bluuebunny/crossref_metadata_2025_split huggingface dataset:
The haemodynamic actions of ZENECA ZD7288, a novel sino‐atrial node function modulator, in the exercising beagle: a comparison with zatebradine and propranolol
Authors: Rouse W. , Stafford P.J. , Johnson I.R. 
Published: July 2012

ZENECA ZD7288 (4‐(N‐ethyl‐N‐phenylamino)‐1,2‐dimethyl‐6‐(methylamino) pyrimidinium chloride, formerly ICID7288) is a novel sino‐atrial node function modulator which selectively slows heart rate.
The haemodynamic effects of ZD7288 (0.1, 0.3 and 1.0 mg kg−1, i.v.) have been evaluated and compared with those of placebo (physiological saline), zatebradine (ULFS 49, 0.1, 0.3 and 1.0 mg kg−1, i.v.) and propanolol (0.03, 0.1, and 0.3 mg kg−1, i.v.) in beagles chronically instrumented for measurement of heart rate, aortic pressure, aortic flow and dPLV/dtmax. The dogs were trained to run at 6.5 k h−1 on a level treadmill for 5 min at half hourly intervals over a period of 4 h. Drugs were dosed cumulatively after the second, fourth and sixth exercise periods.
Control experiments demonstrated a degree of accommodation to repeated exercise over a period of 4 h. Resting heart rate decreased by 21 beats min−1, but heart rate response to exercise was maintained, whereas dPLV/dtmax at rest remained steady while the response to exercise decreased significantly (by 25% after 2 h, P < 0.05).
ZD7288 and zatebradine both decreased heart rate during exercise in a dose‐dependent manner, whilst heart rate at rest did not differ from resting heart rates in saline dosed control animals. In contrast, heart rate at rest and during exercise were lowered equally by the lowest doses of propranolol (approximately by 30 beats min−1), and additional doses caused only minor additional decreases. The exercise‐induced tachycardia was maintained within 12% of pre‐dose levels, presumably by withdrawal of vagal tone.
Cardiac inotropism, as indicated by dPLV/dtmax, was not affected by ZD7288 or zatebradine at rest, although the inotropic response to exercise decreased in proportion to the decreases in exercise‐induced tachycardia. Propranolol caused a marked dose‐dependent decrease in the exercise‐induced inotropic response (by 85% at 0.3 mg kg−1).
Whilst the sino‐atrial node modulators increased stroke volume at rest, and augmented increases in response to exercise, propranolol did not affect resting stroke volume and decreased the responses to exercise.
Cardiac output at rest and cardiac output increases during exercise were well maintained in the presence of ZD7288 and zatebradine in contrast to propranolol which induced a significant depression of cardiac output, both at rest and during exercise. Propranolol also caused significant systemic vasoconstriction.
In conclusion, ZD7288 has haemodynamic actions comparable to those of zatebradine despite their chemical dissimilarity. ZD7288 may be of benefit in the treatment of ischaemic heart disease by reducing heart rate without impairing cardiac function.
Contractile effects of uridine 5′‐triphosphate in the rat duodenum
Authors: Johnson C. R. , Hourani S.M.O. 
Published: July 2012

Previous studies have shown that the rat duodenum relaxes to adenosine and adenosine 5′‐triphosphate (ATP) via Pi and P2Y purinoceptors respectively, but in preliminary studies uridine 5′‐triphosphate (UTP) was found to contract this tissue. The non‐selective P2 antagonist suramin and a number of nucleotides were therefore used to investigate this response further.
ATP, UTP, adenosine 5′‐diphosphate (ADP), adenosine 5′‐0‐(3‐thiotriphosphate) (ATP‐γ‐S), guanosine 5′‐triphosphate (GTP) and uridine 5′‐diphosphate (UDP) each relaxed the duodenum, with an agonist potency order of ATP = ADP > ATP‐γ‐S > > GTP > > UTP = UDP, consistent with the presence of a P2Y purinoceptor mediating relaxation.
