bluuebunny/crossref_metadata_2025 huggingface dataset:
THE SELECTIVITY OF β‐ADRENOCEPTOR ANTAGONISTS ON CARDIOVASCULAR AND BRONCHODILATOR RESPONSES TO ISOPRENALINE IN THE ANAESTHETIZED DOG
Authors: DALY M.J. , FLOOK JUDITH J. , LEVY G.P.
Published: July 2012

The actions of five β‐adrenoceptor antagonists, chosen because of reported differences in their selectivities, were compared using the positive chronotropic, vasodepressor and bronchodilator responses to isoprenaline in anaesthetized dogs.

Propranolol was a potent antagonist of the isoprenaline responses in all three systems.

Practolol and acebutolol (M & B 17,803) blocked the positive chronotropic responses to isoprenaline to a greater extent than the vasodepressor or bronchodilator responses.

Butoxamine and α‐methyl dichloroisoprenaline showed the opposite selectivity, blocking the vasodepressor and bronchodilator responses to isoprenaline to a greater extent than positive chronotropic responses. However, both drugs were considerably less potent than the other antagonists studied and their selectivities were less clear‐cut than those of practolol or acebutolol.

All the antagonists lowered the resting heart rate and to a lesser extent the diastolic blood pressure. The effects of propranolol, practolol and acebutolol on heart rate probably result from cardiac β‐adrenoceptor blockade. With butoxamine and α‐methyl dichloroisoprenaline, however, the effects on heart rate probably result from a direct cardiodepressant action.

The relevance of the results to the problem of the sub‐classification of β‐adrenoceptors is discussed.
THE INHIBITORY ACTION OF OESTRADIOL‐17‐β AND PROGESTERONE ON VENOUS SMOOTH MUSCLE
Authors: McCALDEN T.A.
Published: July 2012

The in vitro action of oestradiol‐17‐β (0.1, 1.0 and 10.0 μg/ml) and progesterone (0.1, 1.0 and 10.0 μg/ml) on the spontaneous activity of the portal veins in female rats at different stages of gestation was studied.

Progesterone caused the spontaneous mechanical activity in the rat portal vein to decrease in amplitude and increase in frequency. This action was dose‐dependent and the sensitivity of the tissue decreased throughout pregnancy.

Oestradiol‐17‐β had a biphasic effect on spontaneous mechanical activity in the rat portal vein. At 0.1 μg/ml the vessel was stimulated while a similar effect to progesterone occurred with higher concentrations. The tissue was more sensitive to oestradiol at 7 days of gestation than at either the 10‐14 or 17‐21 day periods of gestation.

These effects of oestradiol and progesterone were still seen after blockade of the β‐adrenoceptors.

Hydrocortisone (10 μg/ml) had no inhibitory effect on the spontaneous mechanical activity of the vein.

The veins from the 17‐21 days pregnant animals showed a smaller amplitude of contraction than comparable non‐pregnant females.
VARIATION IN ACTIVITY OF MONOAMINE METABOLIZING ENZYMES IN RAT LIVER DURING PREGNANCY
Authors: PARVEZ SIMONE , PARVEZ S.H. , YOUDIM M.B.H.
Published: July 2012

Catechol‐O‐methyltransferase (COMT) and monoamine oxidase (MAO) activities in rat liver were measured during pregnancy, parturition and postpartum. Compared with activity in non‐pregnant controls, both enzymes showed a significant decrease in activity which was most pronounced at day 18.

The metabolism of intravenously infused [3 H]‐adrenaline to [3 H]‐metanephrine and to [3 H]‐acidic metabolites was also significantly depressed during pregnancy but had returned to control values by the 21st day.

The effects of reserpine and/or nialamide on hepatic COMT and MAO were studied in control and 20‐day‐pregnant rats. Their action on COMT activity differed in the two groups. MAO was inhibited to a similar extent in these groups whether the drugs were given separately or in combination.

It seems possible that the changes in endocrine function which occur during pregnancy are responsible for the observed alterations in enzyme activity.
CARDIOVASCULAR DEPRESSANT EFFECTS OF NEOMYCIN AND GENTAMICIN IN RHESUS MONKEYS
Authors: ADAMS H.R.
Published: July 2012

The acute cardiovascular effects of neomycin and gentamicin, representative aminoglycoside antibiotics, were examined in surgically‐prepared anaesthetized rhesus monkeys.

Intravenous administration of 14, 28, and 56 mg/kg of neomycin consistently induced a dose‐dependent depression of systemic blood pressure, cardiac output, left ventricular contractile force, maximum dF/dt of left ventricular contraction, and heart rate. Neomycin produced similar cardiovascular depressant effects when heart rate was maintained constant by electrical pacing.

Maximum depression of haemodynamic values usually occurred within 2 to 5 min after injection of neomycin; values then gradually returned to control levels within 20 to 30 (14 mg/kg) or 60 to 80 (56 mg/kg) minutes.

Injection of CaCl2 (1.35 mEq Ca2+/kg, i.v.) during the peak depressant effect of neomycin produced a rapid and maintained restoration of cardiovascular function to control levels; conversely, noradrenaline (2 μg, i.v.) or isoprenaline (0.5 μg, i.v.) produced only transient reversal of the neomycin effects.

Similar evidence of cardiovascular dysfunction was observed with gentamicin.

These findings demonstrate the direct cardiovascular depressant effects of aminoglycoside antibiotics in a higher primate species, and suggest that this adverse response is related to an alteration of calcium ion function.
REFLEX BRADYCARDIA AND HYPOTENSION PRODUCED BY PROSTAGLANDIN F2α IN THE CAT
Authors: KOSS M.C. , NAKANO J.
Published: July 2012

Intravenous administration of prostaglandin F2α results in a dose‐dependent increase in pulmonary arterial pressure, decrease in systemic arterial pressure and a delayed bradycardia. Pulmonary vasoconstriction was observed at doses as low as 0.1 and 0.3 μg/kg. The systemic depressor and heart rate lowering effects were observed at 1 μg/kg doses and above.

