bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of tyrosine kinase inhibitors on the contractility of rat mesenteric resistance arteries
Authors: Toma Catalin , Jensen Peter E. , Prieto Dolores , Hughes Alun , Mulvany Michael J. , Aalkjær Christian 
Published: July 2012

1 A pharmacological characterization of tyrosine kinase inhibitors (TKI) belonging to two distinct groups (competitors at the ATP‐binding site and the substrate‐binding site, respectively) was performed, based on their effects on the contractility of rat mesenteric arteries.2 Both the ATP‐site competitors (genistein and its inactive analogue, daidzein) and the substrate‐site competitors (tyrphostins A‐23, A‐47 and the inactive analogue, A‐1) reversibly inhibited noradrenaline (NA, (10 μm)) and KCl (125 mm) induced contractions, concentration‐dependently. Genistein was slightly but significantly more potent than daidzein; the tyrphostins were all less potent than genistein, and there were no significant differences between the individual potencies. The tyrosine kinase substrate‐site inhibitor bis‐tyrphostin had no inhibitory effect.3 Genistein, daidzein, A‐23 and A‐47 each suppressed the contraction induced by Ca2+ (1 μm) in α‐toxin permeabilized arteries. A‐1 and bis‐tyrphostin had little or no effect on contraction of the permeabilized arteries.4 Genistein was significantly more potent than daidzein with respect to inhibition of the contraction induced by 200 nm Ca2+ in the presence of NA (100 μm) and GTP (3 μm). The effect of A‐23, A‐47, A‐1 and bis‐tyrphostin was similar in permeabilized arteries activated with Ca2+ (200 nm) + NA (100 μm) + GTP (3 μm) and permeabilized arteries activated with 1 μm Ca2+.5 Genistein (30 μm) reduced the fura‐2 measured intracellular calcium activity ([Ca2+]i) in arteries stimulated with NA but had no effect on [Ca2+]i in arteries stimulated with KCl (125 mm).6 The potent effect of the TKIs in this study is consistent with a role for tyrosine kinases in the mechanisms which regulate both cytoplasmic Ca2+ levels and the effect of Ca2+ on the contractile apparatus in smooth muscle cells in resistance arteries. However, the results must be interpreted cautiously because the enzyme inhibitors may have a poor specificity in intact tissues and because the presumed inactive analogues had potent effects.
Effects of semotiadil fumarate, a novel Ca2+ antagonist, on cytosolic Ca2+ level and force of contraction in porcine coronary arteries
Authors: Kageyama Masaaki , Yanagisawa Teruyuki , Taira Norio 
Published: July 2012

1 The mechanisms of action of semotiadil fumarate, a novel Ca2+ antagonist, were examined by measuring the cytosolic Ca2+ level ([Ca2+]i) and force of contraction in porcine coronary arteries, and by determining [3H]‐pyrilamine binding to bovine cerebellar membranes.2 Semotiadil or verapamil (0.1 and 1 μm) inhibited both the high KCl‐induced increases in [Ca2+]i and force in a concentration‐dependent manner.3 Histamine (30 μm) produced transient increases followed by sustained increases in [Ca2+]i and force, which were inhibited by semotiadil and verapamil (1 and 10 μm).& The agents were different in that semotiadil reduced the maximum [Ca2+]i and force responses to histamine, but not pD2 values, whereas verapamil did reduce the pD2 values for histamine, but not the maximum responses.4 Verapamil (10 μm), but not semotiadil, inhibited histamine‐induced increases in [Ca2+]i and force in Ca2+‐free solution. Neither semotiadil nor verapamil affected the increases in [Ca2+]i and force induced by caffeine. Semotiadil even at the higher concentration (10 μm) did not displace specific binding of [3H]‐pyrilamine to bovine cerebellar membranes.5 These results suggest that semotiadil inhibits both KCl‐ and histamine‐induced contractions mainly by blocking voltage‐dependent L‐type Ca2+ channels.
