bluuebunny/crossref_metadata_2025_split huggingface dataset:
RELATIONSHIP BETWEEN THEOPHYLLINE UPTAKE AND INOTROPIC EFFECT IN THE GUINEA‐PIG HEART
Authors: BELLEMANN P. , SCHOLZ H. 
Published: July 2012

The time course of the positive inotropic effect of theophylline was compared with the time course of the uptake and release of [3H]‐theophylline in guinea‐pig isolated, electrically driven hearts perfused by the Langendorff method.
Formation of theophylline metabolites could not be detected under the experimental conditions used.
Theophylline entered myocardial tissue very rapidly in two different phases. The first process (half‐time 21 s) amounted to 93% and the second (half‐time 5 min 50 s) to 7% of the total uptake. The development of the positive inotropic effect of theophylline was about four times faster than even the rapid component of the uptake of the drug into the myocardium.
The amount of theophylline accumulated in myocardial tissue (after 10 min perfusion) increased proportionally with theophylline concentrations in the perfusion media and no signs of saturation were detected. The tissue‐medium ratio did not exceed 1. The water content of the myocardial tissue amounted to about 80% at all theophylline concentrations examined.
The uptake of theophylline (3 mg/ml) was diminished by 9.2% after pretreatment of the hearts with caffeine (1 mg/ml). Theophylline uptake was also decreased by 13.5% when caffeine‐pretreated hearts were perfused with a solution containing theophylline (300 μg/ml) plus caffeine (1 mg/ml).
Theophylline release from the hearts was also very rapid. The efflux curve was composed of three components (half‐times: 24 s; 1 min 24 s; 6 min 18 seconds). The intercepts of the linear portions of the efflux curve occurred at 61%, 38% and 1%, respectively. Contractile force and theophylline content in myocardial tissue declined in a similar manner.
It is concluded that theophylline enters myocardial tissue very rapidly by passive diffusion. Theophylline distributes itself in the heart as freely as in the perfusion medium. A very small amount may be bound within the cell in a relatively specific way.
It seems possible that the positive inotropic effect of theophylline is partly due to an action of the drug on intracellular calcium binding or storage sites. However, the principal action of theophylline is assumed to be on the sarcolemma where it increases calcium influx from the extracellular space. This conclusion is based on the fact that the time courses of the increase in contractile force and of theophylline uptake into the cell were dissimilar.
THE PHARMACOKINETICS OF NEOSTIGMINE AND 3‐HYDROXYPHENYLTRIMETHYLAMMONIUM IN THE RAT: DOSE‐DEPENDENT EFFECTS AFTER PORTAL VEIN ADMINISTRATION
Authors: BARBER H.E. , BOURNE G.R. 
Published: July 2012

The elimination kinetics of [14C]‐neostigmine iodide and [14C]‐3‐hydroxyphenyltrimethylammonium iodide (3‐OH PTMA) have been studied in the rat.
The presence of a renal secretory pathway for neostigmine and 3‐OH PTMA has been confirmed.
For neostigmine and 3‐OH PTMA, at a given dose level, the fraction of the dose eliminated unchanged was reduced and the metabolite fraction was increased after portal vein administration when compared to jugular vein administration. This indicates that both compounds are subject to extensive metabolism during the first passage through the liver.
Neostigmine was eliminated by dose‐independent kinetics after jugular vein administration but dose‐dependent after portal vein administration. In the latter case the fraction eliminated as neostigmine increased with increasing dose. This increase was not accompanied by any change in the fraction of the metabolites eliminated.
After portal vein administration of 3‐OH PTMA, the fraction of the dose eliminated as 3‐OH PTMA also increased with increasing dose. This change was accompanied by a decrease in the fraction of the metabolites eliminated which were excreted at a constant rate.
METABOLIC AND CARDIOVASCULAR EFFECTS OF ISOPRENALINE AND SALBUTAMOL IN THE DOG
Authors: KELLY J.G. , SHANKS R.G. 
Published: July 2012

