bluuebunny/crossref_metadata_2025 huggingface dataset:
Mediators of the secretory response to kinins
Authors: Cuthbert A.W. , Halushka P.V. , Margolius H.S. , Spayne J. A.
Published: July 2012

The output of immunoreactive (i) 6 keto prostaglandin F1α (i6ketoPGF1α), iPGE2 and ithromboxane B2 (iTXB2) from isolated colonic epithelium of the rat into the apical and basolateral bathing solution has been measured. In some instances tissues were also voltage clamped at 0 mV to measure short circuit current (SCC).

Kallidin (lysylbradykinin) stimulated the output of all three eicosanoids, specifically from the basolateral face of the tissue. The output was similar whether or not the tissues were short circuited.

Both the SCC response and eicosanoid output were dependent upon the concentration of kallidin, but not in a strictly proportional manner, there being relatively more eicosanoid output at submaximal kinin concentrations.

Indomethacin, 5 μm, abolished the eicosanoid output, in response to kinin, while some part of the SCC response remained.

Calcium removal from the basolateral bathing fluid severely attenuated the SCC response, reduced the output of i6ketoPGF1α to half, but left the output of iPGE2 unchanged. In the presence or absence of calcium it is probable that sufficient PGE material is released to cause part of the SCC changes seen with kinin.

Kinin and PGE1 increased the cyclic AMP content of intact epithelia, provided a phosphodiesterase inhibitor was added at the same time.

It is proposed that kinin causes an increase in calcium influx at the basolateral pole of the tissue. This calcium is necessary for the production of some eicosanoids and the subsequent generation of cyclic AMP, which then increases apical chloride permeability. In addition, calcium may facilitate entry of chloride through the basolateral face of the cells by activating a cotransport mechanism.
Inhibition of partially purified K/H+ ‐ATPase from guinea‐pig isolated and enriched parietal cells by substituted benzimidazoles
Authors: Beil W. , Sewing K.‐Fr.
Published: July 2012

The cellular and subcellular distributions of adenosinetriphosphatases (ATPases) were examined in guinea‐pig gastric mucosal cells. All cell types displayed Mg2+‐ATPase and bicarbonate (HCO&3bar;)‐stimulated ATPase activity. K+‐ATPase was located only in fractions derived from parietal cells.

Differential and density‐gradient centrifugation of material prepared from parietal cells revealed that K+‐ATPase activity was located in a tubulo‐vesicular membrane fraction. Enzyme activity was ten fold greater in this fraction than in a crude parietal cell homogenate.

The substituted benzimidazoles, omeprazole and picoprazole, inhibited K+‐ATPase (IC50 1.8 ± 0.5 μmol 1−1 and 3.1 ± 0.4 μmol 1−1, respectively). Detailed kinetic analysis indicated that these compounds were non‐competitive and reversible inhibitors of the enzyme. In contrast cimetidine and verapamil were without effect on the enzyme.

The relevance of the inhibition of K+‐ATPase to the antisecretory activity of the benzimidazoles, in experimental animals and man, is discussed.
Effects of sea‐anemone toxin (ATX‐II) on the frequency of miniature endplate potentials at rat neuromuscular junctions
Authors: Harris J.B. , Tesseraux Irene
Published: July 2012

Soleus and extensor digitorum longus muscles were isolated from rats. The muscles were exposed to ATX‐II, a toxin isolated from extracts of the sea‐anemone Anemonia sulcata. The toxin caused a dose‐dependent increase in the frequency of miniature endplate potentials in both types of muscle. The increase in frequency could be reversed by the application of tetrodotoxin (TTX), and could be prevented by prior exposure of the muscles to TTX. It is concluded that ATX‐II causes a sodium‐dependent depolarization of the nerve‐terminal membrane.
Effects of collagenase on the release of [3H]‐noradrenaline from bovine cultured adrenal chromaffin cells
Authors: Almazan G. , Aunis D. , García A.G. , Montiel C. , Nicolás G.P. , Sánchez‐García P.
Published: July 2012

Bovine isolated adrenal chromaffin cells maintained in culture at 37°C for 1–7 days become polygonal and bipolar, with typical varicosity‐like extensions. Catecholamine levels and dopamine β‐hydroxylase activity decreased after 24–48 h of culture, but recovered to normal levels 3–7 days later.

Incubation of 1–7 day‐old cells in the presence of increasing concentrations of [3H]‐noradrenaline (3.91 to 125 nm) resulted in the retention by the cells of amounts of radioactivity directly proportional to the amine present in the media. One day‐old cells took up and retained only one third of the radioactivity found in 2–7 day‐old cells.

The addition of collagenase to cultured cells caused a decrease in the uptake of tritium. However, the enzyme treatment did not affect the amine taken up by the cell before collagenase treatment.

Release of tritium from cultured cells evoked by nicotine, acetylcholine (ACh) or 59 mm K+ was very poor in 24 h‐old cells; the secretory response to nicotine, ACh or K+ was dramatically increased after 2–7 days of culture. Bethanecol did not cause any secretory response.

When treated with collagenase, cultured cells which had recovered fully their secretory response, lost again the ability to release tritium evoked by ACh or nicotine. However, the responses to high K+, veratridine or ionophore X537A were not affected. The nicotinic response was recovered two days after collagenase treatmen.

The data suggest that the use of collagenase to disperse the adrenomedullary tissue during the isolation procedure might be responsible for the lost secretory response of young cultured chromaffin cells. Since collagenase specifically impairs the nicotinic cholinoceptor‐mediated catecholamine release, it seems likely that the enzyme is exerting its action on the ACh receptor complex. It is unlikely that either voltage‐sensitive Na+ or Ca2+ channels are affected by collagenase as the responses induced by high K+ or veratridine were unaffected by this enzyme.
The importance of endogenous prostaglandins other than prostacyclin, for the modulation of contractility of some rabbit blood vessels
Authors: Förstermann U. , Hertting G. , Neufang B.
Published: July 2012

Helically cut strips of rabbit aorta, extrapulmonary artery, coeliac artery, and femoral artery were set up in organ baths. Contractions of the strips by noradrenaline and angiotensin II were recorded isotonically. The release of prostaglandins 6‐keto‐PGF1α, E2, F2α, D2 and thromboxane B2 from the strips was measured by means of sensitive and specific radioimmunoassays.

