bluuebunny/crossref_metadata_2025 huggingface dataset:
Some effects of leukotriene D4 on the mechanical properties of the guinea‐pig basilar artery
Authors: Nishiye Eiichiro , Itoh Takeo , Kuriyama Hirosi
Published: July 2012

The effects of leukotriene D4 (LTD4) on the mechanical properties of smooth muscle cells from the guinea‐pig basilar artery were investigated in whole and chemically skinned muscle strips.

In strips with an intact endothelium, 5‐hydroxytryptamine (5‐HT; 10 μM), LTD4 and LTC4 (1 μM), STA2 (1 nm‐10nm) and high K+ (30 mm‐128mm) generated contractions. These comprised an initial phasic and subsequently generated tonic response with different amplitudes. Acetylcholine (ACh, 0.1–10 μm) inhibited and methylene blue (1–10 μm) enhanced the tonic component of these contractions in endothelium‐intact muscle strips. In endothelium‐denuded tissues, methylene blue had no effect on mechanical responses and ACh produced a further contraction in the presence of LTD4.

When the endothelium was removed, the amplitude of contractions induced by all tested stimulants markedly increased. In intact muscle strips, the order of potency for the production of a maximum response was; 128 mm K+ > STA2 > LTD4 = LTC4 = 5‐HT. Following removal of the endothelium; STA2 > 128 mm K+ > LTD4 = LTC4 ≤ 5‐HT.

In endothelium‐denuded strips, the selective LTD4 antagonists, ONO‐RS‐411 and FPL 55712 inhibited the LTD4‐induced contraction. In contrast, guanethidine, prazosin, yohimbine, atropine and mepyramine had no effect. Indomethacin and a thromboxane A2(TXA2) antagonist, ONO‐3708 also had no effect on LTD4‐induced contractions in endothelium‐denuded strips.

In endothelium‐denuded strips, nifedipine inhibited the tonic contraction induced by LTD4 but not the phasic component. In Ca2+‐free solution containing 2 mm EGTA, LTD4 produced only the phasic contractions.

In saponin‐treated chemically skinned muscle strips, LTD4 had no effect on either the pCa‐tension relationship or on the release of Ca2+ from intracellular stores. However, inositol 1,4,5‐trisphosphate released Ca2+ from the stores and 1,2‐diolein, an activator of protein kinase C, enhanced the contractions induced by 0.3 μmm Ca2+.

It was concluded that LTD4 acts on both the endothelium and on the smooth muscle cells of the guinea‐pig basilar artery. It stimulates the release of endothelium‐derived relaxing factor (EDRF) which tends to inhibit the LTD4‐induced contraction. It also interacts with receptors on the smooth muscle and produces a contraction as a result of an increase in both voltage‐dependent and receptor‐activated Ca2 influx and, in part, the release of Ca2 + from cellular storage sites.
Na/Ca exchange and tension development in vascular smooth muscle: effect of amiloride
Authors: Bova Sergio , Cargnelli Gabriella , Luciani Sisto
Published: July 2012

The potassium‐sparing diuretic, amiloride, has been shown to inhibit the Na/Ca exchange system in various preparations. The effects of this drug have been investigated on the contractions of guinea‐pig aortic strips elicited by reduction of external K, by addition of ouabain and by removal of external Na.

Amiloride (5 × 10−6 m‐5 × 10−4 m) inhibited the mechanical responses when it was added before giving the stimulus for contractions, but was not effective in relaxing the contracted strips. The drug shifted to the right the dose‐response curve for Ca in low K solution.

The calcium antagonist diltiazem had no effect on the ouabain‐, low K‐ and Na‐free‐induced contractions.

Amiloride decreased the rate of relaxation of aortic strips induced by removal of the low K solution.

The pattern of amiloride action on ouabain‐, low K‐ and Na‐free‐induced contractions suggests that the drug interferes with Ca influx. The effect of amiloride on the relaxation rate of low K‐ contracted aortic strips is consistent with an interference with Ca efflux.

It is suggested that amiloride prevents Ca fluxes through the Na/Ca exchange system of guinea‐pig aortic strips.
Studies on the effects of viprostol in isolated small blood vessels and thoracic aorta of the rat
Authors: Lai Fong M. , Tanikella Tarak , Cobuzzi Agnes , Cervoni Peter
Published: July 2012

The effects of viprostol, prostaglandin E2 (PGE2) and nitroglycerin were studied in basilar artery, small mesenteric artery and the vein parallel to it as well as thoracic aorta of the rat.

In KCl‐contracted basilar artery, viprostol produced a concentration‐related biphasic response, contraction at concentrations < 3 × 10−6 m and relaxation at concentrations >3 × 10−6 m. PGE2 produced a concentration‐related contraction while nitroglycerin produced a concentration‐related relaxation.

In KCl‐contracted small mesenteric artery, viprostol produced a biphasic response which was similar to that in the basilar artery. PGE2 produced a contraction and nitroglycerin produced relaxation in a concentration‐dependent manner.

In KCl‐contracted small mesenteric vein, in contrast to basilar and mesenteric artery, viprostol produced only a concentration‐related relaxation in the range of 1 × 10−6 to 1 × 10−4 m. PGE2 produced a contraction and nitroglycerin produced a concentration‐related relaxation.

In KCl‐contracted thoracic aorta, PGE2 produced a biphasic response, relaxation at concentrations < 3 × 10−7 m and a concentration‐related contraction at concentrations > 3 × 10−7 m. Viprostol only produced a concentration‐related contraction at concentrations >1 × 10−6 m, which was significantly less in magnitude than the contraction produced by PGE2. Nitroglycerin produced a concentration‐related relaxation as seen in the small vessels.

