bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence that the positive inotropic effects of the alkylxanthines are not due to adenosine receptor blockade
Authors: Collis M.G. , Keddie J.R. , Torr S.R.
Published: July 2012

We investigated the possibility that the positive inotropic effects of the alkylxanthines are due to adenosine receptor blockade.

The potency of 8‐phenyltheophylline, theophylline and enprofylline as adenosine antagonists was assessed in vitro, using the guinea‐pig isolated atrium, and in vivo, using the anaesthetized dog.

The order of potency of the alkylxanthines as antagonists of the negative inotropic response to 2‐chloroadenosine in vitro, and of the hypotensive response to adenosine in vivo was 8‐phenyltheophylline > theophylline > enprofylline.

The order of potency of the alkylxanthines as positive inotropic and chronotropic agents in the anaesthetized dog was enprofylline > theophylline > 8‐phenyltheophylline.

The results of this study indicate that the inotropic effects of the alkylxanthines in the anaesthetized dog are not due to adenosine receptor blockade.
Nicorandil attenuates myocardial acidosis during coronary occlusion in dogs
Authors: Abiko Y. , Nishimura T. , Sakai K.
Published: July 2012

In dogs anaesthetized with pentobarbitone, the left anterior descending coronary artery (LAD) was partially occluded. Before and 30 min after partial occlusion, the myocardial pH was 7.52–7.54 and 6.89–6.91, respectively.

Nicorandil (50 μg kg−1, i.v.) increased the pH that had been reduced by partial occlusion and this effect lasted at least 60 min. Thus nicorandil attenuates ischaemic myocardial acidosis.
Tissue response selectivity of calcium antagonists is not due to heterogeneity of [3H]‐nitrendipine binding sites
Authors: Bristow Michael R. , Ginsburg Robert , Laser Jeffrey A. , McAuley Bruce J. , Minobe Wayne
Published: July 2012

[3H]‐nitrendipine binding data and isolated tissue response for five calcium antagonists were evaluated in rabbit myocardium and aorta.

The [3H]‐nitrendipine binding site was qualitatively identical in myocardium and aorta, as the [3H]‐nitrendipine KD, KIs for nicardipine and nifedipine and interactions with verapamil, D600‐and diltiazem were not different in aortic and cardiac membranes prepared by similar means.

In contrast, the inhibition of the Ca2+‐induced contractile response in right ventricular myocardium and aortic ring segments indicated a > 10,000 fold selectivity of nicardipine for antagonism of vascular responses. This resulted in a different order of potency for calcium antagonist interaction with the [3H]‐nitrendipine binding site in cardiac membranes (nicardipine > nifedipine > D600 > verapamil > diltiazem) as compared to antagonism of myocardial tissue response (D600 > verapamil > nifedipine > nicardipine > diltiazem). In heart the difference between the potency of nicardipine in binding experiments and tissue response approached 4 orders of magnitude.

We conclude that tissue response selectivity of calcium antagonists is not explained by heterogeneity of [3H]‐nitrendipine binding sites.
Relaxation of cat tracheobronchial and pulmonary arterial smooth muscle by vasoactive intestinal peptide: lack of influence by peptidase inhibitors
Authors: Altiere Ralph J. , Diamond Louis
Published: July 2012

Vasoactive intestinal peptide (VIP) caused concentration‐dependent relaxation in precontracted segments of trachea, hilar bronchus, intrapulmonary bronchus and intrapulmonary artery (IPA) isolated from cat lungs.

VIP‐induced relaxation responses were abolished by preincubation of tissues with the proteolytic enzyme, α‐chymotrypsin (2 units ml−1). At the concentration employed, α‐chymotrypsin treatment did not adversely affect tissue viability as isoprenaline and bethanechol continued to relax airways and IPA, respectively.

Aprotinin prevented enzymatic degradation of VIP by α‐chymotrypsin as demonstrated by the ability of VIP to relax tissues incubated with both the peptidase inhibitor and α‐chymotrypsin.

A spectrum of peptidase inhibitors, including aprotinin, leupeptin, bestatin, bacitracin, β‐phenylpropionic acid and captopril, individually or in combination, did not augment the relaxant effects of VIP in isolated pulmonary tissues.

These results suggest that local enzymatic degradation may not be a primary route for inactivation of VIP in cat isolated airways and IPA. If VIP acts as a neurotransmitter in these tissues, a mechanism other than enzymatic proteolysis may be responsible for terminating its action.
An investigation into the characteristics of reperfusion‐induced arrhythmias in the anaesthetized rat and their susceptibility to antiarrhythmic agents
Authors: Kane K. A. , Parratt J.R. , Williams F.M.
Published: July 2012

Reperfusion‐induced arrhythmias were elicited in the pentobarbitone‐anaesthetized rat by occlusion of the left main coronary artery and subsequent release.

These arrhythmias were rapid in onset, occurring within 20 s after release of the ligature, and were of short duration (1–2 min). Their severity was dependent upon the duration of the preceding occlusion. A 5 or 15 min occlusion period produced the most severe arrhythmias on release, the incidence of ventricular fibrillation being 56 and 50% respectively.

Evidence that reperfusion had occurred was provided by fluorescein dye distribution and intramyocardial temperature studies.

The severity of reperfusion arrhythmias and mortality was unaffected by bilateral vagotomy, β‐adrenoceptor blockade by atenolol (2 mg kg−1 i.v.) or a combination of the two.

The incidence of reperfusion‐induced ventricular fibrillation was significantly reduced by Org 6001 (which blocks the fast inward sodium current), melperone (which acutely prolongs the cardiac action potential duration) and bepridil (which blocks both fast and slow inward currents). It was unaffected by nitroglycerine and the calcium antagonists verapamil, prenylamine and nifedipine.

