bluuebunny/crossref_metadata_2025_split huggingface dataset:
Vasoreactivity and prostacyclin release in streptozotocin‐diabetic rats: effects of insulin or aldose reductase inhibition
Authors: Stevens E.J. , Willars G.B. , Lidbury P. , House F. , Tomlinson D.R. 
Published: July 2012

Alterations in vasoreactivity and endothelial cell function could underlie some of the vascular abnormalities in diabetes. To examine aspects of these phenomena we studied the effects of 4‐ 6 weeks streptozotocin‐induced diabetes in the rat on basal and angiotensin II (AII)‐stimulated prostacyclin release from isolated lung, perfused at constant flow. In addition, pressure was monitored throughout the lung perfusion as an index of vasomotor tone.
The experiment also included lungs from groups of diabetic rats treated with either insulin or an aldose reductase inhibitor (imirestat), to determine whether these treatments influenced the development of any defects seen in untreated diabetes.
Despite some indication of a trend towards reduced prostacyclin release in lungs from diabetic rats, neither the basal nor AII‐stimulated release was significantly different from that seen in tissues from control animals. There were no significant differences between groups in the average basal perfusion pressure and in either the absolute pressure response to AII or the time of this peak.
The area under the perfusion pressure curve during AII infusion was greater in lungs from diabetic animals than in controls indicating a prolonged vasoconstrictor response. This increased pressor response may indicate increased sensitivity of diabetic tissue to AII or a reduced production of vasodilators in response to the vasoconstriction.
Whichever mechanism was responsible, this alteration was prevented by insulin treatment but not by aldose reductase inhibition, implicating mechanisms probably unrelated to exaggerated polyol pathway flux.
Tachykinin receptors mediating responses to sensory nerve stimulation and exogenous tachykinins and analogues in the rabbit isolated iris sphincter
Authors: Hall Judith M. , Mitchell Debra , Morton Ian K.M. 
Published: July 2012

We have used selective tachykinin receptor agonists and antagonists to investigate the nature of the receptors mediating responses to endogenous and exogenous tachykinins in the rabbit iris sphincter preparation in vitro.
The NK1‐selective agonist, substance P methyl ester, induced contraction with a pD2 of 9.16 indicating the presence of NK1 receptors. In confirmation, the NK1‐selective antagonist, GR82334, competitively antagonized responses to substance P methyl ester with high affinity (pKB 7.46).
NK3 receptors also mediate contraction since NK3‐selective agonists exhibited high potency, e.g. the pD2 of [Me‐Phe7]‐neurokinin B was 9.67, and their responses were not inhibited by GR82334 (10 μm).
NK2 receptor activation does not seem to contribute to contraction since the NK2‐selective agonist [β‐Ala8]‐neurokinin A(4–10) had relatively low potency (pD2 6.43), and the NK2‐selective antagonists MEN10207 (1 μm) and L‐659,877 (10 μm) were inactive or had low affinity, respectively.
GR82334 (1 μm) significantly inhibited responses to electrical field‐stimulation of non‐adrenergic non‐cholinergic sensory nerves (3, 10 and 30 Hz), and caused a rightward shift of the log concentration‐response curve to bradykinin (lateral shift ca. 1000 fold). Higher concentrations of GR82334 (10 μm) significantly attenuated responses to capsaicin (1–60 μm) whilst completely abolishing responses to field‐stimulation (3, 10 and 30 Hz) and bradykinin (1 nm– 3 μm).
In conclusion, NK1 and NK3 receptor activation results in contraction of the rabbit iris sphincter. The contractile response following sensory nerve stimulation by bradykinin, capsaicin and electrical field stimulation results from NK1 receptor activation.
Calcium modulatory properties of 2,6‐dibutylbenzylamine (B25) in rat isolated vas deferens, cardiac and smooth muscle preparations
Authors: Pirisino R. , Banchelli G. , Ignesti G. , Mantelli L. , Matucci R. , Raimondi L. , Buffoni F. 
Published: July 2012

