bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ischaemia/reperfusion selectively attenuates coronary vasodilatation to an adenosine A2‐ but not to an A1‐agonist in the dog
Authors: Cox Bryan F. , Greenland Brett D. , Perrone Mark H. , Merkel Linda A. 
Published: July 2012

The effects of myocardial ischaemia/reperfusion were tested on the coronary vasorelaxant responses to agonists selective for the A1 and A2 adenosine receptor subtypes in the dog. The left anterior descending (LAD) coronary artery was occluded distal to the first diagonal branch. The occlusion was maintained for 1 h, followed by 1 h of reperfusion.
In the first series of experiments, LAD and circumflex arteries were excised and contracted with prostaglandin F2α (PGF2α). Ischaemia/reperfusion did not significantly alter the vasorelaxation produced by either sodium nitroprusside (endothelium‐independent) or acetylcholine (endothelium‐dependent). The A1 selective agonist, cyclopentyladenosine (CPA), produced coronary vasorelaxation in both normally perfused vessels and vessels subjected to ischaemia/reperfusion. In contrast, the relaxation produced by the A2‐selective agonist N6‐{2‐(3,5‐dimethoxyphenyl)‐2‐(2‐methylphenyl) ethyl} adenosine (DPMA) was significantly attenuated by ischaemia/reperfusion (14 fold shift in EC50).
In the second series of experiments, coronary blood flow was increased by administration of the A1 and A2 agonists before and after ischaemia/reperfusion of the LAD in anaesthetized dogs. Both compounds dose‐dependently increased coronary blood flow. The slopes of the dose‐response functions to CPA or DPMA were not significantly altered in the normally perfused circumflex vascular bed. Similarly, the CPA dose‐response function in the LAD was unaltered by ischaemia/reperfusion. However, the slope of the coronary vasodilator response to the A2 agonist was significantly reduced following ischaemia/reperfusion of the LAD.
We conclude that ischaemia/reperfusion reduces responsiveness to an adenosine A2 receptor subtype agonist, but not an A1 receptor subtype agonist. These data confirm the independent nature of A1 and A2‐mediated coronary vasodilatation.
Effect of anti‐fungal imidazoles on mRNA levels and enzyme activity of inducible nitric oxide synthase
Authors: Bogle R.G. , Whitley G.St.J. , Soo S.‐C. , Johnstone A.P. , Vallance P. 
Published: July 2012

Experiments were performed to examine the effects of anti‐fungal imidazole compounds (clotrimazole, econazole and miconazole) on the induction of nitric oxide (NO) synthase and subsequent production of NO in the cultured murine monocyte/macrophage cell line J774 using a specific cDNA probe for inducible NO synthase mRNA and by monitoring nitrite production.
Stimulation of J774 cells with lipopolysaccharide (LPS, 10 μg ml−1) resulted in the induction of NO synthase activity as determined by nitrite accumulation in the culture medium (48 ± 3 nmol per 106cells over 24 h). Production of nitrite was inhibited by co‐incubation of cells with LPS (10 μg ml−1) and either dexamethasone (10 μm) or NG‐monomethyl‐l‐arginine (l‐NMMA; 0.1 mm), however, only l‐NMMA was an effective inhibitor of nitrite production when added after induction of NO synthase had occurred.
Co‐incubation of J774 cells with LPS (10 μg ml−1) and either clotrimazole, econazole or miconazole (1–10 μm) resulted in a concentration‐dependent inhibition of nitrite production over the subsequent 24 h without any evidence for a cytotoxic effect. However, addition of these imidazoles after induction of NO synthase did not inhibit nitrite production.
Messenger RNA for inducible NO synthase was not detected in unstimulated J774 cells. Treatment with LPS (10 μg ml−1) for 4 h resulted in significant expression of mRNA for inducible NO synthase which was not altered in the presence of econazole (10 μm) but was reduced significantly by dexamethasone (10 μm).
These results demonstrate that anti‐fungal imidazoles inhibit the production of nitric oxide by cultured J774 cells by a mechanism which appears to differ from that of dexamethasone and substrate‐type inhibitors of NO synthase. Furthermore, the presence of mRNA for NO synthase does not indicate the presence of functionally active NO synthase.
Differential effects of ω‐conotoxin GVIA and tetrodotoxin on vasoconstrictions evoked by electrical stimulation and nicotinic receptor stimulation in canine isolated, perfused splenic arteries
Authors: Ren Lei‐Ming , Nakane Tokio , Chiba Shigetoshi 
Published: July 2012

