bluuebunny/crossref_metadata_2025 huggingface dataset:
STIMULATORY AND INHIBITORY HISTAMINE RECEPTORS IN CANINE CYSTIC DUCT
Authors: CLANACHAN A.S. , COURTNEY D.R , SCOTT G.W.
Published: July 2012

The effects of histamine receptor stimulation were assessed on the resistance of the canine cystic duct in vivo and on the contractility of circular muscle preparations of canine cystic duct in vitro.

In anaesthetized dogs, the H1‐receptor agonist, 2‐pyridylethylamine (0.05 to 15 μmol, i.a.), elicited dose‐dependent increases in cystic duct resistance, whereas the H2‐receptor agonist, 4‐methylhistamine (0.05 to 15 μmol, i.a.) decreased cystic duct resistance. These responses were antagonized by the H1‐receptor antagonist, diphenhydramine, and the H2‐receptor antagonist, cimetidine, respectively.

Histamine (0.1 to 3000 nmol, i.a.) also increased cystic duct resistance in vivo. In the presence of diphenhydramine, the stimulatory effect of histamine was antagonized and slight decreases in cystic duct resistance became apparent. Cimetidine or prazosin also antagonized the stimulatory effects of histamine.

Histamine (1 to 100 μm) or 2‐pyridylethylamine (1 to 100 μm) contracted, whereas 4‐methylhistamine (1 to 100 μm) relaxed, circular muscle preparations of cystic duct. These excitatory and inhibitory responses were antagonized by diphenhydramine and cimetidine, respectively.

These results indicate that the canine cystic duct possesses excitatory H1‐ and inhibitory H2‐receptors. The predominant effect of histamine is an H1‐receptor‐mediated increase in cystic duct resistance. Histamine, which may be released in association with cholecystitis, may exert significant effects on the regulation of bile flow in and out of the gallbladder and may contribute to gallbladder stasis during biliary disease.
DIRECT AND INDIRECT EFFECTS OF ADENOSINE 5′‐TRIPHOSPHATE ON GUINEA‐PIG ILEUM
Authors: WATT A.J.
Published: July 2012

The inhibitory effects of adenosine 5′‐triphosphate (ATP) were compared on the responses to electrical stimulation, and to direct and indirect stimulation by drugs of the longitudinal smooth muscle of guinea‐pig ileum before and after blocking nervous activity.

While the major inhibitory effect of ATP was an indirect one on the intramural excitatory nerves, there was also a small direct effect on the muscle.

ATP also had direct and indirect excitatory effects. The direct effect particularly was only seen with high concentrations of ATP, but the appearance of these excitatory effects may be affected by the inhibitory actions.
Δ9‐Tetrahydrocannabinol reduces brain regional histamine concentrations
Authors: Fennessy M.R. , Lewis S.J. , Taylor D.A. , Verberne A.J.M.
Published: July 2012

The effect of Δ9‐tetrahydrocannabinol (Δ9‐THC) on rat brain regional histamine concentrations was examined. Δ9‐THC reduced the histamine concentration of the hypothalamus, midbrain and cortex. It is suggested that Δ9‐THC may release histamine in the rat brain and that this amine may mediate some of the pharmacological effects of Δ9‐THC.
Antiarrhythmic actions of meptazinol, a partial agonist at opiate receptors, in acute myocardial ischaemia
Authors: Fagbemi Olu , Kane Kathleen A. , Leprán Istvan , Parratt James R. , Szekeres Laszlo
Published: July 2012

The intravenous administration, to anaesthetized rats, of meptazinol (1 and 2 mg kg−1), a partial agonist at opiate receptors, greatly reduced the incidence of ventricular extrasystoles that resulted from acute coronary artery occlusion. The incidence of ventricular fibrillation (VF) was reduced from 50% (in the controls) to 10% and the mortality from 30% to zero.

In similar doses, pretreatment with meptazinol also reduced ventricular arrhythmias, including fibrillation, in conscious rats subjected to coronary artery occlusion. In this model, survival at 16 h was increased from 27% in the controls to 50% and 83% respectively in rats pre treated with 1 and 2 mg kg−1 of the drug.

In antiarrhythmic doses, meptazinol had little effect on either heart rate or systemic arterial blood pressure.

Intracellular action potential recordings from papillary muscle removed from rats given meptazinol (2 mg kg−1) 15 min previously showed an increase in APD50 and APD90 of more than 40%. There was no effect on dV/dtmax. When superfused with meptazinol in vitro normal rat papillary muscle stimulated at 1 or 3 Hz showed an increase in APD90 and a decrease in dV/dtmax.

The antiarrhythmic effect of meptazinol in these models can probably be explained by direct actions on the cardiac muscle action potential (increase in APD) although effects on opiate receptors cannot be ruled out. It is suggested that meptazinol might be useful in relieving pain, and in reducing the severity of arrhythmias in the early stages of acute myocardial infarction.
Contractions induced by grayanotoxin I in the guinea‐pig vas deferens
Authors: Ohizumi Yasushi
Published: July 2012

In the guinea‐pig vas deferens, grayanotoxin I (G‐I), a diterpenic toxin isolated from certain ericaceous plants caused rhythmic contractions which were dose‐dependent (5 × 10−5 m — 10−3 m); these followed an initial transient contraction.

The G‐I (3 × 10−4 m)‐induced contraction was markedly inhibited or abolished by reserpine (2 mg/kg on 2 days), phentolamine (2 × 10−7 m and 10−6 m) or tetrodotoxin (TTX, 5 × 10−7 m), but remained almost unaffected by atropine (10−6 m) or mecamylamine (3 × 10−5 m). This contraction was also abolished after storage at 4°C for 7 days or incubation in Na‐deficient or Ca‐free medium.

After treatment with G‐I (3 × 10−5 m), which did not alter the tension of the preparation, transmural stimulation (10–50 Hz, 0.5 ms, supramaximal voltage, for 3 s) induced a slower contraction (second contraction) following the first rapid contraction caused by stimulation.