In rat isolated vas deferens the new compound 2,6‐dibutylbenzylamine (B25) evoked a series of repeating rhythmic contractions. Concentration‐response curves constructed for this effect were bell‐shaped, indicating a biphasic effect for this compound. By contrast, B25 depressed heart contractility without any visible positive inotropic or chronotropic activity.
Experiments with tetrodotoxin, reserpine, capsaicin, α‐adrenoceptor blocking compounds and other agents permit us to exclude a release of neuromediators or a direct stimulation of post‐synaptic receptors to account for the rhythmic effect of B25 in the rat vas deferens.
In the same tissue, the increase in 45Ca2+ uptake, the voltage‐dependency as well as the dependence of the B25‐induced rhythmic activity upon the external calcium concentration indicate a direct activation of voltage‐sensitive calcium channels (VSCC).
Verapamil paradoxically stimulated the rhythmic effect of B25 in the rat vas deferens. La3+ was inactive while nifedipine was a weak inhibitor. By contrast Ni2+ and Mn2+ ions were good inhibitors (IC50 < 10−4m), suggesting that a possible opening of T‐type VSCC underlies the rhythmic effect of B25.
In radioligand binding studies competition experiments with [3H]‐nitrendipine indicated that only at high concentrations was B25 able to interact with dihydropyridine‐sensitive binding sites of heart and vas deferens smooth muscle.
B25 (3–30 μm) counteracted the inhibitory effects of ω‐conotoxin GVIA in field‐stimulated rat vas deferens.
Ligand binding properties of putative β3‐adrenoceptors compared in brown adipose tissue and in skeletal muscle membranes
Authors: Sillence Martin N. , Moore Nikki G. , Pegg Graham G. , Lindsay Derek B. 
Published: July 2012

The β‐adrenoceptor population was characterized in membrane preparations from rat brown adipose tissue (BAT) and from soleus muscle by use of the radioligand [125I]‐iodocyanopindolol ([125I]‐ICYP). In addition, atypical binding sites for [125I]‐ICYP found in both tissues were examined, and the relationship between these sites and the putative rat β3‐adrenoceptor is discussed.
It was established that BAT membranes host a mixed population of β1‐ and β2‐adrenoceptors. Of these two sites, 55% showed a high affinity for the β1‐selective ligand CGP 20712A (pK 8.5), and 45% showed a high affinity for the β2‐selective antagonist ICI 118551 (pK 8.6). Soleus muscle membranes were found to host a population of β2‐adrenoceptors, characterized by a high affinity for ICI 118551 (pK 9.1), but β1‐adrenoceptors could not be detected in this preparation. 5‐Hydroxytryptamine receptors were not detected in either preparation.
In addition to β1‐ and β2‐adrenoceptors, atypical binding sites were identified in both tissues using high concentrations of radioligand (0.5–0.6 nm) and in the presence of 1 μm (−)‐propranolol. The atypical sites were abundant, representing 80 and 81% of the total [125I]‐ICYP binding sites in BAT and soleus muscle respectively. When the pK values for 11 ligands were compared, the correlation coefficient for atypical sites in BAT and soleus muscle was 0.94.
The atypical binding sites showed a moderate affinity for (±)‐cyanopindolol (pK 7.3–7.7), poor stereoselectivity for the (+)‐ and (−)‐enantiomers of alprenolol (<10 fold), and a low affinity for β‐adrenoceptor antagonists and partial agonists in the order: (±)‐cyanopindolol>(−)‐alprenolol> (−)‐propranolol = (±)‐ICI 118551 >>(±)‐CGP20712A. The affinity of these ligands for the atypical sites reflects their behaviour in functional studies of putative β3‐adrenoceptors in rat BAT, white adipose tissue, intestine and colon.
The atypical sites labelled by [125I]‐ICYP were resistant to agonist binding, and while the order of affinity of the agonists BRL 37344 > isoprenaline > noradrenaline matches their order of potency at putative β3‐adrenoceptors, none of these compounds caused displacement of the radioligand at concentrations below 10 μm.
It is concluded that the atypical binding sites for [125I]‐ICYP found in rat BAT and soleus muscle membranes are the same, and that these sites show some relationship to the putative rat β3‐adrenoceptor identified in functional studies using antagonists. However, under the conditions used in the present study, pK values obtained for β3‐agonist binding are not useful.
Halothane inhibits the pressor effect of diphenyleneiodonium
Authors: Wang Yong‐Xiang , Pang Catherine C.Y. 
Published: July 2012