The effects of ω‐conotoxin GVIA (ω‐CgTX) and tetrodotoxin (TTX) on vasoconstrictions induced by acetylcholine (ACh) and nicotine were investigated and compared with those induced by periarterial electrical stimulation in the isolated and perfused canine splenic arteries.
ACh and nicotine at doses of 0.01 to 1 μmol constricted the splenic artery, dose‐dependently. ACh induced consistent responses, but the vasoconstrictor responses to nicotine became significantly smaller with repeated administration of nicotine.
Periarterial electrical stimulation produced a vasoconstriction that was abolished by either TTX (30 nmol) or ω‐CgTX (3 nmol), but the vasoconstrictor response to nicotine was not significantly affected by the same doses of TTX and ω‐CgTX. Inhibitions by TTX and ω‐CgTX of ACh‐induced vasoconstrictions were small but statistically significant, showing that the percentage inhibition was less than 15%. TTX and ω‐CgTX did not affect the vasoconstrictor responses to exogenous noradrenaline (NA).
ACh did not produce any vasoconstriction in the preparations treated either with α‐adrenoceptor antagonists (10 μm bunazosin and 10 μm midaglizole) or with 30 μm guanethidine. NA‐induced responses were abolished by α‐adrenoceptor antagonists, but not affected by guanethidine treatment.
Vascular responses to ACh were completely inhibited by 1 μmol hexamethonium. In the preparations treated with 100 nmol nicotine, ACh did not produce any vasoconstriction. However, the NA‐induced vasoconstriction was affected by neither hexamethonium nor nicotine treatment.
Atropine (1 μm) significantly inhibited but did not abolish the vasoconstrictor responses to ACh. The vascular responses to nicotine and NA were also significantly inhibited by atropine treatment.
These results indicate that (1) ACh constricts the splenic artery through the activation of presynaptic nicotinic receptors present on the sympathetic nerves; (2) differential effects of TTX and ω‐CgTX on the vascular responses to ACh and nicotine, and to electrical stimulation suggest that the receptor‐operated ion channels are mainly responsible for NA release induced by nicotinic receptor stimulation, but N‐type VOCCs are responsible for that by electrical stimulation; (3) atropine may have an inhibitory action on nicotine‐related responses, in addition to its inhibitory action on NA.
Investigation of the specificity of FK 888 as a tachykinin NK1 receptor antagonist
Authors: Wang Zun‐Yi , Tung Steven R. , Strichartz Gary R. , Håkanson Rolf 
Published: July 2012

A recently described peptide tachykinin (NK1) receptor antagonist, FK 888, was found to inhibit the electrically‐evoked, tachykinin‐mediated contractile responses of the rabbit iris sphincter in a concentration‐dependent manner; the pIC50 value was 6.6 ±0.08.
Contractions induced by a selective NK1 receptor agonist, [Sar9, Met(O2)11]substance P, were inhibited competitively by FK 888; the pKB value was 7.1.
FK 888 (1 nm‐100 μm) was without effect on the electrically‐evoked, cholinergic response of the rabbit iris sphincter and the electrically‐evoked, sympathetic response of the guinea‐pig vas deferens. The contractions of the rabbit iris sphincter, induced by either carbachol (10 nm‐30 μm) or noradrenaline (0.1–100 μm), were not affected by 10 μm FK 888.
FK 888 (1–30 μm) did not induce histamine release from rat peritoneal mast cells.
FK 888 (33 and 333 μm) was without effect on the electrically‐evoked action potentials of the frog sciatic nerve. Thus, FK 888 is a moderately high affinity and selective tachykinin (NK1) receptor antagonist.
Vasoconstrictor endothelin receptors characterized in human renal artery and vein in vitro
Authors: Maguire Janet J. , Kuc Rhoda E. , O'Reilly Gillian , Davenport Anthony P. 
Published: July 2012

