bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reversal of established responses to endothelin‐1 in vivo and in vitro by the endothelin receptor antagonists, BQ‐123 and PD 145065
Authors: Warner Timothy D. , Allcock Graham H. , Vane John R. 
Published: July 2012

Endothelin‐1 binds almost irreversibly to its receptors and causes prolonged vasoconstrictions. Here we have studied the reversal of established responses to ET‐1 in vivo and in vitro by BQ‐123, an ETA receptor‐selective antagonist, and/or PD 145065, an ETA/ETB receptor non‐selective antagonist.
In anaesthetized rats pretreated with hexamethonium, infusion of ET‐1 (10−11 mol kg−1 min−1) increased the mean arterial pressure (MAP) from 93 ± 1.5 mmHg to 137 ± 2.4 mmHg after 70 min (n = 29). While the ET‐1 infusion was continued an additional infusion of BQ‐123 caused a gradual dose‐dependent reduction in the pressor effect of ET‐1. For instance, after a 60 min infusion of BQ‐123 (10−8 mol kg−1 min−1) the MAP was decreased by 29.3 ± 4.3 mmHg (n = 4).
PD 145065 was a much weaker antagonist of the established pressor effects of ET‐1. At 10−8 mol kg−1 min−1 it had no significant effect and even at 10−7 mol kg−1 min−1 the elevated blood pressure was only reduced by 11.8 ± 8.0 mmHg (n = 5) after 60 min. Co‐infusion of BQ‐123 and PD 145065 caused smaller reductions in the established response to ET‐1 than infusion of BQ‐123 alone.
Sustained contractions of rat aortic rings induced by ET‐1 (3 × 10−9 m) and mediated by ETA receptors were slowly reversed by addition of BQ‐123 (10−5 m) or PD 145065 (10−5 m). For instance, after 40 min the elevated tone was reduced 85.8 ± 5.6% (n = 6) by PD 145065, and 77.1 ± 6.7% (n = 6) by BQ‐123. Thus, on the rat aortic rings in vitro both antagonists were equally effective against established responses to ET‐1.
ET‐1 increased the perfusion pressure of the rat isolated perfused kidney by 138.1 ± 7.6 mmHg (n = 14). Subsequent co‐infusion of BQ‐123 or PD 145065 reversed this increase with PD 145065 being more active. For instance, PD 145065 (10−6 m) reversed the increase in perfusion pressure by 56.9 ± 8.8% (n = 5) and BQ‐123 (10−6 m) reversed it by 22.8 ± 8.0% (n = 5). This fits well with the vasoconstriction induced by ET‐1 in the rat kidney being mediated by ETA and ETB receptors.
Thus, sustained vasoconstrictions to ET‐1 in vitro, mediated by either ETA or ETB receptors, may be reversed slowly by the subsequent application of receptor antagonists. Similarly, endothelin antagonists reverse the pressor effects of ET‐1 in vivo although co‐antagonism of ETA and ETB receptors or the co‐administration of an ETA receptor antagonist, BQ‐123, and a mixed antagonist, PD 145065 produces less reversal than the application of an ETA receptor‐selective antagonist. This may be because PD 145065 also reduces vasodilatations induced by ET‐1 in vivo, or could suggest that because of its peptide structure PD 145065 affects the elimination of ET‐1.
The involvement of endothelial dysfunction, nitric oxide and prostanoids in the rat gastric microcirculatory responses to endothelin‐1
Authors: Lopez‐Belmonte J. , Whittle B.J.R 
Published: July 2012

