures, below the range of autoregulation, prostaglandin E and F concentrations rose and calculated prostaglandin E secretion rate fell.

Meclofenamate (10 mg/kg, i.v.) reduced renal blood flow and prostaglandin E and F secretion rates, but did not abolish autoregulation.

Renal prostaglandins do not appear to mediate autoregulation in the kidney but may affect the level at which flow is controlled.
EFFECTS OF SYMPATHETIC INNERVATION AND TEMPERATURE ON THE PROPERTIES OF RAT HEART ADRENOCEPTORS
Authors: KUNOS G. , NICKERSON M.
Published: July 2012

The pharmacological characteristics of adrenoceptors at different temperatures were assessed on the basis of the effects of various α‐ and β‐adrenoceptor agonists and antagonists on electrically‐driven left atria and spontaneously‐beating pairs of atria from rats.

Phenoxybenzamine (Pbz) potentiated inotropic responses of left atria to noradrenaline (NA) at 31°C, produced significantly less potentiation at 24°C and inhibited responses at 17°C; it had little effect on responses to CaCl2. Both Pbz and phentolamine inhibited responses to phenylephrine more effectively at 17 than at 31°C. N‐cyclohexylmethyl‐N‐ethyl‐β‐chloroethylamine hydrochloride (GD‐131), a haloalkylamine with negligible α‐adrenoceptor blocking activity, caused only potentiation of responses to NA at 17°C.

The presence of phentolamine during incubation with Pbz eliminated block of responses to NA and revealed a potentiation that was equivalent at all three temperatures tested. Phentolamine did not alter the block of responses to 5‐hydroxytryptamine by Pbz. Protection of α‐adrenoceptors by phentolamine during exposure to [3H]‐Pbz significantly decreased the amount of label bound to the myocardium at 17°C, but did not alter binding at 31°C.

Inhibition of responses to NA by propranolol decreased with temperature, and the magnitude of the change increased with the concentration of propranolol. Compared to 31°C, the effect of the highest concentration of propranolol. (4.0 μM) was significantly decreased at 24°C, and the effects of all except the lowest concentration (0.04 μM) were significantly decreased at 17°C.

The potency of isoprenaline decreased and that of phenylephrine increased at low temperatures, and their potency ratio was much lower at 17 than at 31°C for both the inotropic and chronotropic responses of spontaneously‐beating atria. However, the ratio was unaffected by temperature in electrically‐driven left atria. A similar difference between spontaneously‐beating and driven preparations is apparent in the data of other workers, but its basis is not clear.

Atria from rats pretreated with 6‐hydroxydopamine (6‐OHDA) were sensitized to the effects of NA, and there was no increase in α‐adrenoceptor properties at low temperatures. Little α‐adrenoceptor activity could be demonstrated in chemically denervated atria at any temperature. 6‐OHDA pretreatment did not alter the binding of [3H]‐Pbz at 31°C, but decreased it significantly at 17°C. Pretreatment with reserpine caused some sensitization, but did not significantly alter the characteristics of the adrenoceptors or their responses to temperature.

It is concluded that the adrenoceptors of rat atria are affected by temperature in much the same way as those of frog hearts, although the transition from β‐ to α‐adrenoceptor properties may begin at a slightly higher temperature. α‐Adrenoceptor properties appear to require the presence of intact adrenergic nerves but not the presence of normal stores of neurotransmitter.
TIME COURSE OF LITHIUM‐INDUCED ALTERATIONS IN RENAL AND ENDOCRINE FUNCTION IN NORMAL AND BRATTLEBORO RATS WITH HYPOTHALAMIC DIABETES INSIPIDUS
Authors: BALMENT R.J. , JONES I. CHESTER , HENDERSON I.W.
Published: July 2012

A lithium chloride (1.1 g/kg) supplemented diet was given to Long Evans (LE) and Brattleboro (DI) rats to investigate its actions in the presence (LE) and absence (DI) of vasopressin.

During the first 24 h, Li‐supplemented LE rats displayed an initial water deficit (drinking less than renal output), increased plasma antidiuretic (ADH) titres and slightly increased plasma renin activities (PRA) and plasma osmolarities. Such changes were qualitatively similar to those seen in rats fed a normal diet, but deprived of water for 24 hours. After 12 days, the Li‐supplemented rats had elevated plasma ADH titres, but reduced pituitary oxytocic and antidiuretic activities.

