bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cyclopiazonic acid, an inhibitor of the sarcoplasmic reticulum Ca2+‐pump, reduces Ca2+‐dependent K+ currents in guinea‐pig smooth muscle cells
Authors: Suzuki Masanori , Muraki Katsuhiko , Imaizumi Yuji , Watanabe Minora 
Published: July 2012

Effects of cyclopiazonic acid (CPA), a specific inhibitor of the Ca2+‐ATPase in sarcoplamic reticulum (SR), on membrane ionic currents were examined in single smooth muscle cells freshly isolated from ileal longitudinal strips and urinary bladder of the guinea‐pig.
Under whole‐cell clamp, CPA (1–10 μm) reduced peak outward current elicited by depolarization in a concentration‐dependent manner. The concentration of CPA required for 50% decrease in the peak outward current was ∼ 3 μm in ileal cells under these conditions. The current reduced by CPA recovered by more than 70% after washout.
The transient outward current elicited by application of 5 mm caffeine at a holding potential of — 50 mV in Ca2+ free solution was almost abolished, when the preceding Ca2+‐loading of the cell in a solution containing 2.2 mm Ca2+ was performed in the presence of 3 μm CPA.
When the Ca2+‐dependent K+ current (IK‐Ca) and Ca2+ current (ICa) were inhibited by addition of Ca2+, the remaining delayed rectifier type K+ current was not affected by 10 μm CPA. When outward currents were blocked by replacement of K+ by Cs+ in the pipette solution, the remaining ICa was not affected by 10 μm CPA.
CPA (10 μm) did not affect the conductance of single maxi Ca2+‐dependent K+ channels or the Cd2+‐dependence of their open probability in both inside‐ and outside‐out configurations.6 These results indicate that IK‐Ca is selectively and strongly suppressed by CPA. Its effects may be attributed to a decrease in Ca2+‐uptake into SR, resulting in a decrease in Ca2+‐induced Ca2+ release which is triggered by Ca2+ entering through voltage‐dependent Ca2+ channels and therefore less activation of these K channels.7 CPA may be extremely valuable pharmacological tool for investigating intracellular Ca2+ mobilization and ionic currents regulated by intracellular Ca2+.
The actions of nitric oxide donors in the prevention or induction of injury to the rat gastric mucosa
Authors: Lopez‐Belmonte J. , Whittle B.J.R. , Moncada S. 
Published: July 2012

The protective or damaging actions on the gastric mucosa, of locally infused nitrovasodilators that donate nitric oxide (NO), have been investigated in the pentobarbitone‐anaesthetized rat.
Local intra‐arterial infusion of endothelin‐1 (ET‐1; 5 pmol kg−1 min−1 for 10 min) induced extensive, macroscopically apparent, haemorrhagic injury to the rat gastric mucosa. This damage was dose‐dependently reduced by concurrent local intra‐arterial infusion of glyceryl trinitrate (GTN; 10–40 μg kg−1 min−1) which liberates NO on metabolic transformation, or the nitrosothiol, S‐nitroso‐N‐acetyl‐penicillamine (SNAP, 2.5–10 μg kg−1 min−1) which spontaneously liberates NO.
Local infusion of higher doses of SNAP (20 and 40 μg kg−1 min−1, i.a.) did not, however, significantly protect against mucosal injury induced by ET‐1.
Furthermore, local infusion alone of these higher doses of SNAP, as well as sodium nitroprusside (10–40 μg kg−1 min−1, i.a.) which also spontaneously liberates NO, induced significant mucosal injury, as assessed macroscopically and confirmed by histology.
Local infusion of these higher doses of SNAP and nitroprusside reduced systemic arterial blood pressure (BP), but this was not correlated with the extent of mucosal injury.
Furthermore, local infusion of GTN (10–40 μg kg−1 min−1, i.a.) alone, which also reduced BP, failed to induce gastric mucosal damage.
These findings suggest that exogenous NO can protect the rat gastric mucosa from damage induced by the vasoconstrictor peptide ET‐1, which may reflect local microcirculatory interactions. However, the unregulated release of high levels of NO within the microvasculature induces mucosal injury.
Mediation by the same muscarinic receptor subtype of phasic and tonic contractile activities in the rat isolated portal vein
Authors: Pfaffendorf M. , Van Zwieten P.A. 
Published: July 2012