A moderate bradycardia was still observed after atropine blockade but was abolished following bilateral vagotomy. Neither of these procedures affected the pulmonary vascular response.

Injections of submaximal doses of prostaglandin F2α (1–4 μg/kg) produced a greater and longer lasting bradycardia when injected into the left atrium than was observed following intravenous administration. In addition the latency of onset was much shorter following left atrial injection. These doses resulted in no change in heart rate and a minimal hypotension when injected into the brachiocephalic artery or into the aortic arch.

Small doses of prostaglandin F2α administered at the level of the origin of the coronary arteries produced marked decreases in heart rate and blood pressure whereas no change occurred following injection of the same amount into the ascending aorta at more distal sites.

These results suggest that prostaglandin F2α produces bradycardia and hypotension in the cat by activating ‘receptors’ located in the left heart or by acting on structures perfused by means of the coronary arteries.
EFFECTS OF AZAPERONE ON CARDIOVASCULAR AND RESPIRATORY FUNCTIONS IN THE HORSE
Authors: LEES P. , SERRANO L.
Published: July 2012

The butyrophenone tranquillizer, azaperone, was administered intramuscularly, at dose levels of 0.4 and 0.8 mg/kg, to ponies and its effects on cardiovascular and respiratory functions assessed.

Arterial blood pH, CO2 tension (PaCO2) and O2 tension (PaO2) remained relatively constant throughout the course of action of azaperone.

Azaperone did not modify plasma protein concentration but venous blood packed cell volume and haemoglobin concentration were reduced by 5 to 10% for at least 4 hours. These changes were probably caused by uptake of erythrocytes into the splenic reservoir.

Small increases in heart rate occurred for up to 60 min after administration of the drug, and this was followed by a slight bradycardia in some ponies.

Azaperone reduced mean arterial blood pressure (MAP) for at least 4 h, by which time its ataractic action was generally no longer apparent. The hypotension was caused, during the early phase of action at least, by a reduction in peripheral resistance, since cardiac output was increased slightly 20 min after its administration. Possible mechanisms underlying the cardiovascular changes are discussed.

In spite of reductions in arterial blood 02 content and MAP produced by azaperone, it is likely that tissue oxygenation was adequate, since arterial blood lactate concentrations were not increased.
BLOOD PRESSURE RESPONSES TO ADRENAL FIELD STIMULATION AS A MEASURE OF ADRENAL CATECHOLAMINE RELEASE
Authors: CLARKE D.E. , ROMANYSHYN W.M.
Published: July 2012

A new method for studying adrenal medullary release is described in pithed rats using field stimulation of an entire adrenal gland.

The increases in blood pressure in response to field stimulation of the gland consisted of an initial short, variable component, due to stimulation of adrenergic vasomotor neurones and a secondary, longer lasting component, due to medullary catecholamine release.

Removal of the initial component by drugs or cardiac/coeliac ganglionectomy did not affect the magnitude of the secondary pressor component.

The secondary pressor component was frequency‐dependent, reproducible and stable with time. The extent of medullary catecholamine release could be assessed by comparing the blood pressure rise with those obtained after adrenaline injections.

The method appears to provide a reliable means by which adrenal medullary catecholamine release may be assessed without significant interference from vasomotor nerves.
BENZODIAZEPINES AND CENTRAL GLYCINE RECEPTORS
Authors: CURTIS D.R. , GAME C.J.A. , LODGE D.
Published: July 2012

In cats, anaesthetized with pentobarbitone, intravenous diazepam (minimum dose 3.0 mg/kg) enhanced dorsal root potentials but did not significantly diminish the reduction by electrophoretic strychnine of the inhibitory action of electrophoretic glycine on dorsal horn interneurones.

In mice, intraperitoneal diazepam (2.5 mg/kg) had no appreciable effect on the potency of strychnine as a convulsant, although providing some protection against bicuculline.

These observations, together with the failure of chlordiazepoxide to either inhibit the firing of spinal interneurones or reduce antagonism between strychnine and glycine when administered locally, provide no support for the interaction between benzodiazepines and mammalian central glycine receptors which has been proposed on the basis of in vitro studies of strychnine binding.
A COMPARISON OF γ‐AMINOBUTYRIC ACID AND THE SEMI‐RIGID ANALOGUES 4‐AMINOTETROLIC ACID, 4‐AMINOCROTONIC ACID AND IMIDAZOLE‐4‐ACETIC ACID ON THE ISOLATED SUPERIOR CERVICAL GANGLION OF THE RAT
Authors: BOWERY N.G. , JONES G.P.
Published: July 2012

The rat superior cervical ganglion possesses receptors for γ‐aminobutyric acid (GABA). This can be demonstrated in vitro by recording the changes in ganglionic surface potential which occur after the addition of GABA to the bathing solution.

The actions of three conformationally‐restricted analogues of GABA namely 4‐aminotetrolic acid (4‐ATA), trans 4‐aminocrotonic acid (4‐ACA) and imidazole‐4‐acetic acid (IAA) have been examined for activity at this peripheral receptor.

All three analogues depolarized the ganglion in a manner similar to GABA. Their actions were transient and were ‘occluded” by GABA; also the log dose‐response curve in each case was parallel to that of GABA. Molar potencies relative to GABA (=1) were 4‐ACA =1.48, IAA = 0.100, 4‐ATA = 0.0028.

The action of each analogue could be blocked by the GABA antagonists bicuculline and tetramethylenedisulphotetramine at doses which had relatively little effect on responses to the cholinomimetic carbachol.