The role of endothelial dysfunction in the gastric microcirculatory responses during local endothelin‐1 (ET‐1) infusion has been investigated in the pentobarbitone‐anaesthetized rat. Furthermore, the involvement of prostanoids or nitric oxide (NO) in these actions has been investigated by the use of indomethacin to inhibit cyclo‐oxygenase and NG‐nitro‐l‐arginine methyl ester (l‐NAME) to inhibit NO synthase.
Close‐arterial infusion of ET‐1 (1–10 pmol kg−1 min−1 for 10 min) induced a dose‐dependent increase in the gastric leakage of radiolabeled albumin, used as an index of endothelial cell dysfunction.
Close‐arterial infusion of a submaximal dose of ET‐1 (5 pmol kg−1 min−1 for 10 min) significantly increased gastric albumin leakage after 2 min infusion, which reached maximal levels after 10 min, and only slowly declined during the 30 min observation period.
By contrast, gastric blood flow, as assessed by laser Doppler flowmetry, did not significantly increase until after 5 min of infusion of ET‐1 (5 pmol kg−1 min−1 for 10 min), reaching a maximum after 17 min, and was sustained for the 30 min observation period.
Pretreatment with l‐NAME (2 mg kg−1, i.v.) or indomethacin (5 mg kg−1, i.v.) significantly reduced both the hyperaemic response to ET‐1 and the increase in gastric albumin leakage, and in combination abolished these responses.
These results suggest that locally released NO and prostanoids mediate the gastric vasodilator response to close arterial infusion of ET‐1. This hyperaemia is preceded by changes in gastric albumin extravasation and hence may be initiated as a response to direct endothelial injury by ET‐1.
Effect of a 5‐lipoxygenase inhibitor and leukotriene antagonist (PF 5901) on antigen‐induced airway responses in neonatally immunized rabbits
Authors: Herd Caroline M. , Donigi‐Gale Donna , Shoupe T. Scott , Burroughs D.A. , Yeadon M. , Page Clive P. 
Published: July 2012

The effect of a single intratracheal dose (10 mg) of PF 5901 (2‐[3(1‐hydroxyhexyl) phenoxymethyl] quinoline hydrochloride, a specific inhibitor of the 5‐lipoxygenase pathway of arachidonic acid metabolism and a leukotriene D4 antagonist) on airway changes induced in response to Alternaria tenuis aerosol challenge was assessed in adult rabbits neonatally immunized. Leukotriene generation was determined in vivo by measuring leukotriene B4 (LTB4) levels in bronchoalveolar lavage (BAL) fluid and ex vivo by measuring calcium ionophore‐stimulated production of LTB4 in whole blood.
While PF 5901 (10 mg) had no significant effect on the acute bronchoconstriction induced by antigen, this dose was sufficient to inhibit significantly the increase in airway responsiveness to inhaled histamine 24 h following antigen challenge (P < 0.05).
Total leucocyte infiltration into the airways induced by antigen, as assessed by bronchoalveolar lavage, was significantly inhibited by pretreatment with PF 5901 (10 mg). However, the pulmonary infiltration of neutrophils and eosinophils induced by antigen was unaltered by prior treatment with PF 5901 (10 mg).
PF 5901 (10 mg) had no effect on ex vivo LTB4 synthesis in whole blood. However, the antigen‐induced increase in LTB4 levels in BAL 24 h following challenge was significantly inhibited (P < 0.05).
We suggest from the results of the present study that the antigen‐induced airway hyperresponsiveness to inhaled histamine in immunized rabbits is mediated, at least in part, by products of the 5‐lipoxygenase metabolic pathway, and is not dependent on the extent of eosinophil or neutrophil influx into the airway lumen.
Induction of nitric oxide synthase in cultured vascular smooth muscle cells: the role of cyclic AMP
Authors: Hirokawa K. , O'Shaughnessy K. , Moore K. , Ramrakha P. , Wilkins M.R. 
Published: July 2012

Interleukin‐1β (IL‐1β) is a potent stimulant of inducible nitric oxide synthase (iNOS) mRNA and nitric oxide (NO) production in vascular smooth muscle (VSM) cells in culture. These studies investigate the role of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) in this process.
Dibutyryl cyclic AMP (db cyclic AMP, 0.1–1 mm), forskolin (1–10 μm) and the phosphodiesterase inhibitor, Ro 20–1724 (1–10 μm), all of which increase intracellular cyclic AMP, had no effect on NO production when added alone but markedly enhanced NO production by IL‐1β‐stimulated VSM cells in a dose‐dependent manner. Consistent with a cyclic AMP‐mediated action, isoprenaline (1–10 μm) increased NO production from IL‐1β‐stimulated cells. Dibutyryl cyclic GMP (db cyclic GMP) had no effect at concentrations up to 1 mm.
Pursuing these observations, iNOS protein levels were examined by Western blot analysis and iNOS mRNA levels were measured by reverse transcription and amplification of the resultant cDNA using the polymerase chain reaction. In addition to enhancing NO production, db cyclic AMP increased iNOS protein and mRNA above that produced by IL‐1β alone.
These data demonstrate a major effect of cyclic AMP on cytokine‐induced NOS activity in VSM cells, mediated at least in part by regulating synthesis of iNOS, and has implications for the pathogenesis and management of septic shock.
Effect of topical administration of l‐arginine on formalin‐induced nociception in the mouse: a dual role of peripherally formed NO in pain modulation
Authors: Kawabata Atsufumi , Manabe Sachiko , Manabe Yuki , Takagi Hiroshi 
Published: July 2012