The effects of several agonists on the phasic and tonic contractile responses to muscarinic receptor stimulation have been investigated in the rat portal vein in vitro.
Neither chemical denervation with 6‐hydroxydopamine nor the presence of the α1‐adrenoceptor antagonist, prazosin, influenced the spontaneous or the stimulated myogenic activity of the portal vein.
Indomethacin and NG‐nitro‐l‐arginine were used to investigate the influence of vasoactive factors in this preparation. They slightly increased the frequency and the amplitude of the spontaneous myogenic activity of the portal vein, respectively. NG‐nitro‐l‐arginine but not indomethacin enhanced the maximal phasic response to carbachol. Both indomethacin and NG‐nitro‐l‐arginine failed to influence the tonic response to carbachol.
Muscarinic agonists increased phasic activity according to the rank order of potency: acetylcholine > muscarine > methacholine > carbachol > aceclidine > bethanechol. These effects were superimposed on a sustained contracture at higher concentrations. Oxotremorine was more potent than arecoline in increasing the mechanical phasic activity, without inducing a sustained contracture. Pilocarpine and McN A 343 were weak agonists, producing submaximal effects only on phasic activity.
The muscarinic antagonists AF‐DX 116, 4‐diphenylacetoxy‐N‐methylpiperidine (4‐DAMP), P‐fluorohexahydrosiladiphenidol (pFHHSiD) and pirenzepine antagonized the phasic and tonic mechanical responses to carbachol. Although the tonic contracture was slightly more sensitive to all antagonists studied, the rank order of potency: 4‐DAMP > pFHHSiD > pirenzepine > AF‐DX 116 was the same for both types of response, which is indicative of a M3‐receptor subtype.
The tonic contractile response of the rat portal vein to carbachol was more susceptible to partial receptor inactivation with propylbenzilylcholine mustard than the phasic contractile response. The dissociation constants (KA) obtained from an analysis according to Furchgott & Bursztyn (1967) were found to be 4.32 ± 0.31 μm for the phasic and 3.56 ± 0.21 μm for the tonic type of carbachol‐induced response, respectively. Since the EC50‐values for both carbachol‐induced effects were different (phasic 0.232 ± 0.02 μm; tonic 2.75 ± 0.1 μm) the phasic type of response appears to involve a large receptor reserve.
Non‐peptide antagonists, CP‐96,345 and RP 67580, distinguish species variants in tachykinin NK1 receptors
Authors: Barr A.J. , Watson S.P. 
Published: July 2012

The potency of the non‐peptide antagonists CP‐96,345 and RP 67580 on NK1 receptor‐stimulated [3H]‐inositol phosphate accumulation in cell lines or tissue from three different species has been examined.
We have used: UC11 cells, derived from a human astrocytoma, and rat LRM55 glial cells, both of which express large numbers of functional NK1 receptors, and the well characterized guinea‐pig ileum which expresses both NK1 and NK3 receptors.
RP 67580 has an ∼25 fold lower affinity for NK1 receptors in human UC11 cells (Kd = 194 nm) than in rat LRM55 cells (Kd = 7.9 nm), in contrast CP‐96,345 has an ∼200 fold lower affinity in rat LRM55 cells (Kd = 210 nm) relative to human UC11 cells (Kd = 0.99 nm). The pharmacological profile of CP‐96,345 and RP 67580 in guinea‐pig ileum was similar to that observed in human UC11 cells.
In conclusion, we have demonstrated that previously reported species differences in binding affinities for the non‐peptide NK1 antagonists, CP‐96,345 and RP 67580, are also observed in inhibition of NK1 receptor stimulated hydrolysis of inositol phospholipids.
Actions and interactions of NG‐substituted analogues of l‐arginine on NANC neurotransmission in the bovine retractor penis and rat anococcygeus muscles
Authors: Martin William , Gillespie John S. , Gibson Ian F. 
Published: July 2012