The urinary losses of Na, K and Cl exceeded dietary intakes in LE rats on the introduction of the Li‐supplement, and the urinary osmolarity fell by 50%. Electrolyte balances were gradually reestablished, although drinking and urine production increased in parallel to reach twice the control values by day 12 of the supplement.

Aldosterone and corticosterone secretory rates and their peripheral plasma concentrations were unchanged both after 24 h and 28 days of the Li‐supplement.

Li elicited no water deficit or saluresis in DI rats, and although the polyuria and polydipsia were exacerbated, urinary osmolarity did not change over the 12 day observation period.

Li increased Ca excretion in both rat types; after 12 days the PRA of DI but not LE animals was increased.

It is concluded that the overall renal actions of Li are tempered by vasopressin rather than adrenocorticosteroids.
THE EFFECT OF SULPHAMETHOXYPYRIDAZINE ON LIVER AND PLASMA LEVELS OF VITAMIN A IN RATS
Authors: BRAVO MARÍA E. , MONCKEBERG F. , URBINA J.
Published: July 2012

Long‐acting sulphonamides are highly bound to plasma proteins; the present study deals with the effects of this binding property upon a vitamin A compound also transported by plasma proteins.

Sulphamethoxypyridazine was administered in rats either orally or by intraperitoneal injection.

A significant fall in plasma vitamin A level and an increase in hepatic vitamin A concentration were observed.

These results suggest an interference by sulphamethoxypyridazine with the transport of vitamin A, either through competition between the drug and vitamin A for binding sites of plasma proteins, or through altered secretion of the vitamin from the liver.
AN EXCITATORY ACTION OF IONTOPHORETICALLY ADMINISTERED LITHIUM ON MAMMALIAN CENTRAL NEURONES
Authors: HAAS H.L. , RYALL R.W.
Published: July 2012

The action of iontophoretically administered lithium was studied on spinal Renshaw cells and interneurones and on supraspinal neurones in cerebral cortex, thalamus, hypothalamus and brain stem in anaesthetized cats and rats.

There was a correlation between the effects of Li+ and those of acetylcholine (ACh), although rather more cells were unaffected by Li+ than by ACh.

The usual effect was an excitation of rather slow onset, but occasionally effects were produced with time courses similar to those of ACh. The excitation was blocked by ACh antagonists and was best demonstrated with dihydro‐β‐erythroidine on Renshaw cells.

The postsynaptic excitant action of ACh on Renshaw cells was reduced by Li+.

Depressant actions of Li+ were encountered on cells also depressed by ACh.

It is concluded that Li+ may facilitate cholinergic transmission at some sites in the CNS by increasing the release of ACh by an unknown mechanism. Similar effects at non‐cholinergic synapses might also occur but would appear to be of less importance. Since facilitation of neuronal firing with Li+ was usually observed, the depressant effects on postsynaptic responses to ACh may be of little consequence.
CYCLIC ADENOSINE 3′, 5′‐MONOPHOSPHATE AND LEUCOCYTE CHEMOTAXIS in vivo
Authors: DEPORTER D.A.
Published: July 2012

The effect of local elevation of leucocyte cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) content on the continued migration of leucocytes to a site of acute inflammation was studied in the pleural cavity of rats.

Leucocyte cyclic AMP levels were elevated by injecting with the irritant into the pleural cavity dibutyryl cyclic AMP alone or with theophylline.

The treatments both produced a marked reduction in leucocyte migration into a pleural reaction induced by immediate hypersensitivity, but had no effect on cell numbers in pleurisy induced either by pyrophosphate or urate crystals.
THE POSSIBLE ROLES OF HISTAMINE, 5‐HYDROXYTRYPTAMINE AND PROSTAGLANDIN F2α AS MEDIATORS OF THE ACUTE PULMONARY EFFECTS OF ENDOTOXIN
Authors: PARRATT J.R. , STURGESS R.M.
Published: July 2012

In an attempt to investigate the possible role of released vasoactive substances in mediating the pulmonary pressor responses to E. coli endotoxin, cats were pretreated with histamine, 5‐hydroxytryptamine (5‐HT) or prostaglandin antagonists, with a histamine depleting agent (compound 48/80) or with an inhibitor of prostaglandin synthetase (sodium meclofenamate).