ATP‐γ‐S, UTP and UDP each contracted the duodenum with an agonist potency order of ATP‐γ‐S > UTP > UDP, although maximal responses to these agonists were not obtained at a concentration of 267 μm (ATP‐γ‐S) and 300 μm (UTP and UDP). No contractions were observed with any of the other agonists at concentrations up to 300 μm.
Indomethacin (25 μm) did not inhibit the contractions induced by UTP, indicating that they were not mediated via production of prostaglandins.
Suramin (100 μm and 1 μm) inhibited relaxations induced by ATP, shifting the concentration‐response curve to the right, with the maximal response to ATP being decreased by the higher concentration of suramin (1 μm). Suramin (1 μm) inhibited relaxations induced by ATP‐γ‐S, shifting the concentration‐response curve to the right, and completely abolished contractions induced by ATP‐γ‐S. In contrast, suramin (100μm and 1mM) had no effect on contractions induced by UTP. Contractions induced by UTP were, however, less sustained in the presence of suramin, which also affected the basal tone of some tissues when precontracted with carbachol (0.1 μm). In the presence of suramin (1 μm), no contractions to ATP were observed.
These results confirm that in the rat duodenum there is a P2Y purinoceptor that mediates relaxation in response to a number of purine nucleotides, and at which the pyrimidine nucleotides UTP and UDP are almost inactive. There are also receptors at which UTP and ATP‐γ‐S act to cause contraction. Suramin discriminates between the contractile effects of these two agonists, which may indicate the presence of a suramin‐insensitive pyrimidinoceptor as well as a suramin‐sensitive receptor for ATP‐γ‐S. An alternative explanation is that the differential effects of suramin are via its actions as an antagonist in addition to its action as an ectonucleotidase inhibitor.
In vitro studies of release of adenine nucleotides and adenosine from rat vascular endothelium in response to α1‐adrenoceptor stimulation
Authors: Shinozuka K. , Hashimoto M. , Masumura S. , Bjur R.A. , Westfall D.P. , Hattori K. 
Published: July 2012

Noradrenaline‐induced release of endogenous adenine nucleotides (ATP, ADP, AMP) and adenosine from both rat caudal artery and thoracic aorta was characterized, using high‐performance liquid chromatography with fluorescence detection.
Noradrenaline, in a concentration‐dependent manner, increased the overflow of ATP and its metabolites from the caudal artery. The noradrenaline‐induced release of adenine nucleotides and adenosine from the caudal artery was abolished by bunazosin, an α‐adrenoceptor antagonist, but not by idazoxan, an α2‐adrenoceptor antagonist. Clonidine, α 2‐adrenoceptor agonist, contracted caudal artery smooth muscle but did not induce release of adenine nucleotides or adenosine.
Noradrenaline also significantly increased the overflow of ATP and its metabolites from the thoracic aorta in the rat; however, the amount of adenine nucleotides and adenosine released from the aorta was considerably less than that released from the caudal artery.
Noradrenaline significantly increased the overflow of ATP and its metabolites from cultured endothelial cells from the thoracic aorta and caudal artery. The amount released from the cultured endothelial cells from the aorta was also much less than that from cultured endothelial cells from the caudal artery. In cultured smooth muscle cells from the caudal artery, a significant release of ATP or its metabolites was not observed.
These results suggest that there are vascular endothelial cells that are able to release ATP by an α1‐adrenoceptor‐mediated mechanism, but that these cells are not homogeneously distributed in the vasculature.
Effect of activity at metabotropic, as well as ionotropic (NMDA), glutamate receptors on morphine dependence
Authors: Fundytus Marian E. , Coderre Terence J. 
Published: July 2012

The contribution of various excitatory amino acid (EAA) receptors (NMDA, AMPA/kainate and metabotropic) in the brain to the development of morphine dependence was examined. This was performed by measuring the severity of the precipitated withdrawal syndrome following chronic subcutaneous (s.c.) morphine and intracerebroventricular (i.c.v.) EAA antagonist treatment.