The effects and interactions of a series of NG‐substituted analogues of l‐arginine known to inhibit nitric oxide synthase were examined on non‐adrenergic, non‐cholinergic (NANC) neurotransmission in the bovine retractor penis (BRP) and rat anococcygeus muscles.
Treatment of BRP muscle strips with either NG‐nitro l‐arginine (l‐NOARG: 0.1–10 μm) or NG‐nitro l‐arginine meythl ester (l‐NAME; 0.1–100 μm) produced a concentration‐dependent blockade of NANC relaxation: blockade was complete at the highest concentration of each.
Pretreatment with l‐arginine (1–10 mm) had no effect on NANC relaxation by itself, but inhibited, in a concentration‐dependent manner, the subsequent ability of both l‐NOARG (0.1–300 μm) and l‐NAME (0.1–1 mm) to produce blockade. l‐Arginine (1–10 mm) reversed established submaximal blockade of NANC relaxation induced by l‐NOARG (1 μm) or l‐NAME (1 μm), but had little effect on maximal blockade induced by these agents.
In contrast to l‐NOARG and l‐NAME, NG‐monomethyl l‐arginine (l‐NMMA; 1 μm‐1 mm) had no effect by itself on NANC relaxation of the BRP. l‐NMMA (0.1–1 mm) did, however, like l‐arginine, inhibit, in a concentration‐dependent manner, the subsequent ability of both l‐NOARG (0.1–1 mm) and l‐NAME (0.1–3 mm) to produce blockade, but was more potent. As with l‐arginine, l‐NMMA (0.1–1 mm) reversed established submaximal blockade of NANC relaxation induced by l‐NOARG (1 μm) or l‐NAME (1 μm), but had little effect on maximal blockade induced by these agents.
In contrast to the effects on BRP, treatment of rat anococcygeus muscle with either l‐NOARG (0.1–10 μm) or l‐NMMA (1–100 μm) produced concentration‐dependent inhibition of NANC relaxation: the maximal inhibition induced by l‐NOARG and l‐NMMA was 100% and 40.1 ± 5.9% (n = 8), respectively. l‐Arginine (1–10 mm) reversed established submaximal inhibition of NANC relaxation induced by l‐NOARG (1 μm), had little effect on maximal blockade by this agent, and reversed maximal blockade induced by l‐NMMA (100 μm).
In the presence of partial blockade of NANC relaxation on rat anococcygeus by a maximal concentration of l‐NMMA (100 μm), subsequent blockade by l‐NOARG (0.1–100 μm) was inhibited. l‐NMMA (100 μm) produced a partial reversal of established submaximal blockade of NANC relaxation induced by l‐NOARG (1 μm), but had little effect on maximal blockade induced by this agent.
These findings suggest a complex series of interactions between l‐arginine and certain of its NG‐substituted analogues that are commonly used to inhibit nitric oxide synthase. The most striking new finding is that l‐NMMA does not block NANC relaxation in the BRP, but acts with greater potency than the endogenous substrate, l‐arginine, to inhibit the blockade induced by l‐NOARG or l‐NAME. Even on rat anococcygeus where l‐NMMA acts as a partial blocker of NANC relaxation, further blockade by l‐NOARG is inhibited.
A factor released by monocytes in the presence of dexamethasone stimulates neutrophil locomotion
Authors: Chettibi S. , Lawrence A.J. , Stevenson R.D. 
Published: July 2012

Steroid‐treated monocyte supernatants cause a dramatic increase in the speed of locomotion of human neutrophils and a significant decrease in their adhesion to protein‐coated glass. In contrast, control monocyte supernatants have a smaller effect on the speed of locomotion, but cause a large increase in their adhesiveness.
This supernatant activity was produced equally well in the presence or absence of serum after 24 h culture at 37°C with 10−6 m dexamethasone.
The effect of the steroid‐treated monocyte supernatants on the speed of locomotion of human peripheral blood neutrophils was not altered by rabbit polyclonal antisera against lipocortins 1–6.
Rabbit anti‐interleukin‐8 antibody which blocked the effect of IL‐8 on the speed of locomotion of neutrophils did not antagonize the locomotion stimulating action of steroid‐treated monocyte supernatants.
The exocellular release of this factor(s) by human mononuclear leucocytes suggests that it may be an in vivo mediator of the anti‐inflammatory effect of glucocorticoids.
Pharmacological characteristics of the positive inotropic effect of angiotensin II in the rabbit ventricular myocardium
Authors: Ishihata Akira , Endoh Masao 
Published: July 2012