The administration of endotoxin (2 mg/kg) resulted in a rapidly developing pulmonary hypertension (pressure twice normal after 2–3 min), increases in right atrial and intratracheal pressures, systemic hypotension and bradycardia. These effects were unaffected by methysergide in a dose sufficient to prevent the effects of intravenously administered 5‐HT.

Endotoxin responses were also unaffected by a combination of mepyramine and burimamide in doses sufficient to reduce markedly the effects of intravenously‐administered histamine. In cats pretreated (chronically or acutely) with compound 48/80, endotoxin induced a transient pulmonary pressor response which was not maintained.

The pulmonary and systemic responses to endotoxin were prevented by the prior administration of the prostaglandin antagonist, polyphloretin phosphate and by pretreatment with the prostaglandin synthetase inhibitor, sodium meclofenamate.

It is concluded that a pulmonary vasoconstrictor prostaglandin is involved in the acute response to endotoxin in the cat.
THE USE OF FUNCTIONAL ANTAGONISM TO DETERMINE WHETHER β‐ADRENOCEPTOR AGONISTS MUST HAVE A LOWER EFFICACY THAN ISOPRENALINE TO BE TRACHEA‐ATRIA SELECTIVE in vitro IN GUINEA‐PIGS
Authors: O'DONNELL STELLA R. , WANSTALL JANET C.
Published: July 2012

The relative efficacies of three trachea‐atria selective β‐adrenoceptor agonists, fenoterol, Me 506 and Me 454, compared to isoprenaline, were determined on both trachea and atria of guinea‐pigs.

On tracheal preparations the β‐adrenoceptor agonists were used as functional antagonists of carbachol and a comparison of the maximum shifts in the carbachol concentration‐response line produced by each of the β‐adrenoceptor agonists provided a comparison of their efficacies.

On atrial preparations carbachol was used as a functional antagonist of the β‐adrenoceptor agonists and comparison of the maximum responses to the β‐adrenoceptor agonists in the presence of carbachol provided a comparison of their efficacies.

On trachea and atria the order of efficacy of the compounds was Me 454 > Me 506 ≥ isoprenaline = fenoterol.

The results indicated that high efficacy in a non‐catechol β‐adrenoceptor agonist is possible provided there is a favourable N‐substituent group.

Since Me 454, Me 506 and fenoterol, which are trachea‐atria selective, have efficacies equal to or greater than that of isoprenaline, which is non‐selective, it is concluded that low efficacy in a compound is not essential for it to show trachea‐atria selectivity in vitro in guinea‐pigs.
EVALUATION OF THE UPTAKE OF VARIOUS AMINES INTO STORAGE VESICLES OF INTACT HUMAN PLATELETS
Authors: COSTA J.L. , MURPHY D.L. , REVEILLE J.
Published: July 2012

The uptake of various 3H‐labelled amines into a thrombin‐releasable compartment of human platelets, thought to represent the platelet vesicular storage pool, has been evaluated. Measurable amounts of 5‐hydroxytryptamine (5‐HT), dopamine, tyramine, octopamine, and tryptamine accumulate in this pool, and also in a non‐thrombin‐releasable (cytoplasmic) pool during a 30 min incubation period with 10−5 M extracellular amine concentrations.

No differences in the accumulation of vesicular or cytoplasmic 5‐HT, dopamine, and tyramine are found in platelets treated with deprenyl to inhibit platelet monoamine oxidase as compared to controls.

Extracellular tyramine or dopamine in concentrations as high as 10−5 M does not alter the initial rate of 5‐HT uptake across the platelet plasma membrane. Similarly, sizable cytoplasmic pools of either amine do not alter the initial rate at which small amounts of 5‐HT enter platelet cytoplasm or storage vesicles. 5‐HT thus appears to be the preferred substrate for uptake into platelets and for movement from cytoplasm to vesicles.
THE EFFECTS OF ALLOXANATE, NICOTINIC ACID AND IMIDAZOLE ON SECRETORY PROCESSES AND THE ACTIVITIES OF ADENYLATE CYCLASE AND 3‘,5’‐AMP PHOSPHODIESTERASE IN CAT PANCREAS
Authors: BONTING S.L. , DE PONT J.J.H.H.M. , KEMPEN H.J.M. , CASE R.M. , SMITH PAMELA A. , SCRATCHERD T.
Published: July 2012

Nicotinic acid and alloxanate inhibited water and electrolyte secretion in a dose‐dependent fashion when added to the perfusate of the isolated saline‐perfused pancreas of the cat stimulated by a supramaximal dose of secretin.