All blood vessels released a characteristic pattern of cyclo‐oxygenase products. Prostacyclin (PGI2, measured as 6‐keto‐PGF1α) was the major compound formed, followed by smaller amounts of PGE2 and traces of PGF2α, PGD2 and thromboxane A2 (measured as thromboxane B2). The pulmonary and the femoral artery had comparatively high abilities to synthesize PGE2.

Contractions induced by noradrenaline increased prostaglandin release from the pulmonary artery but not from the other blood vessels. Angiotensin II‐induced contractions were accompanied by a marked prostaglandin release from the coeliac artery. After angiotensin II, prostaglandin release was also enhanced in the pulmonary artery, but remained essentially unchanged in the aorta and femoral artery.

Arachidonic acid markedly increased the levels of all prostaglandin formed.

Indomethacin inhibited the formation of all prostaglandins below the detection limits of the respective radioimmunoassays.

Indomethacin treatment induced a qualitatively similar shifting of the concentration‐response curves of noradrenaline and angiotensin II in some vessels: the concentration‐response curves remained unchanged for the aorta, were slightly shifted to the left of the pulmonary artery, were markedly shifted to the left for the coeliac artery, and were shifted to the right for the femoral artery.

Exogenous PGI2 strongly and concentration‐dependently inhibited contractions induced by the approximate EC50 of noradrenaline in the coeliac artery, but was without effect on the other three preparations. PGE2 had no effect on noradrenaline‐induced contractions of the aorta, inhibited those of the pulmonary and the coeliac artery, but markedly potentiated those of the femoral artery. PGF2α significantly enhanced contractions of the femoral artery, but increased contractions of the other preparations were not significant. PGD2 was without effect on any preparation.

In conclusion, the contractility of the aorta does not seem to be modulated substantially by prostaglandins. The major prostanoid regulating the tone of the coeliac artery was found to be PGI2. The contractility of the pulmonary and especially the femoral artery is probably not modulated by PGI2 but rather by PGE2.

These observations suggest that in certain blood vessels, prostaglandins other than PGI2 are important endogenous modulators of contractility.
The actions of antipsychotic drugs on dopamine receptors in the rat substantia nigra
Authors: Pinnock R.D.
Published: July 2012

The activity of neurones in the zona compacta of the rat substantia nigra was recorded extracellularly in vitro. Dopamine produced a dose‐dependent depression of firing, threshold doses being in the 3 μm range.

The inhibitory effects of dopamine were antagonized by (−)−sulpiride (pA27.5), haloperidol (pA28.4) and cis‐flupenthixol (pA26.9). The actions of γ‐aminobutyric acid (GABA) were not affected by these compounds.

The gradients of Schild plots of data for (−)−sulpiride were less than unity while those for haloperidol and cis‐flupenthixol were greater than unity, which suggests that the antagonism was not competitive. This is discussed with regard to the use of a bioassay system in the analysis of the effects of antagonists.

Haloperidol and (−)−sulpiride were found to have similar potencies, as dopamine receptor antagonists, to those predicted from biochemical and clinical efficacy studies, but cis‐flupenthixol was less potent than expected.
Induction of hypoglycaemia and accumulation of 5‐hydroxytryptamine in the liver after the injection of mitogenic substances into mice
Authors: Endo Yasuo
Published: July 2012

Various mitogenic substances (concanavalin A, pokeweed mitogen, polyl: polyC and a phorbol diester), as well as lipopolysaccharides (LPS or endotoxins), produced hypoglycaemia after being injected into mice. However, non‐mitogenic immuno‐stimulants (zymosan, carrageenan, an adjuvant peptide and interferon) did not induce hypoglycaemia.

All of the mitogenic substances also induced an increase in 5‐hydroxytryptamine (5‐HT) in liver, but the non‐mitogenic substances did not have this effect.

The time course of the development of hypoglycaemia was similar to that of the increase in liver 5‐HT.

The dose‐dependence of the hypoglycaemia induced by LPS was similar to that of the increase in liver 5‐HT.

In C3H/HeJ mice, the macrophages and/or lymphocytes of the mice are known to be less responsive to LPS, and both the LPS‐induced hypoglycaemia and increase in 5‐HT were less in these mice than in control mice (C3H/He and ddI mice).

These results suggest that macrophages and/or lymphocytes may participate in the induction of hypoglycaemia and the increase in 5‐HT induced by mitogenic substances and LPS. A possible correlation between hypoglycaemia and the increase in hepatic 5‐HT is discussed, although the relationship is not substantiated.
Cyclic GMP mediates neurogenic relaxation in the bovine retractor penis muscle
Authors: Bowman Anne , Drummond Alan H.
Published: July 2012

Field stimulation of the non‐adrenergic, non‐cholinergic inhibitory nerves to the bovine isolated retractor penis muscle evoked a relaxation that was preceded by a rise in the tissue content of cyclic GMP. There was no change in the content of cyclic AMP.

The selective cyclic GMP phosphodiesterase inhibitor, 2‐o‐propoxyphenyl‐8‐azapurin‐6‐one (M&B 22948), elevated the tissue's cyclic GMP content, and potentiated both the relaxation and the rise in cyclic GMP produced by inhibitory nerve stimulation.

Sodium nitroprusside and an inhibitory factor extracted from the bovine retractor penis muscle mimicked the effects of inhibitory nerve stimulation in that they each produced relaxation associated with a selective rise in cyclic GMP concentration.