The second contraction was inhibited or abolished by reserpine (2 mg/kg on 2 days), phentolamine (2 × 10−7 m and 10−6 m) and TTX (2 × 10−8 m), but was not affected by atropine (10−6 m) and mecamylamine (3 × 10−5 m).

G‐I (3 × 10−5 m) shifted the dose‐response curves for noradrenaline (NA), acetylcholine and high‐K contractions to the left in a parallel manner and slightly increased the maximal response to these agonists.

G‐I (3 × 10−4 m) caused a release of endogenous NA from the vas deferens which was approximately 120 times that of control preparations. This response was inhibited or abolished by TTX (5 × 10−7 m) or incubation in Ca‐free medium.

These results suggest that the G‐I‐induced contraction of the vas deferens and the G‐I‐induced second contraction on electrical stimulation are the result of an indirect action mediated through the release of NA from the adrenergic nerve endings.
Effects of prostaglandin I2 and carbocyclic thromboxane A2 on smooth muscle cells and neuromuscular transmission in the guinea‐pig mesenteric artery
Authors: Makita Yuji
Published: July 2012

In the guinea‐pig mesenteric arteries neither prostacyclin (PGI2) nor carbocyclic thromboxane A2 (cTxA2) affected membrane potential in concentrations below 1 × 10−6 m. Increasing the concentration to 3 × 10−6 m either slightly hyperpolarized or depolarized the membrane with little change in membrane resistance.

At a concentration of 1 × 10−7 m, the amplitude of the first e.j.p. and the enlarged amplitudes of the subsequent e.j.ps evoked by trains of stimuli were reduced consistently by PGI2 or cTxA2. Facilitation was unaffected by either agent.

The inhibitory actions of PGI2 were partly overcome by increased concentrations of 5 mm [Ca]o and were accelerated by a reduced concentration of 1.25 mm [Ca]o.

The amplitude of the contraction evoked by perivascular nerve stimulation was inhibited to a greater extent by PGI2 than by cTxA2 at concentrations below 1 × 10−6 m.

The contraction evoked by 5 × 10−6 m noradrenaline (NA) or excess concentrations of 20.2 mm [K]o was enhanced by 1 × 10−8 m — 1 × 10−6 m cTxA2 and suppressed by 1 × 10−8 m — 1 × 10−6 m PGI2. The minimum concentration of cTxA2 required to produce the contraction was 1 × 10−8 m.

These results indicate that transmission at the neuromuscular junction was inhibited consistently by PGI2 or cTxA2, presumably due to inhibition of NA release by suppression of the Ca influx at the nerve terminals. Whereas PGI2 inhibited, cTxA2 enhanced the mechanical response by a direct action on the smooth muscle cells.
The release of prostanoids during the acute pulmonary response to E. coli endotoxin in anaesthetized cats
Authors: Coker Susan J. , Hughes Bernadette , Parratt J.R. , Rodger I.W. , Zeitlin I.J.
Published: July 2012

The administration of E. coli endotoxin (2 mg/kg i.v.) to anaesthetized cats results in a characteristic acute pulmonary response. This consists of increases in pulmonary artery pressure and airways resistance and a reduction in lung compliance.

Plasma concentrations of prostaglandin E2 (PGE2), PGF2α, thromboxane B2 and 6‐keto PGF1α were measured by radioimmunoassay in aortic and pulmonary arterial blood samples before, during and after the acute pulmonary response to endotoxin.

Endotoxin administration resulted in the rapid release of PGF2α and thromboxane B2 from the lungs. The time course of this release was parallel to that of the pulmonary hypertensive and airways responses to endotoxin. PGE2 and 6‐keto PGF1α were released more gradually and with greater variations between individual animals.

During the delayed shock phase (2 h after endotoxin) the concentrations of PGE2, PGF2α and 6‐keto PGF1α were once again elevated in both the aorta and pulmonary artery. Thromboxane B2 concentrations were not increased at this time.

These results suggest that PGF2α and thromboxane A2 may be mediators of the acute pulmonary responses to endotoxin.
Presynaptic α2‐adrenoceptor antagonism by verapamil but not by diltiazem in rabbit hypothalamic slices
Authors: Galzin Anne‐Marie , Langer S.Z.
Published: July 2012

Rabbit hypothalamic slices prelabelled with [3H]‐noradrenaline and superfused with Krebs solution were stimulated electrically at a frequency of 5 Hz. Exposure to verapamil (0.1 to 10 μm) significantly increased, in a concentration‐dependent manner, the electrically‐evoked overflow of tritium, without affecting the spontaneous outflow of radioactivity.

Exposure to diltiazem in concentrations up to 100 μm had no effect on the electrically evoked release of [3H]‐noradrenaline, but increased the basal outflow of radioactivity at 10 and 100 μm.

The preferential α2‐adrenoceptor antagonist, yohimbine (0.1 μm) significantly antagonized the inhibitory effect of clonidine or adrenaline on [3H]‐noradrenaline overflow elicited by electrical stimulation. Verapamil (3 μm) also antagonized this inhibitory effect of the α2‐adrenoceptor agonists on [3H]‐noradrenaline release. In contrast to these results, exposure to diltiazem (10 μm) was ineffective in blocking the action of the α2‐adrenoceptor agonist.

These results suggest that the two Ca2+‐antagonists verapamil and diltiazem differ in their ability to affect central noradrenergic neurotransmission. While verapamil is a relatively potent α2‐adrenoceptor antagonist, diltiazem is devoid of presynaptic α2‐adrenoceptor antagonist properties.
Modulation of transmission in rat sympathetic ganglia by activation of presynaptic α‐ and β‐adrenoceptors
Authors: Medgett Iain C.
Published: July 2012

Conditions under which transmission in rat isolated superior cervical ganglia may be affected by activation of presynaptic α‐ and β‐adrenoceptors have been investigated by means of an extracellular recording method.