The intravenous infusion of isoprenaline and salbutamol into the greyhound increased heart rate and levels of free fatty acids, lactic acid and glucose.
On terminating the infusions of isoprenaline the changes produced declined rapidly but the effects produced by salbutamol were more persistent. When high doses of salbutamol had been infused, glucose and lactic acid levels in fact increased during the 20 min following the infusions.
These results support suggestions that, in the dog, lipolysis is mediated by β1 ‐adrenoceptors and liver glycogenolysis by β2 ‐adrenoceptors. The β‐adrenoceptors mediating muscle glycogenolysis could not be assigned unequivocally to either subtype.
The differences in the behaviour of isoprenaline and salbutamol in the period following the infusions are considered to be due partly to slower removal of salbutamol. Increases in lactic acid levels after infusion of large amounts of salbutamol may be secondary to the persistence of high glucose levels.
PHARMACOLOGICAL STUDIES ON SURUGATOXIN, THE TOXIC PRINCIPLE FROM JAPANESE IVORY MOLLUSC (Babylonia japonica)
Authors: HAYASHI E. , YAMADA S. 
Published: July 2012

Some pharmacological properties of surugatoxin (SGTX), a purified toxic substance from the Japanese ivory mollusc (Babylonia japonica), have been investigated. SGTX (50 nmol/kg i.v.) produced a prolonged fall of blood pressure in anaesthetized cats. This hypotensive effect was neither blocked by atropine and propranolol nor by spinal cord transection.
SGTX (37‐50 nmol/kg i.v.) inhibited the hypertensive and hypotensive response to 1, 1‐dimethyl‐4‐phenylpiperazinium iodide (DMPP) and to electrical stimulation of the splanchnic and vagal nerve, whereas it usually augmented the hypertensive response to adrenaline and to 4‐(m‐hlorophenylcarbamoyloxy)‐2‐butynyltrimethylammonium chloride (McN‐A‐343) in anaesthetized cats.
Close intra‐arterial injection of SGTX (6.2‐12.3 nmol/kg) to the superior cervical ganglion blocked the contractile response of the nictitating membrane to preganglionic stimulation of cervical sympathetic nerve or injected DMPP, but not to postganglionic stimulation or to injected adrenaline and McN‐A‐343.
SGTX affected neither the indirectly nor the directly stimulated response of the rat isolated phrenic nerve‐diaphragm at concentrations less than 12.3 MM.
The effect of SGTX on the contractile response to some agonists and on the twitch response to transmural stimulation in the guinea‐pig isolated ileum was investigated. At <12.3 MM SGTX did not depress responses to acetylcholine or histamine. The curves for nicotine‐ and DMPP‐induced contractions were shifted to the right and depressed gradually as the concentration of SGTX was increased (12.3 nM‐1.23 μM). SGTX partially inhibited the contraction induced by 5‐hydroxytryptamine and the transmurally‐stimulated twitch response.
These results suggest that SGTX has a ganglion‐blocking action. The mode of anti‐nicotinic action of SGTX in the guinea‐pig isolated ileum seems to differ from that of hexamethonium and tetraethylammonium and to resemble more closely that of mecamylamine.
INFLUENCE OF COCAINE AND SODIUM ON BRETYLIUM UPTAKE BY RESERPINE‐TREATED GUINEA‐PIG LEFT ATRIUM
Authors: GARCÍA A.G. , SÁNCHEZ‐GARCÍA P. 
Published: July 2012