We have identified the endothelin receptors present in the media of human main stem renal artery and vein and characterized the subtypes mediating vasoconstriction in these blood vessels in vitro.
Messenger RNA encoding both ETA and ETB receptors was identified in the smooth muscle layer of human renal artery and vein by reverse transcriptase‐polymerase chain reaction assay. In cryostat‐cut cross‐sections of both vessels autoradiographical visualisation suggested a majority of ETA receptors. Intense binding was obtained to the non‐selective ligand [125I]‐ET‐1 and the ETA‐selective [125I]‐PD151242 but only weak labelling of sites by the ETB‐selective [125I]‐BQ3020.
ET‐1 potently constricted renal artery and vein preparations with EC50 values of 4.06 nm and 1.00 nm, respectively. Sarafotoxin 6b was approximately ten times less potent than ET‐1 with EC50 values of 36.3 nm and 13.8 nm respectively. In the renal artery, ET‐3 and sarafotoxin 6c showed little or no activity up to 300 nm. Responses to these peptides were more variable in the renal vein. Preparations from three individuals did not respond to ET‐3 but in three further cases, although ET‐3 was much less potent than ET‐1, full dose‐response curves were obtained. S6c elicited dose‐related contractions in vein preparations from 5/6 individuals and although more potent than ET‐1, the maximum response was 30–60% of that obtained to ET‐1.
ET‐1‐induced vasoconstriction of renal artery and vein was antagonized by the ETA‐selective, BQ123 (3–10μm). The dose‐response curves to ET‐1 were displaced in a parallel rightward fashion with no attenuation of the maximum responses. pA2 values were estimated to be 6.8 ± 0.1 and 6.8 ± 0.4 for artery and vein respectively.
These data suggest that mRNA encoding both ETA and ETB receptors is present in the media of human main stem renal artery and vein. However, autoradiographical studies indicate that the majority of ET receptors expressed are of the ETA subtype. The relative potencies of ET‐1 and ET‐3 as vasoconstrictors of renal blood vessels in vitro is consistent with this being an ETA‐mediated response, and therefore whilst responses to S6c indicate that constrictor ETB receptors may be present in renal veins from some individuals these are likely to be of less importance in these blood vessels.
The electrophysiological effects of dicentrine on the conduction system of rabbit heart
Authors: Young Ming‐Lon , Su Ming‐Jai , Wu Mei‐Hwan , Chen Chien‐Chih 
Published: July 2012

The electrophysiological effects of dicentrine, an aporphine alkaloid isolated from the root of Lindera megaphylla, were examined in the Langendorff perfused rabbit heart and rabbit isolated cardiac cells.
Standard electrophysiological characters were measured in the Langendorff perfused rabbit heart (control study) and after 5 min exposure to 1, 3 and 9μm of dicentrine and during the subsequent recovery phase sequentially (n = 7). The same study protocols were performed in 0.5 to 4.5 μm quinidine (n = 7), 18 to 162 μm procainamide and N‐acetylprocainamide (n = 7) for comparison.
The results showed that the spontaneously beating heart rate and the sinoatrial (SA) and atrioventricular nodal (AH) conduction time were not significantly affected by dicentrine but were significantly suppressed by the higher doses of quinidine (4.5 μm) and procainamide (162 μm).
The His‐Purkinje conduction time was significantly increased by the higher dose of dicentrine, quinidine and procainamide.
The ventricular repolarization time and its effective refractory period were significantly increased by the higher dose of dicentrine and the other agents.
The effective refractory period of the atrium, AV node and His‐Purkinje system were also significantly increased by dicentrine and the other agents.
A voltage clamp study revealed that the prolongation of atrial action potential duration by dicentrine (9 μm) was associated with a significant inhibition of the transient potassium outward current. As well as inhibition of the transient outward current, a significant inhibition of the sodium inward current by dicentrine was found.
We conclude that (1) dicentrine is potentially a useful antiarrhythmic agent with type Ia and type III antiarrhythmic action; (2) the relative potency of dicentrine on the electrophysiological function of cardiac tissue is 10–20 times more than that of procainamide.
The effect of caffeine on prostaglandin output from the guinea‐pig uterus
Authors: Naderali E.K. , Poyser N.L. 
Published: July 2012