We have shown that reperfusion‐induced cardiac arrhythmias can be consistently elicited in the anaesthetized rat and that they are particularly susceptible to drugs that can block the fast inward sodium current.
Studies on L‐640,035: a novel antagonist of contractile prostanoids in the lung
Authors: Carrier R. , Cragoe E.J. , Ethier D. , Ford‐Hutchinson A.W. , Girard Y. , Hall R. A. , Hamel P. , Rokach J. , Share N.N. , Stone C.A. , Yusko P.
Published: July 2012

The effects of L‐640,035 (3‐hydroxymethyl‐dibenzo [b,f] thiepin‐5,5‐dioxide) have been studied on pulmonary smooth muscle contraction in vitro and in vivo.

When studied in vitro on guinea‐pig tracheal chains, L‐640,035 produced significant shifts in the dose‐response curves to a prostaglandin (PG) endoperoxide analogue (U‐44069) (pA2 7.0), PGF2α (pA2 5.9) and PGD2 (pA2 6.5). L‐640,035 produced no significant shift in the dose‐response curves to leukotriene D4 or histamine and produced a small but statistically significant shift in the dose‐response curve to 5‐hydroxytryptamine (5‐HT) (pA2 5.2). With the exception of PGF2α, Schild analysis did not in general indicate competitive inhibition. The main metabolite of L‐640,035, L‐636,499, also produced significant parallel shifts in the dose‐response curves to U‐44069 (pA2 6.0) and PGF2α (pA2 6.0), but with some reduction in the maximal contraction.

When L‐640,035 was administered intravenously to guinea‐pigs, significant inhibition of increases in pulmonary resistance or insufflation pressure induced by U‐44069 (ED50 0.16 mg kg−1), leukotriene D4 (ED50 0.25 mg kg−1) and 5‐HT (ED50 3.4 mg kg−1) but not histamine (ED50> 10 mg kg−1) was observed.

When L‐640,035 was administered intravenously to dogs a significant inhibition of increases in pulmonary resistance induced by U‐44069 (ED50 0.85 mg kg−1) but not histamine (ED50> 30 mg kg−1) was observed.

When L‐640,035 was administered by the intraduodenal route to dogs at doses of 3 and 10 mg kg−1 significant inhibition of increases in pulmonary resistance induced by sodium arachidonate (3 mg kg−1 i.v.) was observed with a duration of action of > 255 min.

It is concluded that L‐640,035 is a novel, relatively selective, and orally active antagonist of the actions of contractile prostanoids on pulmonary smooth muscle.
Sodium‐potassium ATPase inhibition potentiates compound 48/80‐induced histamine secretion from mast cells
Authors: Amellal M. , Binck M. , Frossard N. , Ilien B. , Landry Y.
Published: July 2012

The effect of ouabain on the histamine secretion induced by compound 48/80 has been studied using rat peritoneal mast cells.

Ouabain did not modify histamine release in the presence of millimolar concentrations of extracellular calcium.

However, when mast cells were previously washed with a calcium‐free buffer, ouabain strongly potentiated histamine release elicited by compound 48/80.

The full potentiation of mast cell secretion by ouabain required 30 min preincubation before adding compound 48/80. It was inhibited by lanthanum and EGTA.

Potassium deprivation mimicked the effect of ouabain. A 30 min preincubation time without potassium was also required.

Potassium concentrations below 2.7 mm increased the effect of ouabain whereas higher potassium concentrations reversed this effect.

The potentiation of compound 48/80‐induced histamine release by ouabain or potassium deprivation was not immediately reversed by washing away ouabain or by adding potassium, respectively.

The data confirm that sodium‐potassium ATPase is involved, through a calcium‐dependent process, in the regulation of histamine release from mast cells.
Identification of benzomorphan‐κ opiate receptors in cerebral arteries which subserve relaxation
Authors: Altura Bella T. , Altura Burton M. , Quirion Remi
Published: July 2012

Several ‘so‐called’ κ‐opiate receptor agonists e.g., ketocyclazocine (Kc), ethylketocyclazocine (Eke), bremazocine, MR‐2034 and U‐50488H, were tested on basilar and middle cerebral arteries of the dog in vitro for relaxant or contractile activities.

Eke, Kc and bremazocine were found to produce concentration‐dependent reductions in basal tone and to relax cerebral arteries contracted with prostaglandin F2α (PGF2α). All three agonists appear to act on benzomorphan‐κ opiate receptors which subserve relaxation in cerebral blood vessels.

MR‐2034 and U‐50488H were found to induce contraction in the cerebral arteries. These opiate agonists appear to act on phencyclidine (PCP) or σ‐opiate receptors which subserve contraction.

A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine, cimetidine, naloxone) did not modify any of the cerebral vascular effects produced by the opiates.

These results suggest: (1) specific benzomorphan‐κ opiate receptors which subserve relaxation exist in cerebral blood vessels; (2) some κ agonists appear to produce, primarily, contraction in cerebral vessels via PCP or σ‐opiate receptors: and (3) cerebral vascular muscle may provide a useful tool to analyse the molecular constitution of these two distinct and opposite‐acting opiate receptors.
Actions of γ‐aminobutyric acid on neurones of guinea‐pig myenteric plexus
Authors: Cherubini E. , North R. A.
Published: July 2012

The effects of γ‐aminobutyric acid (GABA) applied by ionophoresis, pressure ejection and superfusion to myenteric neurones of the guinea‐pig ileum were investigated by intracellular recording techniques.

Ionophoretic or pressure application of GABA (10 pC‐30 nC) caused membrane depolarizations of AH neurones but not S neurones. This depolarization was associated with a conductance increase. It reversed polarity at a membrane potential of — 18 mV when intracellular electrodes contained KCl, and −39 mV when electrodes contained K acetate, citrate or sulphate.

The ionophoretic depolarization was antagonized by bicuculline (1–30 μM) in an apparently competitive manner.