The effects of cocaine and sodium on bretylium uptake into sympathetic nerve terminals were investigated in the reserpine‐treated guinea‐pig left atrium. The ability of bretylium pretreatment to increase the retention of noradrenaline was used as an index of bretylium uptake. Such increased retention has been assessed both by direct measurement and by the ability of tyramine to produce an inotropic response.
The restoration of the response to tyramine after incubation with noradrenaline was abolished when the atrium was pretreated with bretylium in the presence of cocaine. When bretylium was added before cocaine, or when α‐methyl‐noradrenaline (not a substrate for monoamine oxidase) was used for incubation, the responses to tyramine were restored in the normal way.
Bretylium greatly enhanced the retention of [3 H]‐noradrenaline; when bretylium was added in the presence of cocaine, [3 H]‐noradrenaline retention was severely impaired.
Pretreatment with bretylium in a low‐sodium (25 μM) or sodium‐free medium significantly decreased the retention of [3 H]‐noradrenaline, as compared with the control.
Potassium deprivation did not modify the enhanced retention of [3 H]‐noradrenaline induced by bretylium pretreatment.
Bretylium was released from the nerve terminals by exposure of the preparation to a sodium‐free medium or to a solution containing calcium 50 mM, leading to a considerable decrease in [3 H]‐noradrenaline retention.
The results are consistent with the view that both cocaine and sodium deprivation block the uptake of bretylium by the adrenergic nerve terminals, and that bretylium is probably taken up by a mechanism similar to or identical with the uptake system for noradrenaline and other amines.
STUDIES ON THE MECHANISM OF ACTION OF A NEW Ca2+ ANTAGONIST, 8‐(N,N‐DIETHYLAMINO)OCTYL 3,4,5‐TRIMETHOXYBENZOATE HYDROCHLORIDE IN SMOOTH AND SKELETAL MUSCLES
Authors: CHIOU C. Y. , MALAGODI MARJORIE H. 
Published: July 2012

The rabbit aortic strip, guinea‐pig ileum and rabbit skeletal muscle sarcoplasmic reticulum preparations were used to determine at which sites and in what manner 8‐(N,N‐diethylamino)‐octyl 3,4,5‐trimethoxybenzoate (TMB‐8) interferes with Ca2+ availability in smooth and skeletal muscles.
TMB‐8 (50 μM) significantly inhibited equivalent responses of the rabbit aortic strip to KCl and noradrenaline.
TMB‐8 (65 μM) produced no significant alteration in the extracellular space of the guinea‐pig ileum as measured with [3 H]‐sorbitol.
The resting cellular Ca2+ influx as well as the resting 45 Ca2+ efflux in the guinea‐pig ileum preparation were significantly inhibited by TMB‐8 (65 μM).
TMB‐8 (5 μM and 50 μM) had no significant effect on the uptake of 45 Ca2+ by the sarcoplasmic reticulum preparation of skeletal muscle; however, TMB‐8 (5 μM) did significantly inhibit the caffeine (20 μ)‐induced release of 45 Ca2+ from this preparation.
It is concluded that TMB‐8 reduces Ca2+ availability in smooth and skeletal muscles by stabilizing Ca2+ binding to cellular Ca2+ stores and thereby inhibits the release of this Ca2+ by contractile stimuli.
ON THE ACTIONS OF COMPOUNDS RELATED TO DOPAMINE AT A NEUROSECRETORY SYNAPSE
Authors: GINSBORG B.L. , TURNBULL K.W. , HOUSE C.R. 
Published: July 2012

The effects of a number of substances related to dopamine, including all its methylated derivatives, were investigated on the membrane potential and response to nerve stimulation of cockroach salivary gland cells.
Only N‐methyldopamine (epinine), N,N‐dimethyldopamine and N,N‐dimethylnoradrenaline, all with unsubstituted hydroxyl groups, directly resembled dopamine in producing a hyperpolarization which could be as large as that caused by maximal nerve stimulation. During the continued presence of these substances the hyperpolarization waned and responses to nerve stimulation declined.
Many of the compounds caused one or both of two other effects, namely an increase in the rate of ‘spontaneous miniature hyperpolarizations’ and an enhancement of the submaximal responses to single nerve stimuli. There were no obvious structural requirements for these effects.
ACTIONS OF CARBON TETRACHLORIDE, HEXACHLOROETHANE AND THE PRODUCTS OF THEIR METABOLISM IN SHEEP ON Fasciola hepatica
Authors: BARTLET A.L. 
Published: July 2012