The effect of nitric oxide donors on haemodynamics and blood flow distribution in the porcine carotid circulation
Authors: van Gelderen E. Marcel , De Bruijne Emile L.E. , Agteresch Hendrik J. , Saxena Pramod R. 
Published: July 2012

1 The role of nitric (NO) in the regulation of capillary and arteriovenous anastomotic blood flow was evaluated in the carotid circulation of the pig. For this purpose, the effect of intracarotid (i.c.) infusions of saline and two NO donors, nitroprusside sodium (NPR) and S‐nitroso‐N‐acetylpenicillamine (SNAP) in concentrations of 3–100 μg min−1 was studied on systemic haemodynamics and carotid blood flow and its distribution in anaesthetized pigs with low arteriovenous anastomotic blood flow, by use of the radioactive microsphere method.2 Apart from heart rate, which increased after both NPR and SNAP, no major changes in systemic haemodynamic variables were observed. In contrast to saline, both NPR and SNAP increased common carotid blood flow, vascular conductance and vascular pulsations dose‐dependently.3 The distribution of the carotid artery blood flow over capillary and arteriovenous anastomotic fraction remained stable after saline infusions. Both NPR and SNAP enhanced total capillary blood flow and conductance. In contrast to NPR, arteriovenous anastomotic blood flow and conductance were increased by SNAP.4 At the tissue level, capillary blood flow increases following NPR or SNAP were reflected by an increase in both extracerebral and dural blood flow without changes in total brain blood flow.5 These results indicate that both NO donors cause arteriolar dilatation together with enhanced vascular pulsations in the carotid circulation of the pig. Probably by way of a ‘steal’ phenomenon, this pronounced arteriolar dilatation limits the effect of NO donors on arteriovenous anastomoses.6 The results of the present investigation support the contention that dilatation of intra‐ and extracranial arteries and arteriovenous anastomoses leads to increased vascular pulsations, which (rather than increased blood flow) could, at least in part, be responsible for the headache caused by nitrovasodilators.
Characterization of the PGE receptor subtype mediating inhibition of superoxide production in human neutrophils
Authors: Talpain E. , Armstrong R.A. , Coleman R.A. , Vardey C.J. 
Published: July 2012

1 The aims of this study were to characterize the EP receptor subtype mediating the inhibition of superoxide anion generation by formyl methionyl leucine phenylalanine (FMLP)‐stimulated human neutrophils, and to test the hypothesis that adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) is the second messenger mediating the inhibition of the neutrophil by prostaglandin (PG)E2.2 PGE2 (0.001 −10 μm) inhibited FMLP (100 nM)‐induced O2‐generation from human peripheral blood neutrophils in a concentration‐dependent manner, with an EC50 of 0.15 ± 0.03 μm, and a maximum effect ranging from 36–84% (mean inhibition of 68.7 ±2.5%, n = 32).3 The EP2‐receptor agonists, misoprostol, 11‐deoxy PGE1, AH13205 and butaprost, all at 10 μm, inhibited O2‐ generation, causing 95.5 ± 2.9%, 56.8 ± 5.2%, 37.1 ±6.6% and 18.9 ±4.4% inhibition respectively, the latter two being much less effective than PGE2. Similarly, the EP1‐receptor agonist, 17‐phenyl PGE2 (10 μm), and the EP3/EP1‐receptor agonist, sulprostone (10 μm), also inhibited O2‐generation, causing 32.2 ± 7.0% and 15.3 ± 3.4% inhibition respectively.4 The non‐selective phosphodiesterase inhibitor, isobutyl methylxanthine (IBMX, 0.25 mM) inhibited the FMLP response by 54.5 ± 5.0%. In addition, IBMX shifted concentration‐effect curves for PGE2, misoprostol, 11‐deoxy PGE1, butaprost, and AH 13205 to the left, to give EC50S of 0.04 ± 0.03 (n = 13), 0.07 ± 0.03 (n = 4), 0.08 ± 0.03 (n = 4), 0.33 ± 0.13 (n = 4) and 0.41 ± 0.2 μm (n = 3) respectively, allowing equieffective concentration‐ratios (EECs, PGE2 = 1) of 11.5, 5.3, 50.7 