During prolonged or repeated ionophoretic application of GABA, both the depolarization and conductance increase desensitized.

Superfusion of GABA (1–100 μM) caused a membrane depolarization in AH neurones, associated with an increase in membrane conductance. The increase in conductance was always smaller than that evoked by ionophoresis of GABA.

Bicuculline only partially depressed the depolarization induced by superfusion of GABA, particularly slowing its rising phase. β‐p‐Chlorophenyl GABA (baclofen) (10 μM) caused a depolarization similar to that observed with GABA in the presence of bicuculline.

The depolarization induced by baclofen and GABA (in presence of bicuculline) superfusion did not decline during prolonged applications; superfusion of GABA but not baclofen reversibly reduced or eliminated the effects of GABA ionophoresis.

It is concluded that GABA has two effects on the membrane of myenteric neurones. The first is a bicuculline‐sensitive, rapidly desensitizing chloride activation: the second is a bicuculline‐insensitive, non‐desensitizing depolarization.
An investigation into the selectivity of a novel series of benzoquinolizines for α2‐adrenoceptors in vivo
Authors: Paciorek P.M. , Pierce Vanessa , Shepperson N.B. , Waterfall J.F.
Published: July 2012

The potencies and selectivities of a novel series of benzoquinolizines for the α2‐adrenoceptor have been investigated in the rat in comparison with yohimbine and indoramin.

Peripheral postjunctional α2‐ and α1‐adrenoceptor blockade was measured as the reversal of B‐HT 933 and methoxamine‐induced pressor responses, respectively, in the pithed rat.

Peripheral prejunctional α2‐adrenoceptor blockade was measured as the reversal of B‐HT 933‐induced inhibition of an electrically evoked tachycardia in the pithed rat.

Central α2‐adrenoceptor blockade was measured as a reversal of the hypotension induced in anaesthetized rats by central (i.c.v.) administration of clonidine.

Wy 25309, Wy 26392, Wy 26703 and yohimbine (0.3–3 mg kg−1 i.v.) evoked dose‐dependent shifts to the right of the dose‐response curves to B‐HT 933 whilst having minimal effects on the methoxamine dose‐response curve.

The selectivity for α2‐adrenoceptors increased with the dose of antagonist administered. In general, the order of selectivity was Wy 25309 > Wy 26392 > Wy 26703 > yohimbine.

Indoramin (1 mg kg−1 i.v.) shifted the methoxamine pressor dose‐response curve to the right without affecting the B‐HT 933 dose‐response curves, confirming its selective α1‐antagonist activity.

Peripheral administration of all three benzoquinolizines (1–100 μg kg−1 i.v.) led to a dose‐dependent reversal of the hypotension evoked by central administration of clonidine (500 ng i.c.v.). The reversal was incomplete, higher doses causing a further decrease in blood pressure. A similar degree of hypotension induced by the ganglion blocking agent chlorisondamine (1 mg kg−1 i.v.) was not reversed by the benzoquinolizines.

It is concluded that Wy 25309, Wy 26392 and Wy 26703 are selective α2‐adrenoceptor antagonists which readily penetrate the CNS.
Release of kallikrein‐like esterase and tonin from dispersed cells of the rat submandibular gland
Authors: Izumi Hiroshi
Published: July 2012

Viable dispersed cell preparations of rat submandibular gland were obtained by a tissue‐dissociation procedure using collagenase and gentle mechanical force.

The cells released kallikrein‐like esterase in a time‐ and calcium‐dependent manner in response to noradrenaline (10 μM) at 30°C. The net loss of kallikrein‐like esterase content from the dispersed cells corresponded with the increase in kallikrein‐like esterase activity in the suspending medium at all concentrations of noradrenaline. These results indicate the viability and functional integrity of this dispersed cell preparation of rat submandibular gland.

α‐Adrenoceptor agonists such as noradrenaline stimulated kallikrein‐like esterase and tonin release in a dose‐dependent manner, whereas the β‐adrenoceptor agonist isoprenaline and cholinoceptor agonist methacoline were both inactive. Noradrenaline‐induced release of kallikrein‐like esterase and tonin were completely blocked by prior addition of the α‐adrenoceptor antagonist, phenoxybenzamine.

It is concluded that the secretion of kallikrein‐like esterase and tonin in rat submandibular gland is mediated only via stimulation of α‐adrenoceptors.
Substance P in sensory nerve fibres contributes to the development of oedema in the rat hind paw after thermal injury
Authors: Saria A.
Published: July 2012

Immersion of the hind paws of anaesthetized rats in hot water for 5 min induced massive plasma protein leakage as indicated by extravasation of Evans blue dye in the skin. The threshold temperature which caused noticeable plasma extravasation was 45°C, a maximal response was obtained between 55°C and 60°C.

Pretreatment of rats 2 days after birth with 50 mg kg−1 capsaicin significantly reduced the Evans blue extravasation induced by hot water at 50°C, 55°C and 60°C, whereas guanethidine pretreatment 24 h before the experiment caused a significantly increased response at 40°C, 45°C and 50°C.

When Evans blue was injected between 10 and 120 min after immersion of the paw in hot water, a significant extravasation of the dye was no longer detectable. However, the weight of the paw as well as the weight of the piece of skin taken for Evans blue quantification increased during this period indicating the progressive development of oedema in the skin and underlying tissues.

In rats treated with capsaicin as neonates, the increase in paw weight after immersion in water of 50°C for 5 min was significantly delayed during the first hour, but there was no difference after two hours.

In rats pretreated with D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11‐substance P, a substance P (SP) antagonist, the Evans blue extravasation was significantly reduced. However, the response, which remained in rats treated with capsaicin as neonates was not blocked by the SP‐antagonist.