An in vitro preparation of Fasciola hepatica is described which responded to electrical stimulation with tetanic spasms. Both carbon tetrachloride (20–500 nl/ml), and its metabolite chloroform (50–1000 nl/ml), produced contractions in the preparation which extinguished the responses to electrical stimulation. It is suggested that the spasmogenic action of carbon tetrachloride and its metabolite may contribute to the fasciolifugal action of the drug.
Hexachloroethane, another fasciolifuge, had very little effect in the preparation. However, penta‐chloroethane and tetrachloroethylene, the main products of the metabolism of hexachloroethane in sheep, were potent spasmogens in preparations of Fasciola hepatica. Pentachloroethane was about twice as potent as carbon tetrachloride.
Tetrodotoxin (2 μg/ml) did not antagonize the responses of the preparation to electrical stimulation or carbon tetrachloride.
A CENTRALLY MEDIATED PROLONGED HYPOTENSION PRODUCED BY OXOTREMORINE OR PILOCARPINE
Authors: DAGE R.C 
Published: July 2012

Oxotremorine, methyloxotremorine, pilocarpine or arecoline were given intravenously to anaesthetized cats, dogs or rats, and intraperitoneally to conscious normotensive and spontaneously hypertensive rats, pretreated with doses of methylatropine that completely blocked peripheral muscarinic receptors, to ascertain their effects on blood pressure and heart rate.
Oxotremorine but not methyloxotremorine produced a prolonged hypotension in cats and dogs but not in rats. Heart rate was not changed. Pilocarpine, although less potent, produced an identical effect, whereas the effect of arecoline was short by comparison. The hypotensive effect of these drugs was reversed by atropine.
In dogs, oxotremorine produced a prolonged hypotension with no change in heart rate or cardiac output.
A decrease in spontaneous sympathetic nerve activity accompanied the hypotension in cats. Both effects were reversed by atropine but could be reinvoked by large doses of oxotremorine.
The oxotremorine‐induced hypotension in cats was not altered by decerebration but was abolished by high cervical spinal section.
The results indicate that the prolonged hypotension elicited by oxotremorine is mediated by an action at muscarinic receptors in the brain stem resulting in a decrease in sympathetic nerve activity and peripheral resistance but not heart rate or cardiac output.
N‐ARALKYL SUBSTITUTION INCREASES THE AFFINITY OF ADRENERGIC DRUGS FOR THE α‐ADRENOCEPTOR IN RAT LIVER
Authors: AGGERBECK MARTINE , GUELLAEN GEORGES , HANOUNE JACQUES 
Published: July 2012

The α‐adrenoceptor of rat liver plasma membranes was studied by use of the specificα‐antagonist [3H]‐dihydroergocryptine ([3H]‐DHEC). Catecholamines and adrenergic compounds displayed an order of affinity that is typical of anα‐receptor. Nevertheless, protokylol, a potent β‐adrenoceptor agonist, exhibited a higher affinity than that of adrenaline forα‐sites. This result might be due to its bulky substituent on the amino group.
Further displacement experiments between [3H]‐DHEC and four pairs of drugs differently substituted on the amino group (isoprenaline vs Cc‐25, orciprenaline vs fenoterol, AH 3474 vs labetalol, pindolol vs hydroxybenzylpindolol) provided evidence that N‐alkyl substitution decreased the affinity forα‐sites (20 μm < KD < 500 μm), whereas an N‐aralkyl one increased the affinity (0.17 μm < KD < 4.6 μm).
It is concluded that a substitution on the amino group by a bulky, hydrophobic moiety enhances the affinity of drugs for the α‐adrenoceptors.
DIRECT VASODILATATION BY LABETALOL IN ANAESTHETIZED DOGS
Authors: DAGE RICHARD C. , HSIEH CHIH PENG 
Published: July 2012