There were no changes in the concentration of sodium or potassium secreted into the juice, but the anions exhibited changes which were related to flow rate. As the flow rate declined the chloride concentration increased with a reciprocal decrease in bicarbonate concentration.

Nicotinic acid and alloxanate inhibited enzyme secretion stimulated by carbachol.

Imidazole inhibited pancreatic electrolyte secretion, but stimulated amylase secretion. Atropine (0.14 μM) reduced the secretion of amylase but did not abolish the effect.

Adenylate cyclase prepared from cat pancreas, was stimulated by the octapeptide of cholecystokinin‐pancreozymin, secretin and sodium fluoride.

Alloxanate strongly inhibited both basal and hormone‐stimulated adenylate cyclase activity. Nicotinic acid and imidazole stimulated basal adenylate cyclase activity but had little effect on secretin‐stimulated activity.

Alloxanate, nicotinic acid and imidazole were all without effect on phosphodiesterase when tested in the presence of micromolar concentrations of adenosine 3′,5′‐monophosphate (cyclic AMP). At higher cyclic AMP concentrations (2 mM) alloxanate and nicotinic acid were without effect, whereas imidazole had a slight stimulatory effect at 10 mM which was more marked at 50 mM.

Alloxanate (10 mM) strongly inhibited both basal and secretin‐stimulated adenylate cyclase activity.

It is concluded that the effects of nicotinic acid, alloxanate and imidazole on pancreatic secretion are not mediated entirely through their effects on the adenylate cyclase or phosphodiesterase enzyme systems.
RELAXATION OF ISOLATED AORTA OF THE RABBIT BY PICOLINIC ACIDS
Authors: ASANO M. , HIDAKA H.
Published: July 2012

When the isolated thoracic aorta of the rabbit was contracted with prostaglandin F2α, 5‐alkylpicolinic acids produced dose‐dependent relaxations.

Picolinic acid, 2,5‐pyridinedicarboxylic acid and 5‐acetylpicolinic acid which do not have the 5‐alkyl residue failed to relax blood vessels.

The vascular relaxation was dependent on the number of carbon atoms in the 5‐alkyl compounds.

Relaxations which occurred with 5‐alkylpicolinic acids were not affected by pretreatment with either propranolol or atropine.

It is concluded that the 5‐alkyl residue is necessary for the vascular relaxation with 5‐alkylpicolinic acid and that it was not produced by stimulation of β‐adrenoceptors or cholinoceptors but rather through an activation of the basic process.
OPIATE BINDING AND EFFECT IN ILEUM PREPARATIONS FROM NORMAL AND MORPHINE PRETREATED GUINEA‐PIGS
Authors: COX B.M. , PADHYA REKHA
Published: July 2012

Dose‐response curves for normorphine in the absence and presence of naloxone have been obtained from myenteric plexus‐longitudinal muscle strip preparations from normal and morphine pretreated guinea‐pigs. In addition, the high affinity stereospecific binding of [3H]‐etorphine has been measured in homogenates of the same tissue.

Higher concentrations of normorphine were required to produce 50% inhibition of the electrically stimulated contractions of strip preparations from morphine pretreated animals. There was also an increase in the slope of linearized dose‐response curves in opiate‐tolerant preparations. Maximum opiate effect was unchanged, and responses to exogenous acetylcholine were not affected by the pre‐treatment.

There was a slight increase in the apparent equilibrium constant for naloxone after morphine pre‐treatment.

Tolerance to opiate effect was not accompanied by a change in the affinity or number of stereo‐specific binding sites for [3H]‐etorphine. Hill plots of [3H]‐etorphine binding in both control and morphine pretreated preparations gave slopes close to unity.

Most of these results can be explained by the assumption that in tolerant preparations, a certain fractional opiate receptor occupation threshold must be exceeded before opiate effects become apparent. It is suggested that the tissue adapts toward a threshold equivalent to the mean receptor occupancy attained during the period of opiate drug pretreatment.
REDUCED ADRENAL AMINE SYNTHESIS IN SPONTANEOUSLY HYPERTENSIVE RATS AFTER LONG‐TERM TREATMENT WITH PROPRANOLOL
Authors: ÅBLAD B. , ALMGREN O. , CARLSSON A. , HENNING M. , JONASSON J. , UUNG B.
Published: July 2012