4‐ACA and IAA (1 mM) significantly reduced the ganglionic accumulation of [3H]‐GABA (0.2 μM) by 88% and 58% respectively whereas 4‐ATA (1 mM), caused no significant reduction in [3H]‐GABA accumulation.
CALCITONIN: ANTAGONISM AT INTESTINAL MUSCARINIC RECEPTORS
Authors: DREYFUS CHERYL F. , GERSHON M.D. , HAYMOVITS A. , NUNEZ E.
Published: July 2012

The action of calcitonin was studied on the motility of isolated innervated segments of rabbit and guinea‐pig intestines as well as longitudinal muscle with adherent myenteric plexus dissected from the guinea‐pig ileum. Calcitonin (0.25 μm) antagonized contractile responses to acetylcholine and the cholinergic response to electrical field stimulation. This hormonal effect was relatively specific since it was not observed at nicotinic receptors or adrenoceptors, nor did calcitonin act as a local anaesthetic or directly on the contractile machinery of smooth muscle. Perivascular adrenergic and intrinsic non‐adrenergic inhibitory responses also were unaffected by calcitonin. However, calcitonin did have antihistaminic properties directed against H1‐receptors. The concentration of calcitonin required to achieve muscarinic antagonism in our experiments is not reached at the resting level of circulating hormone.
THE EFFECTS OF EDTA AND EGTA ON RENIN SECRETION
Authors: PEART W.S. , QUESADA T. , TENYI I.
Published: July 2012

1The effects of the disodium salt of ethylenediamine tetra‐acetate (EDTA) and 1,2,bis,2 amino‐ethoxyethane‐NNN‘N’‐tetra‐acetic acid (EGTA) on renin secretion and vascular resistance were studied in the isolated perfused kidney of the rat.

2Both substances produced a significant increase of renin release.

3In the absence of calcium and magnesium, EDTA still increased renin release and there was now a considerable increase of perfusion pressure.

4The rise of pressure but not the rise of renin was inhibited by the removal of potassium from the perfusate when EDTA was administered in the absence of calcium.

5Propranolol and phenoxybenzamine had no effect on the vasoconstrictor action of EDTA.

6EGTA was less effective as a renin releaser than EDTA until magnesium was removed from the perfusate. Further, it had only a small effect on perfusion pressure in contrast to EDTA.
THE EFFECT OF (—)‐ISOPRENALINE AND (±)‐SALBUTAMOL ON PEPSINOGEN AND ACID SECRETION IN THE DOG
Authors: DALY M.J. , STABLES R.
Published: July 2012

1The β‐adrenoceptor agonists, (—)‐isoprenaline and (±)‐salbutamol, reduced pepsinogen secretion induced by pentagastrin in conscious dogs with Heidenhain pouches.

2(—)‐Isoprenaline and (±)‐salbutamol also reduced gastric acid secretion while producing a moderate tachycardia.
INHIBITORY EFFECTS OF CLONIDINE ON RESPONSES TO SYMPATHETIC NERVE STIMULATION IN THE PITHED RAT
Authors: DOXEY J.C. , EVERITT J.
Published: July 2012

The spinal sympathetic outflow to the eyelid, heart, splanchnic blood vessels, vas deferens and anococcygeus muscle was stimulated in pithed rats.

Clonidine inhibited sympathetic outflow to all of the tissues studied. The inhibitory effects of clonidine on cardiac nerves and hypogastric nerves were antagonized by phentolamine.

Clonidine produced a postsynaptic a‐adrenoceptor agonist action on the eyelid, splanchnic blood vessels and the anococcygeus muscle. These effects were also antagonized by phentolamine.

The effects of clonidine, naphazoline and oxymetazoline on pre‐ and postsynaptic α‐adrenoceptors were determined.

The presynaptic α‐adrenoceptors employed were situated in either the sympathetic cardiac or hypogastric nerve terminals. Increases in diastolic blood pressure were used to assess concurrent postsynaptic α‐adrenoceptor agonist activity.

The presynaptic α‐adrenoceptor agonist potencies of clonidine, naphazoline and oxymetazoline were very similar on cardiac nerve terminals whereas on the hypogastric nerve terminals oxymetazoline was about 6 times more potent than either naphazoline or clonidine.

The results support the view that presynaptic α‐adrenoceptors regulate transmitter release in sympathetic nerves. There appear to be subtle differences between the presynaptic α‐adrenoceptors of different sympathetic nerve endings.
ESTIMATION AND CHARACTERIZATION OF PROSTAGLANDINS IN THE HUMAN GASTROINTESTINAL TRACT
Authors: BENNETT A. , STAMFORD I.F. , STOCKLEY HELEN L.
Published: July 2012

Prostaglandin‐like material was extracted from muscle and mucosa of surgically removed human stomach, ileum and colon and assayed against prostaglandin E2 on strips of rat gastric fundus. Superfused human isolated gastric mucosa released prostaglandin‐like material and release was increased by stretching or clamping the tissue.

The relative amounts of extracted biological activity were broadly as follows: gastric antral mucosa > colon muscle > gastric body mucosa ≅ ileal mucosa > colon mucosa ≅ gastric muscle ≅ ileal muscle.

Prostaglandin E and F were tentatively identified by chromatography and sensitivity to inactivation by alkali.

Prostaglandin E apparently contributed most to the biological activity, possibly because the assay tissue is more sensitive to prostaglandin E than to F. Chromatography of gastric body mucosal extracts located material running with prostaglandin E2 and a little with E1. Colonic muscle and mucosal extracts contained material with RF values of prostaglandins E1, E2, E3 and F1α, whereas F2α and F3α‐like substances were found only in the mucosa. The proportions of prostaglandin F varied between specimens.

The amount of extracted prostaglandin‐like activity was increased by adding cofactors and arachidonic acid, and lessened by homogenization with acid‐ethanol.

The type and amount of activity generated from arachidonic acid by partly purified colonic mucosal prostaglandin synthetase depended on the substrate concentration.

The possible relationships of prostaglandins to mucus secretion and other physiological and pathological gut functions are discussed.
AN INHIBITORY ROLE FOR NORADRENALINE IN THE MOUSE VAS DEFERENS
Authors: JENKINS D.A. , MARSHALL I. , NASMYTH P.A.
Published: July 2012

Noradrenaline (0.1‐3.0 μM) inhibited the twitch responses to single pulse field stimulation of the isolated vas deferens of the mouse. The higher concentrations of noradrenaline (ca. 0.3‐3.0 μM) were required to make the tissue contract.

Phentolamine (10 μM) abolished the contractor response to higher concentrations of noradrenaline and antagonized the inhibitory effect of lower concentrations on the twitch response.