We have recently found that diphenyleneiodonium (DPI), a novel inhibitor of nitric oxide (NO) synthase, causes pressor and tachycardic responses in pentobarbitone‐ but not halothane‐anaesthetized rats. The present study investigated the mechanism by which halothane suppresses the pressor response of DPI. The effects of halothane on the pressor response of DPI were also compared with those of other anaesthetic agents.
In conscious rats, i.v. bolus injections of DPI (0.025– 1.6 mg kg−1) caused dose‐dependent increases in mean arterial pressure (MAP), with ED50 of 0.07 ± 0.01 mg kg−1 and maximal rise of MAP (Emax) of 59 ± 2 mmHg. While ketamine potentiated Emax without altering the ED50 and pentobarbitone increased the ED50 without changing Emax of the pressor response to DPI, chloralose, urethane and ethanol displaced the curve to the right and potentiated Emax. In contrast, halothane (0.5–1.25%) dose‐dependently and non‐competitively reduced the pressor responses to DPI.
Intravenous bolus injection of a single dose of DPI (1.6 mg kg−1) caused immediate and large increases in plasma noradrenaline and adrenaline, as well as MAP in conscious rats. Halothane (1.25%) almost completely inhibited these increases.
The results suggest that DPI causes a pressor response in conscious rats by activating the sympathetic nervous system and halothane abolishes this pressor response by inhibiting activities of the sympathetic nervous system. The results also show that influences of anaesthetics must be taken into consideration when evaluating pressor response of vasoactive agents.
Selective reduction of N‐methyl‐D‐aspartate‐evoked responses by 1,3‐di(2‐tolyl)guanidine in mouse and rat cultured hippocampal pyramidal neurones
Authors: Fletcher Elizabeth J. , Church John , Abdel‐Hamid Khaled , MacDonald John F. 
Published: July 2012

The effects of 1,3‐di(2‐tolyl)guanidine (DTG) were examined on the responses of cultured hippocampal neurones to the excitatory amino acid analogues N‐methyl‐d‐aspartate (NMDA), kainate, quisqualate and (RS)‐α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionate (AMPA).
In rat hippocampal neurones loaded with the Ca2+‐sensitive dye Fura‐2, DTG (10–100 μm) produced a concentration‐dependent depression of the NMDA‐evoked rises in intracellular free calcium ([Ca2+]i), an effect that was not modified by changes in the extracellular glycine concentration. DTG (at 50 and 100 μm) also attenuated, although to a lesser extent, the rises in [Ca2+]i evoked by naturally‐derived quisqualate. In contrast, 50 and 100 μm DTG did not depress responses evoked by kainate, AMPA and synthetic, glutamate‐free (+)‐quisqualate although on occasions DTG enhanced kainate‐and AMPA‐evoked rises in [Ca2+]i.
DTG attenuated NMDA‐evoked currents recorded from mouse hippocampal neurones under whole‐cell voltage‐clamp with an IC50 (mean ± s.e.mean) of 37 ± 5 μm at a holding potential of −60 mV. The DTG block of NMDA‐evoked responses was not competitive in nature and was not dependent on the extracellular glycine or spermine concentration. The block did, however, exhibit both voltage‐, and use‐, dependency. The steady‐state current evoked by naturally‐derived quisqualate was also attenuated by DTG whereas those evoked by kainate and AMPA were not.
We conclude that DTG, applied at micromolar concentrations, is a selective NMDA antagonist in cultured hippocampal neurones, the block exhibiting both Mg2+‐ and phencyclidine‐like characteristics. Given the nanomolar affinity of DTG for σ binding sites it is unlikely that the antagonism observed here is mediated by σ‐receptors, but the data emphasize the potential danger of ascribing the functional consequences of DTG administration solely to σ receptor‐mediated events.
Blockade of adenosine receptors unmasks a stimulatory effect of ATP on cardiac contractility
Authors: Mantelli Laura , Amerini Sandra , Filippi Sandra , Ledda Fabrizio 
Published: July 2012

The effects of ATP, α,β‐methylene ATP and β,γ‐methylene ATP on the contractile tension of guinea‐pig isolated left atria were evaluated.
ATP (1– 100 μm) produced a concentration‐dependent negative inotropic effect; this response was converted to a positive inotropic effect in the presence of the antagonist of adenosine A1 receptors, 1,3‐dipropyl‐8‐cyclopentylxanthine (DPCPX; 0.1 μm), and in the presence of 8‐phenyltheophylline (10 μm), an antagonist of A1 and A2 receptors.
The positive inotropic effect of ATP was antagonized by the P2 receptor antagonist, suramin (500 μm). Reactive blue 2 (30‐ 500 μm), a putative P2y receptor antagonist, concentration‐dependently reduced and finally abolished the effect of ATP.
In the presence of 8‐phenyltheophylline, the stable analogues of ATP, α,β‐methylene ATP and β,γ‐methylene ATP (1– 30 μm), produced a concentration‐dependent increase in atrial contractility of a lesser degree than that induced by ATP.
The results suggest that when inhibitory adenosine receptors are blocked, ATP produces a positive inotropic effect, probably mediated by P2y receptor stimulation.
Altered cardiac adrenergic neurotransmission in streptozotocin‐induced diabetic rats
Authors: Gando Satoshi , Hattori Yuichi , Kanno Morio 
Published: July 2012