Male spontaneously hypertensive rats were either fed a diet containing 3 mg/g of (±)‐propranolol, giving a mean daily intake of 178 ± 4.2 mg/kg, or a control diet from 7 weeks of age for 6 months. Three days after cessation of propranolol‐treatment, the arterial blood pressure of the treated group was about 10% lower than that of the control group. Adrenal dopamine content and tyrosine hydroxylase activity were reduced to 76% and 71% of the control values, respectively. The results indicate that propranolol causes a reduced sympathetic discharge through its central action, although blockade of β‐adrenoceptor‐mediated local regulatory mechanisms cannot be excluded.
ALTERATIONS IN BRAIN 5‐HYDROXY‐TRYPTAMINE METABOLISM DURING THE ‘WITHDRAWAL’ PHASE AFTER CHRONIC TREATMENT WITH DIAZEPAM AND BROMAZEPAM
Authors: AGARWAL R.A. , LAPIERRE Y.D. , RASTOGI R.B. , SINGHAL R.L
Published: July 2012

Daily administration of diazepam or bromazepam (10 mg/kg) for 22 days significantly increased the activity of mid‐brain tryptophan hydroxylase by 36% and 39%, respectively. The concentration of tryptophan was also enhanced in the mid‐brain region of rats subjected to benzodiazepine treatment.

Chronic therapy with either of the two anti‐anxiety agents enhanced the endogenous levels of 5‐hydroxytryptamine and 5‐hydroxyindoleacetic acid in cerebral cortex, hypothalamus, pons‐medulla, mid‐brain and striatum.

Whereas diazepam treatment decreased (13%) the activity of monoamine oxidase in mid‐brain, bromazepam failed to exert any effect, suggesting that the observed elevation in 5‐hydroxyindoleacetic acid levels is not associated with enhanced deamination of 5‐hydroxytryptamine.

Discontinuation of treatment for 48 h significantly decreased the activity of mid‐brain tryptophan hydroxylase to levels that were significantly lower than those seen for benzodiazepine‐treated and normal rats. The concentrations of mid‐brain tryptophan and 5‐hydroxytryptamine were also reduced in various brain regions examined.

Withdrawal from diazepam or bromazepam therapy further augmented the levels of brain 5‐hydroxyindoleacetic acid.

The results demonstrate that the depressant effects on behaviour of these agents are accompanied by increased metabolism of 5‐hydroxytryptamine in the brain. Withdrawal from these minor tranquillizers, on the other hand, reduces the synthesis of this indoleamine.
CENTRAL MECHANISM OF VASOPRESSIN‐INDUCED CHANGES IN ANTIDIURETIC HORMONE RELEASE
Authors: BHARGAVA K.P. , KULSHRESTHA V.K. , SRIVASTAVA Y.P.
Published: July 2012

Intracerebroventricularly (i.c.v.) administered vasopressin (0.001–1.0 u) in dogs anaesthetized with chloralose produced a dose‐dependent increase in urine flow with a concomitant decrease in the levels of antidiuretic hormone (ADH) in jugular vein blood.

Higher doses of vasopressin (1.5–2.0 u, i.c.v.) on the other hand had an antidiuretic effect and produced an increase in blood ADH level.

Pretreatment (i.c.v.) with a β‐adrenoceptor antagonist completely blocked the diuretic response of low doses of vasopressin (i.c.v.) but did not influence the antidiuretic response obtained with high doses.

Repeated administration of vasopressin (1.0 u, i.c.v.) induced tachyphylaxis; central catecholamine depletion with tetrabenazine significantly inhibited the vasopressin‐induced diuretic response.

It is concluded that intracerebroventricular vasopressin‐induced changes in ADH secretion are mediated through the release of catecholamines in the central nervous system.
PRENYLAMINE‐INDUCED CONTRACTURE OF FROG SKELETAL MUSCLE
Authors: KIRSTEN E.B. , LUSTIG KAREN C.
Published: July 2012

Experiments were performed to determine the influence of prenylamine on excitation‐contraction coupling in frog sartorius muscle.

Prenylamine (0.2‐1.0 mM) produced a biphasic contracture in skeletal muscle characterized by an initial phasic and subsequent tonic contracture.

Neither dantrolene nor procaine blocked the prenylamine‐induced contracture. Pretreatment with 100 mM K+ blocked the phasic but not the tonic component of the prenylamine contracture.