and 12.7 to be calculated. This agrees well with the relative potencies of these agonists at EP2 receptors.5 By contrast, even in the presence of IBMX (0.25 mM), sulprostone and 17‐phenyl PGE2 were only effective at the highest concentration (10 μm), and gave EECs of > 700 and 486 respectively, suggesting that EP1 or EP3 receptors are not involved.6 The selective type IV phosphodiesterase inhibitor, rolipram at 2 and 10 nM did not inhibit the FMLP response, but at the higher concentration of 50 nM, it decreased the FMLP response by 46.6 ±7.3%. However, rolipram shifted concentration‐effect curves for PGE2 to the left to give EC50S of 0.06 ± 0.022, 0.015 ±0.0, 0.012 ± 0.006 μm at 2, 10 and 50 nM respectively, compared to the control EC50 of 0.27 ± 0.09 μm for PGE2.7 The EP4/TP receptor blocking drug, AH 23848B (10 μm, 10 min) did not inhibit O2‐ generation by PGE2, but was found to potentiate significantly the effect of PGE2 at the lower concentrations of PGF2 tested (0.001‐0.1 μm).8 The adenylate cyclase inhibitor, SQ 22,536 (0.1 mM, 2 min) reduced PGE2‐induced inhibition of O2production, giving an EC50 in the absence of SQ 22,536 of 0.24 ±0.1, and 1.9 ±1.1 μm in its presence.9 These results suggest that inhibition of superoxide generation by PGE2 is mediated by stimulation of EP2 receptors and activation of adenylate cyclase, leading to the elevation of intracellular levels of cyclic AMP.
Delayed‐type hypersensitivity‐induced increase in vascular permeability in the mouse small intestine: inhibition by depletion of sensory neuropeptides and NK1 receptor blockade
Authors: Kraneveld A.D. , Buckley T.L. , van Heuven‐Nolsen D. , van Schaik Y. , Koster A. Sj. , Nijkamp F.P. 
Published: July 2012

1 This study investigates the effects of capsaicin‐induced depletion of sensory neuropeptides and of neurokinin! (NK1) receptor blockade on delayed‐type hypersensitivity (DTH)‐induced changes of vascular permeability in the small intestine of the mouse.2 The DTH reaction in the small intestine was elicited by dinitrofluorobenzene (DNFB)‐contact sensitization followed by oral dinitrobenzene sulphonic acid (DNBS) challenge. To assess vascular leakage the accumulation of the plasma marker, Evans blue (EB), was measured 2, 24 and 48 h after the challenge.3 The small intestinal DTH reaction was characterized by a significant increase in vascular permeability 24 h after the challenge of previously sensitized mice when compared to vehicle‐sensitized mice (P<0.05, ANOVA). Capsaicin‐induced depletion of sensory neuropeptides, two weeks before the sensitization, completely inhibited the DTH‐induced increase in small intestinal vascular permeability at 24 h (P<0.05, ANOVA). Vehicle/control: 108.2 ± 8.6 ngEB mg−1 dry weight; vehicle/DTH 207.8 ±25.1 ngEB mg−l dry weight; capsaicin/control: 65.8 ± 11.9 ng EB mg−1 dry weight; capsaicin/ DTH: 84.3 ± 7.6 ng EB mg−1 dry weight.4 The tachykinins, substance P and neurokinin A (1.5 to 50 × 10−11 mol per mouse, i.v.), induced an increase in vascular leakage in the small intestine of naive mice. The specific NK1 receptor antagonist, RP67580 (10−9 mol per mouse, i.v.) was the most effective in reducing the substance P‐induced plasma extravasation when compared with other NK receptor antagonists, FK224 and FK888.5 Treatment of DNFB‐sensitized mice with RP67580 (10−9 mol per mouse, i.v.) immediately before and 1 h after the DNBS challenge resulted in a significant reduction of the DTH‐induced increase in vascular permeability at 24h (vehicle/control: 107.5 ±8.8 ng EB mg−1 dry weight; RP67580/control: 95.4±5.4ng EB mg−1 dry weight; vehicle/DTH: 206.6± 22.6ng EB mg−1 dry weight; RP67580/DTH: 132.6±13.6 ng EB mg−1 dry weight, P<0.05, ANOVA).6 These results suggest that sensory nerves are involved in the development of small intestinal DTH reactions in the mouse. NK1 receptors could play an important role in the initiation of the DTH‐induced changes in vascular leakage.