Haemoglobin (in the form of erythrocyte haemolysate) and N‐methylhydroxylamine, which are known to block guanylate cyclase, blocked the relaxation and the rise in cyclic GMP content produced by inhibitory nerve stimulation, inhibitory factor and sodium nitroprusside. Haemoglobin itself caused a rise in muscle tone and at the same time reduced the cyclic GMP content of the tissue.

8‐Bromocyclic GMP, a permeant derivative of cyclic GMP, produced a relaxation of the muscle that, as expected, was not blocked by haemoglobin.

Vasoactive intestinal polypeptide, prostaglandin E1 and forskolin each produced relaxation associated with a selective rise in cyclic AMP content. Their effects were not blocked by haemoglobin or N‐methylhydroxylamine.

It is concluded that inhibitory nerve stimulation in the bovine retractor penis muscle produces a relaxation that is mediated by cyclic GMP, although some substances relax the muscle without affecting cyclic GMP levels. The results are also compatible with the view that the extracts of muscle contain the inhibitory neurotransmitter.
Triggering by Paf‐acether and adrenaline of cyclo‐oxygenase‐independent platelet aggregation
Authors: Fouque F. , Vargaftig B.B.
Published: July 2012

Platelet‐activating factor (Paf‐acether, 1‐alkyl‐2‐acetyl‐sn‐glycero‐3‐phosphorylcholine) induced full aggregation and a limited release reaction of human platelets in plasma or in blood.

Cyclo‐oxygenase inhibition with aspirin only reduced aggregation when induced by threshold amounts of Paf‐acether, whereas higher concentrations surmounted inhibition whether tested in citrated or in heparinized platelet‐rich plasma or blood. Aspirin‐induced inhibition of platelet secretion by Paf‐acether was insurmountable and independent of the anti‐coagulant used.

Paf‐acether and adrenaline acted synergistically in inducing aggregation in citrate and in heparin. Aspirin in vitro or after oral ingestion at doses that suppressed aggregation induced by arachidonic acid alone, failed to reduce significantly the synergized aggregation induced by Paf‐acether alone or combined with adrenaline. Twenty‐four hours after the oral ingestion of aspirin, when aggregation by arachidonic acid remained blocked, a slight inhibitory activity on the effect of Paf‐acether noted 4 h after aspirin, had ceased. This was probably accounted for by the synthesis of thromboxane A2 by newly formed platelets, since the in vitro addition of aspirin, or of the thromboxane/endoperoxide receptor inhibitor 13‐azaprostanoic acid caused the 24 h platelets to behave in a manner similar to platelets collected 4 h after aspirin.

The α2‐adrenoceptor inhibitor, yohimbine, blocked the direct effect of adrenaline as well as its synergism with Paf‐acether.

Since the synergistic effect of Paf‐acether and adrenaline was maintained when thrombin‐degranulated platelets were used, and aspirin remained ineffective against it, it is clear that the augmented platelet responsiveness is not accounted for by the platelet release reaction.

Paf‐acether and adrenaline act synergistically and stimulate platelets by cyclo‐oxygenase‐independent mechanisms, which may be relevant in human physiopathological conditions.
Effects of isoprenaline on the contraction‐relaxation cycle in the cat trachea
Authors: Ito Yushi , Itoh Takeo
Published: July 2012

Effects of isoprenaline (Isop) on the contractile properties of the smooth muscle cells of cat trachea were investigated using intact and chemically skinned muscle preparations and an isometric tension recording method.

In the intact muscle preparations, Isop 3 × 10−10 or 3 × 10−9m significantly suppressed the amplitude of tonic contractions evoked by acetylcholine (ACh) 10−7 m or 10−5 m, respectively.

Following treatment of the tissue with Ca2+ ‐free 2 mm EGTA‐containing solution after depletion of stored Ca2+ with caffeine, 2.5 mm Ca2+ was applied for 5 min (procedure 1), and subsequently 10 mm caffeine was applied in Ca2+‐free 2 mm EGTA containing solution. The object was to estimate the amount of stored Ca2+ during procedure 1 from the amplitude of the caffeine (10 mm)‐induced contraction (procedure 2).

Isop, applied during procedure 1, did not affect the amplitude of the caffeine‐induced contraction; however, when applied during procedure 2, this agent (10−8m) significantly suppressed the amplitude of the caffeine‐induced contraction to about 90% of the control value.

ACh (10−5m), applied during procedure 1, evoked phasic and tonic contractions. Isop (10−8m), applied simultaneously with ACh (10−5m), suppressed the amplitude of the ACh‐induced contraction yet increased the amplitude of contraction evoked by the subsequent application of caffeine 10 mm (procedure 2).

Effects of conditioning application of ACh (10−7 or 10−5m) on the caffeine‐induced contraction were observed in the presence or absence of Isop during procedure 2. When ACh 10−5m was used, subsequent application of caffeine 10 mm evoked no mechanical response, in control conditions. However, after the pretreatment of the tissue with Isop during procedure 2, the amplitude of the ACh (10−5m)‐induced contraction was not affected, yet the subsequent application of caffeine (10 mm) evoked minute but discrete contractions, indicating that Isop did enhance the sequestration of free Ca2+ into the storage sites.

In the saponin‐treated skinned muscles, the minimum concentration of Ca2+ required to produce contraction was 1 × 10−7m, and the maximum contraction was obtained with 1 × 10−5m Ca2+. Isop (10−6m) had no effect on the relationship between free‐Ca2+ and the amplitude of the contraction. However, simultaneous application of high concentrations of cyclic AMP (10−4m) and cyclic AMP‐dependent protein kinase (50 μg ml−1) significantly suppressed contractions evoked by 3 × 10−7 or 10−5m Ca2+.

