bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cytochrome P450‐dependent effects of bradykinin in the rat heart
Authors: Fulton D. , Mahboubi K. , McGiff J.C. , Quilley J. 
Published: July 2012

Vasodilator responses to bradykinin (BK) in the rat heart are reported to be independent of NO and cyclo‐oxygenase/lipoxygenase products of arachidonic acid (AA).
We verified that inhibition of NO synthase with l‐nitroarginine (50 μm) and cyclo‐oxygenase with indomethacin (2.8 μm) were without effect on vasodilator responses to BK (10–1000 ng) in the Langendorff rat heart preparation.
l‐Nitroarginine elevated perfusion pressure, signifying a crucial role of NO in the maintenance of basal vasculature tone.
In hearts treated with l‐nitroarginine to eliminate NO and elevate perfusion pressure, vasodilator responses were reduced by inhibitors of cytochrome P450 (P450), clotrimazole (1 μm) and 7‐ethoxyresorufin (1 μm). 17‐Octadecynoic acid (17‐ODYA 2 μm), a mechanism based inhibitor of P450‐dependent metabolism of fatty acids, also reduced vasodilator responses to BK.
These results confirm that NO and prostaglandins do not mediate vasodilator responses to BK in the rat heart but suggest a major role for a P450‐dependent mechanism via AA metabolism.
Evidence that nitric oxide from the endothelium attenuates inherent tone in isolated pulmonary arteries from rats with hypoxic pulmonary hypertension
Authors: Wanstall Janet C. , Hughes Ian E. , O'Donnell Stella R. 
Published: July 2012

The inherent contractile tone, and its modulation by the endothelium, have been studied in isolated pulmonary artery preparations taken from rats in which pulmonary hypertension was induced by exposure to a hypoxic environment (10% O2) for 14 days. Control rats were housed in room air.
All preparations in which the endothelium was left intact relaxed in response to acetylcholine (43 ± 4% and 54 ± 9%, reversal of the noradrenaline‐induced contraction in control and hypoxic rats, respectively) indicating that the endothelium was functional in both groups of rats.
Exposure of the preparations to Ca2+‐free physiological salt solution containing 2 mm EGTA for 30–40 min had no effect on preparations from control rats but caused relaxation in preparations from hypoxic rats. The relaxation (taken as a measure of the inherent tone in the preparations) was larger in preparations without endothelium (14.5 ± 1.9 mn mm−2; n = 5) than in preparations with endothelium (9.1 ± 1.2 mn mm−2; n = 5).
In preparations from hypoxic rats the magnitudes of the contractions to 80 mm K+ and to noradrenaline (0.1 μm) were less than in preparations from control rats. This may have been because the preparations from hypoxic rats were already partially contracted due to the inherent tone.
The nitric oxide (NO) synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME, 0.1–100 μm) had negligible effect on preparations from control rats or on endothelium‐denuded preparations from hypoxic rats, but produced concentration‐dependent contractions (maximum contraction 7.4 ± 0.7 mn mm−2 (n = 4) with 100 μm) in endothelium‐intact preparations from hypoxic rats. This effect of l‐NAME was prevented by l‐arginine (1 mm) but not by d‐arginine (1 mm).
Contractions to l‐NAME were also seen in endothelium‐intact arteries from control rats if the preparations were first partially contracted by exposure to K+, endothelin, U46619 (thromboxanemimetic) or noradrenaline.
It is concluded that isolated pulmonary artery rings from hypoxic rats, but not those from control rats, have substantial inherent tone. This inherent tone is normally attenuated by the generation of an endothelium‐derived factor that is probably NO. A stimulus for the release of NO from the endothelium may be the contraction of the underlying smooth muscle, whether the contraction is inherent in the tissue, as in preparations from hypoxic rats, or is induced by a vasoconstrictor spasmogen.
Effects of macrophage depletion on the induction of histidine decarboxylase by lipopolysaccharide, interleukin 1 and tumour necrosis factor
Authors: Endo Yasuo , Nakamura Masanori , Nitta Yasutaka , Kumagai Katsuo 
Published: July 2012