Caffeine increased the outputs of prostaglandin F2α (PGF2α), PGE2 and 6‐keto‐PGF1α from the guinea‐pig uterus on days 7 and 15 of the oestrous cycle. The effect on PGE2 output depended on the age of the animals and was absent in younger guinea‐pigs (<4 months). Theophylline also stimulated the outputs of PGF2α and 6‐keto‐PGF1α, but not the output of PGE2, from the day 7guinea‐pig uterus.
The stimulatory effects of caffeine on the outputs of PGF2α, PGE2 and 6‐keto‐PGF1α from the guinea‐pig uterus were not prevented by lack of extracellular calcium, ryanodine or ruthenium red (both inhibitors of calcium release via the ryanodine receptor), although the increase in PGF2α output tended to be slower when extracellular calcium was absent. Also, ryanodine flattened and broadened the peak of increased PGF2α release.
The calmodulin antagonists, W‐7 and trifluoperazine, had no inhibitory effect on the caffeine‐stimulated increases in uterine prostaglandin output. In fact, W‐7 (but not trifluoperazine) greatly potentiated the action of caffeine on uterine PGF2α output, but had little or no potentiating effect on the action of caffeine on uterine PGE2 and 6‐keto‐PGF1α outputs.
TMB‐8, an intracellular calcium antagonist, inhibited the increase in PGF2α output produced by caffeine without preventing the increases in outputs of PGE2 and 6‐keto‐PGF1α.
These studies suggest that caffeine stimulates uterine PGF2α synthesis and release by a mechanism dependent upon intracellular calcium, but this mechanism is not mediated by activation of any of the three well‐characterized ryanodine receptors or by calmodulin. Furthermore, the increases in the synthesis and release of PGE2 and 6‐keto‐PGF1α in the guinea‐pig uterus induced by caffeine appear to involve mechanism(s) different from that which stimulates PGF2α production.
BMS‐180560, an insurmountable inhibitor of angiotensin II‐stimulated responses: comparison with losartan and EXP3174
Authors: Dickinson K.E.J. , Cohen R.B. , Skwish S. , Delaney C.L. , Serafino R.P. , Poss M.A. , Gu Z. , Ryono D.E. , Moreland S. , Powell J.R. 
Published: July 2012