Functional alterations of the sympathetic neuroeffector junction of the left atria were studied in rats with streptozotocin‐induced diabetes.
Eight to 12 weeks of diabetes resulted in a marked decrease in the positive inotropic response of left atria to electrical field stimulation (EFS).
The overflow of [3H]‐noradrenaline from diabetic left atria caused by EFS was much less than that from control preparations.
The concentration‐response curves showed no change in sensitivities of the left atria to exogenous noradrenaline and tyramine in diabetic rats. The maximum positive inotropic response to these agents were similar in diabetic and control animals.
The left atrial content of noradrenaline was not significantly changed in diabetic rats. The cocaine‐sensitive uptake of [3H]‐noradrenaline was also unaltered.
Atropine enhanced the positive inotropic response and [3H]‐noradrenaline overflow induced by EFS in control left atria. Similarly, yohimbine caused an enhancement of EFS‐evoked inotropic response in control atria. However, these effects of the antagonists were not observed in diabetic left atria.
It is concluded that the decrease in the positive inotropic response of the left atria to EFS in diabetic rats is caused by an impairment of noradrenaline release from the sympathetic nerve terminals through a calcium‐dependent exocytotic mechanism. The present results also indicate that presynaptic α2‐adrenoceptors and muscarinic receptors that are linked to inhibition of the noradrenaline release during nerve stimulation may be functionally impaired in diabetic animals.
Stimulation of angiogenesis by substance P and interleukin‐1 in the rat and its inhibition by NK1 or interleukin‐1 receptor antagonists
Authors: Fan Tai‐Ping D. , Hu De‐En , Guard Steven , Gresham G. Austin , Watling Keith J. 
Published: July 2012

Daily administration of 1 nmol substance P or 3 pmol recombinant human interleukin‐1 alpha (IL‐1α) caused intense neovascularization in a rat sponge model of angiogenesis. Lower doses of substance P (10 pmol) or IL‐1α (0.3 pmol) were ineffective when given alone. When combined at these low doses, substance P and IL‐1α interacted to produce an enhanced neovascular response.
By use of selective tachykinin NK1, NK2 and NK3 receptor agonists, ([Sar9,Met(O2)11]substance P, [β‐Ala8]neurokinin A(4–10), Succ‐[Asp6,MePhe8]substance P(6–11) (senktide), respectively), it was established that the activation of NK1 receptors is most likely to mediate the angiogenic response to substance P in this model.
The angiogenic activity of substance P and IL‐1α (10 pmol and 0.3 pmol day−1, respectively) was abolished by co‐administration of (i) the selective peptide NK1 receptor antagonist, L‐668,169 (1 nmol day−1), (ii) the selective non‐peptide NK1 receptor antagonists, RP 67580 and (±)‐CP‐96,345 (both at 1 nmol day−1) or (iii) the IL‐1 receptor antagonist, IL‐1ra, (50 μg day−1). In contrast, the selective NK2 receptor antagonist, L‐659,874 (1 nmol day−1) was ineffective.
The angiogenic action of substance P and IL‐1α was resistant to modification by mepyramine (1 nmol day−1) and/or cimetidine (10 nmol day−1), indomethacin (7 nmol day−1) or the platelet‐activating factor (PAF) antagonist, WEB‐2086 (22 nmol day−1), indicating that histamine, prostaglandins and PAF are not likely to be involved in this neovascular response.
The inhibition of the substance P/IL‐1 angiogenic response by selective NK1 receptor antagonists or by an IL‐1 receptor antagonist demonstrates that angiosuppression can be achieved by blocking the activity of angiogenic factors at the receptor level.
Membrane current responses to externally‐applied ATP in the longitudinal muscle of the chicken rectum
Authors: Matsuoka T. , Komori S. , Ohashi H. 
Published: July 2012