Our previous work has shown that injection into mice of lipopolysaccharide (LPS) and the cytokines interleukin 1 (IL‐1) and tumour necrosis factor (TNF) induces histidine decarboxylase (HDC), the enzyme forming histamine, in various tissues such as liver, lung, spleen and bone marrow, but not in the blood. The induction of HDC also occurs in nude mice and mast cell‐deficient mice. On the other hand, haematopoietic cytokines such as IL‐3, granulocyte colony‐stimulating factor (G‐CSF) and granulocyte – macrophage CSF (GM‐CSF) only induce HDC in the haematopoietic organs, i.e. bone marrow and spleen. In the present study, the effect of macrophage depletion on the induction of HDC was examined.
On day 1 after a single intravenous injection of a macrophage depletor (liposomes encapsulating dichloromethylene diphosphonate, which is toxic when ingested into macrophages), macrophages were almost completely depleted in the liver and reduced by about 50% in the spleen and bone marrow, but not significantly affected in the lung. On day 3, the degrees of the depletion were similar to those of day 1. In the spleen, macrophages were depleted in the red pulp, and there was a structural destruction.
In macrophage‐depleted mice, the induction of HDC by LPS, IL‐1α or TNF‐α was not impaired in the liver, and was potentiated in the lung and bone marrow. The induction of HDC was decreased only in the spleen at day 3.
HDC was not induced by LPS in the spleen of the adult rat, which is correspondingly inactive in haematopoiesis.
These results indicate that the major cells in which HDC activity is induced in response to LPS, IL‐1 and TNF are not circulating granulocytes, circulating monocytes, T cells derived from thymus, mast cells or phagocytic macrophages. Based on these results, we discuss the possibility that the major cells in which HDC was induced in non‐haematopoietic and haematopoietic organs were endothelial cells and haematopoietic precursor cells respectively.
Pharmacology of the octopamine receptor from locust central nervous tissue (OAR3)
Authors: Roeder Thomas 
Published: July 2012

The present study characterized highly effective agonists from different classes of compounds for the neuronal octopamine receptor (OAR3) of the migratory locust (Locusta migratoria L.). Biogenic amines and phenyliminoimidazolidines (PIIs) were employed for the study of structure‐activity relationships.
The highest affinity PIIs were predominantly those with substitutions at the positions 2 and 4 of the phenolic ring (e.g. NC 7, KI = 0.3 nm, NC 8, KI = 0.81 nm). Substitutions at these positions always had positive effects on the affinity of the respective agonists.
Substitutions at the positions 3, 5 and 6, however, always had negative effects on the affinity. At the position one of the phenolic ring, heterocyclic substituents are preferred.
Some PIIs had a more than 30 times higher affinity for OARs than for α‐adrenoceptors which are the vertebrate homologues of the insect octopamine receptors.
The only non‐PII with subnanomolar affinity was the aminooxazoline derivative AC 6 (KI = 0.92 nm).
A variety of substances with known insecticidal activity such as chlordimeform, demethylchlor‐dimeform, amitraz or AC 6 had high affinity for the locust neuronal octopamine receptor.
Mechanisms of bradykinin‐induced contraction of the guinea‐pig gallbladder in vitro
Authors: Cabrini Daniela A. , Silva Ana M. , Calixto João B. 
Published: July 2012