Continuous subcutaneous (s.c.) treatment with morphine sulphate (36.65 μmol day−1) produced an intense and reliable naloxone‐precipitated withdrawal syndrome.
Chronic i.c.v. treatment with antagonists selective for metabotropic and NMDA receptors, but not AMPA/kainate receptors, significantly attenuated abstinence symptoms. Conversely, EAA antagonists had very little effect on non‐withdrawal behaviours.
These results suggest that, as well as changes elicited by activation of NMDA receptors, metabotropic receptors and intracellular changes in the phosphatidylinositol (PI) second‐messenger system or the cyclic adenosine 3′,5′‐monophosphate (cAMP) second messenger system, to which EAA metabotropic receptors are linked, may be involved in the development of opioid dependence with chronic morphine treatment.
Differences in sensitivity to the specific protein kinase C inhibitor Ro31‐8220 between small and large bronchioles of the rat
Authors: Chopra L.C. , Twort C.H.C. , Ward J.P.T. 
Published: July 2012

The involvement of protein kinase C (PKC) in constriction of small bronchioles has never been investigated. In this study we have examined the effects of the specific PKC inhibitors Ro31‐8220 and Ro31‐7549 and the non‐specific inhibitor H7 on carbachol‐, 5‐hydroxytryptamine (5‐HT)‐ and 4β‐phorbol dibutyrate (4β‐PDBu)‐induced contractions in large and small bronchioles.
The study was performed on isolated bronchioles of the rat with internal diameters of 574 μm ± 11 (small, n= 128), and 1475 μm ± 32 (large, n = 93), using a Mulvaney‐Halpen small vessel myograph.
In these preparations 4β‐PDBu had no effect if added on its own. However, after precontracting with 30 mm K+, 0.5 μm 4β‐PDBu caused a contractile response of 110.4 ± 7.0% TK (TK = maximum response to 75 mm K+ in small and 69.3 ± 6.5% TK in large bronchioles. Ro31‐8220, Ro31‐7549 and H7 all showed concentration‐dependent inhibition of this response.
In small bronchioles 10 μm Ro31‐8220 shifted both the carbachol and 5‐HT concentration‐ response curves to the right, and reduced the maximum response. In contrast, 10 μm Ro31‐8220 had no significant effect on the EC50 to carbachol of larger bronchioles, although the maximum response was reduced, and had no significant effect on the 5‐HT concentration‐ response curve. 200 μm H7 shifted the carbachol concentration‐ response curve to the right as well as reducing the maximal response in both small and large bronchioles.
Large bronchioles exhibited a greater rate of decay of carbachol‐induced contraction than did small bronchioles. Pretreatment with Ro31‐8220 accelerated the rate of decay.
Pretreatment with IOIIM Ro31‐8220 caused a small reduction in the response to 75 mm K+ in both small and large bronchioles (small: to 87.8 ± 3.0% TK; large: to 94.1 ± 0.8% TK). H7 at 200 μm caused a much larger reduction in both preparations (small: to 75.1 ± 3.0% TK); large: to 82.7 ± 0.6% TK).
Small bronchioles were more sensitive than larger bronchioles to agonists and phorbol ester. The protein kinase inhibitor Ro31‐8220 could reduce agonist‐induced constriction in small and large bronchioles, as well as reducing or abolishing phorbol ester‐induced contractions. Small bronchioles were more sensitive than large bronchioles to Ro31–8220. These results suggest that there is a significant PKC involvement in constriction of bronchioles to carbachol and 5‐HT, and that the proportion of the contractile response that can be attributed to PKC is greater in smaller than larger bronchioles.
Calcitonin gene‐related peptide receptors in human gastrointestinal epithelia
Authors: Cox H.M. , Tough I.R. 