It is concluded that activation of peripheral branches of sensory SP neurones contributes to the initial massive protein extravasation and to the subsequent rate of development of oedema following heat injury. Release of histamine did not significantly contribute to this response at the lower temperatures, although the response was reduced by histamine receptor blocking drugs at 55°C and 60°C. Decreasing the sympathetic vasoconstrictor tone by guanethidine resulted in an increased response.
Effects of α‐adrenoceptor stimulation with phenylephrine in the presence of propranolol on force of contraction, slow inward current and cyclic AMP content in the bovine heart
Authors: Brückner Reinhard , Scholz Hasso
Published: July 2012

The mechanism of the cyclic AMP‐independent positive inotropic effect of cardiac α‐adrenoceptor stimulation was studied by analyzing the effects of phenylephrine on force of contraction, calcium‐dependent slow action potentials and the slow inward current (Isi) in bovine ventricular trabeculae. The preparations were electrically driven at 0.3 Hz in the presence of propranolol 1 μmol l−1.

Phenylephrine increased the force of contraction in a concentration‐dependent manner (maximum about 200% of control at 30 μmol l−1). The effect was surmountably antagonized by phentolamine.

The positive inotropic effect of phenylephrine was accompanied by a concentration‐dependent increase in time to peak force and occurred without any detectable increase in cyclic adenosine 3′,5′‐monophosphate (cyclic AMP) levels.

The positive inotropic effect of phenylephrine was accompanied by an increase in action potential duration both at 20% and 90% repolarization.

Calcium‐dependent slow action potentials were also prolonged by phenylephrine and there was a distinct increase in the maximal rate of depolarization (dV/dtmax) of these slow potentials. These effects were also completely reversible on washing and surmountably blocked by phentolamine. However, the increase in dV/dtmax was smaller than that of isoprenaline in concentrations producing similar inotropic effects.

Voltage‐clamp experiments with the single sucrose‐gap method showed that the phenylephrine‐induced increase in force of contraction was associated not only with an increase in peak slow calcium inward current, Isi max, but also with a delay in the inactivation of Isi. Outward currents were not detectably altered by phenylephrine.

It is concluded that the α‐adrenoceptor mediated, cyclic AMP‐independent positive inotropic effects of phenylephrine in bovine cardiac muscle are associated with an increase in slow inward current. Additionally, the amount of calcium influx during excitation is probably increased by a delay in the inactivation of Isi. Both effects can explain the phenylephrine‐produced prolongation of the action potential, and probably contribute to the positive inotropic effect of α‐adrenoceptor stimulation. However, as the effect on dV/dtmax is smaller than that of isoprenaline, other (still unknown) mechanisms may also be involved.
A parametric study of the effects of the noradrenaline neurotoxin DSP4 on avoidance acquisition and noradrenaline neurones in the CNS of the rat
Authors: Archer Trevor , Jonsson Gösta , Ross Svante B.
Published: July 2012

The effects of various doses of DSP4 on two‐way active avoidance acquisition in rats and on central noradrenaline neurones were compared.

Doses of DSP4 from 3 mg kg−1 i.p. and upwards injected one week before the onset of the avoidance trials significantly impaired two‐way avoidance learning.

The learning impairment caused by DSP4 (50 mg kg−1 i.p.) lasted for at least 10 weeks.

Desipramine (20 mg kg−1) injected either 30 or 60 min before DSP4 (50 mg kg−1) antagonized the active avoidance impairment.

A high dose of DSP4 (50 mg kg−1 i.p.) produced profound decreases in dopamine‐β‐hydroxylase activity in the frontal cortex and in the concentrations of noradrenaline in various brain regions indicating degeneration of the locus coeruleus noradrenaline system.

Low doses of DSP4 (3 and 6 mg kg−1 i.p.) produced small but significant decreases in the concentrations of noradrenaline (NA) in some regions, e.g. cerebral cortex, hippocampus, olfactory bulb and spinal cord.

The avoidance impairment caused by the low dose of DSP4 (3 mg kg−1) was absent when rats were tested 10 weeks after treatment nor was NA depletion present when NA was analysed 3 months after treatment.
Failure of drugs that selectively inhibit thromboxane synthesis to modify endotoxin shock in conscious rats
Authors: Furman Brian L. , McKechnie Kenneth , Parratt James R.
Published: July 2012

The effects of two thromboxane synthetase inhibitors (dazoxiben and UK 38485) were investigated on the cardiovascular and metabolic effects of Escherichia coli endotoxin infusion in the conscious, unrestrained rat.

Infusion of E. coli endotoxin (41.7 ng kg−1 min−1) for 4 h produced a fall in mean arterial pressure, an increase in heart rate, a transient hyperglycaemia (at 1 h) followed by hypoglycaemia (evident at 6 h), an elevation in plasma lactate and a profound thrombocytopenia.

The above changes were accompanied by a marked elevation in plasma thromboxane B2 concentrations (e.g. endotoxin‐treated 935 ± 150 pg ml−1 at 1 h compared with pre‐endotoxin values of 125 ± 30 pg ml−1).

The administration of either dazoxiben (30 mg kg−1 i.v., given 30 min before starting the endotoxin infusion) or UK 38485 (15 mg kg−1 given 30 min before, and again 4 h after, starting the endotoxin infusion) prevented the rise in plasma thromboxane B2 concentrations.

Neither dazoxiben nor UK 38485 prevented the metabolic, cardiovascular or thrombocytopenic effects of endotoxin and did not modify mortality.

These results suggest that, although large amounts of thromboxane are generated in response to endotoxin, they do not play an important role in the major pathophysiological consequences of acute endotoxaemia.
Regional differences in the response to vasoconstrictor agents of dog and monkey isolated coronary arteries
Authors: Miwa Kunihisa , Toda Noboru
Published: July 2012

Contractile responses to vasoconstrictor agents were compared in helical strips of dog and monkey epicardial coronary arteries of different sizes. Contractions of large, medium and small arteries induced by KCl (30mM) were virtually identical.