Propranolol (10 μM) potentiated both the contractor and the inhibitory effect of noradrenaline on the twitch response.

Isoprenaline (0.1‐3.0 μM) and salbutamol (1.0‐3.0 μM) both inhibited the twitch response. Their effects were antagonized by propranolol (10 μM), but not by practolol (10 μM).

The effects of uptake1 and uptake2 blocking agents were determined. Cocaine (10 μM) reduced the size of the twitch response in 2 out of 4 experiments. Imipramine (0.18 μM) also reduced the size of the twitch, as did oestradiol (3.7 μM) and a combination of cocaine and oestradiol.

Contractor responses to exogenous noradrenaline showed tachyphylaxis, but when this was not very marked, the response could be shown to be potentiated by uptake blocking agents.

The inhibitory effect of noradrenaline on the twitch response was greatly potentiated by cocaine (10 μM) and much less so by oestradiol (3.7 μM).

It is concluded that the transmitter responsible for the twitch response is either an unknown substance released from the sympathetic neurone, or noradrenaline acting upon a receptor with none of the characteristics of known α‐ or β‐adrenoceptors. In either case, noradrenaline can inhibit the output, probably by stimulation of presynaptic α‐adrenoceptors.
EFFECT OF NEUROLEPTICS AND OTHER DRUGS ON MONOAMINE UPTAKE BY MEMBRANES OF ADRENAL CHROMAFFIN GRANULES
Authors: PLETSCHER A.
Published: July 2012

The effects have been investigated of various reserpine‐like, neuroleptic, antidepressant and other compounds on the adenosine‐5′‐triphosphate (ATP)‐dependent uptake of noradrenaline (NA) (reserpine‐sensitive) and tryptamine (reserpine‐resistant) by membranes of isolated chromaffin granules of bovine adrenal medulla.

Reserpine and Ro 4–1284 (2‐hydroxy‐2‐ethyl‐3‐isobutyl‐9,10‐dimethoxy‐hexahydro‐11bH‐benzo(a)quinolizine) as well as neuroleptics (e.g. chlorpromazine and haloperidol) inhibited the NA uptake, but the reserpine‐like drugs were more potent. In contrast, Ro 4–1284 showed a considerably weaker effect than the neuroleptics in interfering with tryptamine uptake. Chlorpromazine had about the same potency in inhibiting NA and tryptamine uptake, whereas the action of haloperidol was more pronounced on the uptake of NA than of tryptamine.

The relative potencies of neuroleptic drugs in inhibiting NA uptake by granule membranes in vitro corresponded only partly to their relative potencies in enhancing dopamine turnover in vivo.

The inhibition of NA uptake by chlorpromazine and Ro 4–1284 appeared to be of the noncompetitive type.

Chlorpromazine did not influence the decrease in ATP induced by granule membranes in the incubation medium.

Other basic, but not acidic compounds also inhibited NA uptake by granule membranes; their potency was of the order of that of chlorpromazine (antidepressants) or weaker (e.g. benzodiazepines).

In conclusion, the mechanism of action of neuroleptics probably differs from that of reserpine‐like drugs in the inhibition of monoamine uptake by membranes of catecholamine storage organelles. While interference with the granular storage of dopamine at the granule membrane level may contribute to the in vivo action of neuroleptics (e.g. in enhancing dopamine turnover), additional effects of these drugs must be involved in vivo, e.g. blockade of pre‐ and postsynaptic dopamine receptors.
THE DEVELOPMENT OF TACHYPHYLAXIS TO ELECTRICAL STIMULATION IN GUINEA‐PIG ILEAL LONGITUDINAL MUSCLES AND THE POSSIBLE PARTICIPATION OF ADENOSINE AND ADENINE NUCLEOTIDES
Authors: HAYASHI E. , KUNITOMO M. , MORI M. , SHINOZUKA K. , YAMADA S.
Published: July 2012

Electrically (30 Hz) induced contractions of guinea‐pig isolated ileal longitudinal muscles were reduced by tetrodotoxin (1 μm), atropine (1 μm), adenosine (30 μm) and morphine (10 μm).

When stimulated with 10 or 30 Hz for 10 s at 1 min intervals, a progressive decline of amplitude of the contraction was seen (development of tachyphylaxis). At this time, the contractile response to 1,1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) (10 μm) was also greatly reduced.

The smaller responses to electrical stimulation and DMPP during tachyphylaxis were restored to their initial amplitude by the addition of theophylline (10 μm). The appearance of tachyphylaxis was prevented by pretreatment with theophylline (1 to 10 μm) and was greatly accelerated by pretreat‐ment with dipyridamole (0.1, 1 μm).

In [14C]‐choline or [3H]‐adenosine preloaded muscle strips, electrical stimulation (30 Hz) increased the 14C‐ or 3H‐output, the effect being sensitive to tetrodotoxin blockade. The tachyphylaxis to electrical stimulation was accompanied by a considerable and sustained increase in 3H‐output, an effect that was accelerated by dipyridamole (1 μm). The 14C‐output initially increased but fell off gradually with the development of tachyphylaxis at which time theophylline (30 1) reversed the fall.

There was a marked increase in the proportion of released [3H]‐adenosine to its derivatives during the development of tachyphylaxis. Approximately 60% of the released total radioactivity after tachyphylaxis was found to be [3H]‐adenosine.

These results suggest that the development of tachyphylaxis may be closely associated with the release of endogenous adenosine derivatives (mostly adenosine) which have presynaptic inhibitory actions on the cholinergic elements in guinea‐pig ileum.
EFFECT OF LABETALOL ON THE UPTAKE OF [3H]‐(‐)‐NORADRENALINE INTO THE ISOLATED VAS DEFERENS OF THE RAT
Authors: DREW G.M. , HILDITCH A. , LEVY G.P.
Published: July 2012

The effects of the combined a‐ and, B‐adrenoceptor blocking drug, labetalol, on the uptake of [3H]4‐)‐noradrenaline into the isolated vas deferens of the rat have been determined and compared with those of some other ca‐adrenoceptor blocking drugs and cocaine.