The mechanisms underlying bradykinin (BK)‐mediated contractions in strips of guinea‐pig gallbladder (GPG) were examined by use of selective bradykinin (BK) receptor agonists and antagonists.
Addition of BK and related kinins (0.1 pM‐10μm) after 2 h of equilibration of the preparation caused graded contractions characterized by two distinct phases: high affinity (0.1 pM‐1 nM) and low affinity (3 nM‐10 μm). The rank order of potency for the first phase (mean EC50, PM) was: BK (1.36) = Hyp3‐BK (1.44) = Lys‐BK (1.54)>Tyr8‐BK (2.72)> Met‐Lys‐BK (4.30). The rank order of potency for the second phase (mean EC50, nM, at concentration producing 50% of the contraction caused by 80 mM KC1) was: Hyp3‐BK (8.95)> Met‐Lys‐BK (12.78)>Tyr8‐BK (33.75)> Lys‐BK (60.92)> BK (77.35). The contractile responses (g of tension) to 3 μm of BK (the highest concentration tested) were: Hyp3‐BK, 1.76 ±0.09; BK, 1.65 ±0.12; Lys‐BK, 1.45 ±0.13; Tyr8‐BK, 1.36 ±0.15 and Met‐Lys‐BK, 1.36 ±0.15. The selective B1 agonist, des‐Arg9‐BK, caused only a weak contraction with maximal response (0.21 ± 0.05 g), which corresponded to approximately 10% of that induced by BK.
BK‐induced contraction in GPG was inhibited by indomethacin (3 μm) or ibuprofen (30 μm), and was partially reduced by phenidone (30 μm), but was not affected by atropine (1 μm), nicardipine (1 μm), Ca2+‐free medium plus EGTA, dazoxiben (30 μm), L‐655,240 (10 nM, a selective receptor antagonist of thromboxane A2), MK‐571 (0.1 μm, a selective leukotriene D4 receptor antagonist), tetrodotoxin (0.3 μm), CP 96,345 (0.3 μm, a NK1 receptor antagonist), mepyramine (1 μm), glibenclamide (1 μm), H‐7 (3 μm), staurosporine (100 nM), or phorbol 12‐myristate 13‐acetate (1 μm). However, BK‐induced contractions in GPG maintained in Ca2+‐free medium were markedly attenuated by ryanodine (10 μm).
Prostaglandin E2, prostaglandin F2α or U46619 (0.1 nM to 100 μm), caused concentration‐dependent contractions in GPG with mean EC50S of 3.1 μm; 1.7 μm and 0.47 nM and maximal responses of 1.36 ±0.15; 1.32 ±0.20 and 0.96 ± 0.09 g, respectively.
The selective B2 receptor antagonists, Hoe 140, NPC 17731 and NPC 17761 (0.01‐1 μm), caused concentration‐dependent displacements to the right of the contractile concentration‐response curve for BK. The selective B1 receptor antagonist, des‐Arg9‐[Leu8]‐BK (1 μm), did not affect BK‐induced GPG contraction.
These data suggest that both high and low affinity BK responses in GPG are mediated by activation of B2 receptors, and that BK‐mediated contraction in GPG depends on the release of intracellular Ca2+ sources sensitive to ryanodine. In addition, BK‐induced contraction in GPG is mediated by release of proinflammatory eicosanoid(s) derived from the cyclo‐oxygenase pathway from arachidonic acid metabolism unrelated to thromboxane A2, and seems not to be coupled to activation of a protein kinase C‐dependent mechanism.
Functional interaction between losartan and central tachykinin NK3 receptors in the conscious rat
Authors: Picard Pierre , Chretien Louise , Couture Réjean 
Published: July 2012

The cardiovascular and behavioural effects elicted by the intracerebroventricular (i.c.v.) injection of substance P (SP), neurokinin A (NKA), [MePhe7]neurokinin B ([MePhe7]NKB) or angiotensin II (All) in the conscious rat were assessed before and 5 min after i.c.v. pretreatment with antagonists selective for angiotensin AT1 (losartan and its active metabolite EXP 3174), angiotensin AT2 (PD 123,319) or tachykinin NK3 (R 486) receptors.
I.c.v. administration of 25 pmol All evoked an increase in mean arterial blood pressure (MAP) and water intake behaviour, accompanied by a transient bradycardia, whereas 25 pmol [MePhe7]NKB caused a transient increase in MAP and heart rate (HR) concurrently with marked wet dog shake behaviour. At the same dose, SP and NKA were more potent than [MePhe7]NKB in increasing MAP and HR, but did not produce water intake or wet dog shake behaviours.
Losartan (650 pmol, i.c.v.) reduced significantly the cardiovascular and behavioural responses to All or [MePhe7]NKB, but not to SP or NKA. While 65 pmol losartan was inactive, 260 pmol inhibited selectively the central effects of AII Whereas EXP 3174 (6.5 nmol) blocked both All and [MePhe7]NKB‐mediated responses, the dose of 650 pmol blocked only the responses to AII.
The central responses to All and [MePhe7]NKB were not affected by PD 123,319 (650 pmol). On the other hand, the [MePhe7]NKB‐induced central effects were significantly reduced by R 486 (650 pmol). The NK3‐selective antagonist had no effect against AII.
This study provides functional evidence, to support earlier binding data, that losartan (and to some extent its active metabolite EXP 3174) interact with the tachykinin NK3 receptor in rat brain. However, the cardiovascular and behavioural responses induced by central tachykinin agonists (SP, NKA and [MePhe7]NKB) and All are mediated by unrelated mechanisms.
Cardiovascular actions of the furoxan CAS 1609, a novel nitric oxide donor
Authors: Bohn Helmut , Brendel Joachim , Martorana Piero A. , Schönafinger Karl 
Published: July 2012