In conclusion, the present data demonstrate that viprostol is a vasorelaxant agent which effectively dilates KCl‐contracted basilar, small mesenteric artery and vein, but not the thoracic aorta of rat. The potent antihypertensive action of viprostol is probably due to its relaxant effect on the small arteries and veins but not on the large conduit artery.
Modulation of cholinergic neurotransmission in guinea‐pig trachea by neuropeptide Y
Authors: Stretton C.D. , Barnes P.J.
Published: July 2012

Neuropeptide Y (NPY) is localized to adrenergic nerves in guinea‐pig airways but its function is not known.

NPY (1 × 10−10‐3 × 10−7 m) had no direct effect on guinea‐pig tracheal smooth muscle in vitro.

NPY produced a concentration‐ and frequency‐dependent inhibition of the cholinergic component of responses elicited by electrical field stimulation (EFS) whilst having no effect on the contractile response to exogenously applied acetylcholine (ACh).

Yohimbine was able to reverse significantly the inhibitory effect of noradrenaline on the cholinergic component to EFS without having any significant effect on the inhibition produced by NPY.

Neither blockade of β‐adrenoceptors by propranolol, nor depletion of adrenergic nerves by incubation with 6‐hydroxydopamine caused any significant alteration in the response to EFS in the presence of 3 × 10−7 m NPY. Bretylium tosylate incubation to prevent noradrenaline release produced a small but significant enhancement of the inhibitory effect of NPY on EFS at high frequencies.

NPY appears to reduce the cholinergic component to EFS via a prejunctional mechanism, acting directly on receptors on cholinergic nerve terminals, rather than affecting adrenergic mechanisms. NPY released by adrenergic nerves may modulate cholinergic neurotransmission in guinea‐pig airways.
Development of non‐cholinergic, non‐adrenergic excitatory and inhibitory responses to intramural nerve stimulation in rat stomach
Authors: Ito Shigeo , Kimura Atsuko , Ohga Akira
Published: July 2012

The onset and development of functional innervation of intramural neurones were examined by transmural nerve stimulation in circular muscle strips isolated from the rat stomach during the period from embryonic day (ED) 15 to 7‐days postnatal.

At ED 15, transmural stimulation elicited an atropine‐sensitive contraction in about half of the preparations. From ED 16, it caused a frequency‐dependent contraction in all preparations. Physostigmine significantly potentiated the amplitude of the nerve‐mediated contraction until ED 18.

Atropine inhibited but failed to abolish the contractile response to nerve stimulation in all preparations from ED 16.

During the contraction induced by carbamylcholine (CCh), transmural stimulation caused a biphasic response consisting of a contraction followed by a relaxation at ED 18 and ED 19, but caused a triphasic response consisting of a rapid relaxation followed by the biphasic response after birth.

CCh and substance P (SP) elicited contractions at ED 15 and vasoactive intestinal polypeptide (VIP) caused a relaxation at ED 16. The sensitivity to CCh and VIP increased with development but that to SP did not change.

The results suggest that functional intramural cholinergic and non‐cholinergic excitatory innervations in the rat stomach are established almost simultaneously by ED 16, and the onset of functional intramural non‐adrenergic inhibitory innervation lags about 2 days behind that of functional excitatory innervations.
Influence of epithelium on the responsiveness of guinea‐pig isolated trachea to adenosine
Authors: Advenier Charles , Devillier Philippe , Matran Régis , Naline Emmanuel
Published: July 2012

The influence of epithelium removal on the effects of adenosine on airway contractility was investigated on the guinea‐pig isolated trachea.

In preparations under resting tone or precontracted with histamine 10−5 m, removal of the tracheal epithelium resulted in similar shifts to the left of the adenosine concentration‐response curves (0.61 ± 0.18 (P < 0.05) and 0.80 ± 0.09 (P < 0.001) log units; n = 5), corresponding to 4.07 and 6.31 fold potentiations of the relaxant effect of adenosine.

In the presence of dipyridamole 10−5 M the relaxant effects of adenosine were potentiated 85.1 fold on tracheae with epithelium; removal of the epithelium did not produce a significant additional shift to the left of the adenosine concentration‐response curves (0.07 ± 0.03 log units; n = 5; NS).

In the absence of dipyridamole, the theophylline‐adenosine antagonism was not of the competitive type, irrespective of whether the tracheae were with or without epithelium.

In the presence of dipyridamole, this antagonism was likely to be of the competitive type and its characteristics were the same when the epithelium was present or absent. Regression slope and pA2 values were 0.84 and 5.07, respectively, in the presence of epithelium and 0.76 and 4.89, respectively, in its absence.

It is suggested that, at least in the guinea‐pig isolated trachea model, the airway epithelium seems to be involved only in the uptake and metabolism of adenosine.
Spasmogen action in guinea‐pig isolated trachealis: involvement of membrane K+‐channels and the consequences of K+‐channel blockade
Authors: Boyle J.P. , Davies J.M. , Foster R.W. , Good D.M. , Kennedy I. , Small R.C.
Published: July 2012

Acetylcholine (ACh), histamine, prostaglandin E2 and potassium chloride (KCl) each evoked concentration‐dependent spasm of guinea‐pig isolated trachealis treated with indomethacin (2.8 μm).

Neither tetraethylammonium (TEA; 0.1–10 mm) nor procaine (0.1–10 mm) potentiated these spasmogens. Indeed, procaine (10 mm) depressed the log concentration‐effect curves of all the spasmogens while TEA (1–10 mm) caused some depression of the log concentration‐effect curve of prostaglandin E2.