Clonidine caused a small hyperpolarization of the ganglia (mean EC50˜‐2 nm) in unstimulated preparations; with continuous preganglionic stimulation at 0.2 Hz, clonidine markedly decreased the height of the compound action potential (mean EC50˜18 nm).

Phentolamine (0.1–3 μm) per se increased the height of the compound action potential by up to 15%, and antagonized the inhibitory effects of adrenaline and clonidine.

Using a higher frequency of stimulation (0.5 Hz), the effect of phentolamine (1 μm) was unchanged, whereas the inhibitory effectiveness of adrenaline on the height of the compound action potential was reduced.

(±)‐Propranolol (0.1 μm) did not affect the height of the compound action potential, whereas the inhibitory effects of high concentrations of adrenaline were enhanced.

During an infusion of clonidine (1 μm), adrenaline (1–100 μm) and, less effectively, noradrenaline (10–100 μm) increased the height of the compound action potential by up to 14%; these effects were antagonized by propranolol (0.1 μm).

In the presence of noradrenaline (10 and 30 μm) adrenaline (100 μm) caused a small (up to 5%) enhancement of the height of the compound action potential.

The results obtained are consistent with the existence of presynaptic α‐ and β‐adrenoceptors on preganglionic terminals. The α‐adrenoceptor may be part of a trans‐synaptic inhibitory feedback mechanism; however the functional role of the facilitatory β‐adrenoceptor is not clear.
Influence of diabetes on the reactivity of mesenteric microvessels to histamine, bradykinin and acetylcholine
Authors: Fortes Zuleica B. , Leme J. Garcia , Scivoletto Regina
Published: July 2012

Noradrenaline (NA) evoked a vasoconstrictor response in rat mesenteric microvessels in situ, the latency and nature of which was analogous in normal and alloxan‐diabetic animals.

Histamine and bradykinin (Bk) were capable of antagonizing the response to NA in normal but not in diabetic animals. In contrast, acetylcholine (ACh) was equally effective as an antagonist to NA in both groups of animals.

The altered responses to histamine and Bk were not associated with hyperglycaemia since fasting rendered the diabetic animals normoglycaemic and yet did not restore the reactivity of microvessels. Previous administration of insulin to diabetic animals corrected the impaired responses to histamine and Bk.

A similar condition of impaired responses to histamine and Bk was produced in normal animals by the intravenous injection of 2‐deoxyglucose although ACh remained fully active.

Apparently, the functional changes observed in the response to histamine or Bk, as antagonists of the vasoconstrictor reaction to NA, were not associated with a defective response of all smooth muscle. First, because ACh remained active in diabetic animals, and, second, because extravascular smooth muscles obtained from either normal or diabetic rats were equally relaxed by histamine or Bk in vitro.

It is suggested that histamine and Bk antagonized the vasoconstrictor response of microvessels to NA through an action on lining endothelial cells resulting in increased vascular permeability and hyperosmolarity of extracellular fluids.

The process depended on the availability of insulin, and, therefore, might be affected by intracellular glucopaenia as occurring in diabetes.

Intracellular glucopaenia markedly affected other structures. Reduced atria rates were observed in diabetes, despite the fact that the isolated preparation responded normally to NA, ACh or tyramine. Partial substitution of glucose in the bathing fluid by 2‐deoxyglucose or addition of NaF to the organ bath evoked similar changes in atria from normal animals.

ACh which has little effect on vascular permeability must exert its vasodilator effects through mechanisms which are different from those influenced by the biochemical changes occurring in diabetes.
Neostigmine augments responses of the rat anococcygeus muscle to field stimulation
Authors: Smith J. A. , Spriggs T.L.B.
Published: July 2012

The effects of neostigmine on noradrenergic transmission have been studied in the field stimulated, isolated anococcygeus muscle of the rat.

In those muscles where the excitatory response to field stimulation was not completely inhibited by guanethidine (5 × 10−6 to 10−5m) or phentolamine (10−6m), atropine (5 × 10−8m) gave no further inhibition of the response.

The shape of the response to field stimulation was altered in a dose‐dependent manner by neostigmine (5 × 10−7 to 5 × 10−6m), such that a ‘shoulder’ appeared during the relaxation phase. The ‘shoulder’, present at all stimulation frequencies tested between 3 and 40 Hz, was abolished by atropine (5 × 10−8 M) and unaffected by tubocurarine (10−6 m).

Neostigmine (2.5 × 10−6 m), whether alone or in the presence of atropine (5 × 10−8 m), had no effect on the uptake or stimulation‐induced release of [3H]‐noradrenaline.

Using electron microscopy, small Schwann/axon bundles close to smooth muscle cells rarely showed Cholinesterase staining, whereas larger bundles at the outer serosal aspects of the muscle exhibited dense staining.

It is concluded that the observed effects of neostigmine are not due to a presynaptic effect on noradrenergic transmission.
An in vivo model for measuring antigen‐induced SRS‐A‐mediated bronchoconstriction and plasma S RS‐ A levels in the guinea‐pig
Authors: Anderson Wayne H. , O'Donnell Margaret , Simko Beverly A. , Welton Ann F.
Published: July 2012

Pharmacological modulation of antigen‐induced anaphylaxis in actively sensitized guinea‐pigs with intravenously administered indomethacin (10 mg/kg), pyrilamine (2.0 mg/kg) and propranolol (0.1 mg/kg) resulted in a delayed onset, slowly developing bronchoconstriction indicative of a slow‐reacting substance of anaphylaxis (SRS‐A) response.

Measurements of pulmonary mechanics on the drug‐pretreated animals challenged with ovalbumin demonstrated a more prominent effect on dynamic compliance than resistance. This is consistent with the more potent effects of SRS‐A on peripheral rather than central airways.

The slowly developing bronchoconstriction obtained after treatment with indomethacin, pyrilamine and propranolol was inhibited by the standard SRS‐A antagonist, FPL 55712 and the SRS‐A synthesis inhibitors, phenidone, BW 755C and nordihydroguaiaretic acid.