This study examines the cardiovascular effects of CAS 1609 (4‐hydroxymethyl‐furoxan‐3‐carboxamide) in vitro as well as in vivo in various animal models.
CAS 1609 relaxed guinea‐pig pulmonary artery strips without endothelium with IC50‐values of 0.9 μm (phenylephrine contracted) and 15 μ (KCl‐depolarized). This effect was inhibited by oxyhaemoglobin. In these arteries CAS 1609 significantly increased (+ 192%) guanosine 3′:5′‐cyclic monophosphate levels, which indicates that the compound acts as a donor of nitric oxide (NO).
In the anaesthetized pig, CAS 1609 (0.3‐1.0 mg kg−1, i.d.) significantly lowered blood pressure and left ventricular end‐diastolic pressure. Left ventricular contractility was slightly reduced and heart rate remained almost unchanged.
In anaesthetized dogs, i.v. or i.d. administration of CAS 1609 (0.3‐3.0 mg kg−1) decreased, in a dose‐related fashion, preload and afterload of the heart, cardiac output, left ventricular work and myocardial oxygen consumption. This haemodynamic profile is similar to that of known NO‐donors.
In anaesthetized dogs with acute heart failure due to intracoronary injection of microspheres, CAS 1609 (0.3mgkg−1, i.v.) improved the haemodynamic condition and reduced mortality by 80%.
In conscious dogs, oral treatment with a dose of 0.5 mg kg−1 given twice daily at 07 h 00 min and 19 h 00 min (each dose had a duration of action ≤ 12 h) for 5 days showed no signs of tolerance to the haemodynamic effects of the drug.
All these data indicate that CAS 1609 is a potent, long‐lasting orally active donor of NO, devoid of tolerance development.
Conversion of inhaled nitric oxide to nitrate in man
Authors: Westfelt Ulla Nathorst , Benthin Günther , Lundin Stefan , Stenqvist Ola , Wennmalm Åke 
Published: July 2012

Nitric oxide (NO) is potentially useful as a selective vasodilator drug in infants and adults with pulmonary hypertension. In vitro and in vivo observations demonstrate that NO may be converted to nitrate in the blood, to be further excreted into the urine. The aim of the present study was to assess quantitatively the importance of this pathway for inhaled NO in human subjects.
Healthy subjects inhaled 15NO (25 p.p.m.) for 1 h. The plasma and urine levels of 15NO3‐ were followed for 2 and 48 h, respectively.
The measured retention of 15NO in the lungs was 224 ± 13 μmol, corresponding to 90 ± 2% of the inhaled amount. Plasma 15NO3‐ increased during the inhalation of 15NO, to about 15μmoll_1, and fell when inhalation of 15NO was terminated.
Urinary excretion of 15NO3‐ during the first 24 h after inhalation was 154 ± 12μmol. During the following 24 h another 8 ± 2 μmol of 15NO3 appeared in the urine.
We conclude that conversion of inhaled NO to nitrate is a major metabolic pathway in man, covering more than 70% of its inactivation. The metabolic fate of the remaining NO inhaled requires further study.
Comparative effects of activation of soluble and particulate guanylyl cyclase on cyclic GMP elevation and relaxation of bovine tracheal smooth muscle
Authors: Ijioma Samuel C. , Challiss R.A. John , Boyle John P. 
Published: July 2012

The effects of nitric oxide‐donating compounds and atrial natriuretic peptide on cyclic GMP accumulation and mechanical tone were compared with the effects of isoprenaline in bovine tracheal smooth muscle.
Sodium nitroprusside, glyceryl trinitrate, S‐nitroso‐N‐acetylpenicillamine (SNAP), atrial natriuretic peptide and isoprenaline each caused concentration‐dependent inhibitions of histamine‐maintained tone (EC50 values 320 ±80, 150 ±45, 14,000 ±4,000, 2.8 ±0.8 and 6.6 ±4.3 nM respectively).
When compared with their effects on histamine‐induced tone, sodium nitroprusside was equally potent and effective in causing relaxation of methacholine‐supported tone (EC50 290 ± 90 nM) while isoprenaline was as effective, but less potent (EC50 30 ± 7 nM). SNAP was more potent and equi‐effective as a relaxant of methacholine‐supported tone (EC50 340 ± 140 nM). At the maximum concentrations of glyceryl trinitrate and atrial natriuretic peptide tested against methacholine‐supported tone, relaxations of 52% and 14% of the isoprenaline maximum were seen.
Sodium nitroprusside, glyceryl trinitrate and atrial natriuretic peptide each induced concentration‐dependent increases in cyclic GMP accumulation. The time‐courses of accumulation correlated closely with the relaxant actions of these compounds.
Pretreatment of tracheal smooth muscle with sodium nitroprusside or SNAP caused a rightward shift of the concentration‐effect curve for histamine while reducing the maximum response.
LY 83583, a putative guanylyl cyclase inhibitor, caused a concentration‐dependent reduction in basal cyclic GMP accumulation in tracheal smooth muscle and inhibited the effects of sodium nitroprusside on cyclic GMP accumulation.
LY 83583 also inhibited the relaxation of histamine‐supported tone by glyceryl trinitrate, sodium nitroprusside, SNAP and atrial natriuretic peptide, and also sodium nitroprusside‐ and SNAP‐induced relaxation of methacholine‐supported tone. However, it had no significant effect on glyceryl trinitrate‐induced relaxation of methacholine‐supported tone.
It is concluded that the relaxant actions of sodium nitroprusside, glyceryl trinitrate, SNAP and atrial natriuretic peptide follow as a result of their ability to activate either soluble or particulate guanylyl cyclase leading to cyclic GMP accumulation. Although there does not seem to be any functional difference in the relaxant response to cyclic GMP generated by the particulate as opposed to soluble form(s) of guanylyl cyclase, atrial natriuretic peptide receptor/guanylyl cyclase activation was much less effective in causing relaxation of methacholine‐supported tone when compared to activators of soluble guanylyl cyclase.
A role for endothelin in bicuculline‐induced neurogenic pulmonary oedema in rats
Authors: Herbst C. , Tippler B. , Shams H. , Simmet Th. 
Published: July 2012