In order to elucidate the mechanism underlying the positive inotropic effect (PIE) of angiotensin II (AII), we measured changes in phosphoinositide hydrolysis and contractile force induced by AII in the rabbit ventricular myocardium.
AII (1.0 nm−3 μm) produced a PIE in a concentration‐dependent manner in the presence of bupranolol (0.3 μm) and prazosin (0.1 μm), the maximal response being about 40% of that to isoprenaline and the EC50 30 nm.
The PIE of AII was associated with a concentration‐dependent increase in the total duration of contraction; the time to peak force and the relaxation time were prolonged.
AII (10 nm −30 μm) elicited an accumulation of [3H]‐inositol monophosphate in a concentration‐dependent manner in rabbit ventricular slices prelabelled with myo‐[3H]‐inositol.
The PIE and the accumulation of [3H]‐inositol monophosphate induced by AII were inhibited by a non‐selective AII receptor antagonist, saralasin (10 nm −1 μm) and by a selective AT1 receptor antagonist, losartan (10 nm −1 μm), but not a selective AT2 receptor antagonist, PD 123319 (1 μm).
A tumour‐promoting phorbol ester, phorbol 12,13‐dibutyrate (PDBu, 10–100 nm), inhibited the AII‐induced PIE and [3H]‐inositol monophosphate accumulation in a concentration‐dependent manner.
These results suggest that AII exerts a PIE through activation of AT1 receptors and subsequent acceleration of phosphoinositide hydrolysis. Activation of protein kinase C by PDBu may inhibit the AII‐induced stimulation of phosphoinositide hydrolysis and thereby the PIE of AII in the rabbit ventricular myocardium.
Regulation of neural responses in the canine pyloric sphincter by opioids
Authors: Bayguinov Orline , Sanders Kenton M. 
Published: July 2012

Regulation of excitatory and inhibitory junction potentials (e.j.ps and i.j.ps) by opioid peptides was studied in isolated muscle strips from the pyloric sphincter of the dog.
Methionine enkephalin (MetEnk; 10−10 to 10−6 m) and [d‐Ala2, d‐Leu5] enkephalin (DADLE; 10−11 to 10−7 m), a δ‐specific opioid agonist, inhibited i.j.ps and e.j.ps recorded from cells in the myenteric and submucosal regions of the circular muscle layer. These compounds had no effect on resting potential or slow wave activity suggesting that the effects on junction potentials were not due to direct effects on smooth muscle cells.
MetEnk and DADLE caused similar effects on junction potentials in preparations in which the myenteric plexus was removed, suggesting that opioids inhibit pre‐junctional effects on nerve fibres within the muscularis externa.
Inhibition of junction potentials by MetEnk and DADLE was blocked by approximately the same extent by naloxone (10−6 m) and ICI 174,864 (10−6 m), a δ‐specific antagonist.
MetEnk and DADLE blocked a portion of the i.j.p. that was sensitive to arginine analogues; after treatment with Nω‐nitro‐l‐arginine methyl ester (l‐NAME, 10−4 m), MetEnk and DADLE had no further effect on i.j.ps. These data suggest that opioids regulate nitric oxide‐dependent neurotransmission.
Naloxone (10−6 m) alone had no effect on i.j.ps elicited by short trains of electrical field stimuli.
I.j.p. amplitude was reduced after a period of conditioning stimulation (2 min, 30 Hz, 30 V). Naloxone blocked the post‐stimulation inhibition. Repetitive stimulation at high frequencies (30 Hz) resulted in sustained hyperpolarization. Naloxone increased the amplitude of the hyperpolarization responses elicited by high frequency stimulation.
These results show that e.j.ps and i.j.ps in the canine pylorus are inhibited by opioids. A portion of the inhibitory effects appears to be mediated via δ receptors.
Although pyloric muscles are richly innervated by nerves containing opioid peptides, brief trains of stimuli do not appear to release concentrations of opioids that are effective in regulating junction potentials. Higher frequency stimulation (or longer durations of stimulation) appear to be necessary to release concentrations of opioids that are effective in modulating the amplitude of junction potentials.
Inhibition of nerve stimulation‐induced vasodilatation in corpora cavernosa of the pithed rat by blockade of nitric oxide synthase
Authors: Finberg John P.M. , Levy Shulamit , Vardi Yoram 
Published: July 2012