Prenylamine produced a sustained increase in 45Ca efflux at all concentrations that produce contracture. These concentrations of prenylamine also depressed the action potential, muscle twitch and resting potential.

Low concentrations of prenylamine (0.05 mM) which produced neither contracture, 45Ca efflux nor 45Ca influx, depressed the action potential, muscle twitch and K+ contracture.

The results suggest that prenylamine not only alters calcium mobility but also membrane permeability to other ions.
SELECTIVE INHIBITORY ACTIONS OF SODIUM‐p‐BENZYL‐4‐[1‐OXO‐2‐(4‐CHLOROBENZYL)‐3‐PHENYL PROPYL] PHENYL PHOSPHONATE (N‐O164) AND INDOMETHACIN ON THE BIOSYNTHESIS OF PROSTAGLANDINS AND THROMBOXANES FROM ARACHIDONIC ACID
Authors: EAKINS K.E. , KULKARNI P.S.
Published: July 2012

Sodium p‐benzyl‐4‐[1‐oxo‐2‐(4‐chlorobenzyl)‐3‐phenyl propyl]phenyl phosphonate (N‐0164) selectively inhibited the formation of thromboxane‐A2 from prostaglandin endoperoxides by human platelet microsomes in a dose‐dependent manner (IC50 2.2 × 10−5 m or 11.6 μg/ml).

N‐0164 was approximately 15 to 20 times as potent as indomethacin as an inhibitor of thromboxane‐A2 formation. In contrast, indomethacin was 20 times as potent as N‐0164 as an inhibitor of prostaglandin endoperoxide formation from arachidonic acid (IC50 2.6 × 10−5 m or 9.4 μg/ml).

Spiral strips of dog coronary arteries relaxed in the presence of prostaglandin endoperoxides and were contracted by prostaglandin E2 and thromboxane‐A2 and were therefore used to distinguish between prostaglandins and their intermediate precursors, the endoperoxides.

Neither indomethacin nor N‐0164 (both 50 μg/ml) significantly inhibited the formation of prostaglandin‐like activity from the endoperoxides following incubation with indomethacin‐pretreated rabbit kidney medulla microsomes.

It is not known whether this action of N‐0164 is related to its ability to antagonize certain actions of prostaglandins (and related compounds) or whether N‐0164 can penetrate the cell membrane to inhibit thromboxane formation in the intact cell.

Selective inhibition of thromboxane formation by drugs such as N‐0164 may be useful both clinically and as a pharmacological tool to elucidate the patho‐physiological roles of the thromboxanes.
THE EFFECTS OF GASTRIN AND GASTRIN ANALOGUES ON PANCREATIC ACINAR CELL MEMBRANE POTENTIAL AND RESISTANCE
Authors: IWATSUKI N. , KATO K. , NISHIYAMA A.
Published: July 2012

Intracellular recordings of membrane potentials and input resistance have been made from the exocrine acinar cells of mouse and rat pancreas placed in a tissue bath perfused with Krebs‐Henseleit solution.

The resting acinar cell membrane potential was about −38 mV. The acinar cells were stimulated by cholecystokinin‐pancreozymin (CCK‐PZ), gastrin and the gastrin‐related polypeptides, caerulein and desulphated caerulein. The immediate effect of stimulation with these secretagogues was always a depolarization and a concomitant reduction in input resistance and time constant. Depolarization of the acinar cell membrane by these secretagogues was not abolished in the presence of atropine (1.4 μm).

These peptide secretagogues were divided into the gastrin group and the CCK‐PZ group according to the time course of the depolarizations and the shape of the dose‐response curve. The depolarization evoked by the gastrin group returned quickly to the resting level but that evoked by the CCK‐PZ group was long lasting. The time course and the dose‐response curve for desulphated caerulein was identical with that of gastrin.

It was confirmed electrophysiologically that the activity of gastrin is exerted by the C‐terminal tetrapeptide; but the activity of caerulein depends on the C‐terminal heptapeptide, especially the presence in the molecule of the sulphated tyrosyl residue at position 7 (numbering from the C‐terminus). The equivalent sulphated tyrosyl residue in CCK‐PZ is probably necessary for optimal activity of this polypeptide.

The dose‐response curves obtained by electrophysiological methods indicated that the relative potencies of the peptides on mouse pancreatic acinar cells were caerulein > CCK‐PZ > gastrin. Synthetic human gastrin I was found to have a higher potency than either tetra‐ or pentagastrin.