These results indicate that Isop suppresses the contraction evoked by various agonists in the cat trachea, mainly through sequestration of Ca2+ into the intracellular storage sites, rather than by direct or indirect (through cyclic AMP) actions on the contractile proteins.
Solubilization of dopamine‐D2receptors from synaptosomal membranes of the bovine caudate nucleus
Authors: Kidrič Marjetka , Petrović Jelena , Šoškić V. , Trajković Divna
Published: July 2012

Dopamine D2‐receptors were solubilized from synaptosomal membranes of the bovine caudate nucleus using different detergents. They were labelled with [3H]‐spiperone and assayed by polyethylene glycol precipitation.

CHAPS was found to be the best solubilizing agent among all detergents used. Optimal conditions for solubilization were: 0.25% CHAPS, 3.5 mg ml−1 protein, 25 min, 4 °C and the yield of D2‐receptors was 18.6%.

Addition of some sulphobetain detergents increased the extent of solubilization, 125 mm NaCl and 0.25 m sucrose decreased it, while SH‐group protecting agents (2 mm dithiothreitol and 6 mm β‐mercaptoethanol), as well as MEGA‐9 and MEGA‐12 were almost ineffective.

—log IC50 values for solublized dopamine D2‐receptors are in linear correlation with the corresponding values for membrane‐bound receptors (r = 0.962, slope factor 0.96) and Kd value of solubilized receptors was 3.61 ± 0.94 nm, while that of membrane‐bound receptors was 1.25±0.10 nm.

Specific binding of [3H]‐spiperone to the solubilized receptors resolved by linear sucrose density gradient centrifugation shows two maxima, one in the first several fractions from the bottom and the other with an apparent 5 value of 7.3.
The antagonism of histamine‐induced tracheal and bronchial muscle contraction by diphenhydramine: effect of maturation
Authors: Douglas James S. , Duncan Pamela G. , Mukhopadhyay Asoke
Published: July 2012

Airway reactivity in spontaneously breathing unanaesthetized female guinea‐pigs was significantly reduced as a consequence of maturation. Threshold doses to histamine (% w/v base) were 0.08% ± .01 and 0.27% ± .04 in immature (110g ± 2; 1 week old) and mature (837 g ± 29; 4 months old) animals, respectively.

The potency of 2‐(2‐thiazolyl) ethylamine in tracheal tissues from mature animals was significantly less than that in tissues from immature animals (5.06 ± .03 vs 5.26 ± .07). There was no change in the potency of this agonist in bronchial tissues (5.0 ± .09 vs 4.9 ± .13).

Diphenhydramine reduced tissue contractility in tracheal (30% at 0.1 μm; 50% at 3 μm) but not bronchial tissues. The antihistamine in concentrations ranging from 0.1 μm to 3 μm reduced the potency of histamine 2 to 50 fold in both tissues.

Schild plots were linear but slopes were significantly less than unity. pA2 values ± 95% fiducial limits derived from data from tracheal tissues of immature and mature animals using constrained Schild plots (unit slope) were 7.7 (7.6−7.7) and 7.1 (7.0−7.2), respectively (P<0.05). pA2 values for diphenhydramine in bronchial tissues using constrained Schild plots were 7.8 (7.7−7.9) and 7.5 (7.3−7.5), respectively (P<0.05).

The data emphasize the unique nature of tracheal and bronchial tissues. We conclude that, with maturation, the characteristics of the histamine receptor change. We suggest that the remission of asthma which frequently occurs at puberty may be related to alteration in the properties of membrane receptors.
Selectivity and potency of 2‐alkyl analogues of the α2‐adrenoceptor antagonist idazoxan (RX 781094) in peripheral systems
Authors: Doxey J.C. , Roach A.G. , Strachan Diane A. , Virdee Narinder K.
Published: July 2012

The profiles of four analogues of idazoxan have been examined at α‐adrenoceptors and the results compared to those obtained with idazoxan and yohimbine. The compounds possessed either a methyl (RX 801079), ethyl (RX 811033), n‐propyl (RX 811054) or isopropenyl (RX 811005) group at the two position of idazoxan.

The rank order of antagonist potency against UK‐14,304 at prejunctional α2‐adrenoceptors of the rat isolated vas deferens was RX 811054 > RX 811033 > idazoxan > RX 811005 > yohimbine = RX 801079. All compounds were competitive antagonists.

The rank order of antagonist potency against noradrenaline at postjunctional α1‐adrenoceptors of the rat isolated anococcygeus muscle was RX 811054 = RX 811033 = idazoxan = yohimbine > RX 811005 = RX801079. All compounds were competitive antagonists. The rank order of α‐adrenoceptor selectivity (α2/α1) was RX 811005 > RX 801079 > RX 811054 > RX811033 > idazoxan > yohimbine.

In pithed rats, intravenous administration of all compounds fully reversed the prejunctional α2‐adrenoceptor agonist effects of clonidine and guanabenz on electrically‐induced contractions of the vas deferens and anococcygeus muscle respectively.

In pithed rats the rank order of antagonist potency against UK‐14,304 at cardiac prejunctional α2‐adrenoceptors was RX 811054 > RX811033 > idazoxan > yohimbine > RX811005 > RX 801079. In contrast, the rank order of antagonist potency against cirazoline pressor effects (vascular postjunctional α1‐adrenoceptors) was RX 811054 > RX 811033 > yohimbine > idazoxan > RX 811005 > RX 801079. The rank order of α2‐adrenoceptor selectivity was RX 811033 = RX 801079 = RX 801005 > RX 811054 > idazoxan > yohimbine.

Although idazoxan produced contractions of the anococcygeus muscle and increased blood pressure in pithed rats, three of the analogues (RX 811005, RX 801079 and RX 811033) were inactive.