The possible contribution of endogenous endothelin (ET) to the pathogenesis of seizure‐associated pulmonary oedema was examined in mechanically ventilated rats after intravenous bolus injection of the γ‐aminobutyric acid (GABA) antagonist, bicucuiline (1.2 mg kg−1).
Recurrent seizure activity elicited by bicucuiline injection led to rapidly developing pulmonary oedema. Within 4 min after bicucuiline application (1.2mg kg_1), arterial O2 partial pressure (PaO2) significantly dropped from 17.49±1.20 kPa to 7.51 ±2.21 kPa (P<0.01) and arterial CO2 partial pressure (PaCO2) significantly increased from 4.64±0.56 kPa to 8.15±0.99 kPa (P<0.01). Gradually a progressive acidosis developed. Moreover, mean arterial blood pressure (MABP) and end‐inspiratory airway pressure (Paw) rapidly increased.
Concomitantly there was a time‐dependent increase of big ET‐1 and ET‐1 levels in bronchoalveolar lavage (BAL) as determined by combined reverse phase high performance liquid chromatography (h.p.l.c.) and radioimmunoassay. BAL levels of both peptides increased up to 8 min after bicucuiline injection and slowly decreased subsequently. In contrast, BAL from animals injected with vehicle did not contain detectable amounts of ET.
Pretreatment with the endothelin‐converting enzyme inhibitor, phosphoramidon (5.4 mg kg−1, i.v.) for 5 min significantly (P< 0.001) reduced peak ET‐1 levels in BAL fluid by 65.4 ±9.9% at 8 min after bicucuiline injection. Simultaneously it afforded protection from hypoxia. PacO2 did not increase and PaO2 decreased only slightly from 14.63 ±1.00 kPa to 12.97 ±0.61 kPa (P>0.05) after phosphoramidon pretreatment. In contrast, vehicle‐treated animals that received bicucuiline showed both significant hypercapnia as well as profound hypoxia. Phosphoramidon significantly diminished the maximum increase in Paw by 76.7 ±12.4% (P< 0.005), but only slightly affected the MABP. Phosphoramidon pretreatment had no effect on the acidosis.
Pretreatment with the ETA receptor antagonist, BQ‐123 (1 mg kg−1, i.v.), for 5 min did not affect the levels of ET‐1 in the BAL fluid at 8 min after bicucuiline injection but did ameliorate the development of hypoxia. No hypercapnia developed and Pao2 decreased only moderately from 16.65 ± 0.25 kPa to 14.19 ±2.15 kPa (P>0.05) in BQ‐123‐treated animals. In contrast, vehicle‐treated animals that received bicuculline exhibited significant hypercapnia as well as profound hypoxia. BQ‐123 significantly reduced the increase in Paw by 51.3 ± 12.8% (P<0.01). It affected MABP only slightly and had no effect on the acidosis.
These results suggest that ET peptides play a significant role in this model of neurogenic pulmonary oedema and may act as mediators of respiratory distress. The deleterious effects of endogenous ET in this model are primarily mediated via the ETA receptor, for they were inhibited by the ETA receptor antagonist, BQ‐123. ETA receptor antagonists may therefore be of potential therapeutic value in respiratory distress.