This study compares the activity of BMS‐180560 (2‐butyl‐4‐chloro‐1‐[[1‐[2‐(2H‐tetrazol‐5‐yl)phenyl]‐1H‐indol‐4‐yl]methyl]‐1H‐imidazole‐5‐carboxylic acid), an insurmountable angiotensin II (AII) receptor antagonist, with that of losartan and EXP3174 in functional and biochemical models of AII‐receptor activation.
BMS‐180560 selectively inhibited [125I]‐Sar1Ile8AII ([125I]SI‐AII) binding to rat aortic smooth muscle (RASM) cell and rat adrenal cortical AT1 receptors (Ki = 7.6 ± 1.2 and 18.4 ± 3.9 nm respectively) compared to adrenal cortical AT2 receptors (Ki = 37.6 ± 1.3 μm). The Ki values of BMS‐180560 and EXP3174, but not losartan, varied as a function of the BSA concentration used in the assays, indicating that the diacid drugs bound to albumin.
BMS‐180560 (3–300 nm) increased the KD of SI‐AII for RASM cell AT1 receptors. Only at high concentrations of BMS‐180560 (300 nm) were Bmax values decreased.
BMS‐180560 inhibited AII‐stimulated contraction of rabbit aorta with a calculated KB = 0.068 ± 0.048 nm and decreased maximal AII‐stimulated contraction at 1 nm BMS‐180560 by 75%. In the presence of 0.1% BSA, a higher KB value (5.2 ± 0.92 nm) was obtained. Losartan behaved as a competitive antagonist with a KB = 2.6 ± 0.13 nm. Contraction stimulated by endothelin‐1, noradrenaline, KC1, or the TXA2 receptor agonist U‐46619 were unaffected by BMS‐180560 (1 nm).
All stimulated the acidification rates of RASM cells as measured by a Cytosensor microphysiometer with an EC50 of 18 nm. Losartan (30 nm) shifted the AII concentration‐effect curves in a competitive manner whereas BMS‐180560 (0.01 and 0.1 nm) decreased the maximum responses by 60 and 75% respectively. Inhibition by losartan and BMS‐180560 could be reversed following washout although recovery took longer for BMS‐180560.
In [3H]‐myoinositol‐labelled RASM cells, losartan (30 and 200 nm), shifted the EC50 for AII‐stimulated [3H]‐inositol monophosphate formation to higher values, with no change in the maximal response. By contrast, EXP3174 (0.1 to 1 nm) decreased the maximal response in a concentration‐dependent manner (17–55%). BMS‐180560 (3 and 10 nm) increased the EC50 for AII and decreased the maximum response by 30 and 80% respectively. The inhibition by EXP3174 and BMS‐180560 could be reversed by inclusion of losartan (200 nm) indicating that the inhibition was not irreversible.
In conclusion, BMS‐180560 is a potent, specific, predominantly competitive, reversible AII receptor antagonist, which displays insurmountable receptor antagonism. At concentrations of BMS‐180560 which have no effect on receptor number, BMS‐180560 produced insurmountable antagonism of AII‐stimulated second messenger formation, extracellular acidification, and smooth muscle contraction.
Abolition of flow‐dependent EDRF release before that evoked by agonists in hypercholesterolaemic rabbits
Authors: Hutcheson Iain R. , Smith Jerry A. , Griffith Tudor M. 
Published: July 2012

We have used a pulsatile cascade bioassay system to investigate the effects of dietary‐induced hypercholesterolaemia on EDRF release evoked by acetylcholine and by the oscillatory and time‐averaged components of flow, in isolated segments of rabbit abdominal aorta.
Flow pulsatility (frequency range 0.1–10 Hz) was studied with constant flow (9 ml min−1) at a pulse pressure amplitude of 2 mmHg. Frequency‐related EDRF release, maximal at 6 Hz, was slightly attenuated after 4 weeks and abolished after 8 weeks of cholesterol feeding.
Time‐averaged shear stress was manipulated with dextran (1–4% w/v, 80000 mol. wt.), to increase perfusate viscosity. EDRF release induced by increased perfusate viscosity was unaffected after 4 weeks but abolished after 8 weeks of cholesterol feeding.
Endothelium‐dependent relaxations to acetylcholine (0.1–10 μm) were not influenced after 4 weeks and only partially attenuated (by 60% of the maximal response, EC50 unchanged at 6.45 ± 0.04 vs. 6.4 ± 0.1 μm) after 8 weeks of cholesterol feeding.
Blood cholesterol levels were significantly (P<0.001) increased after 4 weeks (26 ± 3.6 vs 2.6 ± 0.6 mmol 1−1) and 8 weeks (56.2 ± 3.8 vs 1.3 ± 0.1 mmol 1−1) of cholesterol feeding but after 8 weeks plasma L‐arginine levels were not significantly different from the age‐matched controls (0.2 ± 0.05 vs. 0.19 ± 0.04 mmol 1−1).
We conclude that hypercholesterolaemia impairs flow‐related (pulsatile‐ and time‐averaged shear‐induced) EDRF release earlier than acetylcholine‐induced relaxation in rabbit aorta. This is consistent with the view that different transduction mechanisms mediate EDRF release in response to agonists and flow.
Antifibrillatory effects of clofilium in the rabbit isolated heart
Authors: Friedrichs Gregory S. , Chi Liguo , Green Alysia L. , Lucchesi Benedict R. 
Published: July 2012