Contractions induced by 5‐hydroxytryptamine (5‐HT) (10−9‐2 × 10−6 M) were in the order of large > medium > small arteries in dogs, and large = medium > small arteries in monkeys. Cinanserin suppressed these responses.

In contrast, contractions produced by angiotensin II (AII) (10−7 M) were in the order of small > medium > large arteries in dogs, and small > medium = large arteries in monkeys. Sar1‐Ala8‐angiotensin II markedly attenuated the peptide‐induced contractions.

Contractions induced by prostaglandin F2α (PGF2α) were significantly greater in large and medium sized arteries than in small arteries in dogs, while those of the arteries of different sizes isolated from monkeys did not differ. Contractions induced by carbocyclic thromboxane A2 (c‐TXA2), in arteries of different sizes in dogs and monkeys, did not differ.

These results suggest that the sensitivity and/or the population of 5‐HT receptors are greater in proximal coronary arteries than in distal arteries, while, in contrast, the sensitivity and/or population of AII receptors are greater in distal coronary arteries. Receptors for PGF2α and c‐TXA2 appear to react to a similar degree in monkey arteries of different sizes, although receptors for PGF2α appear to be fewer in distal coronary arteries in dogs.
Changes in carotid body amine levels and effects of dopamine on respiration in rats treated neonatally with capsaicin
Authors: McQueen D.S. , Mir A.K.
Published: July 2012

Dopamine levels in rat carotid bodies and the effects of intravenous dopamine injections on respiration in adult rats anaesthetized with pentobarbitone have been studied in animals which were treated with capsaicin neonatally.

Levels of dopamine were five fold higher in the carotid bodies of capsaicin‐treated rats as compared with vehicle‐treated controls, but there was no significant difference between capasicin‐treated and vehicle‐treated rats in their ID50 values for dopamine‐induced respiratory depression.

Domperidone, a dopamine D2‐receptor antagonist, substantially reduced the respiratory depression caused by dopamine, both in capsaicin‐treated and in control animals, suggesting that a D2‐receptor was involved in the response. Cutting the carotid sinus nerves greatly reduced the ventilatory‐depressant effect of dopamine, showing that sensory receptors, most probably arterial chemoreceptors, were responsible for most of the response.

Substantially less reflex hyperventilation was evoked in capsaicin‐treated rats by the peripheral chemoreceptor stimulants hypoxia and sodium cyanide, in comparison with the controls, and domperidone did not increase the responsiveness. About 80% of the reflex ventilatory change originated from carotid body chemoreceptors.

The hypoventilation caused by breathing 100% O2 was not significantly different in capsaicin‐treated rats when compared with controls. Domperidone substantially reduced this response in capsaicin‐treated rats, but not in vehicle‐treated animals.

Dopamine‐induced respiratory depression in capsaicin‐treated rats was slightly enhanced, rather than reduced, by oxygen breathing; domperidone remained an effective antagonist of dopamine‐induced ventilatory depression.

Most of the reduction in respiration caused by dopamine in rats anaesthetized with pentobarbitone can be attributed to actions on a dopamine D2‐receptor located in the carotid body. However, despite the increased levels of dopamine found in the carotid bodies, the reduced peripheral chemosensitivity observed in anaesthetized capsaicin‐treated rats does not appear to result from a change in sensitivity to dopamine.
Effects of adenosine, adenosine triphosphate and structural analogues on glucagon secretion from the perfused pancreas of rat in vitro
Authors: Chapal J. , Loubatières‐Mariani M.M. , Roye M. , Zerbib A.
Published: July 2012

The effects of adenosine, adenosine triphosphate (ATP) and structural analogues have been studied on glucagon secretion from the isolated perfused pancreas of the rat in the presence of glucose (2.8 mM).

Adenosine induced a transient increase of glucagon secretion. This effect was concentration‐dependent in the range of 0.165 to 165 μM. ATP also induced an increase, but the effect was no greater at 165 μM than at 16.5 μM.

2‐Chloroadenosine, an analogue more resistant to metabolism or uptake systems than adenosine, was more effective. Among the three structural analogues of ATP or ADP studied, β,γ‐methylene ATP which can be hydrolyzed into AMP and adenosine had an effect similar to adenosine or ATP at the same concentrations (1.65 and 16.5 μM); in contrast α,β‐methylene ATP and α,β‐methylene ADP (resistant to hydrolysis into AMP and adenosine) were ineffective.

Theophylline (50 μM) a specific blocker of the adenosine receptor, suppressed the glucagon peak induced by adenosine, 2‐chloroadenosine, ATP and β,γ‐methylene ATP (1.65 μM).

An inhibitor of 5′ nucleotidase, α,β‐methylene ADP (16.5 μM), reduced the glucagon increase induced by ATP and did not affect the response to adenosine (1.65 μM).

These results support the hypothesis of adenosine receptors (P1‐purinoceptors) on the pancreatic glucagon secretory cells and indicate that ATP acts after hydrolysis to adenosine.
Systemic capsaicin treatment impairs the micturition reflex in the rat
Authors: Holzer‐Petsche Ulrike , Lembeck Fred
Published: July 2012

Filling the urinary bladder via a urethral cannula and preventing its voiding in anaesthetized rats led to rhythmic contractions of the detrusor muscle, which lasted for more than 1 h. This rhythmic activity ceased about 30 min after a s.c. injection of 50 mg kg−1 capsaicin. The contractile response of the detrusor to topically applied capsaicin was lost after systemic administration of the toxin, whereas no change in the sensitivity to acetylcholine was observed.