Labetalol, like cocaine, produced a simple competitive inhibition of [3H]‐(‐)‐noradrenaline uptake and was about 4 times less potent than cocaine. It is concluded that labetalol is a potent inhibitor of uptake1. Phentolamine and thymoxamine also inhibited [3H]‐(‐)‐noradrenaline uptake, and were respectively 8 and 14 times less potent than cocaine. Tolazoline, piperoxan and yohimbine were inactive in concentrations up to 30 ig/ml.

The uptake1 blocking action of labetalol could explain, at least in part, the previously reported difference in its ability to block noradrenaline and phenylephrine vasopressor responses in the anaesthetized dog.

The possibility that uptake1 inhibitory concentrations of labetalol could be present in the blood of subjects receiving normal antihypertensive doses of the drug is discussed.
THE EFFECTS OF DILTIAZEM (CRD‐401) ON THE MEMBRANE AND MECHANICAL PROPERTIES OF VASCULAR SMOOTH MUSCLES OF THE RABBIT
Authors: ITO YUSHI , KURIYAMA HIROSI , SUZUKI HIKARU
Published: July 2012

The effects of diltiazem on electrical and mechanical properties of vascular smooth muscles of the rabbit were examined by various experimental procedures.

In the pulmonary artery, diltiazem (0.1 to 10 μg/ml) did not modify the membrane potential (‐56 mV), length constant of the tissue (1.47 mm) or rectifying properties of the membrane. Diltiazem (0.1 to 10 μg/ml) did not modify the membrane potential of the mesenteric artery (‐62.5 mV).

Diltiazem (1 to 10 μg/ml) suppressed mechanical responses of pulmonary and mesenteric arteries induced either by direct stimulation of the muscle (1.0 s pulse) or by neural activation (0.5 ms pulse, 30 Hz and 10 s total duration). Diltiazem suppressed the contraction induced by nerve stimulation to a greater extent than that induced by direct muscle stimulation.

When the depolarization‐contraction relationship of the smooth muscle of the pulmonary artery was observed by voltage clamp technique, diltiazem (1 to 10 μg/ml) raised the critical membrane potential to evoke contraction from 5 mV to 12 mV, and reduced the amplitude of contraction obtained at any given depolarization level.

In the pulmonary artery, diltiazem (10 μg/ml) suppressed K‐induced contraction and raised the mechanical threshold, while K‐induced depolarization was not suppressed. Diltiazem (1 to 10 μg/ml) also suppressed noradrenaline‐induced contraction, raised the mechanical threshold and suppressed noradrenaline‐induced depolarization.

The vasodilator actions of diltiazem on the vascular smooth muscle were compared to vasodilator actions observed with other Ca‐antagonists.
MODULATION OF NORADRENERGIC TRANSMISSION IN THE RABBIT EAR ARTERY BY DOPAMINE
Authors: HOPE WENDY , McCULLOCH MARIAN W. , RAND M.J. , STORY D.F.
Published: July 2012

The effects of dopamine on vasoconstrictor responses to field stimulation of sympathetic nerves and to exogenous noradrenaline were studied in the isolated ear artery of the rabbit. Responses to sympathetic nerve stimulation were depressed, initially, by infusions of dopamine (0.5 to 1 μm), but the responses partially recovered in the continued presence of dopamine. Responses to noradrenaline were unchanged at the start of the dopamine infusions but were enhanced as the infusions continued and also after cessation of the infusion.

Dopamine (0.5 μm) reduced the stimulation‐induced efflux of tritium from segments of ear artery labelled with [3H]‐noradrenaline. The reduction persisted during 65 min of dopamine infusion, after which time the vasoconstrictor responses had generally recovered to 93% of control level. On ceasing the infusion, the stimulation‐induced efflux and the vasoconstrictor responses were enhanced.

Metoclopramide, haloperidol and ergometrine, each in a concentration of 0.2 μm, prevented the inhibitory effect of 0.5 μm dopamine on the stimulation‐induced tritium release, but not the inhibitory effect of 0.5 μm noradrenaline. Phenoxybenzamine (0.2 and 1 μm) and phentolamine (1 μm) prevented the inhibitory effects of both noradrenaline and dopamine on the stimulation‐induced efflux, and phentolamine (0.2 μm) prevented the inhibition of the stimulation‐induced release by noradrenaline but only partially prevented the inhibitory effect of dopamine on the stimulation‐induced efflux.

A possible rôle for dopamine in the modulation of noradrenergic transmission is suggested.
4‐AMINOPYRIDINE AND EVOKED TRANSMITTER RELEASE FROM MOTOR NERVE ENDINGS
Authors: ILLES P. , THESLEFF S.
Published: July 2012

In the presence of tetrodotoxin, electrotonic depolarization of frog motor nerve terminals causes the appearance of stimulus‐graded endplate potentials. When 4‐aminopyridine is added, the graded endplate potential is converted into a triggered all‐or‐none response resulting in giant endplate potentials of about 70 mV amplitude and 50 ms duration. The triggered endplate potentials are abolished in Ca2+ ‐free saline and are blocked by Mn2+ ions. Sr2+ but not Ba2+ can replace Ca2+ in supporting transmitter release. Mg2+ fails, even in concentrations as high as 32 mm, to affect the amplitude and the shape of the endplate potential but abolishes it when the Ca2+ concentration is reduced to 0.2 mm.

Despite the large amplitude of the triggered endplate potential in the presence of 4‐aminopyridine and tetrodotoxin, repetitive stimulation up to 10 Hz causes only a small decline in amplitude of successive endplate potentials. However, in the presence of (+)‐tubocurarine or gallamine, repetitive nerve stimulation produces a marked decline in successive endplate potential amplitude. The fall is counteracted when evoked transmitter release is reduced in the presence of 0.2 mm Ca2+. The results suggest that in the presence of 4‐aminopyridine such large amounts of transmitter are released that even during repetitive stimulation (5 to 10 Hz) endplate potentials are of maximal amplitude.