The effect of inhibition of nitric oxide synthase by NG‐nitro‐l‐arginine methyl ester (l‐NAME) on nerve stimulation‐induced vasodilatation in corpora cavernosa was studied in the pithed rat. Corporal vasodilatation was estimated by the increase in ratio (corpora cavernosal pressure/systemic blood pressure; CP/BP) following electrical stimulation of the sacral part of the spinal cord.
l‐NAME (2, 5, 10 and 25 mg kg−1) caused an increase in BP and a dose‐dependent inhibition of the rise in the CP/BP ratio following stimulation.
The inhibitory effect of l‐NAME (25 mg kg−1) on the corporal response to spinal cord stimulation, as well as the pressor response, was partially prevented by prior administration of l‐ but not d‐arginine (400 mg kg−1, i.v.).
l‐NAME (20 mg kg−1, i.v.) did not inhibit the rise in corporal pressure resulting from direct intracavernosal administration of papaverine (400 μg over 2 min). However, this response was inhibited by 5‐hydroxytryptamine (20 μg kg−1, i.v.).
The results are indicative of a role of nitric oxide (NO) in the corporal vasodilator response to erectile stimulation.
Modulation of cholinergic and substance P‐like neurotransmission by nitric oxide in the guinea‐pig ileum
Authors: Wiklund Claes U. , Olgart Caroline , Wiklund N. Peter , Gustafsson Lars E. 
Published: July 2012

The role of endogenous nitric oxide (NO) as a modulator of enteric neurotransmission was investigated in longitudinal muscle myenteric plexus (LMMP) preparations of guinea‐pig isolated ileum.
In tissues previously incubated with [3H]‐choline, exogenous NO inhibited electrically‐evoked [3H]‐choline overflow as well as responses to exogenous agonists, indicating that NO has the potential of neuromodulation both pre‐ and postjunctionally.
A series of NO synthase inhibitors enhanced contractile responses to nerve stimulation indicating inhibitory neuromodulation by endogenous NO.
The potency order of the NO synthase inhibitors and their consistent effects after dexamethasone, on responses to nerve stimulation, indicate action on a constitutive NO synthase.
Responses enhanced by NO synthase inhibitors were inhibited by the substance P receptor antagonist, spantide, suggesting a neuromodulatory influence on substance P‐like neurotransmission by the endogenous NO.
NO synthase inhibition did not modify contractile responses to application of acetylcholine or substance P, or [3H]‐choline overflow, indicating that endogenous NO mainly has a prejunctional inhibitory action on substance P‐like neurotransmission. Nor did it modify responses to direct electrical muscle stimulation in the presence of tetrodotoxin. This suggests a prejunctional enhancing effect by NO synthesis inhibition.
Evidence for endogenous NO modulation of acetylcholine release was obtained when NO synthase inhibition modified atropine‐sensitive, nerve‐mediated contractile responses. However, [3H]‐choline overflow was unaltered by NO synthase inhibition.
NO synthase inhibition did not modify responses to inhibitory neurotransmission.
The findings suggest that endogenous NO inhibits substance P‐like motor neurotransmission, probably via prejunctional mechanisms. Cholinergic transmission may also be reduced by endogenous NO, acting prejunctionally.
The effect of cyclic AMP elevating agents on bradykinin‐ and carbachol‐induced signal transduction in canine cultured tracheal smooth muscle cells
Authors: Yang Chuen Mao , Hsia Hui‐Chuan , Luo Shue‐Fen , Hsieh Jen‐Tsung , Ong Richard 
Published: July 2012