Urinary bladders of normal rats had a capacity of about 1 ml. Bladders of rats treated with capsaicin as neonates held a volume of more than 5 ml without contracting. Such bladders were insensitive to topically applied capsaicin but they contracted to acetylcholine as strongly as the bladders of control rats.

During an observation period of 3 days control rats gained weight at night and lost weight by day. Rats treated with capsaicin as neonates showed little fluctuation in body weight. Such rats hardly excreted any urine by day although at night they excreted as much as controls.

A water load of 5 ml 100 g−1 was excreted by control rats within 3 h. Rats treated with capsaicin as neonates excreted only half as much. In addition, 50% of the water load was excreted far later by capsaicin treated rats than by controls. Few changes were observed in rats treated with capsaicin as adults.

It is concluded that all primary afferent fibres mediating the sensation of a full bladder are capsaicin‐sensitive. An additional effect of capsaicin on renal mechanisms cannot be excluded.
Interactions of inhibitors of the lipoxygenase and cyclo‐oxygenase pathways with a supplementary binding site on soybean lipoxygenase
Authors: Baumann I. , Baumann J. , Wurm G.
Published: July 2012

The oxygenation of [1‐14C]‐arachidonic acid by a soluble soybean lipoxygenase (E.C.1.13.11.12) preparation was determined in the presence of various cyclo‐oxygenase and lipoxygenase inhibitors. The results showed that several non‐inhibitory compounds drastically blunted the inhibitory potency of potent lipoxygenase inhibitors.

Studies on the combined effects of a variety of structurally unrelated inhibitors of lipoxygenase, cyclo‐oxygenase or both oxygenation pathways provided strong evidence for the existence of a supplementary binding site on soybean lipoxygenase which reduces the effective interactions of inhibitors with the catalytic site.

Thus several cyclo‐oxygenase inhibitors (which do not inhibit at the lipoxygenase catalytic site), as well as low concentrations of lipoxygenase inhibitors, interact with this putative supplementary site and blunt the inhibitory efficacy of potent lipoxygenase inhibitors.

Although the degree of interaction with the catalytic site determines the absolute potency of inhibitors, the additional interaction at the putative supplementary binding site is also obligatory for inhibitory potency.

In this new multiple‐site model the potent lipoxygenase inhibitors (e.g. acetone phenylhydrazone, phenidone) possess high affinities for both sites, whereas weak inhibitors and certain cyclo‐oxygenase inhibitors (e.g. benoxaprofen, phenylbutazone, indomethacin) interact predominantly with the supplementary site on the lipoxygenase but lack affinity for the catalytic site.
Effects on rabbit cardiac potentials of aprindine and indecainide, a new antiarrhythmic agent, in normoxia and hypoxia
Authors: Dennis P.D. , Williams E.M. Vaughan
Published: July 2012

Intracellular potentials were recorded from rabbit atria, cardiac Purkinje cells and papillary muscles before and after exposure to various concentrations of indecainide. The effects of aprindine also were studied in the atrial preparations.

Both drugs depressed the maximum rate of depolarization (MRD) in a dose‐related manner, indecainide being approximately ten times more potent than aprindine.

Aprindine caused a dose‐related bradycardia, but indecainide had no significant effect on sinus node frequency.

Indecainide had a dose‐related negatively inotropic effect in normal, half‐normal and twice‐normal extracellular calcium concentrations.

Indecainide shortened action potential duration (APD) in atrium and Purkinje cells but prolonged APD to 50% repolarization in ventricular muscle.

The actions of indecainide were extremely persistent. No significant recovery of MRD was observed after pauses in stimulation of up to 16 s.

Indecainide had no effect on effective refractory period (ERP) measured by interpolated premature stimuli.

Indecainide is therefore categorized as a Class 1c antiarrhythmic agent.

The effects of both aprindine and indecainide on MRD were increased in hypoxic atria. Conduction velocity in hypoxic atria exposed to indecainide was greater than in controls, however, suggesting the possibility of improved cell‐to‐cell coupling.
A microiontophoretic study of the actions of the putative sleep factor, piperidine, in the rat brainstem
Authors: Horton R.C. , Logan S.D. , Wolstencroft J.H.
Published: July 2012

By means of microiontophoresis, we have compared the actions of a putative sleep substance, piperidine, with other neurotransmitters in the rat anaesthetized with urethane.

In the pons and midbrain, piperidine mimicked the actions of acetykholine on more than 200 neurones. Piperidine‐ and acetylcholine‐induced excitations were equally effectively antagonized by hexamethonium or atropine.

In 32 neurones piperidine showed no affinity for the receptors for the excitatory amino acid agonists, quisqualate and N‐methyl‐D‐aspartate, piperidine‐evoked excitations being unaffected by the antagonists glutamate diethylester or 2‐amino‐5‐phosphonovalerate.

Similarly, piperidine‐evoked excitations in 23 neurones were unaffected by α‐methylnoradrenaline, suggesting that piperidine does not act at receptors for noradrenaline.

Twenty per cent of neurones responsive to piperidine were inhibited. These inhibitions in 12 neurones were insensitive to either strychnine or bicuculline indicating that piperidine does not act on receptors for glycine or γ‐aminobutyric acid.

In a further 68 neurones, neither hexamethonium (4 out of 59 cells) nor atropine (0 out of 9 cells) was effective in antagonizing the inhibitions evoked by piperidine or by acetylcholine.

It is suggested that piperidine may exert its central hypnogenic effects by an action at cholinoceptors in brainstem areas involved in sleep regulation.
Ventilatory stimulation by dopamine‐receptor antagonists in the mouse
Authors: Olson L.G. , Saunders N.A.
Published: July 2012

Ventilation was measured by a plethysmographic method in awake mice before and after intraperitoneal injection of neuroleptic drugs to test the hypothesis that dopaminergic mechanisms modulate control of breathing in this species.