This study was designed to determine whether clofilium exhibits antifibrillatory activity in a pinacidil + hypoxia‐induced model of ventricular fibrillation (VF) in Langendorff‐perfused hearts.
Ten minutes after exposure to vehicle or clofilium (0.1, 1.0 and 10.0 μm), hearts were exposed to pinacidil (1.25 μm), then subjected to 12 min of hypoxia and reoxygenated. Onset to VF was recorded. Additional groups of hearts were pretreated with UK‐68,798 (1.0, 3.0 and 10.0 μm), a delayed rectifier channel blocker, and 5‐hydroxydecanoate (10 μm), a known ATP‐dependent K+ channel blocker, and subjected to an identical protocol.
Clofilium decreased the incidence of VF in a concentration‐dependent manner; 7/9 control hearts developed VF vs 1/9 hearts (P = 0.007, Fisher's Exact) treated with 10.0 μm clofilium. In addition, 5‐hydroxydecanoate protected hearts from VF, while UK‐68,798 pretreatment did not.
In a separate group of hearts, electrically‐induced VF was converted to sinus rhythm in 10/11 hearts after clofilium was introduced as a bolus.
Clofilium is capable of preventing VF in the rabbit isolated heart in a concentration‐dependent manner. We have data to suggest that the ability of clofilium to attenuate the effects of pinacidil + hypoxia in our model may include blockade of metabolically active K+ channels, i.e., KATP (glibenclamide‐sensitive) channel.
Ca2+ release induced by myotoxin a, a radio‐labellable probe having novel Ca2+ release properties in sarcoplasmic reticulum
Authors: Furukawa Ken‐Ichi , Funayama Kaori , Ohkura Masamichi , Oshima Yoshiteru , Tu Anthony T. , Ohizumi Yasushi 
Published: July 2012

Myotoxin a (MYTX), a polypeptide toxin purified from the venom of prairie rattlesnakes (Crotalus viridis viridis) induced Ca2+ release from the heavy fraction (HSR) but not the light fraction of skeletal sarcoplasmic reticulum at concentrations higher than 1 μm, followed by spontaneous Ca2+ reuptake by measuring extravesicular Ca2+ concentrations using the Ca2+ electrode.
The rate of 45Ca2+ release from HSR vesicles was markedly accelerated by MYTX in a concentration‐dependent manner in the range of concentrations between 30 nM and 10 μm, indicating the most potent Ca2+ releaser in HSR.
The Ca2+ dependency of MYTX‐induced 45Ca2+ release has a bell‐shaped profile but it was quite different from that of caffeine, an inducer of Ca2+‐induced Ca2+ release.
45Ca2+ release induced by MYTX was remarkable in the range of pCa between 8 and 3, whereas that by caffeine was prominent in the range of pCa, i.e., between 7 and 5.5.
MYTX‐induced 45Ca2+ release consists of both early and late components. The early component caused by MYTX at low concentrations (30–300 nM) completed within 20 s, while the late component induced by it at higher concentrations (>0.3μm) was maintained for at least 1 min.
Both the components were almost completely inhibited by inhibitors of Ca2+ release such as Mg2+, ruthenium red and spermine.
45Ca2+ release induced by caffeine or β,γ‐methyleneadenosine 5′‐triphosphate (AMP‐PCP) was completely inhibited by high concentrations of procaine. Procaine abolished the early component but not the late one, suggesting that at least the early component is mediated through Ca2+‐induced Ca2+ release channels.
On the basis of these results, the character of Ca2+ release induced by MYTX was quite different from that caused by caffeine or AMP‐PCP, suggesting that MYTX induces Ca2+ release having novel properties in HSR. MYTX is the first polypeptide Ca2+ inducer and has become a useful pharmacological tool for clarifying the mechanism of Ca2+ release from skeletal muscle SR.