Plasma SRS‐A levels were determined in guinea‐pigs following antigen challenge. The appearance of SRS‐A in the plasma preceded the onset of bronchoconstriction and SRS‐A levels remained elevated throughout its development. Coincident with the inhibition of bronchoconstriction by the SRS‐A synthesis inhibitor, phenidone, was a dose‐dependent reduction in plasma SRS‐A. The intravenous ED50 in each case was 4 mg/kg.

This model of antigen‐induced SRS‐A‐mediated bronchoconstriction should prove useful for the in vivo evaluation and development of therapeutics which regulate the synthesis of SRS‐A.
Selective inhibition of thromboxane B2 accumulation and metabolism in perfused guinea‐pig lung
Authors: Hoult J.R.S. , Robinson C.
Published: July 2012

U46619, a prostaglandin H2 endoperoxide analogue and thromboxane A2 agonist, dose‐dependently inhibited accumulation and metabolism of thromboxane B2 in the isolated perfused lung of the guinea‐pig. At similar doses prostaglandins E1, E2, F2α, F2α, I2, 5,6‐trans‐PGE2 and 8‐iso‐PGE1 were ineffective.

U46619 did not affect accumulation and metabolism of prostaglandin F2α under similar conditions.

The pulmonary disposition of thromboxane B2, which occurs by uptake into pulmonary cells or binding to a specific macro molecular component, is mediated by a mechanism distinct from that handling prostaglandin F2α. The possible relevance of these findings to the pulmonary disposition of thromboxane A2 is discussed.
Indirect action of 5‐hydroxytryptamine on the isolated muscularis mucosae of the guinea‐pig oesophagus
Authors: Kamikawa Yuichiro , Shimo Yasuo
Published: July 2012

The site of action of 5‐hydroxytryptamine (5‐HT) was examined on the isolated muscularis mucosae attached to the submucous plexus of the guinea‐pig oesophagus. Isotonic responses of the longitudinal muscularis mucosae were recorded.

5‐HT produced a transient contraction of the muscularis mucosae at concentrations higher than 3 μm. The contraction was rapid in onset, reaching a peak in about 15 s or less, and was restored to the basal level after 20 to 30 s without washing out 5‐HT. When the 5‐HT‐induced contraction faded to the basal tone, successive applications of 5‐HT no longer produced any contracture.

Nicotine (Nic), at concentrations higher than 10 μm, also produced a transient contraction which had a very similar pattern to that induced by 5‐HT. Again, the successive application of Nic no longer produced any contracture following prior treatment with Nic itself. However, the 5‐HT‐induced contraction was not modified by the presence of Nic.

Exogenously applied acetylcholine (ACh) produced a concentration‐dependent contraction of the muscularis mucosae, the 50% effective concentration (EC50) was 69 ± 5.6 nm. The contraction was sustained during incubation with ACh, and was not modified by prior treatment with 5‐HT or Nic.

The 5‐HT (100 μm)‐induced contraction was completely abolished by tetrodotoxin (0.2 μm) and atropine (0.2 μm). This means that the action is mediated by stimulating cholinergic nerves in the submucous plexus attached to muscularis mucosae. Moreover, the stimulating action of 5‐HT does not involve nicotinic receptors, since the action was not blocked by hexamethonium (100 μm).

Among several 5‐MT antagonists examined, methysergide (1 μm), ketanserin (1 μm) and morphine (100 μm) failed to modify the 5‐HT (100 μm)‐induced contraction significantly. Cinanserin (0.1–3 μm), cyproheptadine (3–100 nm) and phenoxybenzamine (0.1–3 μm) inhibited the 5‐HT‐induced contraction, in a concentration‐dependent manner, and each highest concentration abolished the response. However, none of these antagonists was specific for 5‐HT, but the Nic (100 μm) or ACh (0.1 μm)‐induced contractions were also inhibited by them.

The present results indicate that 5‐HT contracts the muscularis mucosae of the guinea‐pig oesophagus indirectly by stimulating cholinergic nerves in the submucous plexus, and has no direct action on the muscularis mucosae. In addition, the type of 5‐HT receptors responsible for the stimulant action may be different from those in other parts of the gastrointestinal tract, blood vessels or brain, because of the different effects of 5‐HT antagonists.
Occurrence of α1s‐adrenoceptors in the mouse but not in the rabbit isolated anococcygeus preparations
Authors: Coates Jill , Weetman D.F.
Published: July 2012

Both Sgd 101/75 (4(2‐imidazoline‐amino‐2‐methylindazol‐chlorhydrate) and noradrenaline contracted anococcygeal preparations from the mouse and rabbit.

The maximal response to and sensitivity (EC30 values) of each drug on the mouse was similar, whereas in the rabbit, Sgd 101/75 was a partial agonist relative to noradrenaline (intrinsic activity 0.50) and the EC30 value was 14.5 times higher than for noradrenaline.

In both species, phenoxybenzamine (0.3 nm for 30 min followed by 20 washes over 30 min) reduced the effects of Sgd 101/75 preferentially. When noradrenaline was then added in the presence of a high concentration of Sgd 101/75 (400 μm), its maximum response and EC30 value were decreased in the rabbit, but not in the mouse.

When a range of concentrations of phenoxybenzamine (30 pm‐3μm for 30 min followed by 20 washes over 30 min) was tested, the maximum response of the rabbit anococcygeus to noradrenaline declined in a concentration‐dependent manner. Similar experiments in the mouse resulted in two distinct sensitivities of the maximum response of noradrenaline to phenoxybenzamine (at 0.3 and 300 nm).

The results indicate that noradrenaline acts on two receptors to contract the mouse anococcygeus (α1 and α1s‐adrenoceptors), but only one (α1‐adrenoceptor) in preparations derived from the rabbit.
Inhibition of gastric acid secretion by intracerebroventricularly administered prostaglandin E2 in anaesthetized rats
Authors: Puurunen Juhani
Published: July 2012

The effect of intracerebroventricularly (i.c.v) administered prostaglandin E2 (PGE2) on gastric acid secretion was studied in anaesthetized rats.