An enhancing effect of 5‐hydroxytryptamine on electrically evoked atropine‐resistant contraction of guinea‐pig proximal colon
Authors: Kojima Shu‐Ichi , Shimo Yasuo 
Published: July 2012

In the presence of atropine (0.2 μm) and indomethacin (2 μm), the effects of 5‐hydroxytryptamine (5‐HT) have been studied on electrically‐evoked, neurogenic contractions of the guinea‐pig proximal colon in vitro.
5‐HT, at higher concentrations than 1 nm, caused an increase in electrically (1 Hz, 0.3 ms, 160 mA)‐evoked, atropine‐resistant contractions in a concentration‐dependent manner and at 30 nm produced a maximal effect (pEC50 value of 8.20 ± 0.11, n = 6). The enhancing effects of 5‐HT on the electrically evoked contractions were mimicked by α‐methyl‐5‐HT (pEC50 value of 6.59 ± 0.05, n = 6).
Both hexamethonium (100 μm) and spantide (10 μm), selective antagonists for nicotinic and tachykinin receptors respectively, significantly reduced the enhancement of the electrically evoked contractions by 5‐HT (30 nm).
DAU 6285 (3 μm), a 5‐HT4 receptor antagonist, abolished the enhancing action of 5‐HT (30 nm), but metitepine (0.03 μm), a 5‐HT1/5‐HT2 receptor antagonist, ketanserin (0.01 μm), a 5‐HT2 receptor antagonist, and ondansetron (1 μm), a 5‐HT3 receptor antagonist, had no effect on the enhancement. The enhancing effects of a‐methyl‐5‐HT (1 μm) were also abolished by DAU 6285 (3 μm).
Both 5‐HT (30 nm) and α‐methyl‐5‐HT (1 μm) had no effect on contractions to exogenous substance P (0.15–0.3 nm).
These results indicate that in the guinea‐pig proximal colon, 5‐HT produced an enhancement of atropine‐resistant neurogenic contraction induced by electrical field stimulation through pre‐junctional mechanisms and that the enhancement is mediated by the stimulation of 5‐HT4 receptors located on intramural preganglionic cholinergic neurones and tachykininergic neurones.
Acute versus chronic administration of phosphodiesterase inhibitors on allergen‐induced pulmonary cell influx in sensitized guinea‐pigs
Authors: Banner Katharine H. , Page Clive P. 
Published: July 2012

The aims of this study were to determine which phosphodiesterase (PDE) isoenzymes are involved in the control of eosinophil accumulation in the airways of ovalbumin (OVA)‐immunized guinea‐pigs by the use of isoenzyme selective inhibitors and to compare the effects of acute versus chronic administration of PDE isozyme inhibitors on pulmonary cell influx in ovalbumin‐immunized guinea‐pigs.