Intracellular electrophysiological recording was performed in trachealis bathed by normal Krebs solution or by Krebs solution containing 2.8 μm indomethacin. In either medium the majority of trachealis cells exhibited spontaneous electrical slow waves while some cells were electrically quiescent. In either medium the spasmogenic effects of ACh (1 mm) and histamine (0.2 mm) were accompanied by depolarization and abolition of slow wave discharge. In many cases the record of membrane potential subsequently exhibited noise which incorporated fast, hyperpolarizing transients.

In the absence and presence of indomethacin, TEA (10 mm) and procaine (5 mm) markedly reduced the membrane noise and hyperpolarizing transients evoked by ACh or histamine without augmenting the evoked tension.

It is concluded that slow wave discharge does not depend on prostaglandin synthesis. The membrane noise and hyperpolarizing transients evoked by ACh and histamine represent the opening of membrane K+‐channels. While such K+‐channel opening may offset spasmogen‐induced depolarization it does not moderate the evoked tension.
Effects of chronic oral administration of the antidepressants, desmethylimipramine and zimelidine on rat cortical GABAB binding sites: a comparison with 5‐HT2 binding site changes
Authors: Cross Jacqueline A. , Horton Roger W.
Published: July 2012

The effects of chronic oral administration of desmethylimipramine (DMI) or zimelidine (1.25 and 5 mg kg−1 twice daily for 21 days) were studied on rat whole cortical γ‐aminobutyric acidB (GABAB) binding sites. No changes in receptor affinity or number were found with either drug.

A subsequent study of GABAB binding sites using higher doses of these drugs (5 and 10 mg kg−1) and rat frontal cortex was also without effect, when investigated 24 h after termination of drug administration or 72 h after DMI administration (5 mg kg−1).

The number of frontal cortical 5‐hydroxytryptamine2 (5‐HT2) binding sites was significantly and dose‐dependently decreased after both drugs, whereas the number of hippocampal 5‐HT2 binding sites was not significantly altered after either drug.

As the number of frontal cortical GABAB binding sites was unaltered whereas the number of 5‐HT2 binding sites was significantly decreased under identical study conditions, it may be concluded that the effects of antidepressant administration upon GABAB binding sites is a less consistent observation than their effects on 5‐HT2 binding sites.
Phentolamine lacks α2‐adrenoceptor agonist activity in anaesthetized dogs
Authors: Bell C.
Published: July 2012

This study was performed in order to determine whether the blockade of sympathetic vasoconstriction in anaesthetized dogs by phentolamine is due to the antagonist action of the drug at postjunctional adrenoceptors, or is due to depression of neurotransmitter release by an agonist action at prejunctional adrenoceptors.

In dogs made areflexic by ganglion blockade with hexamethonium, phentolamine (0.5 mg i.a. or 0.5 mg kg−1 i.v.) elevated or did not affect femoral blood flow. By contrast, clonidine (0.5‐2.5 nmol, i.a.) produced femoral vasoconstriction, which was attenuated by prior administration of phentolamine.

Prior blockade of prejunctional α2‐adrenoceptors with yohimbine (30 μg kg−1, i.v.) did not reduce the blocking effect of phentolamine (0.5 mg kg−1, i.v.) on neurogenic vasoconstriction.

The results indicate that, in anaesthetized dogs, phentolamine lacks appreciable agonist activity at either prejunctional or postjunctional α2‐adrenoceptors. The blockade of neurogenic responses by phentolamine is therefore likely to be due to postjunctional adrenoceptor blockade.
Central inhibition by γ‐aminobutyric acid of the release of vasopressin by carbachol in the rat
Authors: Chowdrey H.S. , Bisset G.W.
Published: July 2012

γ‐Aminobutyric acid (GABA) inhibited the antidiuretic response and the increased urinary excretion of vasopressin produced by carbachol when both drugs were injected into a lateral cerebral ventricle (i.c.v.) in the water‐loaded rat under ethanol anaesthesia.

The inhibitory effect of GABA was mimicked by muscimol and 3‐amino‐1‐propane sulphonic acid (3‐APS) and blocked by bicuculline.

GABA injected i.v. or into the cisterna magna (i.cist.) did not inhibit the release of vasopressin by carbachol injected i.c.v.

The results suggest a role for GABA as a putative inhibitory transmitter in the hypothalamo‐neurohypophysial system, acting directly on the supraoptic or paraventricular nuclei in the anterior hypothalamus.
Long‐term regulation of synaptic acetylcholine release and nicotinic transmission: the role of cyclic AMP
Authors: Briggs Clark A. , McAfee Donald A. , McCaman Richard E.
Published: July 2012

Using the rat superior cervical ganglion in vitro, the relative efficacy of nicotinic synaptic transmission was estimated by recording the postganglionic compound action potential and the amount of endogenous acetylcholine (ACh) released. These two parameters were correlated in individual ganglia by sampling the bathing medium for the assay of ACh while simultaneously recording the postganglionic response.

The β‐adrenoceptor agonist isoprenaline potentiated both the evoked release of ACh and the postganglionic response by about 20% during preganglionic stimulation at 0.2 Hz.

The adenosine receptor agonist 2‐chloroadenosine inhibited ACh release and the postganglionic response by about 35%.

Tetanic preganglionic stimulation for a few seconds induced a long‐term potentiation of nicotinic responses and of ACh release. Both of these potentiations were dependent upon extracellular Ca2+ during the tetani.

Forskolin and analogues of cyclic AMP also caused a long‐lasting potentiation of both the evoked release of ACh and the postganglionic response, indicating that cyclic AMP may regulate transmission by a presynaptic mechanism. The specificity of the cyclic AMP analogues was tested using various butyryl‐ and bromo‐purine nucleotides.