Intracerebroventricular injections of 1 and 3 μg of PGE2 inhibited gastric acid secretion induced by insulin, electrical vagal stimulation and acetylcholine in a dose‐dependent manner.

Intravenous injections of 1, 3 and 10 μg of PGE2 had no effect on insulin‐stimulated gastric acid output.

The results indicate that upon i.c.v. administration PGE2 inhibits gastric acid secretion by acting centrally and not peripherally after leakage from the central nervous system.
Effects of prostaglandin E2 on fast and slow components of the response of the rat vas deferens to field stimulation
Authors: Bedwani J.R. , Blanning P.E.
Published: July 2012

The response of the rat vas deferens to field stimulation with single pulses is biphasic. The first, rapid component of the response is dominant at the prostatic end and is thought by some to be mediated by non‐adrenergic, non‐cholinergic neurotransmission. The second, slower component predominates at the epididymal end and has the usual properties associated with adrenergic responses.

Prostaglandin E2 (PGE2, 10−8 to 10−5 mol/l) inhibited the ‘fast component’ responses elicited by field stimulation of the prostatic vas from reserpine‐treated rats. The prostaglandin was more potent in the presence of 1.25 than 2.5 mmol/l Ca2+.

PGE2 (10−7 to 10−5 mol/l) had similar effects on prostatic preparations from normal rats, but was less active on these.

PGE2 (10−9 to 10−5 mol/l) did not inhibit the ‘slow component’ responses resulting from field stimulation of the epididymal vas but rather, at the two highest concentrations used (5 × 10−6 and 10−5 mol/l), potentiated them. These high concentrations of the prostaglandin also potentiated the contractions of the epididymal vas elicited by exogenous noradrenaline.

These effects of PGE2 on the two components of the response of the rat vas deferens are not as might be expected from its inhibitory effects on the ‘typical’ adrenergic neurotransmission in several other sympathetically‐innervated tissues.
Effects of antiarrhythmic drugs on ventricular fibrillation thresholds of normal and ischaemic myocardium in the anaesthetized rat
Authors: Marshall R.J. , Muir A.W. , Winslow E.
Published: July 2012

The effects of agents which produce membrane stabilization (class I), β1‐adrenoceptor blockade (class II), prolongation of the cardiac action potential (class III) or inhibition of the slow inward current (class IV) were investigated for their ability to increase the ventricular fibrillation threshold (VFT) or to modify the fall in VFT consequent upon coronary artery ligation in the anaesthetized rat.

The class I agent, Org 6001, increased VFT of normal myocardium and in lower doses reduced the postligation fall in VFT.

The class II agent, metoprolol, failed to increase VFT of normal myocardium but reduced the postligation fall.

The class III agent, melperone, increased VFT of both normal and ischaemic myocardium whereas the class IV agent, nifedipine failed to influence VFT in either region.

Bepridil (class I and IV) was similar to Org 6001 and sotalol (class II and III) in that it increased VFT of normal myocardium and in lower doses reduced the postligation fall in VFT.

Measurement of VFT before and after coronary artery ligation in the rat constitutes a rapid and reproducible screen to detect antifibrillatory activity.

The results also suggest that in the rat, the low currents used (˜400 μA) do not release substantial quantities of catecholamines whereas these may be released by coronary artery ligation.
The effect of an inhibitory factor from the bovine retractor penis on the gastro‐intestinal tract and gall bladder of the guinea‐pig
Authors: Crossley A.W.A. , Gillespie J.S.
Published: July 2012

The effect of a smooth muscle inhibitory factor extracted from the bovine retractor penis has been examined on a variety of in vitro smooth muscle preparations from the guinea‐pig alimentary canal and on the guinea‐pig gall bladder.

The inhibitory factor caused relaxation of spontaneous and carbachol‐induced tone in the taenia coli, the stomach fundal strip and the duodenum and colon. There was little effect on the ileum. Sensitivity was highest in the taenia coli where the response to the inhibitory factor mimicked the response to stimulation of the non‐adrenergic, non‐cholinergic (NANC) inhibitory nerves.

In the taenia coli the inhibitory response to stimulation of the NANC nerves and to ATP was abolished by apamin 5 × 10−8 m, whereas this or higher concentrations had no effect on the response to the inhibitory factor. This makes it unlikely that the latter is the neurotransmitter in these NANC nerves.

The inhibitory factor had no effect on the gall bladder. Inhibitory responses to field stimulation were obtained in this tissue but these were insensitive to tetrodotoxin in concentrations greater than those needed to block the motor cholinergic nerves.
Thyrotropin releasing hormone‐induced hyperthermia in mice: possible involvement of adrenal and pituitary glands
Authors: Boschi Gabrielle , Nomoto Teruko , Rips Richard
Published: July 2012

To investigate the hyperthermic effect of thyrotropin releasing hormone (TRH) and its potentiation by exogenous catecholamines (CA), the role of the adrenal medulla and of the pituitary gland was studied in unoperated, adrenal‐demedullated or hypophysectomized mice.

In unoperated mice, TRH 40 mg kg−1 i.p. produced a hyperthermia which was accompanied by an increase in plasma noradrenaline (NA) and adrenaline (Ad). NA or Ad, both at a dose of 1 mg kg−1 i.p., enhanced the TRH‐induced hyperthermia.

Adrenal demedullation suppressed the hyperthermia and the increase of plasma CA produced by TRH but not the potentiation of this hyperthermia by exogenous CA.

Hypophysectomy abolished the TRH‐induced hyperthermia but not the increase of plasma CA or the potentiation of this hyperthermia by exogenous CA.