The effects of cholera toxin (CTX), forskolin and dibutyryl cyclic AMP on bradykinin (BK)‐ and carbachol‐induced accumulation of inositol phosphates (IPs) and Ca2+ mobilization were investigated in canine cultured tracheal smooth muscle cells (TSMCs). The BK‐induced responses were mediated via a G protein which was not inhibited by CTX or pertussis toxin treatment.
BK‐stimulated IPs accumulation and Ca2+ mobilization were potentiated by CTX (10 μg ml−1) pretreatment which was time‐dependent. Maximal increase of these responses occurred after 24 h treatment with CTX. The concentration‐effect relationship of BK‐induced responses were shifted to the left and BK was substantially more effective in CTX‐treated cells than in the control cells. This enhancing effect of CTX did not occur with carbachol.
Short‐term (< 4 h) treatment with forskolin (10 μm) or dibutyryl cyclic AMP (1 mm) failed to accentuate BK‐induced responses, but long‐term (> 4 h) treatment of TSMCs with these agents mimicked the enhancing effect of CTX, suggesting that CTX‐induced enhancement of BK responsiveness might be due to a rise in cyclic AMP.
Prolonged treatment of TSMCs with these agents was accompanied by an increase in cell surface [3H]‐BK binding sites, which was inhibited by concurrent incubation with cycloheximide, an inhibitor of protein biosynthesis. Cycloheximide also abolished the potentiating actions of CTX, forskolin, and dibutyryl cyclic AMP on BK‐induced IPs formation and Ca2+ mobilization.
The locus of this enhancement was further investigated by examining the effects of CTX, forskolin and dibutyryl cyclic AMP on AlF4‐induced IPs accumulation in canine TSMCs. AlF4−‐induced IPs accumulation was not affected by CTX, forskolin, or dibutyryl cyclic AMP treatment, supporting the contention that this stimulatory effect is located at the BK receptor level.
These results demonstrate that the augmentation of BK‐induced IPs accumulation and Ca2+ mobilization produced by CTX, forskolin and dibutyryl cyclic AMP involves a cyclic AMP‐dependent mechanism which is induced by a sustained increase in the level of intracellular cyclic AMP. CTX and forskolin may promote an increase of the synthesis of BK receptors, and thereby enhance BK‐induced responses.
Effects of bosentan (Ro 47–0203), an ETA‐, ETB‐receptor antagonist, on regional haemodynamic responses to endothelins in conscious rats
Authors: Gardiner S.M. , Kemp P.A. , March J.E. , Bennett T. 
Published: July 2012

Regional haemodynamic responses to endothelin (ET)‐1, −2 and −3 and big ET‐1 (all at 500 pmol kg−1) were assessed in the same conscious Long Evans rats (n = 8) in the absence or presence of the mixed ETA‐, ETB‐receptor antagonist, Ro 47–0203 (bosentan; 30 mg kg−1).
Bosentan blocked the initial depressor, tachycardic and hindquarters hyperaemic vasodilator effects of ET‐1, −2 and −3, and substantially curtailed the primary renal and secondary hindquarters vasoconstrictor responses. Bosentan did not inhibit the initial mesenteric vasoconstrictor action of ET‐1, but reduced the duration of the later mesenteric vasoconstriction. In contrast, bosentan delayed the rate of onset, and reduced the duration, of the mesenteric vasoconstrictor actions of ET‐2 and ET‐3. The most likely explanation of this finding is that ET‐1, but not ET‐2 or ET‐3, triggered a covert mesenteric vasodilator mechanism which was antagonized by bosentan.
Bosentan blocked all the effects of big ET‐1, and, in a separate group of rats (n = 7), blocked all the haemodynamic effects of a lower dose of ET‐1 (50 pmol kg−1), with the exception of a slight mesenteric vasoconstriction.
The most straightforward explanation of the results is that the major haemodynamic effects of ET‐1, −2 and −3, and all the effects of big ET‐1, are mediated through ETA‐ and/or ETB‐receptors that are effectively antagonized by bosentan.