The effects of forskolin and 8‐bromo‐cyclic AMP did not appear to be dependent upon extracellular Ca2+.

The potentiation caused by forskolin was consistently augmented by three phosphodiesterase inhibitors ‐ AH 21–132, papaverine and SQ 20‐006. However, the effect of forskolin was not consistently enhanced by theophylline, nor was it reduced by the adenylate cyclase inhibitor SQ 22–536.

The neurogenic long‐term potentiation was augmented by two of the phosphodiesterase inhibitors that also augmented the forskolin‐induced potentiation ‐ papaverine and SQ 20‐006.

It was concluded that cyclic AMP can enhance nicotinic transmission, and can do so by increasing the evoked release of ACh. However, it was not possible to prove that cyclic AMP mediates the long‐term potentiation induced by tetanic preganglionic stimulation.
Chronic prazosin attenuates the natriuretic response to a modest saline load in anaesthetized rats
Authors: Penner S. Brian , Smyth Donald D.
Published: July 2012

The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min−1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml−1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml−1 prazosin in 0.5% dextrose (high dose).

The selectivity of the prazosin for α1‐adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for α1‐adrenoceptors.

In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin.

The results indicate that chronic α1‐adrenoceptor blockade with prazosin attenuates the ability to excrete a saline load in a dose‐related manner. Whether this inability to excrete a saline load is analogous to the sodium and water retention observed with the clinical use of prazosin remains to be determined.
Effects of prolonged exposure to α,β‐methylene ATP on non‐adrenergic, non‐cholinergic excitatory transmission in the rectum of the chicken
Authors: Komori Seiichi , Kwon Seong‐Chun , Ohashi Hidenori
Published: July 2012

Effects of prolonged exposure to α,β‐methylene ATP (α,β‐Me ATP) on contractions and excitatory junction potentials (e.j.ps) evoked by non‐adrenergic, non‐cholinergic (NANC) excitatory nerve stimulation have been investigated in the chicken isolated rectum and longitudinal muscle strip from chicken rectum pretreated with atropine (0.5 μm), methysergide (2 μ m) and pyrilamine (3 μm).

α,β‐Me ATP (20 nm‐4 μm) caused a rapid rise in tension of the longitudinal muscle of the isolated rectum preparation which returned to the baseline levels after a few minutes. The magnitude of the contractile response to NANC nerve stimulation was reduced after exposure to the drug. The inhibitory effect was related to the drug concentration; at 4 μm the nerve‐mediated contraction was abolished and frequently converted to a relaxation.

Adenosine 5′‐triphosphate (ATP, 100 μm), bovine neurotensin (2.5 nm) and K+‐rich solutions (30 mm and 60 mm) all produced a transient contraction of the isolated rectum preparation. The exposure to α,β‐Me ATP (0.2 and 4 μm) also rendered the preparation less sensitive to these stimulant substances.

α,β‐Me ATP (0.2 and 4 μm caused a membrane depolarization in cells of the longitudinal muscle strip. The depolarization reached a peak within 2–3 min after application and then decayed to a steady level that was still more positive than the baseline level. The electrotonic potentials were reduced in amplitude to 44 ± 8% (n = 7) of the normal amplitude if measured at the peak depolarization produced with 0.2 μm α,β‐Me ATP, and to 62 ± 10% (n = 7) if measured at the steady‐state depolarization. With 4 μm, the corresponding percentages were 33 ± 7% (n = 8) and 55 ± 7% (n = 8), indicating a decrease in membrane resistance.

The e.j.ps in response to field stimulation of the intramural nerves and Remak's nerve stimulation were decreased in amplitude and duration during exposure to α,β‐Me ATP (0.2 and 4 μm).

The smooth muscle cells regained normal membrane resistance and sensitivity to ATP on washout of α,β‐Me ATP (4 μm) more rapidly than the responses to NANC nerve stimulation.

It can be argued from the results that the suppression by α,β‐Me ATP of the contraction and e.j.p. evoked by NANC nerve stimulation in the chicken rectum, unlike the mammalian preparations described previously, is due mainly to a change in the electrical properties of the membrane of the smooth muscle cells, rather than being due, or only partly due, to desensitization of the purine receptor.
Interference of the Paf antagonist Ro 19–3704 with Paf and antigen‐induced bronchoconstriction in the guinea‐pig
Authors: Lagente Vincent , Desquand Stéphanie , Hadvary Paul , Cirino Maria , Lellouch‐Tubiana Arielle , Lefort Jean , Vargaftig B. Boris
Published: July 2012

In vitro, Ro 19–3704, a structurally related antagonist of platelet‐activating factor (Paf) inhibited selectively rabbit platelet aggregation. In vivo, administered intravenously, it inhibited bronchoconstriction, leukopenia, thrombocytopenia and the accompanying accumulation of platelet aggregates in guinea‐pig lung microvessels induced by i.v. Paf. Administered by aerosol, Ro 19–3704 failed to inhibit bronchoconstriction, thrombocytopenia or leukopenia due to i.v. Paf.

Bronchoconstriction induced by Paf, in aerosol form, was blocked by Ro 19–3704 administered by the i.v. or aerosol route, which suggests that it interacts with pulmonary cells responsible for bronchoconstriction.

Ro 19–3704 has free radical scavenging properties, since it inhibited the production of superoxide anions by macrophages stimulated by Paf and by N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP). Ro 18–7715, another Paf antagonist and analogue of Ro 19–3704, failed to inhibit the production of superoxide anions by macrophages stimulated by FMLP at concentrations which were effective against Paf.