These results suggest that, in mice, both the adrenal medulla and the pituitary gland play an essential role in TRH‐induced hyperthermia but not in its potentiation.
Hypoxia‐induced cardiac hypertrophy in rabbits treated with verapamil and nifedipine
Authors: Dukes I.D. , Williams E.M. Vaughan
Published: July 2012

Young rabbits were exposed, eight at a time, to 310 h of hypoxia (O2 at 70–80 torr), at atmospheric pressure. The animals were injected with 1 mg kg−1 nifedipine (F) or 5 mg kg−1 verapamil (V) or an equivalent volume of the vehicle (H) (Cremophor EL), i.p. twice a day. A fourth group (N), also injected with vehicle, was not made hypoxic.

The animals were from 6 litters, 6 rabbits in each litter, and were distributed so that every group had litter mates in the other groups.

Right ventricular hypertrophy was induced in all the hypoxic groups (H, + 39%; V, + 46%; F, + 44%). Differences between groups were not statistically significant, but all were significantly hypertrophied relative to their normoxic litter mates (N). The right atria were less hypertrophied (H, + 3.6%; V, + 20%; F, + 21.6%), but there was no left ventricular or left atrial hypertrophy.

There was also a small increase in haematocrit in the hypoxic groups (H, + 20.6%; V, + 17.5%; F, + 28.8%).

The doses administered were equivalent to the highest used clinically producing blood levels of verapamil and nifedipine within or above the clinical range and had no effect on the development of cardiac hypertrophy.
Effects of increasing the frequency of twitches and of isoprenaline on maximal twitches and cyclic AMP levels in slow‐ and fast‐contracting cat skeletal muscles
Authors: Merican Zainuddin , Nott M.W. , Sunbhanich M.
Published: July 2012

Increasing the frequency of twitches and treatment with isoprenaline have been been compared for effects on twitch tension, tension‐time integral and cyclic adenosine 3′, 5′‐monophosphate (cyclic AMP) levels in the slow‐contracting soleus muscle of cats, anaesthetized with chloralose and pentobarbitone. The effect of change in frequency of contractions on cyclic AMP in the fast‐contracting extensor digitorum longus muscle was also examined.

Although both isoprenaline and increasing the frequency of contractions depressed twitch tension in the soleus, only isoprenaline enhanced cyclic AMP levels. The effects of isoprenaline were independent of the existing frequency of contractions of the muscle. Increasing the frequency of contractions enhanced twitches in the extensor digitorum longus muscle but did not change cyclic AMP levels.

It is concluded that cyclic AMP may mediate effects of β‐adrenoceptor agonists but not those caused by increasing the frequency of contractions on slow‐ or fast‐contracting skeletal muscles.
Effects of cyproheptadine on electrophysiological properties of isolated cardiac muscle of dogs and rabbits
Authors: Neto Francisco Riccioppo
Published: July 2012

The effects of cyproheptadine were studied on cardiac Purkinje and ventricular muscle fibres of the dog and on cells of the sinoatrial (SA) node region of rabbit hearts, by means of electrophysiological techniques.

Cyproheptadine (2–8 μm) decreased, in a dose‐dependent manner, the plateau amplitude and the action potential duration to 50% repolarization of Purkinje and ventricular muscle cells. Higher concentrations also depressed the action potential amplitude, the overshoot and the maximum rate of rise of the upstroke. These effects were only partially reversed on washing.

A four fold increase in Ca concentration of the standard Tyrode solution antagonized the effects of cyproheptadine on the action potential characteristics.

The ‘slow response’ obtained in K‐depolarized isoprenaline‐treated fibres was blocked by cyproheptadine (4 μm).

Cyproheptadine (10 μm) depolarized and suppressed the automaticity of spontaneously beating Purkinje fibres.

The frequency of discharge of the SA node cells was slowed or abolished by cyproheptadine (2–4 μm). Atropine (2.6 μm) did not affect the negative chronotropic effect, whereas adrenaline (5 μm) reversed it.

It is suggested that cyproheptadine depresses the slow inward current in all types of myocardial fibres studied. Higher concentrations might also affect the fast inward sodium current system.
Demonstration of α1s‐adrenoceptors after exposure of the rat anococcygeus to benextramine
Authors: Coates Jill , Weetman D.F.
Published: July 2012

Sgd 101/75 (4(2‐imidazoline‐amino)‐2‐methylindazol‐chlorhydrate) and noradrenaline exerted similar, full agonist effects on the α‐adrenoceptors of the rat anococcygeus.

Benextramine (30 μm for 30 min, followed by 20 washes over 30 min) abolished contractions of the anococcygeus to Sgd 101/75, but only reduced those to noradrenaline.

Sgd 101/75 (400 μm) did not significantly reduce contractions of the benextramine‐treated (30 μm) anococcygeus to noradrenaline.

It is concluded that benextramine can replace phenoxybenzamine as the alkylating agent in the demonstration of α1s‐adrenoceptors in the rat anococcygeus.
Two distinct interactions of barbiturates and chlormethiazole with the GABAA receptor complex in rat cuneate nucleus in vitro
Authors: Harrison N.L. , Simmonds M. A.
Published: July 2012

Some pharmacological properties of the GABAA receptor complex in the rat cuneate nucleus slice have been assessed from depolarization responses to the γ‐aminobutyric acid (GABA) analogue muscimol and antagonism of the responses by bicuculline and picrotoxin.

Responses to muscimol were potentiated by the following drugs, in descending order of potency with regard to the concentrations required in the Krebs medium: (±)‐5‐(1,3‐dimethylbutyl)‐5‐ethylbarbituric acid ((±)‐DMBB) = (±)‐quinalbarbitone = (± pentobarbitone > (±)‐methyl‐phenobarbitone = (−)‐methylphenobarbitone > butobarbitone = chlormethiazole > phenobarbitone > barbitone = (+)‐methylphenobarbitone. Primidone and phenylethylmalonamide were inactive. Calculation of the concentrations likely to be present in membrane lipids for equal potentiations of muscimol revealed little difference between quinalbarbitone, pentobarbitone, phenobarbitone and barbitone.

The effect of picrotoxin as a muscimol antagonist was selectively reduced only by DMBB, chlormethiazole, phenobarbitone and (−)‐methylphenobarbitone in concentrations that caused only a modest potentiation of muscimol.