In conclusion, alkyl substitution in the 2‐position of idazoxan can enhance either α2‐adrenoceptor antagonist potency or selectivity or both and furthermore, the weak partial α1‐adrenoceptor agonist properties of idazoxan can be removed.
The endothelium‐dependent relaxation of rabbit aorta: effects of antioxidants and hydroxylated eicosatetraenoic acids
Authors: Förstermann U. , Neufang B.
Published: July 2012

Acetylcholine (ACh) induced concentration‐dependent relaxations of rabbit aortic strips precontracted with noradrenaline. The relaxations were abolished if the endothelium of the strips was disrupted. Three different antioxidants (butylated hydroxytoluene, dithiothreitol and α‐tocopherol) reversed the endothelium‐dependent vasodilatation in a concentration‐dependent manner. However, the antioxidant ascorbic acid did not alter the vasodilatation. The hydroxylated eicosatetraenoic acids 5‐HETE, 12‐HETE, 15‐HETE and 5,12‐diHETE had no effect on aortic strips under basal or induced tension. These results suggest, that (non‐cyclo‐oxygenase) oxidation processes, insensitive to the action of ascorbic acid, represent a crucial step in the endothelium‐dependent dilatation of rabbit aorta by ACh. The hydroxylated fatty acids tested are unlikely to mediate this relaxation.
Role of metabolism in the immediate effects and pneumotoxicity of 3‐methylindole in goats
Authors: Breeze R.G. , Laegreid W.W. , Olcott B.M.
Published: July 2012

Rapid infusion of 3‐methylindole (3‐MI) dissolved in 10% Cremophor EL in water was immediately followed by pulmonary arterial hypertension, systemic arterial hypotension, decreased minute volume and periods of apnoea in goats.

Rapid intravenous infusion of Cremophor EL/water alone caused similar immediate effects to those of Cremophor EL plus 3‐MI in various dosages.

Pretreatment of goats with piperonyl butoxide or phenobarbitone did not significantly alter these immediate cardiopulmonary responses. But pretreatment with piperonyl butoxide prevented clinical signs and pulmonary lesions of 3‐MI toxicity, whereas phenobarbitone pretreatment shortened survival time and enhanced pulmonary pathology.

Cremophor EL and 3‐MI dissolved in Cremophor EL caused severe in vitro haemolysis of caprine and bovine erythrocytes.

There was no relationship between the immediate effects of 3‐MI and the subsequent development of 3‐MI‐induced pneumotoxicity and deaths in control goats or in goats pretreated with piperonyl butoxide or phenobarbitone. Induction or inhibition of mixed function oxidase activity had no influence on immediate responses to 3‐MI but did change the severity of clinical and pathological responses.

It is concluded that there is no apparent relationship between the immediate and the pneumotoxic effects of 3‐MI. It is possible that the immediate effects are the result of intravascular haemolysis.
Effect of chemical destruction of adrenergic neurones on some cholinergic mechanisms in adult rat sympathetic ganglia
Authors: Collier B. , Johnson G. , Quik M. , Welner S.
Published: July 2012

Rats were treated for 2–6 weeks with guanethidine after which their superior cervical ganglia were removed.

Ganglionic tyrosine hydroxylase and α‐bungarotoxin binding sites were reduced by the guanethidine treatment indicating adrenergic cell body destruction.

Choline acetyltransferase activity and acetylcholine content of ganglia were not clearly changed by the guanethidine treatment, indicating that the drug does not destroy presynaptic terminals and that these presynaptic indicators do not adapt markedly to postsynaptic loss.

The Cholinesterase in the ganglia was reduced by guanethidine treatment, but such ganglia retained their ability to accumulate surplus acetylcholine when they were incubated with physostigmine. This is interpreted as indicating surplus acetylcholine accumulation is a presynaptic phenomenon.

Choline uptake by resting ganglia was not reduced as a result of guanethidine treatment nor was it affected by preganglionic denervation. This is interpreted as indicating that during rest, choline uptake is into supporting cells or intraganglionic cells rather than cholinergic nerve terminals or adrenergic cell bodies.
A pharmacological study of oesophageal muscularis mucosae from the cat, dog and American opossum (Didelphis virginiana)
Authors: Christensen J. , Percy W. H.
Published: July 2012

Strips of muscularis mucosae from the oesophagi of cat, dog and opossum have been studied to determine their responses to drugs and to electrical field stimulation.

All tissues were contracted by acetylcholine, histamine and, with the exception of strips of muscularis mucosae from the opossum proximal oesophagus, noradrenaline. The effects of acetylcholine and histamine were competitively antagonized by atropine (50 nM) and mepyramine (50 nM) and were abolished by atropine (1 μM) and mepyramine (1 μM) respectively. Contractile responses to noradrenaline were competitively antagonized by phentolamine (50 nM) but were converted to propranolol (50 nM)‐sensitive relaxations by phentolamine (1 μM). Relaxations were abolished by propranolol (1 μM).

Cholecystokinin octapeptide, gastrin 1 and vasoactive intestinal polypeptide were ineffective on any of the tissues examined. Substance P caused contractions in tissue from all three species. These effects were atropine and tetrodotoxin insensitive.

All tissues gave atropine (50 nM)‐ and tetrodotoxin (100 nM)‐sensitive contractions in response to electrical field stimulation. Contractions were not followed by relaxations and spontaneous mechanical activity was not suppressed between periods of stimulation. No evidence was obtained for the presence of non‐adrenergic, non‐cholinergic inhibitory innervation of the oesophageal muscularis mucosae in any species.

During electrical field stimulation noradrenaline always reduced the amplitude of evoked contractions and, with the exception of tissue from proximal opossum oesophagus, increased resting tension.

In opossum distal oesophageal muscularis mucosae, the effects of noradrenaline during electrical field stimulation were abolished by a 30 min pretreatment of the tissue with phentolamine (1 μM) and propranolol (1 μM). To achieve this in all other tissues, it was also necessary to use yohimbine (1 μM).

In all tissues where noradrenaline caused a phentolamine (1 μM)‐and propranolol (1 μM)‐resistant depression of electrically evoked responses, clonidine produced a yohimbine (1 μM)‐sensitive depression.