The effects of several doses of labetalol (0.03 to 1 mg/kg) given intravenously and into the vertebral artery were examined in anaesthetized dogs. Labetalol produced no immediate (5 min) change in blood pressure or heart rate when given by either route, with one exception. Heart rate increased after the first dose (0.03 mg/kg i.v.) of labetalol. By contrast, clonidine (1 μg/kg) elicited an immediate and prolonged fall in blood pressure and heart rate when given into the vertebral artery, but not intravenously.
In the isolated perfused gracilis muscle of the dog, following α‐ and β‐adrenoceptor blockade, intra‐arterial injections of labetalol (0.3 to 10 mg) or diazoxide (0.3 to 1 mg) produced decreases in perfusion pressure that were dose‐related in both magnitude and duration. The doses of labetalol and diazoxide required to produce a half‐maximal vasodilatation were 1.5 mg and 0.7 mg respectively.
In adrenalectomized, vagotomized spinal dogs, both labetalol (0.1 to 1 mg/kg i.v.) and hydralazine (1 mg/kg i.v.) elicited a fall in blood pressure without changing heart rate or cardiac output.
These results suggest that the hypotension produced by systemically administered labetalol does not involve an action in the brain. It may involve instead a direct vasodilatation of resistance blood vessels, since labetalol in sufficient amounts, directly dilates resistance vessels and lowers blood pressure in dogs devoid of adrenergic tone. Direct vasodilatation may be a component of the hypotensive action of labetalol.
CORONARY VASOCONSTRICTION BY LOCALLY ADMINISTERED ACETYLCHOLINE, CARBACHOL AND BETHANECHOL IN ISOLATED, DONOR‐PERFUSED, RAT HEARTS
Authors: SAKAI K. 
Published: July 2012

Experiments were carried out on rat isolated heart preparations in which the coronary vasculature was perfused through the aorta at a constant flow rate with arterial blood from donor animals. Single doses of drugs were injected into the aortic cannula.
Small doses of acetylcholine, carbachol or bethanechol decreased perfusion pressure (PP) without markedly affecting left ventricular pressure (LVP) and heart rate (HR); larger doses of these drugs increased PP (vasoconstriction), and decreased LVP and HR in a dose‐dependent manner.
Acetylcholine, carbachol and bethanechol had almost no effects when perfused through the aorta in such a way as to exclude the coronary vessels.
Coronary vasoconstriction in response to acetylcholine, carbachol and bethanechol was not significantly affected by reserpine pretreatment, phentolamine or hexamethonium, but was antagonized by small doses of atropine.
From these results it is concluded that in the coronary vasculature of the rat, the receptors involved in the vasoconstrictor actions of acetylcholine, carbachol and bethanechol are muscarinic.
CHARACTERISTICS OF 5‐HYDROXYTRYPTAMINE TRANSPORT IN PANCREATIC ISLETS
Authors: LINDSTRÖM PER , SEHLIN JANOVE , TÄLJEDAL INGE‐BERT 
Published: July 2012

Transmembrane transport of 3H‐labelled 5‐hydroxytryptamine (5‐HT) by isolated pancreatic islets of non‐inbred ob/ob mice was studied.
5‐HT was vigorously accumulated in a temperature‐dependent way by the islet cells.
Studies of the concentration‐dependence of [3H]‐5‐HT uptake revealed complex kinetics with one component being saturated at 1 to 3 um 5‐HT (apparent association constant 0.6 × 106 m−1) and the other non‐saturated up to 1 mm 5‐HT.
The saturable uptake was inhibited by Na+‐deficiency and metabolic poisoning with 2,4‐dinitro‐phenol and antimycin A, whereas the non‐saturable component was not affected.
Omission of K+, Ca2+ or Mg2+ did not affect the uptake rate.
It is concluded that 5‐HT is taken up by pancreatic β‐cells by mechanisms very similar to those observed in thrombocytes and neurones.
SEDATIVE ACTIVITY OF CANNABIS IN RELATION TO ITS Δ‘‐trans‐TETRAHYDROCANNABINOL AND CANNABIDIOL CONTENT
Authors: PICKENS JOAN T. 
Published: July 2012