Published: July 2012

The secretory responses to calcitonin gene‐related peptide (CGRP) receptor agonists have been characterized in two human adenocarcinoma cell lines, namely HCA‐7 and Colony‐29 (Col‐29) epithelia. These cells form polarized epithelial layers when grown on permeable supports and allow changes in electrogenic ion transport in response to agonists to be monitored continuously.
α‐CGRP (rat and human sequences), rat β‐CGRP and human [Tyr0]CGRP applied to the basolateral surface were found to be full agonists, causing prolonged increases in short‐circuit current. Concentration‐response curves exhibited EC50 values of 0.6‐1.5 nm in HCA‐7 cells. The same agonists were less effective in Col‐29 epithelia, the EC50 values ranging from 1 to 10 nm in these cells. [Cys(ACM)2,7]CGRP was effective in both cell lines and was more potent in HCA‐7 cells.
CGRP receptors were preferentially located on the basolateral surface in both cell types. Addition of rα‐CGRP to the apical domain produced significantly smaller secretory responses (8.1% in HCA‐7 and 29.2% in Col‐29) compared with those produced following basolateral application (100%).
In both cell lines rα‐CGRP‐elevated short‐circuit current was inhibited by the loop diuretic piretanide (200μm) and by somatostatin (100 nm). Pretreating epithelia with the cyclo‐oxygenase inhibitor, piroxicam (5μm) had no significant effect upon CGRP responses in either cell line.
Rat α‐CGRP (0.2 nm) responses in HCA‐7 epithelia were inhibited by the C‐terminal fragment CGRP(8–37) (1 μm). Pretreatment of Col‐29 cells with CGRP(8–37) did not, however, alter the size or profile of responses to rα‐CGRP (1 nm).
We conclude that high‐affinity CGRP receptors exist on the basolateral surface of both cell lines, however they differ in their sensitivity to CGRP(8–37) and agonist orders of potency. Thus different CGRP receptor subtypes appear to predominate in these two epithelial cell types.
Block of Endothelin‐1‐induced release of thromboxane A2 from the guinea pig lung and nitric oxide from the rabbit kidney by a selective ETB receptor antagonist, BQ‐788
Authors: D'Orléans‐Juste Pedro , Claing Audrey , Télémaque Sabine , Maurice Marie‐Claude , Yano Mitsuo , Gratton Jean‐Philippe 
Published: July 2012

The present study characterizes the receptors responsible for endothelin‐1‐induced release of thromboxane A2 from the guinea pig lung and of endothelium‐derived nitric oxide from the rabbit perfused kidney, by the use of the selective ETA receptor antagonist, BQ‐123, and a novel selective ETB receptor antagonist, BQ‐788.
In the guinea pig perfused lung, endothelin‐1 (ET‐1) (5 nm) induced a marked increase of thromboxane A2 which was reduced by 17 ± 5.0, 70 ± 1.0 and 93 ± 1.2% by BQ‐788 infused at concentrations of 1, 5 and 10 nm respectively. In contrast, BQ‐123 (0.1 and 1.0 μm) had little or no effect on the ET‐1‐induced release of thromboxane A2.
In the same perfused model, the selective ETB agonist, IRL 1620 (50 nm), stimulated the release of thromboxane A2, but not prostacyclin. The eicosanoid‐releasing properties of IRL 1620 were abolished by BQ‐788 at 10 nm, yet were unaffected by BQ‐123 (1 μm).
In the rabbit perfused kidney, BQ‐788 (10 nm) potentiated the increase of perfusion pressure induced by endothelin‐1 (1,5 and 10 nm) by approximately 90%, but not that induced by angiotensin II (1 μm). Furthermore, the selective ETB receptor antagonist did not reduce the release of prostacyclin triggered by either peptide.
In another series of experiments, pretreatment of the perfused kidney with a nitric oxide synthase inhibitor, L‐NAME (100 μm), potentiated the pressor responses to both endothelin‐1 and angiotensin II. Under L‐NAME treatment, BQ‐788 did not further potentiate the pressor response to endothelin‐1.