Membrane current responses to ATP in enzymically‐dispersed single smooth muscle cells from the chicken rectum were investigated by the whole‐cell voltage clamp technique.
In cells dialysed with a KCl‐rich solution under voltage clamp at a holding potential of −40 mV, ATP (10 μm) produced an inward current followed by an outward current. When the holding potential was changed to 0 mV and −80 mV, the biphasic current response to ATP was converted to an outward current alone and an inward current alone, respectively.
External application of tetraethylammonium (TEA, 5 mm), intracellular dialysis with a CsCl‐rich solution, or inclusion of EGTA (10 mm) in the pipette abolished the outward current response to ATP.
Neither depletion of Ca2+ store with caffeine (10 mm) nor block of voltage‐gated Ca2+ channels with nifedipine (10 μm) affected the biphasic current response to ATP. After removal of the extracellular Ca2+ the outward current response to ATP was abolished.
α,β‐methylene ATP (100 μm) elicited a current similar to the ATP‐induced current. In the presence of α,β‐methylene ATP (100 μm), application of ATP (100 μm) was without effect.
In CsCl‐filled cells, ATP analogues elicited an inward current and the order of potency was ATP ≒ α,β‐methylene ATP > ADP > > AMP.
Inclusion of GTP γ S (0.2 mm) or GDP β S (2 mm) in the pipette did not affect the ATP‐induced inward current in CsCl‐filled cells. The reversal potential of the ATP‐induced inward current was about 0 mV and was completely inhibited after replacement of the cations in the bath solution by Tris. The reversal potential remained almost unchanged after replacement of Na+ in the bath solution with 110 mm Ca2+, but shifted in the negative direction after replacement of Na+ or both Na+ and Ca2+ with glucosamine.
The results suggest that ATP acts on P2 purinoceptors to cause activation of cation channels with selectivity for Ca2+ over Na+. Moreover, it appears that no G‐protein‐mediated mechanism is involved and increased Ca2+ entry through the cation channels causes activation of Ca2+‐activated K+ channels.
Effects of l‐ and d‐arginine and some related esters on the cytosolic mechanisms of α‐thrombin‐induced human platelet activation
Authors: Failli Paola , Cecchi Enrica , Ruocco C. , Fazzini A. , Giotti A. 
Published: July 2012

In Fura‐2 preloaded human platelets, the increase in cytosolic calcium induced by α‐thrombin was reduced by some l‐ and d‐arginine ester compounds the IC50 (μm) values of which were 7.4 for TAEE, 56.9 for BAEE, 77.6 for TAME, 560 for T(d)AME, 656.3 for l‐ArgOMe and 2206.7 for d‐ArgOMe. α‐tosyl‐l‐Arginine, l‐ and d‐arginine were inactive.
The inhibitory activity of the l‐arginine esters was not modified when platelets were pretreated with 100 μm Nω‐monomethyl‐l‐arginine.
The l‐arginine esters did not increase cyclic GMP content in platelets either in the presence or absence of indomethacin and apyrase at rest and after α‐thrombin stimulation.
The kinetic parameters of platelet Na+/H+ antiporter (amiloride‐inhibitable, evaluated after cytosolic nigericin‐induced acidification) were modified by l‐ and d‐arginine esters, while the native amino acids were ineffective.
The inhibitory effects of the l‐ and d‐arginine esters on platelet activation appear to be mainly due to their inhibitory effect on Na+/H+ antiporter.
The effects of ATP and α,β‐methylene‐ATP on cytosolic Ca2+ level and force in rat isolated aorta
Authors: Kitajima Satoshi , Ozaki Hiroshi , Karaki Hideaki 
Published: July 2012

The effects of a non‐selective P2‐receptor agonist ATP and a selective P2x‐receptor agonist α,β‐methylene‐ATP on intracellular free Ca2+ level ([Ca2+]i) and force were examined in rat isolated aorta without endothelium.
Both ATP (1–1000 μm) and α,β‐methylene‐ATP (0.1–100 μm) induced transient increase followed by small sustained increase in [Ca2+]i in a concentration‐dependent manner. Compared with the force induced by a high concentration of KCl, the force induced by α,β‐methylene‐ATP was smaller and that induced by ATP was much smaller at a given [Ca2+]i.
An L‐type Ca2+ channel blocker, verapamil (10 μm), completely inhibited the high K+‐stimulated [Ca2+]i and force. Verapamil partially inhibited the transient and sustained increases in [Ca2+]i induced by 10 μm α,β‐methylene‐ATP and the sustained increase but not the transient increase induced by 1 mm ATP.
In the absence of extracellular Ca2+ (with 0.5 mm EGTA) 1 mm ATP caused transient increase in [Ca2+]i while 10 μm α,β‐methylene‐ATP was ineffective
ATP, but not α,β‐methylene‐ATP, increased the tissue adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) level.
These data suggest that ATP and α,β‐methylene‐ATP increase [Ca2+]i by an activation of both L‐type and non‐L‐type Ca2+ channels. In addition, ATP, but not α,β‐methylene‐ATP, increases [Ca2+]i by a release of Ca2+ from an intracellular Ca2+ store. Possible reasons are discussed as to why the increase in [Ca2+]i due to ATP and α,β‐methylene‐ATP resulted in only a small contraction.