It is suggested that a specific site of action in the GABAA receptor complex is involved in the reduction of picrotoxin effect and that this may be relevant to the anticonvulsant properties of chlormethiazole, phenobarbitone and (−)‐methylphenobarbitone. The potentiation of muscimol by chlormethiazole and the barbiturates in general involves a distinctly different site that is less selective and this may underlie the hypnotic properties of these drugs.
Conversion of prostacyclin to 6 oxo prostaglandin E1 by rat, rabbit, guinea‐pig and human platelets
Authors: Griffiths R.J. , Moore P.K.
Published: July 2012

The enzymatic catabolism of prostacyclin (PGI2) to 6 oxo prostaglandin E1 (6 oxo PGE1) was studied in platelet‐rich and platelet‐poor‐plasma of rat, rabbit, guinea‐pig and man.

Rat, rabbit and human platelets convert PGI2 to a product with biological activity and thin layer chromatographic mobility identical to that of authentic 6 oxo PGE1. Platelets from these species also converted 9β‐[3H]‐PGI2 to non‐radioactive 6 oxo PGE1 as shown by the progressive loss of extracted radioactivity following incubation. Formation of 6 oxo PGE1 was inhibited by the flavonoid drugs, rutin and naringenin.

Guinea‐pig platelets did not convert PGI2 to 6 oxo PGE1.

Rat, rabbit and guinea‐pig platelets do not spontaneously release a 6 oxo PGE1‐like substance when incubated at 37°C in the absence of added PGI2 or aggregating agents.

The relevance of these findings to the possible physiological and pathophysiological roles of 6 oxo PGE1 in the regulation of platelet function is discussed.
The effect of sulphydryl block on the binding of H1‐antagonists to the muscarinic receptor
Authors: Burgen A.S.V. , Harbird C.J.
Published: July 2012

The treatment of brain muscarinic receptors by p‐chlormercuribenzoate is known to change structure‐activity relationships for antagonists. The changes in binding affinity of H1‐antagonists for this receptor have been measured; the, changes are similar to those for intrinsic muscarinic antagonists.
A comparison of adenine and some derivatives on pig isolated tracheal muscle
Authors: Bach‐Dieterle Yvonne , Holden William E. , Junod Alain F.
Published: July 2012

We studied the muscle relaxation induced by adenine and several adenine derivatives in strips of tracheal smooth muscle from pigs; in addition their metabolism by the tissue was examined.

Adenine relaxed tissue which was contracted by carbachol, histamine, or KCl. Adenine's potency was similar to that of adenosine and ATP (threshold about 4 × 10−5 m).

In tissues with carbachol‐induced tone, the adenine effect differed from adenosine and ATP by being slower in onset and in ‘washout’ time. Furthermore, neither dipyridamole nor theophylline modified the response to adenine.

The relationship was examined between pharmacological effects and the metabolism of [3H]‐adenosine and [3H]‐adenine. Both substrates were taken up by the tissue and converted to nucleotides, but relaxation correlated with nucleotide accumulation only in the case of [3H]‐adenine.

We conclude that the site and mechanism of adenine‐induced relaxation is different from that of adenosine and ATP in porcine tracheal muscle.
Inhibition by propranolol of the contractile response of the rat diaphragm to tetanic field stimulation in vitro
Authors: Drazen Jeffrey M. , Lacouture Peter G. , Miller Michael J.
Published: July 2012

Contraction of the rat isolated diaphragm in response to maximal tetanic stimulation was examined before and after isoprenaline or propranolol.

Isoprenaline (10−4m) did not affect maximum isometric force, whereas propranolol depressed maximum force in a concentration‐dependent manner (10−6‐10−4m).

Inhibition due to propranolol (10−4m) could not be overcome by increasing the intensity or duration of electrical stimulation, and was only partially reversed (mean 73% ± 10 s.e.mean) after washing.

Pretreatment with isoprenaline did not alter the response of the muscle to propranolol, nor did neuromuscular blockade with (+)‐tubocurarine.

The response to either stereoisomer of propranolol was similar to that obtained with the racemate.

Atenolol, a β‐adrenoceptor blocking agent without membrane stabilizing activity, had minimal (< 10%) depressant effects on diaphragmatic force development.

Lignocaine (8.5 × 10−6‐8.5 × 10−5m) produced a concentration‐related decrease in isometric force, similar to that with propranolol.

It is concluded that propranolol decreases the contractile force of the rat isolated diaphragm by a mechanism related to stabilization of excitable membranes.
Characterization of adenosine receptors in isolated cerebral arteries of cat
Authors: Edvinsson Lars , Fredholm Bertil B.
Published: July 2012

The effect of some adenosine analogues and xanthine derivatives were studied on isolated cerebral arteries from cats.

The adenosine analogues caused an almost complete relaxation of cerebral arteries contracted by prostaglandin F2α (PGF2α, 30 μm). The order of potency was: 5‐N‐ethylcarboxamide adenosine (NECA) > 2‐chloroadenosine > adenosine > l‐N6‐phenylisopropyl adenosine (l‐PIA). The analogue d‐PIA was very weak and its maximum effect was small.

NECA and l‐PIA enhanced [3H]‐cyclic AMP accumulation in [3H]‐adenine labelled feline pial vessels with similar absolute and relative potency to their relaxant effects.

The relaxant effects of adenosine and of NECA were competitively antagonized by 8‐phenyl‐theophylline (pA2 = 6.5). The effect of theophylline and enprofylline could not be tested in higher concentrations than 30 or 10 μm because they affected the vessels directly. At these concentrations they were essentially inactive as adenosine antagonists. The non‐xanthine phosphodiesterase inhibitor rolipram (0.1 and 100 μm) caused a slight but non‐significant potentiation of the relaxant effect of adenosine.