Our results illustrate the predominant role of ETB receptor activation in the release of thromboxane A2 and nitric oxide triggered by endothelin‐1 in the guinea pig perfused lung and rabbit kidney respectively.
Voltage‐ and time‐dependent inhibitory effects on rat aortic and porcine coronary artery contraction induced by propafenone and quinidine
Authors: Pérez‐Vizcaíno Trancisco , del Pozo Buensuceso Fernández , Zaragozá Francisco , Tamargo Juan 
Published: July 2012

Class I antiarrhythmic drugs (e.g. Na+ channel blockers) such as propafenone and quinidine also inhibit voltage‐gated Ca2+ and K+ channels. In the present paper the voltage‐ and time‐dependent inhibitory effects of propafenone and quinidine were studied on depolarization‐induced vascular contractions and 45Ca2+ uptake in isolated endothelium denuded rat aorta and pig left descending coronary artery.
Quinidine and propafenone (10−7m‐5 × 10−5m) produced a concentration‐dependent relaxation of the contractions induced by 80 mm KCl. Propafenone was significantly more potent (P < 0.05) than quinidine in both rat aorta and pig coronary arteries but both drugs were more potent (P < 0.05) in relaxing rat aorta than pig coronary arteries. In rat aortic rings, the relaxant effects of propafenone were unaffected by pretreatment with the Na+ channel blocker, tetrodotoxin.
The degree of inhibition produced after prolonged exposure (40 min) to propafenone and quinidine differed as the time of depolarization with 80 mm KCl was increased. Quinidine (3 × 10−6 m, 10−5 m and 3 × 10−5 m) not only produced an inhibition at the very early stage of contraction, but also a time‐dependent inhibition was observed. In contrast, propafenone (10−6 m, 3 × 10−6m and 10−5 m) produced a more marked concentration‐dependent early block but only a mild time‐dependent inhibittion.
The voltage‐dependence of propafenone‐ and quinidine‐induced inhibition, was studied in rat aorta and coronary arteries which had been incubated in 5 or 40 mm KCl Ca2+‐free solution and then contracted by changing the bath solution to 100 mm KCl and 2 mm CaCl2 solution. The inhibitor effects of quinidine were significantly enhanced (P < 0.05) when the preparations were preincubated in 40 mm KCl (depolarizing) solution. In contrast, the effects of propafenone were quite similar in 5 or in 40 mm KCl solution.
Quinidine, 10−5 m, produced a greater inhibition (P < 0.05) of 100 mm KCl‐stimulated 45Ca2+ uptake in aortic rings preincubated in depolarizing as compared to normal solution. In contrast, the inhibition produced by 3 × 10−6 m propafenone was similar in aortic rings incubated in 5 or 40 mm KCl solution.
It is concluded that both quinidine and propafenone inhibited vascular smooth muscle contraction which could be attributed to reduced Ca2+ entry. The voltage‐ and time‐dependent inhibitory effects of quinidine may reflect an increased binding of the drug to Ca2+ channels at depolarized potentials.
The effects of β‐adrenoceptor stimulation on adhesion of human natural killer cells to cultured endothelium
Authors: Benschop Robert J. , Nijkamp Frans P. , Ballieux Rudy E. , Heijnen Cobi J. 
Published: July 2012

The circulation of natural killer (NK) cells in vivo is influenced by physical exercise, mental stress, and infusion of β‐adrenoceptor agonists. We have previously presented in vitro data, showing that β2‐adrenoceptor agonists induce detachment of NK cells from endothelial cells (EC), supporting the hypothesis that NK cells can be recruited from the marginating pool in blood vessels.
Because NK cells as well as EC express β2‐adrenoceptors, the present study was conducted to investigate whether stimulation of the β‐adrenoceptors on NK cells, EC or both cell types is required to induce detachment from EC.