4‐Aminopyridine causes a parallel shift to the right of the dose‐response curve to Mg2+ for blockade of nerve impw/se‐evoked transmitter release (in the absence of tetrodotoxin). A similar parallel shift occurs in the presence of tetraethylammonium and guanidine.

It is concluded that 4‐aminopyridine increases transmitter release by enhancing the transport efficacy for Ca2+ across the nerve terminal membrane during nerve terminal depolarization.
PRESYNAPTIC INHIBITORY ACTION OF 5‐HYDROXYTRYPTAMINE IN DOG ISOLATED SAPHENOUS VEIN
Authors: FENIUK W. , HUMPHREY P.P.A. , WATTS A.D.
Published: July 2012

The effect of 5‐hydroxytryptamine on contractile responses to sympathetic nerve stimulation has been studied in the dog isolated saphenous vein.

Electrical stimulation (0.1 to 10 Hz) of dog saphenous vein strips produced frequency‐dependent contractions. Contractions produced by stimulation at 2 Hz were almost completely blocked by tetrodotoxin (3.1 × 10−8 mol/l) or phentolamine (5.0 × 10−6 mol/l) but mecamylamine (5.0 × 10−6 mol/l) had little effect. This suggests that the contractions were mediated predominantly through noradrenaline release from postganglionic noradrenergic nerves.

Contractions produced by intermittent electrical stimulation at 2 Hz were inhibited by 5‐hydroxytryptamine (1.0 × 10−9 to 1.0 × 10−7 mol/l) in a concentration‐dependent manner whilst contractions induced by exogenous noradrenaline were not affected.

The inhibitory action of 5‐hydroxytryptamine was most marked at low frequencies of stimulation and with low pulse numbers.

High external calcium concentrations (3.9 and 5.2 × 10−3 mol/l) reduced the inhibitory action of 5‐hydroxytryptamine.

Cyproheptadine (1.0 × 10−8 mol/l to 1.0 × 10−6 mol/l) or morphine (1.0 × 10−7 mol/l to 1.0 × 10−5 mol/l) did not antagonize the inhibitory action of 5‐hydroxytryptamine. Methysergide (1.0 × 10−7 mol/l) slightly reduced the contractions produced by electrical stimulation and only weakly antagonized the action of 5‐hydroxytryptamine.

It is suggested that a 5‐hydroxytryptamine receptor exists presynaptically in the dog isolated saphenous vein strip and that stimulation of this receptor by low concentrations of 5‐hydroxytryptamine inhibits the release of noradrenaline from noradrenergic nerves. This receptor type is resistant to blockade by ‘classical’ 5‐hydroxytryptamine antagonists.
EFFECTS OF CLONIDINE, PRAZOSIN AND PHENTOLAMINE ON HEART RATE AND CORONARY SINUS CATECHOLAMINE CONCENTRATION DURING CARDIOACCELERATOR NERVE STIMULATION IN SPINAL DOGS
Authors: CAVERO I. , DENNIS T. , LEFÈVRE‐BORG FRANÇOISE , PERROT P. , ROACH A.G. , SCATTON B.
Published: July 2012

In spinal dogs, continuous electrical stimulation of the cardioaccelerator nerve produced a transient rise in aortic blood pressure and a sustained increase in both heart rate and coronary sinus blood flow. The latter effects were accompanied by a significant elevation in the coronary sinus plasma noradrenaline concentration without significant changes in the levels of dopamine and adrenaline. The concentrations of the three catecholamines in thoracic aorta plasma were not significantly changed by cardioaccelerator nerve stimulation.

Clonidine (20 μg/kg, i.v.), given during cardioaccelerator nerve stimulation, increased both mean aortic blood pressure and coronary sinus blood flow and decreased heart rate and coronary sinus venous plasma noradrenaline overflow.

Phentolamine (0.3 mg/kg, i.v.) completely antagonized these effects of clonidine. Prazosin (0.3 mg/kg, i.v.) inhibited by only 43 and 38% the respective reductions in heart rate and noradrenaline overflow elicited by clonidine.

On termination of cardioaccelerator stimulation (about 10 min after either prazosin or phentolamine), heart rate and coronary sinus noradrenaline overflow returned to control prestimulation levels.

Phentolamine or prazosin, administered alone during stimulation of the cardioaccelerator nerve, increased heart rate and noradrenaline overflow into the coronary sinus plasma. However, intravenous phentolamine and prazosin, in contrast to desipramine (0.3 mg/kg, i.v.) or tyramine (1.0 mg, i.a.), failed to change the tachycardia resulting from the local administration of noradrenaline into the sinus node artery (i.a.).

These results show that in spinal dogs the clonidine‐induced reduction in heart rate (elevated by electrical stimulation of the cardioaccelerator nerve) is accompanied by a fall in the quantity of noradrenaline overflowing into the coronary sinus plasma. The latter effect is presumably the result of an action of clonidine on cardiac presynaptic α‐adrenoceptors, the activation of which is followed by a reduction in the release of noradrenaline per nerve impulse. Phentolamine and prazosin are both antagonists of cardiac presynaptic α‐adrenoceptors in spinal dogs, as suggested by their action against clonidine and by their positive chronotropic effect when administered during stimulation of the cardioaccelerator nerve.
EVIDENCE FOR AN ENDOGENOUS DOPAMINE‐MEDIATED HYPOTHERMIA IN THE RAT
Authors: COX B. , LEE T.F.
Published: July 2012

Unilateral intrahypothalamic injection of either dopamine (10 μg) or amphetamine (10 μg) caused a fall in core temperature in the rat. Pimozide (0.5 mg/kg, i.p.) significantly reduced the hypothermic response, whereas pretreatment with phentolamine (1 mg/kg, i.p.) or methysergide (5 mg/kg, i.p.) was ineffective.

Systemic pretreatment with cocaine (20 mg/kg) abolished the hypothermic effect of amphetamine, but slightly enhanced the hypothermic response to dopamine.

Systemic pretreatment with tranylcypromine (10 mg/kg) had no significant effect on the fall in core temperature induced by either amphetamine or dopamine.