We investigated the effects of intraplantar (i.pl.) administration of l‐arginine and NG‐nitro‐l‐arginine methyl ester (l‐NAME) on formalin‐induced behavioural nociception in the mouse.
l‐ but not d‐arginine, at 0.1 − 1 μg per paw, coadministered with i.pl. formalin, enhanced the second‐but not the first‐phase nociceptive responses, whereas it was without significant effects at 3 μg per paw, and conversely, produced antinociception at 10 μg per paw, resulting in a bell‐shaped dose‐response curve.
l‐NAME at 0.1 − 1 μg per paw, when administered i.pl., exhibited antinociceptive activity in the second phase in a dose‐dependent manner, although its d‐enantiomer produced no effect.
An antinociceptive dose (1 μg per paw) of l‐NAME (i.pl.) considerably reduced the increase in second‐phase nociception elicited by low doses (1 μg per paw) of i.pl. l‐arginine. The second‐phase nociception decrease induced by a large dose (10 μg per paw) of i.pl. l‐arginine was markedly reversed by i.pl. l‐NAME at 0.1 μg per paw, raising it to a level above that of the control (formalin only).
These results suggest that peripheral NO plays a dual role in nociceptive modulation, depending on the tissue level, inducing either nociceptive or antinociceptive responses.
Adrenoceptors mediating relaxation to catecholamines in rat isolated jejunum
Authors: MacDonald A. , Forbes I.J. , Gallacher D. , Heeps G. , McLaughlin D.P. 
Published: July 2012

The characteristics of adrenoceptors mediating relaxation to catecholamines in rat isolated jejunum were investigated.
Catecholamines and BRL 37344 produced relaxation of the KCl‐contracted strips with an order of potency of isoprenaline (1.0) > BRL 37344 (0.63) > noradrenaline (0.1) > adrenaline (0.04).
In the presence of both prazosin (1 μm) and propranolol (1 μm) only small dextral shifts of the concentration‐response curves to agonists were observed and an order of potency of BRL 37344 (2.5) > isoprenaline (1.0) > noradrenaline (0.2) > adrenaline (0.1) was obtained.
In the presence of prazosin (1 μm) and propranolol (1 μm), cyanopindolol (0.1 − 10 μm) produced a concentration‐dependent rightward shift of the concentration‐response curve to adrenaline with a Schild slope not significantly different from unity and a mean pA2 value of 7.01.
The resistance of relaxant responses to propranolol, the relatively high potency of BRL 37344 compared to catecholamines and the competitive antagonism of relaxant responses to adrenaline by cyanopindolol suggest that β‐adrenoceptors in rat small intestine are mainly atypical in nature.
Agonistic and antagonistic properties of the bradykinin B2 receptor antagonist, Hoe 140, in isolated blood vessels from different species
Authors: Félétou Michel , Germain Martine , Thurieau Christophe , Fauchère Jean‐Luc , Canet Emmanuel 
Published: July 2012