Guinea‐pigs were sensitized and subsequently challenged with aerosolized OVA. Twenty four hours later bronchoalveolar lavage (BAL) was performed to permit assessment of inflammatory cell accumulation. A significant increase in the number of eosinophils was observed in the lavage fluid from OVA‐immunized (13.6 ± 1.4 × 104ml−1 in acute experiments and 10.1 ± 1.4 × 104 ml−1 in chronic experiments) animals compared with sham‐treated controls (5.6 ± 0.6 × 104 ml−1 in acute experiments and 5.1 ± 0.6 × 104 ml−1 in chronic experiments). There was no difference in neutrophil, mononuclear cell or total cell numbers between the two groups.
Acute administration of a high dose of selective and non‐selective PDE inhibitors by the i.p. route had no significant effect on eosinophil accumulation in the airways.
Chronic administration of a low dose (3 mg kg−1, i.p., twice daily for 7 days) of the type IV PDE inhibitor, RO 20–1724, and the PDE III/IV inhibitor, zardaverine, produced a significant inhibition of eosinophil accumulation (46% and 59% respectively).
These results suggest that the type IV PDE isoenzyme plays a role in the control of allergen‐induced eosinophil infiltration into the airways, but indicate that a period of low dose chronic treatment with a type IV or mixed type III/IV PDE inhibitor is necessary for eosinophil accumulation in the airways to be reduced.
Inhibition of calcium release from the sarcoplasmic reticulum of rabbit aorta by hydralazine
Authors: Gurney Alison M. , Allam Marina 
Published: July 2012

The mechanism of hydralazine‐induced vasorelaxation was investigated in rabbit isolated aorta, by determining its ability to interfere with force development under a variety of conditions.
Hydralazine relaxed phenylephrine‐contracted aorta with half maximal relaxation at 17 μm and maximal relaxation above 100 μm. At 200 μm, hydralazine had little effect on contractions induced by 25 mm or 50 mm K+.
Hydralazine was equally effective at inhibiting contractile responses to phenylephrine in the absence or presence of extracellular Ca2+. Responses to phenylephrine in Ca2+‐free solution were blocked to the same degree whether hydralazine was applied during filling of the sarcoplasmic reticulum (SR) Ca2+ stores or after filling was complete. Caffeine‐induced contractions were less sensitive to block by hydralazine.
Thapsigargin, cyclopiazonic acid, ryanodine, nifedipine and diltiazem all failed to block the inhibitory effect of hydralazine on tonic contractions to phenylephrine in the presence of extracellular Ca2+. However, when cyclopiazonic acid was applied either with diltiazem or ryanodine, substantial inhibition of the hydralazine response was observed.
We propose that tonic contractions to phenylephrine are largely maintained by Ca2+ cycling through the SR, with Ca2+ entering the smooth muscle cell being sequestered by the SR eventually to leak out through IP3‐activated channels close to the contractile proteins. Sequestration of Ca2+ would employ two pathways, one sensitive to inhibitors of the SR Ca2+‐ATPase and the other to Ca antagonists. We further suggest that, in the presence of extracellular Ca2+ and phenylephrine, the leakage of Ca2+ through IP3‐activated channels is significantly reduced only if both routes for SR Ca2+ accumulation are blocked or the Ca2+‐ATPase is blocked while the SR is made leaky with ryanodine.
We conclude that the main action of hydralazine is to block the IP3‐dependent release of Ca2+ from the sarcoplasmic reticulum. Thus conditions that diminish the contribution of IP3‐induced Ca2+ release to tension can inhibit the hydralazine‐induced vasorelaxation.
Stimulation of human umbilical vein endothelial cell proliferation by A2‐adenosine and β2‐adrenoceptors
Authors: Sexl Veronika , Mancusi Gudrun , Baumgartner‐Parzer Sabina , Schütz Wolfgang , Freissmuth Michael 
Published: July 2012

Adenosine is known to stimulate capillary outgrowth and endothelial cell proliferation, but the underlying mechanism has not been identified. In order to identify the receptor subtype involved, the effects of adenosine receptor agonists and antagonists on human umbilical vein endothelial cell (HUVEC) proliferation were investigated.