The oral sedative potencies of cannabis herb, crude ethanolic and petroleum‐ether fractions, were assayed against Δ′‐trans‐tetrahydrocannabinol (THC) administered orally to mice, by measuring spontaneous motor activity over 30 min periods, at selected times, up to 6 h.
The THC contents of the extracts were determined chemically by gas‐liquid chromatography analysis and the B/C ratio (biological activity divided by chemical activity) calculated for each. The B/C values for cannabis herb, which contained THC but no CBD, was 4.47 and for ethanolic and petroleum‐ether extracts, 5.26 and 4.39, respectively.
The sedative potency expressed as SDA50, the dose required to give 50% effect over 6 h, was 1.06 (0.98 to 1.15) mg/kg for THC; 4.72 (4.22 to 5.27) mg/kg for cannabidiol and 1.26 (1.22 to 1.80) mg/kg for chlorpromazine.
An infusion of cannabis herb made with boiling water was shown to have sedative activity of very low potency.
When the cannabinoids were completely extracted from a sample of herb with petroleum‐ether the aqueous and ethanolic extracts of the marc had some sedative activity; but the 70% ethanolic fraction had none.
The sedative activity of THC, cannabis herb and a water soluble fraction is blocked by aspirin, a cyclo‐oxygenase inhibitor, and restored by prostaglandin E2 (PGE2).
The sedative effect of chlorpromazine is not blocked by aspirin.
AFFINITIES OF THE PROTONATED AND NON‐PROTONATED FORMS OF HYOSCINE AND HYOSCINE N‐OXIDE FOR MUSCARINIC RECEPTORS OF THE GUINEA‐PIG ILEUM AND A COMPARISON OF THEIR SIZE IN SOLUTION WITH THAT OF ATROPINE
Authors: BARLOW R.B. , WINTER ELIZABETH A. 
Published: July 2012

At 37°C in 0.1 m NaCl the pKa of hyoscine (10 mm) is 7.53; the non‐protonated form has about one‐tenth of the affinity (log K = 8.58) of the protonated form (log K = 9.58) for muscarine‐sensitive receptors of the guinea‐pig ileum at 37°C.
In the same conditions the pKa of hyoscine N‐oxide is 5.78 and the non‐protonated form is inactive on the ileum whereas the protonated form is highly active with log K estimated to be 9.9, at least as active as hyoscine methobromide (log K = 9.85).
Hyoscine methobromide appears to occupy less space in water than atropine methobromide; hyoscine hydrochloride occupies less space than hyoscyamine hydrochloride: the non‐protonated forms are slightly bigger. Hyoscine N‐oxide hydrobromide is slightly smaller than hyoscine methobromide but the removal of the proton is accompanied by a reduction in volume, such as is seen with other zwitterions.
These differences in volume indicate a reduction in entropy on solution which may allow a greater increase in entropy on binding to receptors and hence greater affinity. The higher activity of hyoscine itself could also be due to the presence of the N‐methyl group in the axial position, rather than equatorial as in hyoscyamine or atropine.
The different position of the N‐methyl group may partly explain why the pKa of hyoscine is 2 units lower than that of hyoscyamine or atropine. It is also probable that the unionized form of hyoscine is stabilized by hydration.
Although hyoscine N‐oxide is only weakly active at pH 7.6, it is present in a highly active form in the acid environment of the stomach and so might be expected to act selectively at this site.
DOWN‐REGULATION OF THE SODIUM PUMP FOLLOWING CHRONIC EXPOSURE OF HeLa CELLS AND CHICK EMBRYO HEART CELLS TO OUABAIN
Authors: AITON J.F. , LAMB J.F. , OGDEN P. 
Published: July 2012

HeLa cells and primary cultures of embryonic chick heart cells were grown in medium containing low concentrations of ouabain for 24 h.
Compared with normal cells, cells grown in ouabain have fewer free sodium pump sites, an increased intracellular sodium concentration and a decreased intracellular potassium concentration. The cells are able to maintain their intracellular ion contents because the remaining pump sites have an increased turnover rate.
When cells that have been chronically exposed to ouabain are returned to normal growth medium, the sodium pump site numbers increase; the recovery process begins within 6 to 8 h and is complete within 24 h. Recovery of pump site numbers is primarily dependent upon de novo protein synthesis since the protein synthesis inhibitor, cycloheximide, prevents recovery.