Hoe 140, a recently described bradykinin B2 antagonist, and NPC 567 from an earlier generation of bradykinin B2 antagonists, were tested in rabbit and sheep isolated blood vessels.
In rabbit jugular vein, a bradykinin B2 preparation, NPC 567 was an antagonist (apparent pA2: 8.67 ± 0.16) with marked residual agonistic activity (log[EC50]: −7.29 ± 0.13). Hoe 140 was a potent non‐competitive antagonist devoid of agonistic properties (slope of the Schild plot: 2.02; estimated pA2: 9.04).
In rabbit aorta, a bradykinin B1 preparation, NPC 567 was a competitive antagonist (pA2: 6.32 ± 0.13) but Hoe 140 was ineffective. The two antagonists did not show any agonistic properties in this tissue.
In sheep femoral artery without endothelium, bradykinin and Hoe 140 induced contractions with identical efficacy and similar potency (log[EC50]: −8.05 ± 0.12, −7.73 ± 0.10; maximal contraction in % of KCl [60 mm]: 59.5 ± 15.1, 62.0 ± 13.1; for bradykinin and Hoe 140, respectively). In contrast NPC 567 was an extremely weak agonist. The contractile responses to bradykinin and Hoe 140 were inhibited by NPC 567 (apparent pKB: 6.89 ± 0.22 and 6.58 ± 0.08 versus bradykinin and Hoe 140, respectively) but not by a B1 bradykinin antagonist, suggesting that the receptor involved was a bradykinin B2 receptor.
In sheep femoral artery with endothelium, bradykinin induced a biphasic response: an endothelium‐dependent relaxation and a contraction which were both inhibited by NPC 567 (apparent pKB: 7.10 ± 0.15) and Hoe 140 (pA2: 8.38 ± 0.12). As bradykinin B2 receptor antagonists, Hoe 140 and NPC 567 were less potent in the sheep femoral artery than in the rabbit jugular vein. Neither Hoe 140 nor NPC 567 were agonists for the endothelial receptor.
This study demonstrates that Hoe 140, a new bradykinin B2 receptor antagonist, is more selective and more potent than NPC 567; however, it may possess, depending on the tissue studied, marked residual agonistic properties. Furthermore, bradykinin B2 receptors are subject to important species specificity. Finally, two different bradykinin B2 receptor subtypes may coexist in the sheep femoral artery with endothelium.
Comparative pharmacology of analogues of S‐nitroso‐N‐acetyl‐dl‐penicillamine on human platelets
Authors: Salas E. , Moro M.A. , Askew S. , Hodson H.F. , Butler A.R. , Radomski M.W. , Moncada S. 
Published: July 2012

The effects of two new analogues of S‐nitroso‐N‐acetyl‐dl‐penicillamine (SNAP), S‐nitroso‐N‐formyl‐dl‐penicillamine (SNFP) and S‐nitroso‐dl‐penicillamine (SNPL), on platelet function were examined in vitro.
SNAP and its analogues were potent inhibitors of platelet aggregation and inducers of disaggregation.
All compounds inhibited fibrinogen binding to platelets.
They also decreased the release of P‐selectin from platelets.
Both inhibition of fibrinogen binding and release of P‐selectin correlated with an increase in intraplatelet cyclic GMP concentrations.
At concentrations sufficient to inhibit platelet function and induce cyclic GMP formation (0.01–3 μm), the release of NO could be detected from SNPL but not from SNAP and SNFP.
Release of NO from all compounds was detected at concentrations ≥ 10 μm.
Thus, the spontaneous release of NO from SNPL explains the actions of this compound on platelet function; however, platelet‐mediated mechanisms may be involved in the release of NO from SNAP and SNFP.
Effects of cyclopiazonic acid on rhythmic contractions in uterine smooth muscle bundles of the rat
Authors: Kasai Yasuyo , Iino Masamitsu , Tsutsumi Osamu , Taketani Yuji , Endo Makoto 
Published: July 2012