The results are compatible with the opinion that adenosine relaxes cerebral vessels by an action on adenosine A2‐receptors. The effect may be linked to adenylate cyclase and can be antagonized by 8‐phenyl‐theophylline.
Pharmacological characterization of the inhibitory effects of neurotensin on the rabbit ileum myenteric plexus preparation
Authors: Huidobro‐Toro J.Pablo , Yoshimura Kohji
Published: July 2012

Neurotensin in picomolar concentrations caused a concentration‐related inhibition of the spontaneous contractile activity of the longitudinal muscle from the rabbit isolated ileum. Neurotensin was approximately 100 times more potent than adrenaline and about 10000 times as active as adenosine triphosphate (ATP) in producing similar relaxations.

The neurotensin‐induced inhibitory effect did not follow activation of adrenoceptors or P1‐purinoceptors since the effect of the neuropeptide was not antagonized by a combination of phentolamine plus (−)‐propranolol, nor by pretreatment with theophylline.

Tetrodotoxin did not reduce the potency of neurotensin in relaxing the rabbit ileum, suggesting that the neurotensin‐induced inhibition is not neuronally mediated. The inhibitory responses of neurotensin were blocked non‐competitively by apamin.

The inhibitory effect of neurotensin was short‐lived with the subsequent development of tachyphylaxis, which was not crossed to the inhibitory action of adrenaline or ATP. Similarly, when tachyphylaxis to adrenaline or to ATP was established, the inhibitory action of neurotensin was unaffected. Desensitization was characterized by a gradual shift of the neuropeptide concentration‐response curve to the right and downwards.

Preincubation of rabbit ileum strips with 10 nm dynorphin (1–13) significantly increased the inhibitory action of neurotensin.
The use of neurally released agonist in the measurement of antagonism at α‐adrenoceptors
Authors: French Andrew M. , Scott Neil C.
Published: July 2012

Graded contractile responses of the rat vas deferens were obtained to trains containing varying numbers of pulses delivered transmurally at 500 Hz, allowing construction of pulse‐response curves.

In the presence of postjunctional adrenoceptor blocking drugs, these curves were displaced to the right in a parallel manner, allowing the estimation of pA2 values for the drugs.

Activity of drugs at prejunctional adrenoceptors was estimated from the reduction of inhibition of the response to a second pulse delivered 3 s after trains containing different numbers of pulses.

It is suggested that the technique is more physiological than others used to determine the antagonistic activity of drugs at adrenoceptors.
Effect of desamino‐cholecystokinin‐octapeptide (CCK‐7) on the intraluminal pressure and myoelectrical activity of the gall‐bladder, stomach, and small intestine in conscious dogs
Authors: Milenov E. , Nieber K. , Niedrich H. , Oehme P. , Vogt W.‐E.
Published: July 2012

Desamino‐cholecystokinin‐octapeptide (CCK‐7) increased the gall‐bladder pressure and decreased the gastric pressure following i.v. infusion in conscious dogs.

In small intestine and Heidenhain pouch CCK‐7 exerted an initial excitatory effect followed by an inhibitory effect on intraluminal pressure and peristalsis.

In all organs the effect of CCK‐7 on pressure was correlated with a change of spike discharge.

CCK‐7 is more potent on gastrointestinal motor activity than a Boots preparation of pancreozymin.

The results suggest that CCK‐7 at doses within the physiological range could be involved in the regulation of gastrointestinal motility.
Heterogeneity of 5‐hydroxytryptamine receptors in the rat uterus and stomach strip
Authors: Wrigglesworth Susan J.
Published: July 2012

Experiments were performed using the rat isolated uterus and the rat stomach strip to investigate the effects of 5‐hydroxytryptamine (5‐HT) on 5‐HT receptors in the presence of different antagonists. Amitriptyline, methysergide and trazodone were used to antagonize the response to 5‐HT in these tissues.

The pA2 value for amitriptyline with 5‐HT as the agonist was estimated from the Schild plot analysis and found to differ significantly (P<0.05) in the stomach strip (6.36) from that in the isolated uterus (9.06).

A similar difference was found using trazodone; here the pA2 value was 6.74 in the stomach strip and 8.49 in the isolated uterus.

These results indicate a difference between the two tissues. This difference is discussed in terms of heterogeneity of 5‐HT receptors.
Antagonism of enkephalin action on acetylcholine release by methylxanthines: lack of a purine link
Authors: Elliott Janet , Jhamandas Khem , Notman Holly , Sutak Maaja
Published: July 2012

Theophylline (Theo) and caffeine antagonized the inhibitory effect of methionine (Met)‐enkephalin, leucine (Leu)‐enkephalin and morphine on the twitch height of the field stimulated myenteric plexus longitudinal muscle (MPLM) preparation of the guinea‐pig ileum. Antagonism by Theo was observed only in tissues stimulated submaximally, but that by caffeine was observed in tissues stimulated submaximally and supramaximally.

Injection of Theo (20, 40 mg kg−1) or caffeine (40 mg kg−1) reversed or blocked the inhibitory effects of Leu‐enkephalin (50 μg i.c.v.) and a systemically active enkephalin FK 33,824 (0.5 mg kg−1) on the release of acetylcholine (ACh) from the rat cortex in vivo.

Injections of morphine (2.5, 5.0 mg kg−1 i.v.) did not modify the in vivo release of radiolabeled purines from the cerebral cortex prelabelled with [3H]‐adenosine (2.8 × 10−7 m). Application of K+ (60 mm) to the cortex readily stimulated this release. Injection of morphine (5.0 mg kg−1 i.v.) increased the spontaneous release of radiolabeled purines from the cortex prelabelled with a higher concentration of [3H]‐adenosine (10−4 m) in six out of eleven experiments. Under similar conditions neither Leu‐enkephalin (50 μg i.c.v.) nor FK 33,824 (0.5 mg kg−1 i.v.) stimulated purine release.

It is concluded that methylxanthines can antagonize the inhibitory action of opioids on the peripheral and central release of ACh. However, this antagonism does not reflect an intermediary purine step in the action of opioids on the release of ACh.