Raising intracellular adenosine levels by use of the adenosine transport inhibitor, 4‐nitro‐benzylthioinosine (NBMPR) did not affect cell growth. This observation suggests that stimulation of an extracellular adenosine receptor generates the mitogenic signal.
In the presence of adenosine deaminase (ADA), which was used to remove adenosine present in the culture medium, the adenosine receptor agonists N‐ethylcarboxamidoadenosine (NECA, non‐selective) and CGS21680 (A2A‐receptor‐selective) stimulated [3H]‐thymidine incorporation with a half‐maximum effect at about 10 nM, while N6‐cyclopentyladenosine (CPA, A1selective) was about 100 fold less potent. The adenosine receptor antagonist, xanthine amine congener (XAC) produced a concentration‐dependent decrease in endothelial cell proliferation with a half‐maximum effect at about 10 nM. Hence, stimulation of an endothelial A2A‐adenosine receptor seems responsible for the mitogenic signal.
In the presence of ADA, isoprenaline is also able to stimulate [3H]‐thymidine incorporation with a half maximal effect of about 3 nM, an effect, which is reversed by the highly β2‐selective antagonist, ICI 118,551. In the absence of ADA, isoprenaline exerts only a minor stimulatory effect. Combination of A2A adenosine and β2‐adrenoceptor agonists did not further enhance [3H]‐thymidine incorporation when compared to the sole addition of each agonist. We therefore conclude that both receptors stimulate endothelial cell proliferation via a common signal transduction pathway.
Both receptors are coupled to stimulation of adenylyl cyclase via the stimulatory G protein Gs. However, direct activation of downstream effectors in the cyclic AMP‐signalling cascade (Gs with cholera toxin, adenylyl cyclase with forskolin, protein kinase A with 8Br‐cyclic AMP) not only failed to mimic the action of receptor‐activation, but even reduced cell proliferation.
Similarly, pertussis toxin‐treatment which inactivated the Gi2 protein present in HUVEC and thus inhibited cell proliferation per se, did not impair the ability of A2A‐receptor agonists to stimulate cell proliferation. This suggests that the A2A‐adenosine and β2‐adrenoceptor‐mediated stimulation of endothelial cell proliferation occurs via a mechanism that is independent of Gs and Gi.
Hypertension and enhanced β‐adrenoceptor‐mediated facilitation of noradrenaline release produced by chronic blockade of adenosine receptors
Authors: Guimarães S. , Albino‐Teixeira A. , Paiva M.Q. 
Published: July 2012

The study was undertaken to compare the β‐adrenoceptor‐mediated facilitation of noradrenaline release in the tail artery of vehicle‐treated rats and of rats rendered hypertensive by chronic administration of 1,3‐dipropyl‐8‐sulphophenylxanthine (DPSPX). Artery rings were loaded with [3H]‐noradrenaline, and five periods of electrical stimulation (1 Hz for 2 min) were applied. To eliminate the influence of prejunctional α2‐adrenoceptors, the tissues were pre‐exposed to 1 μm phenoxybenzamine.
Isoprenaline caused a concentration‐dependent increase of tritium overflow elicited by electrical stimulation. It was more effective in arteries from DPSPX‐treated than in those from vehicle‐treated rats; isoprenaline (27.8 nM) increased by 30% tritium overflow in vessels from vehicle‐treated rats whereas isoprenaline (7.0 nM) produced a 30% increase in vessels from DPSPX‐treated animals. Furthermore, the maximal effect of isoprenaline was a 32.6% increase in control rats but a 48.6% increase in DPSPX‐treated rats.
These results show that the sympathetic nerve endings of the rat tail artery are endowed with prejunctional β‐adrenoceptors which mediate facilitation of noradrenaline release elicited by electrical stimulation. They also suggest that adenosine receptors and β‐adrenoceptors interact at the prejunctional level and that impairment of this ‘talk’ may lead to the development of a hypertensive state.