Administered intravenously, Ro 19–3704 failed to block bronchoconstriction induced by an i.v. injection of ovalbumin to guinea‐pigs passively sensitized with anti‐ovalbumin antiserum. Passive pulmonary anaphylaxis due to an aerosol of ovalbumin was blocked by i.v. Ro 19–3704.
Evidence for reduced β‐adrenoceptor coupling to adenylate cyclase in femoral arteries from spontaneously hypertensive rats
Authors: Asano Masahisa , Masuzawa Kaoru , Matsuda Tomohiro
Published: July 2012

Arterial relaxant responses via β‐adrenoceptors have been demonstrated to be decreased in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar‐Kyoto rats (WKY). To determine which process of the β‐adrenoceptor adenylate cyclase (AC) system is involved in the decreased responsiveness to β‐adrenoceptor stimulation, relaxant responses to forskolin and dibutyryl cyclic AMP (db cyclic AMP) were compared between strips of femoral and mesenteric arteries isolated from 13 week‐old SHR and age‐matched WKY.

The relaxant response to either forskolin, an activator of AC, or db cyclic AMP was not significantly different between the SHR and WKY, when the strips of both arteries from both strains were contracted with K+ to an equivalent magnitude (85% of the maximum).

Under the same conditions, however, the relaxant response to noradrenaline (NA) via β‐adrenoceptors was significantly decreased in the SHR arteries.

When the strips of femoral arteries were contracted with the same concentration of K+, there was a precontraction of greater magnitude in response to the K+ and a decreased relaxation in response to forskolin, db cyclic AMP or NA in the SHR. On the other hand, when the strips of mesenteric arteries were contracted with the same concentration of K+, the precontraction was smaller in magnitude and there was an increased relaxation in the SHR.

The relationship between the relaxant responses and the K+‐induced precontractions clearly showed that the ability of forskolin and NA to relax the K+‐contracted strips depends on the magnitude of precontraction. Therefore, a difference in magnitude of precontraction between the two groups may produce a meaningless difference.

The relaxant responses to forskolin and NA were significantly potentiated by the addition of isobutyl methylxanthine (IBMX), an inhibitor of cyclic AMP phosphodiesterase. Even in the presence of IBMX, relaxant responses to forskolin were the same for the two strains. The difference in the pD2 value for NA‐induced relaxation between the two strains was the same in the presence and absence of IBMX.

The relaxant effect of either nitroprusside or nifedipine, agents which are independent of this system, was not significantly different between the strips from SHR and WKY. These relaxations were not potentiated by IBMX.

From these results, it is concluded that the reduced β‐adrenoceptor coupling to AC is mainly involved in the decreased responsiveness to β‐adrenoceptor stimulation. Furthermore, for an accurate comparison to be made, it is necessary to minimize the influence of variations in the magnitude of precontraction on the relaxant responses.
On the adenosine receptor and adenosine inactivation at the rat diaphragm neuromuscular junction
Authors: Sebastião A.M. , Ribeiro J.A.
Published: July 2012

The effects of adenosine and adenosine analogues 2‐chloroadenosine (CADO), l‐N6‐phenylisopropyladenosine (l‐PIA), d‐N6‐phenylisopropyladenosine (d‐PIA), N6‐cyclohexyladenosine (CHA) and 5′‐N‐ethylcarboxamide adenosine (NECA) on evoked endplate potentials (e.p.ps) and on twitch tension were investigated in innervated diaphragms of the rat.

Adenosine and its analogues decreased, in a concentration‐dependent manner, the amplitude of both the e.p.ps and the twitch responses evoked by nerve stimulation. The order of potency in decreasing the twitch tension was CHA, l‐PIA, NECA > d‐PIA > CADO > adenosine. l‐PIA was about 8 times more potent than d‐PIA. Neither adenosine nor the adenosine analogues affected the twitch responses of directly stimulated tubocurarine‐paralysed muscles.

8‐Phenyltheophylline (8‐PT), theophylline and isobutylmethylxanthine (IBMX), in concentrations virtually devoid of effect on neuromuscular transmission, antagonized the inhibitory effect of 2‐chloroadenosine. The order of potency of the alkylxanthines as antagonists of the adenosine receptor at the rat diaphragm neuromuscular junction was 8‐PT > IBMX > theophylline. The antagonism by these xanthines was shown to be competitive, the pA2 value for 8‐PT being 7.16. In concentrations slightly higher than those used to test its ability to antagonize the adenosine receptor, IBMX and 8‐PT increased the amplitude of e.p.ps without modifying their decay phase or the resting membrane potential of the muscle fibre.

The adenosine uptake inhibitor, nitrobenzylthioinosine (NBI) and the adenosine deaminase inhibitor, erythro‐9(2‐hydroxy‐3‐nonyl)adenine (EHNA), in concentrations virtually devoid of effect on neuromuscular transmission, potentiated the inhibitory effect of adenosine at the rat diaphragm neuromuscular junction. The potentiation factors were about 2.6 for NBI (5 μm), 2.2 for EHNA (25 μm) and 4.6 for the combination of NBI (5 μm) and EHNA (25 μm).

It is concluded that both uptake and deamination contribute to the inactivation of adenosine at the rat diaphragm neuromuscular junction and that in this preparation the inhibitory effect of adenosine on transmission is mediated by a xanthine‐sensitive adenosine receptor with an agonist profile which does not fit the criteria for its classification either as an A1 or A2‐adenosine receptor.
Inhibition by chloride channel blockers of anion secretion in cultured epididymal epithelium and intact epididymis of rats
Authors: Wong P.Y.D.
Published: July 2012

Anion secretion by primary monolayer cultures of rat epididymal cells was studied by the short circuit current technique.