Evidence was obtained for the presence of excitatory α1‐and inhibitory α2‐ and β‐adrenoceptors. Inter‐species differences in their distribution are discussed.
Inhibition of vasoconstriction by frusemide in the rat
Authors: Gerkens John F. , Smith Anthony J.
Published: July 2012

Mesenteric blood flow was measured in anaesthetized rats with a non‐cannulating electromagnetic flow probe around the superior mesenteric artery. Reductions in blood flow were produced by intravenous bolus injections of angiotensin II (1–300ng) and noradrenaline (3–300ng) before and after the administration of frusemide (5 mg kg−1, i.v.). Loss of volume after frusemide was prevented by either a urinary bladder‐intravenous shunt or replacement of urinary output by intravenous saline.

Frusemide administration caused a small increase in baseline blood pressure of 3.2 ± 1.3 mmHg (P<0.05) but did not change mesenteric blood flow. This dose of frusemide inhibited the vasoconstrictor responses to both angiotensin II and noradrenaline (P<0.01, two way analysis of variance). Responses to angiotensin II were inhibited to a greater extent.

Acute bilateral nephrectomy or treatment with indomethacin (2 mg kg−1, i.v.) completely prevented the inhibitory effect of frusemide on the responses to angiotensin II and noradrenaline.

To test whether frusemide‐induced increased endogenous levels of angiotensin II may be responsible for the effects of frusemide on the vasoconstrictor responses, a separate group of rats were not given frusemide but were infused with exogenous angiotensin II (12.5–25 ng kg−1 min−1). This produced a small increase in mean blood pressure (4.0± 1.4 mmHg, P<0.05) but did not change baseline mesenteric blood flow. Unlike frusemide, the responses to bolus injections of angiotensin II and noradrenaline were not changed by the infusion of angiotensin II.

It is suggested that frusemide may release directly or indirectly a prostanoid from the kidney (or a substance from the kidney which leads to the formation of a prostanoid) which inhibits constrictor responses in the peripheral vasculature.
Biological evaluation of substance P antagonists
Authors: Folkers K. , Håkanson R. , Hörig J. , Jie‐Cheng Xu , Leander S.
Published: July 2012

Five undeca‐ and six C‐terminal heptapeptide substance P (SP) analogues were tested for their capacity to block the contractile effect of SP on the guinea‐pig isolated taenia coli. They had one feature in common, namely substitutions in positions 7 and 9 in the SP molecule. In the majority of analogues D‐tryptophan was used for these substitutions.

All analogues tested were found to be competitive antagonists to exogenous SP and to be capable of blocking the electrically induced non‐cholinergic, non‐adrenergic neuronal contraction of the taenia.

Of the undecapeptides, (D‐Arg1, D‐Pro2, D‐Trp7,9, Leu11) SP and (D‐Arg1, D‐Trp7,9, Leu11) SP (Spantide) had the highest pA2 value, 7.1–7.2, and the lowest IC50 value, 10−6 M. The pA2 values of the heptapeptides were generally lower.

Three of the most potent antagonists were tested for specificity and found to block the smooth muscle contraction induced by SP, physalaemin, eledoisin and bombesin but not that induced by bradykinin, carbachol, 5‐hydroxytryptamine, histamine, prostaglandins and vasopressin.

The SP antagonists were also tested for spasmogenic effect on the taenia and for their capacity to release histamine from rat isolated peritoneal mast cells. The spasmogenic activity displayed by most of the SP antagonists tested is likely to be related to their ability to release histamine since the contractile response was reduced by mepyramine, a histamine H1‐receptor antagonist.

(D‐Arg1, D‐Trp7, 9, Leu11) SP was notable for combining a high antagonistic potency with a weak spasmogenic effect (and poor histamine releasing effect).
Purinoceptor mediated stimulation of prostacyclin release in the porcine pulmonary vasculature
Authors: Hellewell Paul G. , Pearson Jeremy D.
Published: July 2012

Prostacyclin (PGI2) release from the piglet isolated perfused lung was measured by radioimmunoassay of 6‐keto‐PGF1α in the venous effluent.

Basal release of PGI2 was transiently stimulated up to 30 fold, in a dose‐dependent manner, by bolus injections of ATP (0.03–3 μmol). A continuous infusion of ATP also produced a transient response.

Dose‐response curves for purinergic stimulation of PGI2 release showed that ADP was equipotent with ATP, while AMP and adenosine were virtually inactive.

The non‐hydrolyzable ATP analogue, ATP‐γ‐S, elicited PGI2 release of similar magnitude and duration to that of ATP, suggesting that pulmonary catabolism of ATP is not required to induce PGI2 release.

The results suggest that the porcine pulmonary vasculature possesses P2‐purinoceptors through which the synthesis and release of PGI2 can be mediated.
Pro‐ and anti‐convulsant properties of PK 11195, a ligand for benzodiazepine binding sites: development of tolerance
Authors: File Sandra E.
Published: July 2012

Ro 5–4864 is a benzodiazepine that differs from diazepam only in a p‐chloro substituent and yet is inactive at the classical CNS binding sites. However it is a potent ligand for the peripheral type of benzodiazepine binding sites. PK 11195 is an isoquinoline carboxamide derivative that potently displaces [3H]‐Ro 5–4864 from its binding sites.

PK 11195 (30–60 mg kg−1) significantly reduced the incidence of convulsions caused by Ro 5–4864 (30 mg kg−1). PK 11195 (up to 120 mg kg−1) was ineffective at counteracting seizures caused by the convulsant benzodiazepine Ro 5–3663, although this dose did increase the latency to seize after injection with pentylenetetrazole. PK 11195 had no anticonvulsant actions against picrotoxin, and at 60 mg kg−1 reduced the latency to seize. This possible proconvulsant property of the isoquinoline was further explored.

PK 11195 (30–90 mg kg−1) had proconvulsant actions when combined with subconvulsant doses of strychnine and picrotoxin, but had none when combined with pentylenetetrazole.

No significant tolerance developed to the anticonvulsant action of PK 11195 (30 mg kg−1) even after 25 days of dosing daily. In contrast, there was rapid tolerance (within 5 days) to the proconvulsant action of PK 11195 (60 mg kg−1) with picrotoxin (3 mg kg−1).