Dose‐dependent augmentation of ventilation at rest and during hypoxia, and reduced ventilation during hypercapnia was demonstrated for haloperidol, droperidol, prochlorperazine and chlorpromazine (P < 0.05 or less for each drug).

Doses of drugs causing maximal increase of the ventilatory response to hypoxia were linearly related (r = 0.98, P < 0.001) to in vitro affinity of the drugs for dopamine receptors.

Despite presumed equal dopamine‐receptor blockade, the drugs had unequal effects on the ventilatory response to hypoxia. Droperidol augmented hypoxic ventilation to 290% of the control value, chlorpromazine to 250% control, prochlorperazine to 190% control and haloperidol to 120% control. These differences in efficacy were in the same order as the affinities of the drugs for α‐adrenoceptors.

The effect of combined haloperidol (90 nmol kg−1) and varying doses of phentolamine (175–900 nmol kg−1) was assessed to test the hypothesis that α‐antagonism was a factor in determining the increase in ventilation following dopamine blockade. Phentolamine caused dose‐dependent augmentation of the ventilatory effects of haloperidol (P < 0.01) but had no ventilatory effect when given alone.

Carotid body resection in anaesthetized mice abolished the stimulation of hypoxic ventilation caused by droperidol.

It is concluded that dopaminergic mechanisms in the carotid body modulate ventilatory control in the awake mouse. The drugs most effective in augmenting hypoxic ventilation are those that block both dopamine and α‐adrenoceptors.
Effects of 3,4‐diaminopyridine and tetraethylammonium on the pre‐ and post‐junctional α‐adrenoceptor mediated inhibitory actions of noradrenaline in the guinea‐pig ileum
Authors: Bauer V.
Published: July 2012

The effects of potassium channel blockers, 3,4‐diaminopyridine (DAP) and tetraethylammonium (TEA) were studied on the pre‐ and post‐junctional α2‐adrenoceptor mediated effects of noradrenaline in the guinea‐pig proximal ileum.

Both DAP (4 to 500 μmol 1−1) and TEA (0.3 to 3 mmol 1−1) transiently increased the basal tension of the ileum. However, DAP also increased the amplitude of the smooth muscle twitches evoked by transmural nerve stimulation, whereas TEA marginally depressed them.

Atropine (2 μmol 1−1) antagonized the contractions induced by DAP but did not affect the similar effects of TEA. On the other hand, DAP restored the smooth muscle twitches depressed by atropine, while TEA did not.

DAP, in a concentration‐dependent manner, reduced or abolished the prejunctional inhibitory α2‐adrenoceptor mediated effect of noradrenaline, whereas TEA (up to 3 mmol 1−1) was almost ineffective.

The postjunctional inhibitory α2‐adrenoceptor mediated effect of noradrenaline was attenuated even at the smallest TEA concentration used (0.3 mmol 1−1) and its postjunctional stimulatory α1‐adrenoceptor mediated effect was unmasked. However, DAP, was only marginally effective, even at the highest concentrations used (100 and 500 μmol 1−1).

From these results it would appear that in both the pre‐ and post‐junctional inhibitory α2‐adrenoceptor mediated actions of noradrenaline in the guinea‐pig ileum the primary step might be an increased potassium conductance. However, the potassium channels on the neuronal and the smooth muscle membrane have different sensitivities to DAP and TEA.
The potencies and selectivities of four calcium antagonists as inhibitors of uterine contractions in the rat in vivo
Authors: Abel Margaret H. , Hollingsworth M.
Published: July 2012

The potencies of four calcium antagonists (nifedipine, gallopamil, verapamil and diltiazem) at inhibiting uterine contractions in vivo have been assessed in the conscious ovariectomized, post‐partum rat. Their selectivities for this action, relative to their effects on blood pressure and heart rate, have been compared with salbutamol.

All compounds produced a dose‐dependent inhibition of intra‐uterine pressure cycles. The rank order of potency was salbutamol >nifedipine > diltiazem = gallopamil > verapamil.

All compounds produced a dose‐dependent fall of mean blood pressure. The rank order of potency was salbutamol > nifedipine > gallopamil > verapamil > diltiazem.

Salbutamol and nifedipine produced a tachycardia, which was very marked with salbutamol. Gallopamil, verapamil and diltiazem induced a moderate tachycardia at low doses but temporary cessation of heart beat occurred at high doses.

Nifedipine and diltiazem, like salbutamol, exhibited some selectivity for inhibition of uterine contractions relative to their cardiovascular actions. Gallopamil and verapamil showed no selectivity for the uterus.
PACPX ‐ a substituted xanthine ‐ antagonizes both the A1 and A2 subclasses of the P1‐purinoceptor: antagonism of the A2 subclass is competitive but antagonism of the A1 subclass is not
Authors: Burnstock Geoffrey , Hoyle Charles H.V.
Published: July 2012

1,3‐Dipropyl‐8‐(2‐amino‐4‐chlorophenyl)xanthine (PACPX) was examined for its ability to antagonize adenosine acting on the A1 and A2 subclasses of the P1‐purinoceptor. A1‐purinoceptors were studied in the isolated, driven left atria of the guinea‐pig, and A2‐purinoceptors in the isolated, carbachol‐contracted taenia coli of the guinea‐pig.

PACPX antagonized the actions of adenosine in both types of preparation and was a more potent antagonist than 8‐phenyltheophylline.

The antagonism at the A2‐purinoceptor was competitive with a pA2 of 5.95.

The antagonism at the A1‐purinoceptor was not competitive, although antagonism at the A1‐purinoceptor was greater than that at the A2‐purinoceptor, based on a comparison of pD2 values.