Monolayers had a transepithelial potential difference of 1.34 mV, apical side negative and a short circuit current of 2.45 μA cm−2. The transepithelial resistance was 504 Ω cm2.

Addition of anthracene‐9‐carboxylate (9‐AC) to the apical side caused a biphasic response, a decrease followed by an increase in the short circuit current (SCC) which then returned to the basal level. Addition of 9‐AC to the basolateral side also caused a biphasic response but the increase in current was sustained.

Addition of diphenylamine‐2‐carboxylate (DPC) and 5‐nitro‐2‐(3‐phenylpropylamino)‐benzoate (NPPB) caused an inhibition of the SCC when added to the apical or basolateral side.

When the epithelium was stimulated with adrenaline (0.23 μm, basolaterally), the SCC rose to a peak value of 10.36 μA cm−2 and then stabilized at 3.82 μA cm−2 after 15 min. Addition of 9‐AC to the apical side caused a triphasic response: a decrease, reversal to the original level followed by a slow inhibition which was sustained. The inhibition achieved at the steady state was concentration‐dependent with an apparent IC50 value of 2.51 mm. Addition of 9‐AC to the basolateral side produced a similar response but a time lag of 20 s was observed.

DPC and NPPB also caused the SCC to decrease when added to the apical side of the monolayers stimulated with adrenaline. The IC50 values were 0.148 mm and 0.049 mm for DPC and NPPB, respectively. Basolateral application also caused an inhibition but higher concentrations were required to inhibit 50% of the adrenaline stimulated SCC.

Serosal to mucosal flux of chloride was studied in intact epididymis luminally perfused in vivo. 9‐AC added to the luminal perfusion solution inhibited the C1 flux in a dose‐dependent manner with an IC50 value similar to that observed in cultured epithelium in vitro.

It is concluded that anion secretion by the epididymal cells may conform to models proposed for other Cl secreting epithelia and may involve anion diffusion across the apical channels which are blocked by Cl channel blockers.
Effect of a Paf antagonist, WEB 2086, on airway microvascular leakage in the guinea‐pig and platelet aggregation in man
Authors: Evans Timothy W. , Dent Gordon , Rogers Duncan F. , Aursudkij Boonrut , Chung K. Fan , Barnes Peter J.
Published: July 2012

The triazolodiazepine WEB 2086 has been evaluated as an antagonist of platelet‐activating factor (Paf) by studying its effects on Paf‐induced human platelet aggregation and microvascular leakage in guinea‐pigs.

WEB 2086 inhibited Paf‐induced platelet aggregation in platelet‐rich plasma in vitro (IC50 = 117 ± 35 nm, mean ± s.d.) but had no effect on adenosine 3′,5′‐diphosphate‐induced aggregation.

Paf‐induced microvascular leakage, measured by the extravasation of intravenously‐injected Evans blue dye, was inhibited in a dose‐related fashion in the airways and other tissues by WEB 2086, achieving a maximal inhibitory effect at 10 μg kg−1, i.v.

However, WEB 2086 (10 μg kg−1, i.v.) did not inhibit a comparable increase in vascular permeability induced by ovalbumin in sensitized guinea‐pigs.

We conclude that WEB 2086 is a potent antagonist of Paf and that Paf does not appear to be responsible for antigen‐induced microvascular leakage.
Opiates distinguish spinal excitation from inhibition evoked by noxious heat stimuli in the rat: relevance to theories of analgesia
Authors: Harris N.C. , Ryall R.W.
Published: July 2012

Experiments were performed to test the hypothesis that a significant part of the action of opiates in reducing responses to noxious stimuli is a reduction in the release of neurotransmitter from primary afferent fibres.

The effects of locally and systemically administered opiates were examined on the excitatory and γ‐aminobutyric acid (GABA)‐mediated inhibitory responses of spinal dorsal horn neurones to noxious heat stimulation in the anaesthetized rat: the inhibitions are thought to involve the same C‐fibre afferents as the excitation.

Microionophoretically administered morphine reduced the excitatory response in a small proportion of the cells, reduced the background firing in a larger proportion but was ineffective on the inhibition.

Intravenously injected morphine (0.5–6 mg kg−1) or etorphine (0.1–2 μg kg−1) invariably attenuated the excitation of dorsal horn neurones by noxious stimuli but had no effect on the inhibition.

It was concluded that the data do not support the hypothesis that the production of analgesia is due mainly to a reduction in the release of transmitter from primary afferent fibres.
Effects of the muscarinic antagonists pirenzepine and gallamine on spontaneous and evoked responses of rat cerebral cortical neurones
Authors: Swanson Thomas H. , Phillis John W.
Published: July 2012

The muscarinic receptor antagonists gallamine and pirenzepine were iontophoretically applied to rat cerebral cortical cholinoceptive neurones, including corticospinal neurones, to assess their effects on spontaneous firing, and firing induced by: stimulation of the nucleus basalis magnocellularis (NBM); contralateral hindpaw stimulation; application of acetylcholine (ACh); and application of glutamate.

Both compounds potently inhibited firing induced by ACh iontophoresis, whilst neither compound consistently altered firing induced by application of glutamate.

Gallamine was very effective and pirenzepine less effective, at inhibiting both spontaneous firing and the delayed firing induced by NBM stimulation. The short‐latency excitations elicited by NBM stimulation were enhanced by these muscarinic antagonists.

Gallamine and pirenzepine enhanced cortical cholinoceptive cell firing induced by contralateral hindpaw stimulation.