There was no cross‐tolerance between the anticonvulsant actions of diazepam and PK 11195, which suggests that these two drugs act at different sites, as would be predicted from the results of the binding studies.

The possible sites of action and clinical relevance of these effects are discussed.
Evidence for the lack of interaction between (±)‐ 1‐O‐octadecyl‐2‐acetylglyceryl‐3‐phosphorylcholine and α‐adrenoceptors in vivo and in vitro
Authors: Cervoni P. , Goldstein B.M. , Herzlinger H. , Lai F.M. , Quirk G.J.
Published: July 2012

The interactions of (±)‐1‐O‐octadecyl‐2‐acetylglyceryl‐3‐phosphorylcholine (octadecyl‐AGPC) with α‐adrenoceptors were studied in rat mesenteric artery, cat nictitating membrane and on the blood pressure of the cat and spontaneously hypertensive (SH) rat.

Using a direct radioligand α‐adrenoceptor binding assay in particulate fractions of rat mesenteric arteries, octadecyl‐AGPC was found to be 5 × 107 and 75 times less potent than prazosin and noradrenaline (NA), respectively, in displacing (2,6‐dimethoxyphenoxyethyl)‐aminomethyl‐1,4‐benzodioxane ([3H]‐WB 4101 — a selective probe for the identification of α‐adrenoceptors).

In the cat, intravenous infusions of octadecyl‐AGPC, which produce a hypotensive response, did not attenuate nictitating membrane contractions in vivo in response to intravenous injections of NA, adrenaline (Ad) or to electrical stimulation of the postganglionic fibres of the superior cervical ganglion. In these experiments, the pressor responses to NA or Ad were not affected by octadecyl‐AGPC. Phentolamine, on the other hand, attenuated nictitating membrane contractions and blood pressure responses to Ad or NA.

In the SH rat, octadecyl‐AGPC decreased mean arterial blood pressure (MABP). After an intravenous dose of phentolamine which lowered MABP, the depressor response to octadecyl‐AGPC was reduced. When MABP in the phentolamine‐treated SH rat was restored to its initial level with an infusion of angiotensin II (AII), the depressor response to octadecyl‐AGPC was restored to its original magnitude. The effectiveness of α‐adrenoceptor blockade under these experimental conditions was monitored with intravenous NA and Ad.

Thus, based on radioligand binding studies and pharmacological studies, it is concluded that octadecyl‐AGPC lacks the ability to interact with α‐adrenoceptors.
Negative inotropic effect of somatostatin in guinea‐pig atrial fibres
Authors: Diez J. , Tamargo J. , Valenzuela C.
Published: July 2012

The effect of somatostatin (SS, 1 × 10−7M‐5 × 10−6 M) was studied on the electrical and mechanical properties of isolated atria of the guinea‐pig.

On spontaneously beating right atria, SS produced a dose‐dependent negative inotropic effect which was accompanied by a decrease in atrial rate and a prolongation of the sinus node recovery time.

In electrically driven left atria, SS produced a dose‐dependent negative inotropic effect which occurred concomitantly with a decrease in the amplitude and duration of the plateau phase of the action potential of atrial fibres.

SS also decreased the amplitude and maximum rate of depolarization of the slow action potential as well as the amplitude of the slow contractions induced by isoprenaline and caffeine in K‐depolarized atrial fibres.

The negative inotropic effect of SS varied with the concentration of Ca and Na in the bathing media and the frequency of stimulation.

SS, 1 × 10−6 M and 5 × 10−6 M, decreased 45Ca uptake in electrically driven atria.

All these results suggest that the negative inotropic effect produced by SS on rat isolated atria is related to its ability to reduce Ca influx via the slow inward Ca current.
Evidence for an A2‐subtype adenosine receptor on pancreatic glucagon secreting cells
Authors: Chapal J. , Loubatières‐Mariani M.M. , Petit P. , Roye M.
Published: July 2012

The effects of a 5′‐substituted analogue of adenosine, 5′‐N‐ethylcarboxamidoadenosine (NECA) have been studied on glucagon secretion in vitro, using the isolated pancreas of the rat perfused in the presence of glucose (2.8 mM).

NECA provoked a peak of glucagon secretion, the kinetics of which were comparable to those previously obtained with adenosine. The effect was concentration‐dependent and appeared at nanomolar concentrations. The EC50 was approximately 4 × 10−8 M.

A comparison of relative potency between adenosine and NECA showed that NECA was about 800 fold more potent than adenosine in inducing glucagon secretion.

Theophylline (50 μM) considerably decreased the peak of glucagon secretion induced by 1.65 μM NECA and totally suppressed the effect of 16.5 nM NECA. These results indicate the involvement of an adenosine receptor.

These and other previous results (low stereoselectivity of N6‐phenylisopropyladenosine) provide evidence for an adenosine receptor of the A2‐subtype being involved in glucagon secretion.
The effects of methyl β‐carboline‐3‐carboxylate on social interaction and locomotor activity when microinjected into the nucleus raphé dorsalis of the rat
Authors: Hindley S.W. , Hobbs A. , Paterson I.A. , Roberts M.H.T.
Published: July 2012

Intraperitoneal and intracerebral injections of methyl β‐carboline‐3‐carboxylate (βCCM) and intracerebral injections of RO 15–1788 were given to rats. The performance of the rats in the social interaction test was measured to determine if changes in social interaction induced by βCCM were mediated in part by the nucleus raphé dorsalis (NRD).

Intraperitoneal injections of βCCM, 2 and 4 mg kg−1, reduced social interaction.

Intracerebral microinjections of βCCM (10‐0.1 ng in 0.5 μl) into the NRD reduced social interaction. Injections outside the NRD did not have this effect.