The manner of antagonism of PACPX on the A1‐purinoceptors of the heart was different from that found for the A1‐receptors in bovine brain, implying that there is a fundamental difference between these central and peripheral A1 subclasses of P1‐purinoceptor.
Pharmacological modulation of responses of guinea‐pig airways contracted with arachidonic acid
Authors: Burka John F.
Published: July 2012

Arachidonic acid (AA) was used to induce contractions of guinea‐pig tracheal and lung parenchymal preparations in the presence of indomethacin.

Prior addition of FPL55712, nordihydroguaiaretic acid (NDGA), piriprost, benoxaprofen or nafazatrom, in order of potency, inhibited AA‐induced contractions of trachea. Higher concentrations (2–3 fold) were necessary to inhibit contractions of parenchyma.

FPL55712 and piriprost appeared to act as pharmacological antagonists of leukotrienes because they rapidly reduced the tone of the airways established by AA.

Administration of exogenous AA to indomethacin‐treated trachea appears to be a good model to examine leukotriene receptor antagonists and inhibitors of the lipoxygenase pathway.
Effects of raised intracranial pressure on regional cerebral blood flow: a comparison of effects of naloxone and TRH on the microcirculation in partial cerebral ischaemia
Authors: Koskinen Lars‐Owe D.
Published: July 2012

The effects on regional cerebral blood flow (rCBF) of raised intracranial pressure (ICP) and of naloxone and thryrotropin releasing hormome (TRH) during this condition were studied in anaesthetized rabbits.

The ICP was elevated until a central ischaemic response was observed. The regional blood flow was determined with the microsphere technique before and during elevation of the ICP (ICPc) and after drug treatment.

Total CBF was reduced by about 70% during ICPc while the uveal blood flow increased slightly and some other peripheral tissue blood flows remained unaffected.

The administration of TRH caused an increase in mean arterial blood pressure (MAP) from 11.9 ± 0.6 to 14.6 ± 0.7 kPa and a normalization of the rCBF. In some peripheral tissues, e.g. gastric mucosa and spleen, TRH reduced the blood flow by 53% and 76%, respectively. In blood pressure stabilized animals no effect on rCBF was seen after TRH.

Naloxone had no consistent effect on MAP or local blood flow.

It was concluded that in the range of cerebral perfusion pressure studied there was a passive relationship between cerebral blood flow and perfusion pressure. The lack of effect of naloxone and the marked effect of TRH during cerebral ischaemia are consistent with a mechanism of action of TRH not related to a ‘physiological’ antagonism of opioids.
Two types of receptors for 5‐hydroxytryptamine on the cholinergic nerves of the guinea‐pig myenteric plexus
Authors: Kilbinger H. , Pfeuffer‐Friederich I.
Published: July 2012

The effects of 5‐hydroxytryptamine (5‐HT) on spontaneous and electrically‐evoked release of [3H]‐acetylcholine (ACh) from guinea‐pig myenteric plexus preparations preincubated with [3H]‐choline have been investigated in the absence of cholinesterase inhibitors.

5‐HT caused a transient increase in spontaneous release and an inhibition of the electrically‐evoked release of [3H]‐ACh. The 5‐HT‐induced contractions of the longitudinal muscle were clearly related to the increase in spontaneous release. The inhibitory effect was not due to activation of α‐adrenoceptors since it was also observed in the presence of tolazoline and on strips from reserpine‐pretreated guinea‐pigs.

After desensitization of the excitatory 5‐HT receptors with 5‐HT or metoclopramide the effects of 5‐HT on spontaneous [3H]‐ACh release were largely reduced. A variety of established antagonists at neuronal 5‐HT receptors (i.e. metitepine 0.1‐1 μM; methysergide 1 μM; ketanserin 0.1‐1 μM; MDL 72222 0.1 μM; tropacocaine 1 μM) failed to block the excitation.

The inhibition by 5‐HT of the electrically evoked [3H]‐ACh release was competitively antagonized by metitepine (pA2 7.6) and methysergide (pA2 7.0) but not by ketanserin. Tachyphylaxis to the inhibitory action of 5‐HT did not occur.

The results suggest that the excitatory 5‐HT receptor (‘M’‐receptor) differs in its pharmacological properties from other neuronal 5‐HT receptors. The presynaptically located inhibitory receptor may roughly correspond to the 5‐HT, receptor subtype but probably differs from the 5‐HT autoreceptor.
Modification of blood pressure and nictitating membrane response to sympathetic amines by selective monoamine oxidase inhibitors, types A and B, in the cat
Authors: Finberg J.P.M. , Youdim Moussa B.H.
Published: July 2012

The selective monoamine oxidase (MAO) inhibitors clorgyline, selegiline and AGN 1135 did not cause a change in responses of the cat nictitating membrane to preganglionic sympathetic nerve stimulation at 5 Hz.

Both selective MAO‐A and MAO‐B inhibitors markedly potentiated nictitating membrane contractions in response to β‐phenylethylamine (PEA). However, the responses to tyramine were unchanged.

The pressor responses to tyramine were potentiated by the selective MAO‐A inhibitor clorgyline (2 mg kg−1) but not by selegiline (1.0 mg kg−1) and AGN 1135 (1.5 mg kg−1), selective MAO‐B inhibitors.

At the doses used selegiline and AGN 1135 caused a near total selective inhibition of liver and brain MAO‐B, while clorgyline inhibited MAO‐A only in the brain.

AGN 1135, like selegiline, could be a useful drug in potentiating the action of L‐DOPA in Parkinson's disease.
Kinin effects on ion transport in monolayers of HCA‐7 cells, a line from a human colonic adenocarcinoma
Authors: Cuthbert A.W. , Kirkland Susan C. , MacVinish Lesley J.
Published: July 2012

Using epithelial monolayers of HCA‐7 cells, derived from a primary human colonic adenocarcinoma and grown on pervious supports, it is shown that responses to lysylbradykinin can be elicited from either side. It is proposed that kinin receptors are inserted into both apical and basolateral membrane domains.