It is concluded that gallamine depresses spontaneous activity more than pirenzepine, and that both compounds can affect the cortical cell firing evoked by stimulation of the NBM and of thalamo‐cortical afferent fibres.
Prejunctional muscarinic (M1)‐receptor interactions on guinea‐pig ileum: lack of effect of cisapride
Authors: Schuurkes J.A.J. , Van Bergen P.J.E. , Van Nueten J.M.
Published: July 2012

Cisapride stimulates gastrointestinal motility, probably by enhancing the release of acetylcholine from myenteric nerve endings. Such an effect could be mediated via presynaptic muscarinic (M1)‐receptors. Our aim was to determine whether cisapride could antagonize the inhibitory effects of a M1‐agonist, McN‐A‐343 or mimic the effects of a M1‐antagonist, pirenzepine.

Longitudinal segments were suspended in Krebs solution (95% O2, 5% CO2, 37.5°C) for isometric tension recording (preload 1 g) during electrical transmural stimulation (0.1 Hz, 1 ms, sub‐ or supramaximal current).

McN‐A‐343 (2.0 times 10−6 m) reduced the contractile response to supramaximal stimulation (EC50 = 1.6 × 10−6 m), but had no effect on the contractions induced by exogenous acetylcholine.

The inhibitory effect of McN‐A‐343 on the contractile response to electrical stimulation could be reversed by pirenzepine (EC50 = 1.6 × 10−8m) but not by atropine. At these concentrations pirenzepine itself did not modify the contractile response to electrical stimulation. However, at 50 times higher concentrations pirenzepine inhibited the response to electrical stimulation as well as the response to exogenous acetylcholine (EC50 = 8.5 × 10−7m).

Cisapride enhanced the contractile response to submaximal electrical stimulation by 49 ± 10%. This stimulating effect of cisapride was not affected by the presence of pirenzepine but was reduced in the presence of McN‐A‐343 (22 ± 7%).

In conclusion: the effects of McN‐A‐343 and pirenzepine on the electrically stimulated guinea‐pig ileum are compatible with an interaction on presynaptic muscarinic‐(M1)‐receptors. Cisapride enhances the twitch amplitude via mechanisms independent of such M1‐receptor interactions.
Inhibitory effect of 1,2,3,4‐tetrahydro‐9‐aminoacridine on the depolarization‐induced release of GABA from cerebral cortex
Authors: de Belleroche Jacqueline , Gardiner Ian M.
Published: July 2012

1,2,3,4‐Tetrahydro‐9‐aminoacridine (THA) has an inhibitory effect on the activity of acetylcholinesterase which has led to its use in the treatment of Alzheimer's disease. Other actions of THA include the inhibition of voltage‐dependent ion channels. In this paper we describe the effect of THA on the depolarization‐induced release of [14C]‐γ‐aminobutyric acid (GABA) from tissue slices of rat cerebral cortex. THA produced a dose‐dependent inhibition of the 30mM K+‐evoked release of [14C]‐GABA with an IC50 of 56 μm. The maximal response was an 84% inhibition of the evoked response. THA (up to a concentration of 1 mm) had no effect on the basal release of GABA. A similar inhibitory effect on the K+‐evoked release of [14C]‐GABA was seen with 4‐aminopyridine (4‐AP) but no inhibition was obtained with tetraethylammonium up to a concentration of 20 mM. The maximal inhibitory effect of 4‐AP (39%) occurred at 1mM (IC50 of 112 μm) and this response was much smaller in magnitude than that obtained with THA.
Different effects of bombesin on glucose‐ and tolbutamide‐induced insulin release in man
Authors: Scarpignato Carmelo , Gioffré Mara , Gulino Filippo Mario , Micali Biagio
Published: July 2012

The effect of bombesin, a neurograstrointestinal peptide, on basal and stimulated insulin release was studied in man.

Two different stimuli were used, hyperglycaemic (20 g glucose) and hypoglycaemic (1 g tolbutamide). They were injected intravenously to two groups of male healthy volunteers during saline or bombesin (5 ng kg−1 min−1 for 60 min) infusion.

The peptide had no significant effect on basal levels of glucose and insulin. However, the insulin response to intravenous glucose was strongly potentiated by bombesin, the integrated insulin response being 2.23 ± 0.59 mu ml−1 · 90 min and 0.98 ± 0.19 mu ml−1 · 90 min during infusion of bombesin and saline, respectively (P < 0.05). The behaviour of plasma glucose was not significantly modified by the peptide. Indeed, the glucose disappearance rate (K of Conard, mg min 10−2) changed from 2.5 ± 0.3 during saline to 2.4 ± 0.4 during bombesin infusion.

When the hypoglycaemic stimulus (i.e. tolbutamide) was used, no effect of the peptide on insulin release could be detected. Here again, the drop in plasma glucose (expressed as Marigo's coefficient) was not affected by the peptide, with a value of 92.8 ± 12.6 and 84.0 ± 10.9 during bombesin and saline administration.

These data therefore show that, at normal or low blood glucose levels, the dose of bombesin used is unable to modify insulin release and suggest that this peptide might be regarded as a glucose‐dependent insulinotropic peptide.
Effect of acute lung injury on metabolism of adenine nucleotides in rat perfused lung
Authors: Grantham C.J. , Bakhle Y.S.
Published: July 2012

The hydrolysis of adenosine di‐ and monophosphate (ADP, AMP) was studied in perfused lungs isolated from rats treated with α‐naphthylthiourea (ANTU) to induce acute lung injury. This injury is associated with damage to the endothelium, the locus of the ADP and AMP hydrolysing enzymes.

Treatment with ANTU did not change the proportion of [3H]‐ADP surviving a single passage through the pulmonary circulation, at any time up to 50 h after ANTU. Less than 8% and 2% respectively of 1 or 0.1 μmol ADP, given as a bolus, appeared in lung effluent.