Intraperitoneal injection of cocaine and tranylcypromine, on their own, caused a fall in core temperature in the rat, which was significantly antagonized by either systemic or central pretreatment with pimozide. Phentolamine and methysergide failed to block the hypothermia.

Unilateral intrahypothalamic injection of cocaine (20 μg) or tranylcypromine (10 μg) also caused a significant fall in core temperature, which was reduced by intrahypothalamic pretreatment with pimozide (0.5 μg), but not significantly changed by pretreatment with phentolamine (25 μg) or methysergide (5 μg).

These results provide evidence for the presence of a dopaminergic system within the preoptic region, which mediates a lowering of core temperature in the rat.
A COMPARISON OF THE FACILITATORY ACTIONS OF 4‐AMINOPYRI‐DINE METHIODIDE AND 4‐AMINOPYRIDINE ON NEUROMUSCULAR TRANSMISSION
Authors: HORN A.S. , LAMBERT J.J. , MARSHALL I.G.
Published: July 2012

4‐Aminopyridine methiodide (4‐APMI), a quaternary analogue of aminopyridine (4‐AP), was tested for neuromuscular facilitatory actions on the chick biventer cervicis and frog sartorius nerve‐muscle preparations.

In the chick, 4‐APMI (10−4 to 10−2m) augmented indirectly elicited twitches and reversed tubocurarine‐induced neuromuscular block. Reversal of tubocurarine block was observed after treatment of the muscle with an anticholinesterase. 4‐APMI did not itself produce contracture but augmented responses to added acetylcholine.

4‐APMI (10−4m) prolonged the time courses of endplate potentials (e.p.ps) and miniature end‐plate potentials (m.e.p.ps) in the frog.

4‐APMI (10−4m) increased e.p.p. quantal content. 4‐AP was about 100 times more active than 4‐APMI in increasing quantal content. Both compounds prolonged muscle action potentials at similar concentrations.

4‐APMI (10−3 to 3 × 10−3m) possessed anticholinesterase activity in homogenates of chick biventer cervicis muscle.

It is concluded that 4‐APMI increases evoked acetylcholine release and also possesses a weak anticholinesterase action. The greater action of 4‐AP on quantal content is probably due to an intracellular action, possibly involving the release of calcium ions.
EXOCYTOTIC RELEASE OF CATECHOLAMINES AND DOPAMINE‐β‐HYDROXYLASE FROM THE PERFUSED ADRENAL GLAND OF THE RABBIT AND CAT
Authors: SORIMACHI MASARU , YOSHIDA KENICHI
Published: July 2012

Secretion of catecholamines (CA) and dopamines‐hydroxylase (DBH) activity from the perfused rabbit and cat adrenal gland was studied following stimulation by a number of substances, including the physiological transmitter, acetylcholine (ACh), added to the perfusion fluid.

Stimulation caused a proportional secretion of DBH and CA from the untreated rabbit adrenal. The ratio of DBH/CA was 11.2 + 0.9 (mean + s.e.) which was close to that found in the crude granule fraction of the contralateral gland (11.4 ± 0.7).

After treatment with insulin (40 u/kg) for 3 h or with reserpine (0.25 mg/kg) for 24 h, CA and DBH contents decreased in a parallel fashion in the granule fraction, thus resulting in a similar ratio of DBH/CA in the gland. The ratio in the effluents after stimulation was similar to that found in the untreated gland.

Higher doses of reserpine (0.7 to 2.5 mg/kg) increased the ratio of DBH/CA in the granule fraction and was dependent on the doses employed. The ratio in the effluents from these glands after stimulation paralleled these increased values.

Concomitant secretion of CA and DBH in response to stimulation was also observed in the perfused cat adrenal. However, the ratio of DBH/CA in the effluents tended to be lower than that found in the granule fraction.

These results support the concept of exocytotic secretion of CA in the adrenal medulla.
STUDIES ON THE MECHANISM OF ACTION OF GLUCAGON IN STRIPS OF RABBIT RENAL ARTERY
Authors: GAGNON G. , REGOLI D. , RIOUX F.
Published: July 2012

The vasodilator effects of glucagon and adenosine cyclic 3′,5′‐monophosphate (cyclic AMP) were evaluated in strips of rabbit renal artery contracted with noradrenaline (NA) in the absence and presence of phosphodiesterase inhibitors or calcium (Ca2+) antagonists.

The vascular relaxant effect of glucagon was markedly potentiated by various concentrations of four different phosphodiesterase inhibitors (papaverine, theophylline, 3‐isobutyl‐1‐methylxanthine (IBMX) and indomethacin), while that of cyclic AMP was potentiated by only two of them (papaverine and indomethacin) and inhibited by the others (theophylline and IBMX).

Amongst the four phosphodiesterase inhibitors, IBMX (10 μg/ml) was found to produce the largest potentiation (e.g. the sensitivity increased by a factor of 10) of glucagon‐induced vascular relaxations (ED50 of glucagon in the presence of IBMX = 9.2 ± 1.0 ng/ml).

Ca2+ antagonists such as verapamil and SKF 525A produced a dose‐dependent inhibition of the vasodilator action of glucagon. Verapamil (2.5 μg/ml) also antagonized cyclic AMP‐induced vascular relaxations.

The vasodilator effect of verapamil was inhibited dose‐dependently by raising the concentration of extracellular Ca2+ from 0.05 to 0.2 g/l (or 1.25 to 5.0 mm) while those elicited by glucagon or cyclic AMP were not influenced, thus suggesting that the latter two drugs do not interfere with Ca2+ influx.

Disodium edetate (Na2EDTA, 210 to 840 μg/l) produced a dose‐dependent vasodilator effect which was attributed to the facilitation of Ca2+ extrusion from the smooth muscle cells and/or Ca2+ binding to the cell membrane. The relaxation produced by Na2EDTA was significantly blocked by verapamil (10 μg/ml) or SKF 525A (10 μg/ml).