Cells were pretreated (15min) with a selective β2‐adrenoceptor antagonist, GR81706, at various concentrations. The duration of β‐adrenoceptor blockade was tested by determining the adenosine 3′,5′‐cyclic monophosphate (cyclic AMP) production induced by terbutaline (a β2‐adrenoceptor specific agonist). This receptor‐mediated response was effectively inhibited for at least 4 h, whereas the cyclic AMP production in response to forskolin (a direct activator of adenylate‐cyclase) was not affected.
Functional adhesion assays were then performed to determine the role of β‐adrenoceptors on the different cell types involved (NK and EC) in catecholamine‐induced detachment. Peripheral blood mononuclear cells were allowed to adhere for 1 h to monolayers of unstimulated EC in the presence or absence of cyclic AMP inducing agents, and the percentage of NK cells in the adhering lymphocyte fraction was determined by flow cytometry.
Both adrenaline (10−5 m) and forskolin (10−5 m) caused detachment of NK cells from EC. After blockade of the β2‐adrenoceptors on NK cells by pretreatment with GR81706 (10−6 m), the effect of adrenaline on NK cells adhesion was pretented; after blockade of the β2‐adrenoceptors on EC, NK cell adhesion was still significantly reduced by adrenaline. In all cases, forskolin caused detachment of NK cells.
To establish further that stimulation of β‐adrenoceptors on NK cells is sufficient to cause detachment, we showed that adrenaline also reduced adhesion of NK cells to monolayers of Chinese hamster ovary cells, which do not express β‐adrenoceptors.
Together, these results show that stimulation of β2‐adrenoceptors on NK cells negatively influences their capacity to adhere to EC, and that β2‐adrenoceptors on EC play a negligible role in this phenomenon.
The interaction of α‐human atrial natriuretic peptide (ANP) with salbutamol, sodium nitroprusside and isosorbide dinitrate in human bronchial smooth muscle
Authors: Nally Jane E. , Clayton Robert A. , Thomson Neil C. , McGrath John C. 
Published: July 2012

Contractions in human bronchial rings evoked by methacholine (10−6 m) were reversed by single contractions of α‐human atrial natriuretic peptide (10−6 m), salbutamol (10−6 m), sodium nitroprusside (10−6 m) or isosorbide dinitrate (4.2 × 10−5 m) and the extent of the relaxations compared. The activity of combinations of ANP with salbutamol, sodium nitroprusside and isosorbide dinitrate were compared with those for each agonist alone.
ANP and salbutamol were equipotent in reversing methacholine‐evoked contraction and, in combination these agonists evoked an additive response. ANP and sodium nitroprusside also evoked similar degrees of relaxation and were additive, as were ANP and isosorbide dinitrate; however, with isosorbide dinitrate a higher concentration was required to evoke the same degree of relaxation as ANP, sodium nitroprusside or salbutamol.
Cumulative concentration‐response curves to methacholine (10−9‐3 × 10−4 m) were examined in the presence and absence of the above bronchodilator substances, alone and in combination allowing their abilities to protect against contraction to be compared. ANP (10−6 m) and salbutamol (10−6 m) each attenuated subsequent contractions evoked by methacholine, an ability not shared with sodium nitroprusside (10−6 m) or isosorbide dinitrate (4.2 × 10−5 m). Indeed at lower concentrations of methacholine (< 3 × 10−7 m), sodium nitroprusside evoked a paradoxical enhancement of methacholine‐evoked contractions.
In combination, ANP and salbutamol attenuated contractions evoked by methacholine to a significantly greater degree than that seen with either agonist alone, whilst a combination of ANP and sodium nitroprusside evoked no greater effect than that seen with ANP alone. By contrast, isosorbide dinitrate and ANP together evoked a greater inhibition than ANP alone.
These results suggest that a combination of agents such as ANP and salbutamol evokes a greater effect than either alone, both in reversing and protecting against methacholine‐evoked contractions. Such combinations may be of benefit in the treatment of patients, allowing lower doses of drug to be used. Combinations of ANP and isosorbide dinitrate may likewise be of interest; however, the mechanism underlying the enhancement of ANP responses by isosorbide dinitrate requires further study.