The metabolites of ADP, AMP and adenosine in lung effluent were increased from 2 h after ANTU.

Metabolism of [3H]‐AMP as substrate was always low but, following ANTU treatment, the adenosine content of lung effluent increased four fold.

It appears that, in spite of considerable endothelial cell damage, as demonstrated by pulmonary oedema, the ectoenzymes catalysing ADP and AMP hydrolysis were relatively little affected by ANTU.
Effect of calcium and calmodulin antagonists on contractile responses of the human uterine artery
Authors: Kostrzewska A. , Laudanski T. , Batra S.
Published: July 2012

The dependence on extracellular calcium of contractile responses of intramyometrial arteries (0.5–2 mm diameter), as well as the effects of various types of calcium antagonists on these responses, were studied. Contractions were induced by K‐depolarization (K) and noradrenaline (NA).

Whereas the K response was completely abolished in a calcium‐free medium containing 2 mM LaCl3, the NA response was substantially maintained.

Nimodipine strongly inhibited the K response but had a relatively weak effect on the NA response; the IC50 values for the K and NA responses being 2 nM and 6 μm, respectively. Corresponding values for verapamil were about 0.7 and 10 μm.

Calmodulin antagonists, particularly trifluoperazine and flunarizine, caused a greater inhibition of the NA than of the K response.

These results indicate that besides the extracellular calcium which appears to be the major source of activator calcium, there is an intracellular pool of calcium which can be utilized to activate, albeit to a limited extent, drug‐induced contractile responses.
The competitive antagonistic effect of compounds from Mandevilla velutina on kinin‐induced contractions of rat uterus and guinea‐pig ileum in vitro
Authors: Calixto João B. , Pizzolatti Moacir G. , Yunes Rosendo A.
Published: July 2012

Pure non‐peptide compounds obtained in crystal form from the crude extract of the plant Mandevilla velutina (Apocynaceae) were analysed for their antagonistic effects on rat uterine and guinea‐pig smooth muscle contractions induced by bradykinin (Bk), lisyl‐bradykinin (L‐Bk), acetylcholine (ACh), oxytocin and histamine, in vitro.

Pre‐incubation of rat uterine muscle with compounds MV 8608, MV 8609, MV 8610, MV 8611 and MV 8612 (5 to 40 μg ml−1) caused parallel and concentration‐dependent rightward displacements of the Bk concentration‐response curves (1 to 1000 nm). Schild plots of these data were linear (correlation close to 1) and yielded nominal pA2 values (gml−1) of 5.7, 5.6, 5.4, 5.7 and 5.3, respectively. Compounds MV 8608, MV 8611 and MV 8612 (5 to 20 μg ml−1) also caused concentration‐dependent and parallel displacements to the right of the concentration‐response curve to L‐Bk (1 to 10,000 nm). The Schild plots were linear and furnished nominal pA2 values (g ml−1) of 5.4, 5.8 and 5.1, respectively. With the exception of the antagonist effect of compound MV 8606 against Bk‐induced contraction, all compounds behaved as simple competitive kinin antagonists since the calculated slopes were not different from unity.

In the guinea‐pig ileum, both MV 8608 and MV 8612 (5 to 20 μg ml−1), produced concentration‐dependent rightward displacements of the concentration‐response curve to Bk (0.1 to 1000 nm) when the experiments were performed in the presence but not in the absence of atropine (2.5 μm). However, in contrast to the result obtained in the rat uterus, compound MV 8608 also caused a significant reduction of the maximal response to Bk. The Schild plot for compound MV 8612 was linear (correlation close to unity) and furnished a nominal pA2 value (g ml−1) of 5.3 and a slope not different from unity.

In rat uterine muscle, compounds MV 8608 and MV 8612 at concentrations producing marked rightward displacements of the kinin concentration‐response curves (10 and 20 μg ml−1), did not influence the uterine contractile response to oxytocin or ACh, indicating some selectivity towards kinin receptors. Similarly, compound MV 8612 (10 and 20 μg ml−1) did not interfere with the sensitivities or the maximal responses to ACh and histamine in the guinea‐pig ileum, whereas compound MV 8608 (10 and 20 μg ml−1) caused a slight reduction of ACh‐ and histamine‐induced maximal contractions, allied to decrease of the sensitivity to histamine at concentrations of 20 μg ml−1 or more.

These results extend our previous data, indicating the existence of several non‐peptide compounds in the crude extract of Mandevilla velutina that act as simple, competitive, selective and reversible kinin receptor antagonists in the rat isolated uterus and guinea‐pig ileum smooth muscle.
Protection of rat atrial myocardium against electrical, mechanical and structural aspects of injury caused by exposure in vitro to conditions of simulated ischaemia
Authors: Northover Ann M. , Northover B.J.
Published: July 2012

Rat isolated and superfused atria were exposed for varying periods to a solution simulating the composition of extracellular fluid during myocardial ischaemia (SI).

Atria subjected to SI showed a loss of systolic contractile tension, a rise in diastolic tension, a shortening of electrical refractory periods, a slowing of action potential conduction velocity and disruption of the mitochondrial ultrastructure. All these features were reversible when the muscle was returned to normal superfusate.

Atria pretreated with a superfusate containing a calcium channel antagonist, a calmodulin inhibitor or an intracellular calcium antagonist showed fewer features of the response to SI than did controls.

Atria pretreated with a superfusate containing various non‐steroidal anti‐inflammatory agents did not show identical responses to SI. Sulphinpyrazone protected against all features of the response to SI but ibuprofen, flurbiprofen and GP25671 (a metabolite of sulphinpyrazone) had little effect. Flufenamate, phenylbutazone and salicylate enhanced the responses to SI.