The results were taken as an indication that glucagon produces at least a fraction of its vasodilator effect by promoting Ca2+ extrusion from the vascular smooth muscle cells and/or Ca2+ binding to or sequestration into intracellular sites, presumably via a cyclic AMP‐dependent mechanism.
ANTIGEN‐INDUCED BRONCHIAL ANAPHYLAXIS IN ACTIVELY SENSITIZED GUINEA‐PIGS: ANTI‐ANAPHYLACTIC EFFECTS OF SODIUM CROMOGLYCATE AND AMINOPHYLLINE
Authors: ANDERSSON PER
Published: July 2012

The inhibitory effects of sodium cromoglycate (SCG) and aminophylline on antigen‐induced bronchial anaphylaxis in guinea‐pigs, actively sensitized according to different regimens, were examined.

SCG (1 mg/kg administered intravenously) reduced the anaphylactic response in animals sensitized with 1 μg ovalbumin (OA) together with Al(OH)3 100 mg, and challenged at 14 and 40 days after sensitization. If higher doses of antigen (10 μg OA together with Al (OH)3 or 5 mg OA on day 0 plus 10 mg OA on day 2) were used for sensitization, the protective effect of SCG was found only in animals tested 14 days after sensitization.

A low dose of aminophylline (0.3 mg/kg) that was without a direct bronchodilator effect when tested against a histamine (4 μg/kg)‐induced bronchospasm, produced an anti‐anaphylactic effect. The anti‐anaphylactic effect of aminophylline varied slightly with the way the animals were immunized and the time at which they were tested.

It is concluded that bronchial anaphylaxis in guinea‐pigs sensitized with low doses of ovalbumin is a suitable model for the evaluation of anti‐anaphylactic properties of drugs.
EFFECTS OF CLONIDINE ON CANINE CARDIAC NEUROEFFECTOR STRUCTURES CONTROLLING HEART RATE
Authors: CAVERO I. , ROACH A.G.
Published: July 2012

In intact dogs anaesthetized with pentobarbitone, clonidine (10 μg/kg, i.v.) produced a sustained decrease in heart rate. This effect was significantly smaller in vagotomized dogs in which the sympathetic drive to the heart was either left intact or experimentally created by continuous electrical stimulation of the decentralized cardioaccelerator nerve. In the latter preparation, the negative chronotropic action of clonidine was reversed by an intravenous injection of phentolamine, whereas in the former experimental situation it was antagonized only by an intravenous plus an intravertebral artery injection of phentolamine.

In dogs with denervated hearts the tachycardia produced by electrical stimulation of the cardioaccelerator nerve was accompanied by a rise in noradrenaline overflowing into the coronary sinus plasma. Clonidine inhibited both these effects and phentolamine restored them to pre‐clonidine levels.

Clonidine decreased heart rate in dogs with an intact parasympathetically innervated heart and decentralized stellate ganglia. When the low basal heart rate of this preparation was elevated by electrical stimulation of the cardioaccelerator nerve, clonidine had a negative chronotropic effect, the degree of which was similar to that observed in intact dogs.

Clonidine neither modified baseline heart rates of dogs with denervated hearts nor the levels of heart rate which in this preparation were reduced by a sustained electrical stimulation of the right vagus or increased by intravenous infusions of either isoprenaline or noradrenaline.

These findings indicate that in the intact dog, bradycardia induced by clonidine resulted both from a reduction of sympathetic drive and from a concomitant increase in parasympathetic tone. The latter action did not occur at the level of cardiac neuroeffector structures since it was observed only in the presence of centrally connected vagal pathways. The inhibition of cardiac sympathetic tone was of both peripheral and central origin. Clonidine, in fact, diminished the quantity of noradrenaline overflowing into the coronary sinus plasma in cardiac denervated dogs with a tachycardia elicited by electrical stimulation of the decentralized cardioaccelerator nerve. This peripheral effect was probably due to an activation of α‐adrenoceptors located on sympathetic nerve terminals since it was antagonized by phentolamine. However, in vagotomized dogs (intact sympathetic pathways) intravenous phentolamine failed to antagonize the heart rate effects of clonidine which were abolished by a subsequent injection of phentolamine into the vertebral artery. Thus, the clonidine‐induced inhibition of both the peripheral and central sympathetic drive to the heart would appear to be mediated via α‐adrenoceptors.
β‐ADRENOCEPTOR ANTAGONISTS: STUDIES ON BEHAVIOUR (DELAYED DIFFERENTIATION) IN THE MONKEY (Macaca mulatta)
Authors: NICHOLSON A.N. , WRIGHT CATHERINE M.
Published: July 2012

Activity of six β‐adrenoceptor antagonists was studied on behavioural activity (delayed differentiation) in the monkey (Macaca mulatta). The drugs, three relatively lipophilic antagonists (propranolol, oxprenolol and metoprolol), and three relatively hydrophilic antagonists (acebutolol, atenolol and sotalol), were given by intraperitoneal injection (5 to 30 mg/kg).

With atenolol (25 to 30 mg/kg), total response time was increased, but there was no effect on the number of correct responses. With acebutolol (25 to 30 mg/kg), the number of correct responses was reduced, but there was no effect on total response time. With metoprolol (25 to 30 mg/kg), there was an increase in total response time and a decrease in the number of correct responses, and correct responses were decreased 4 h after injection over the whole dose range (5 to 30 mg/kg).

Some animals failed to respond or complete the task with 30 mg/kg oxprenolol, 25 mg/kg sotalol and 20 mg/kg propranolol. With 25 mg/kg oxprenolol, the total response time was increased and the number of correct responses was decreased. With 5–20 mg/kg sotalol, total response time was increased, but there was no effect on the number of correct responses. With 15 mg/kg of (±)‐propranolol and its isomers, there were increases in total response time and decreases in correct responses.

The studies suggest that lipophilic antagonists, such as propranolol, oxprenolol and metoprolol, are likely to have, at least, effects on the central nervous system, while hydrophilic antagonists may modify the peripheral nervous system. In the dose‐ranges studied, propranolol had the greatest, and atenolol and acebutolol had the least effects. Atenolol and acebutolol may prove to be particularly useful in man when disturbances of the nervous system are to be avoided.