Intracerebral microinjections of RO 15–1788 (1 ng in 0.5 μl) into the NRD had no effect when given alone, but blocked the reduction in social interaction caused by intracerebral or intraperitoneal injections of βCCM.

No effect was observed when R 15–1788 was microinjected into sites outside the NRD.

Changes in social interaction may reflect changes in anxiety. The NRD may be one of the important sites for the expression of the anxiogenic actions of βCCM.
Dopexamine: a novel agonist at peripheral dopamine receptors and β2‐adrenoceptors
Authors: Brown R.A. , Dixon J. , Farmer J.B. , Hall Janet C. , Humphries R.G. , Ince F. , O'Connor S.E. , Simpson W.T. , Smith G.W.
Published: July 2012

Dopexamine is an agonist at peripheral dopamine receptors and at β2‐adrenoceptors.

Dopexamine has approximately one‐third the potency of dopamine in stimulating the vascular DA1‐receptor in the dog, resulting in a fall in renal vascular resistance of 20% at 2.3 × 10−8 mol kg−1 (i.a.).

Prejunctional DA2‐receptors are also stimulated by dopexamine, resulting in a reduction of neurogenic vasoconstriction in the rabbit isolated ear artery (IC50 of 1.15 × 10−6 M) and of neurogenic tachycardia in the cat (ID50 of 5.4 × 10−8 mol kg−1, i.v.), with a potency six and four times less respectively than that of dopamine.

By contrast, dopexamine is approximately 60 times more potent than dopamine as an agonist at the β2‐adrenoceptor of the guinea‐pig isolated tracheal chain, with an EC50 of 1.5 × 10−6 M.

Both dopexamine and dopamine are weak agonists at the guinea‐pig atrial β1‐adrenoceptor over the concentration range 10−7 to 10−4 M, but dopexamine has an intrinsic activity of only 0.16 relative to dopamine.

Dopexamine does not stimulate postjunctional α1 or α2‐adrenoceptors in the canine isolated saphenous vein, whereas dopamine is an agonist, approximately 120 times less potent than noradrenaline.

Unlike dopamine and salbutamol, dopexamine does not cause arrhythmias in the guinea‐pig isolated perfused heart at doses of up to 10−5 mol, which is a thousand times the minimum cardiostimulant dose.

The combination of agonist properties at peripheral dopamine receptors and at β2‐adrenoceptors, with little or no activity at α‐ and β1‐adrenoceptors gives dopexamine a novel pharmacological profile. This may confer advantages over dopamine in the treatment of acute heart failure.
The effects of dopexamine on the cardiovascular system of the dog
Authors: Brown R.A. , Farmer J.B. , Hall Janet C. , Humphries R.G. , O'Connor S.E. , Smith G.W.
Published: July 2012

The cardiovascular effects of dopexamine and dopamine were compared in the anaesthetized and conscious dog by the use of intravenous infusions over the dose range 3 × 10−9 − 10−7 mol kg−1 min−1.

In the anaesthetized dog, dopexamine produced a dose‐related fall in blood pressure due to peripheral vasodilatation and a small rise in heart rate and contractility. By contrast, dopamine did not significantly reduce blood pressure but produced a larger dose‐related increase in contractility. At the highest infusion rate (10−7 mol kg−1 min−1) blood pressure and heart rate were increased by dopamine.

Dopexamine dilated the renal and mesenteric vascular beds with a potency similar to that of dopamine. Femoral vascular responses produced by both agents were inconsistent but the highest infusion rate of dopamine did produce vasoconstriction.

With the aid of selective receptor antagonists (haloperidol, propranolol and bulbocapnine) the vasodepressor activity of dopexamine was shown to be mediated by stimulation of DA2‐, β‐ and DA1‐receptors. The cardiac stimulation and renal vasodilatation produced by both compounds were due to stimulation of β‐adrenoceptors and DA1‐receptors respectively.

In the conscious dog, intravenous infusion of dopexamine caused a dose‐related fall in blood pressure, renal vasodilatation and an increase in cardiac contractility and heart rate. Dopamine also increased cardiac contractility, and renal blood flow due to renal vasodilatation but without affecting heart rate. At the highest infusion rate, blood pressure was increased.

Dopexamine and dopamine produced a similar incidence of panting and repetitive licking at 3 × 10−8 mol kg−1 min−1 and emesis at 10−7 mol kg−1 min−1, due to stimulation of dopamine receptors in the chemoreceptor trigger zone.

Dopexamine produces a different cardiovascular profile from dopamine in the anaesthetized and conscious dog. Both compounds reduce renal vascular resistance, but in contrast to dopamine, dopexamine reduces afterload and produces only mild inotropic stimulation. These differences reflect contrasting activity at adrenoceptors.
Prolongation of inhibitory postsynaptic currents by pentobarbitone, halothane and ketamine in CA1 pyramidal cells in rat hippocampus
Authors: Gage Peter W. , Robertson Brian
Published: July 2012

Spontaneous inhibitory postsynaptic currents (i.p.s.cs) were recorded in voltage‐clamped CA1 neurones in rat hippocampal slices.

The exponential decay of i.p.s.cs was prolonged by concentrations of sodium pentobarbitone as low as 50 μM. With concentrations up to 100 μM, there was no change in the amplitude or rise time of the currents but current amplitude was depressed at 200 μM. The prolongation of currents increased with drug concentration within the range tested (50 to 200 μM).

Halothane, at concentrations from 1 to 5%, also increased the time constant of decay of i.p.s.cs. The effect increased with concentration and was fully reversible.

Ketamine, at a concentration of 0.5 mM, increased the time constant of decay of i.p.s.cs by 50 to 80% and the effect was reversible.

Ethanol (10–200 mM), nitrous oxide (75–80%), and caffeine (10 μM‐5 mM) had no detectable effect on the i.p.s.cs.

It is suggested that pentobarbitone, halothane and ketamine increase the time constant of decay of the i.p.s.cs by stabilizing the open state of channels activated by γ‐aminobutyric acid.