We studied the effects of cyclopiazonic acid (CPA) on rhythmic contractions and on Ca2+ uptake by the intracellular stores in longitudinal muscle strips of the rat uterus at 30°C.
Oxytocin (1 μm) in Ca2+‐free solution induced a transient rise in the intracellular Ca2+ concentration ([Ca2+]i) and contraction after Ca2+ loading of the stores in high‐K+‐ and Ca2+‐containing solution. CPA inhibited oxytocin‐induced Ca2+ release and contraction, the half and full inhibitory concentrations of CPA being 0.3 and 10 μm, respectively. In contrast, addition of CPA after Ca2+ loading exerted no significant inhibitory effects.
Oxytocin (10 nM) applied in Ca2+‐containing solution induced rhythmic increases in both force and [Ca2+]i. CPA (10 μm) had no effect on oxytocin‐induced rhythmic contractions.
At a high concentration (300 μm), CPA inhibited the rhythmic contractions induced by 10 nM oxytocin; the frequency and the peak height were decreased, and in many bundles contractions were completely abolished. These inhibitory effects were reversed after CPA washout.
CPA (300 μm) inhibited the rate of rise of [Ca2+]i due to depolarization induced by high‐K+‐containing solution.
These results suggest that low concentrations of CPA inhibit the loading of Ca2+ into intracellular stores in intact tissue strips, and that the Ca2+ stores are not directly involved in the uterine rhythmic contractions. It is also suggested that a high concentration of CPA inhibits the mechanism that is responsible for the generation of rhythmic contractions as well as voltage‐dependent Ca2+ channels.
Potentiation by forskolin of both SNP‐ and ANP‐stimulated cyclic GMP accumulation in porcine isolated palmar lateral vein
Authors: Wright I.K. , Amirchetty‐Rao S. , Kendall D.A. 
Published: July 2012

The aim of this study was to examine the effect of modulation of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) levels (by using forskolin, a direct activator of adenylyl cyclase, or rolipram, a cyclic AMP selective phosphodiesterase inhibitor) on basal and stimulated guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels in the porcine isolated palmer lateral vein by use of a [3H]‐guanine prelabelling technique.
Sodium nitroprusside (SNP; 10−5‐10−3M) and atrial natriuretic peptide (ANP; 10−8‐10−6M), produced concentration‐dependent increases in [3H]‐cyclic GMP levels via stimulation of soluble and particulate guanylyl cyclase respectively. The SNP‐stimulated [3H]‐cyclic GMP response peaked after 5 min in the presence and absence of the phosphodiesterase inhibitor, 3‐isobutyl‐1‐methylxanthine (IBMX).
In the absence of IBMX, forskolin (3 × 10−5 M) significantly increased [3H]‐cyclic GMP levels to 118.5 ± 8.7% of basal values (P < 0.05, n = 8), and significantly increased both the SNP‐ and ANP‐stimulated [3H]‐cyclic GMP accumulation at all concentrations of SNP and ANP used. For example, effects at the maximal SNP (10−3M) and ANP (10−6M) concentrations were: SNP: 154.7 ± 15.4% of basal; SNP + forskolin: 191.3 ± 14.8% of basal (P < 0.05, n = 4); ANP: 161.4 ± 17.4% of basal; ANP‐ + forskolin: 220.0 ± 20.0% of basal (P < 0.05, n = 4).
The cyclic AMP‐selective phosphodiesterase inhibitor, rolipram (10−5 M), had no effect on basal or SNP‐stimulated [3H]‐cyclic GMP levels; however, the combination of forskolin and rolipram produced an increase in the basal (158.7 ± 27.1% of basal) and SNP‐stimulated [3H]‐cyclic GMP accumulation (SNP (10−3M): 165.3 ± 8.7% of basal; SNP + forskolin + rolipram: 510.7 ± 64.8% of basal; P < 0.05, n = 5), greater than either forskolin or rolipram alone. The phosphodiesterase inhibitor, IBMX (10−3 M) significantly raised [3H]‐cyclic GMP levels, and forskolin (3 × 10−5 M) in the presence of IBMX had no significant effect on either basal or SNP‐stimulated [3H]‐cyclic GMP levels (e.g. in the presence of IBMX: SNP (10−3M): 660 ± 90% of basal; SNP + forskolin: 790 ± 86% of basal, n = 3).
The data indicate the presence of both soluble and particulate guanylyl cyclase in the porcine isolated palmar lateral vein. The ability of forskolin to potentiate SNP‐ and ANP‐stimulated [3H]‐cyclic GMP accumulation may suggest a cyclic AMP‐cyclic GMP interaction at the level of the phosphodiesterases. Further, the ability of cyclic AMP to influence cyclic GMP levels may indicate that the two nucleotides, as well as having independent mechanisms to induce smooth muscle relaxation, could produce vasodilatation via a common mechanism.
Mechanism of bile salt vasoactivity: dependence on calcium channels in vascular smooth muscle
Authors: Pak Jung‐Min , Adeagbo Ayotunde S.O. , Triggle Christopher R. , Shaffer Eldon A. , Lee Samuel S. 
Published: July 2012

The vasoactive mechanisms of bile salts have been investigated in rat isolated portal venous and superior mesenteric arterial rings and perfused mesentery.
The isolated perfused mesentery was precontracted with a selective α1‐adrenoceptor agonist, cirazoline. Incremental doses of tauroursodeoxycholate (TUDC), taurochenodeoxycholate (TCDC) and taurodeoxycholate (TDC) caused a dose‐dependent vasorelaxation. The order of potency of the vasodilator effect was TDC > TCDC > TUDC.
The effect of TDC (1.9 × 10−8 −1.9 × 10−6 mol) was examined before and after propranolol (3 μm), tetraethylammonium (5 mM), ouabain (10−5 M), NG‐nitro‐l‐arginine methyl ester (10−4 M) and capsaicin (50 mg kg−1) to block, respectively, β‐adrenoceptors, K+‐channels, Na+, K+‐ATPase, nitric oxide synthase, and primary sensory nerves. The vasodilator effect of TDC was not affected by any of these blocking agents or by denuding vascular endothelium with distilled water.
Infusion of TDC (1.9 × 10−8 −1.9 × 10−6 mol) with K+‐free or high K+ (60 mM) physiological salt solution (PSS) did not affect the vasodilator effect of TDC.
Contractions induced by KCl (0.01–1.0 M), arginine vasopressin (AVP, 10−10 −10−7 M) or cirazoline (10−7 × 10−5 M) were all inhibited by TDC (300 μm).
TDC (10−6 to 10−3 M) also inhibited the basal tension and the development of spontaneous contractions in the isolated portal vein.
TDC (300 μm), however, did not affect noradrenaline‐induced phasic contractions elicited in Ca2+‐free PSS by Ca2+ release from intracellular stores.
We conclude that TDC inhibits Ca2+ entry through both voltage‐operated and receptor‐operated calcium channels, whereas intracellular Ca2+ release is not affected.
Antagonism by lipophilic quaternary ions of the K+ channel opener, levcromakalim, in vascular smooth muscle
Authors: McPherson Grant A. , Piekarska Anna E. 
Published: July 2012

The aim of this study was to characterize the interaction between the K+ channel opener levcromakalim (LKM) and several quaternary ions, in vascular smooth muscle, in vitro. Segments of isolated, thoracic aorta of the rat were suspended in organ baths filled with Krebs solution at 37°C. Cumulative concentration‐response curves to LKM were obtained in the absence and in the presence of increasing concentrations of quaternary ions using a number of agents to pre‐constrict the vessel. The ions tested were tetraphenylphosphonium (chloride TPP‐Cl and bromide TPP‐Br salts), tetrapentylam‐monium (TPeA), tetraethylammonium (TEA), tetraphenylarsonium (TPAs) and tetraphenylboron (TPB).
For the compounds which antagonized the vasorelaxation responses of LKM, ‘apparent pKB’ values were estimated on the basis of a single concentration of antagonist. These were then used to obtain the following order of potency: TPP‐Br (7.22 ± 0.25) = TPAs (7.12 ± 0.04) = TPP‐Cl (7.11 ± 0.15) > TPeA (6.23 ± 0.20). TEA and TPB were both found to be inactive at the maximum concentrations used.
The interaction between the cationic TPP and anionic TPB was also investigated. The shift in the LKM concentration‐response curve constructed in the presence of both of these compounds was compared to that when each agent was present separately. We found that TPB, at concentrations greater than 1 μm, reversed the blockade of the LKM‐mediated relaxation induced by TPP (3 μm).
Similar experiments were undertaken combining TPB with either alinidine or glibenclamide (both functional antagonists of K+ channel openers). It was found that TPB (10 μm) partially reversed the antagonism induced by alinidine (30 and 100 μm) but had no effect on the action of glibenclamide (3 μm).
These studies show that lipophilic cations such as TPP and TPAs are potent antagonists of levcromakalim‐mediated vasorelaxation responses in the rat thoracic aorta. The mechanism by which these compounds cause their antagonism is not known. However, given the lipophilicity of these compounds, it is possible they may act at a number of sites including the KATP channel itself or possibly via some other intracellular mechanism.