bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hypotensive effect of 13‐hydroxylinoleic acid in the rat: mediation via the release of a CGRP‐like mediator from capsaicin‐sensitive nerves
Authors: van Heuven‐Nolsen Dicky , Muis Thea , Engels Ferdi , Henricks Paul A.J. , Buckley Theresa L. , Nijkamp Frans P. 
Published: July 2012

The effect of 13‐hydroxylinoleic acid (13‐HODE) on changes in blood pressure in the rat was measured.
13‐HODE (0.1 −100 μg kg−1) had no direct eifect on blood pressure in the rat and had no eifect on histamine (0.1–1000 μg kg−1‐induced changes in blood pressure. In contrast, it was found that 13‐HODE itself induced a decrease in diastolic arterial blood pressure when it was injected intravenously after either a single dose of histamine (10, 100 or 1000 μg kg−1) or after a dose‐response curve of histamine (0.1–1000 μg kg−1).
This hypotensive eifect of 13‐HODE was not observed after administration of the endothelium‐dependent vasodilator, acetylcholine (0.1–10 μg kg−1), the endothelium‐independent vasodilator, sodium nitroprusside (0.1–100 μg kg−1) or the inflammatory mediator, leukotriene B4 (0.1–300 μg kg−1). However, prior injection of bradykinin (0.1–100 μg kg−1) allowed a dose‐dependent hypotensive effect of 13‐HODE to be revealed.
The hypotensive effect of 13‐HODE after histamine and bradykinin could be inhibited by neonatal capsaicin treatment of the rats (50 mg kg−1, s.c. on day 1 and 2 after birth).
Ruthenium red (120 μg kg−1 min−1), an inhibitor of excitatory effects on sensory nerves, and the CGRP antagonist, CGRP8.37 (1–3 μg kg−1 min−1) also inhibited the hypotensive effect of 13‐HODE.
It is concluded that the hypotensive effect of 13‐HODE in the rat after histamine and bradykinin is due to the release of a CGRP‐like substance from sensory nerves. These results highlight the possibility that endogenous 13‐HODE could be involved in the neurogenic regulation of blood pressure.
Evidence for ETA and ETB receptors in rat skin and an investigation of their function in the cutaneous microvasculature
Authors: Lawrence E. , Siney L. , Wilsoncroft P. , Knock G.A. , Terenghi G. , Polak J.M. , Brain S.D. 
Published: July 2012

The relative contribution of ETA and ETB receptors in the response of rat skin to endothelins was investigated by use of the selective ETB agonist IRL‐1620 and the selective ETA antagonist BQ‐123.
Binding data suggest the presence of ETA and ETB receptors as preincubation with [Ala3′11,18Nle7]‐endothelin‐1 reduced ET‐1 binding by approximately 40%.
Intradermal injection of endothelin‐1 (ET‐1, 1–10 pmol/site) and ET‐3 (3–100 pmol/site) induced a dose‐dependent decrease in local blood flow assessed by 133Xe clearance at test sites in rat skin.
The endothelin analogue [Ala3′11,18Nle7]‐ET‐l (30–1000 pmol/site) induced significant vasoconstriction (P<0.05) at the highest doses used and the selective ETB receptor agonist, IRL‐1620 [Suc‐[Glu9, Ala11,15] endothelin (8–21)], (0.01–100 pmol/site) acted in a potent manner to induce a significant (P<0.01) dose‐dependent decrease in 133Xe clearance.
Co‐injection with the selective ETA receptor antagonist, BQ‐123 (1 nmol/site), completely abolished the vasoconstriction to ET‐1 and partially to ET‐3, but had no effect on IRL‐1620‐induced vasoconstriction. In addition, IRL‐1620 responses were not altered at sites treated with submaximal doses of a nitric oxide synthase inhibitor or a prostaglandin synthase inhibitor.
ET‐1 and IRL‐1620 (100 fmol‐1 pmol/site) did not induce oedema formation as measured by [125I]‐albumin accumulation in the presence or absence of the vasodilator, calcitonin gene‐related peptide (CGRP). ET‐1 (1–3 pmol/site) inhibited substance P‐induced oedema formation and this effect, suggested to be secondary to a vasoconstrictor effect, was significantly reversed by BQ‐123 (1 nmol/site).
The findings in this study indicate that there are ETA and ETB receptors in rat skin and agents which activate either receptor act to mediate a decrease in cutaneous blood flow, but have no effect on increased microvascular permeability.
Role of nitric oxide in learning and memory and in monoamine metabolism in the rat brain
Authors: Yamada Kiyofumi , Noda Yukihiro , Nakayama Shinobu , Komori Yumiko , Sugihara Hisayoshi , Hasegawa Takaaki , Nabeshima Toshitaka 
Published: July 2012

We investigated the effects of NG‐nitro‐L‐arginine methyl ester (L‐NAME), an inhibitor of nitric oxide (NO) synthase, on the performance of rats in a radial arm maze and in habituation tasks, and on monoamine metabolism in the brain.
Daily administration of L‐NAME (10–60 mg kg−1) resulted in a dose‐dependent impairment of performance during the acquisition of the radial arm maze task, while it failed to affect performance in those rats that had previously acquired the task.
The rate of decrease in locomotor activity in the habituation task in the L‐NAME‐treated rats was significantly less than that in control rats.
NG‐nitro‐D‐arginine methyl ester (D‐NAME, a less active inhibitor of NO synthase) showed no effects in the above behavioural tasks.
NO synthase activity was significantly decreased in both the L‐NAME and D‐NAME‐treated rats, with the magnitude of inhibition being greater in the L‐NAME‐treated animals.
The content of 5‐hydroxyindoleacetic acid (5‐HIAA) in the hippocampus and the 5‐HIAA/5‐hydroxytryptamine ratio in the hippocampus and cortex were significantly decreased in the L‐NAME (60 mg kg)‐treated rats compared with these values in the controls.
Striatal 3,4‐dihydroxyphenylacetic acid (DOPAC) content was significantly increased in the L‐NAME (60 mg kg_1)‐treated rats compared with the values in the controls, while the DOPAC/dopamine ratio was not changed.
These results suggest that: (i) NO may play an important role in performance during the acquisition, but not retention, of the radial arm maze task, and (ii) that endogenous NO may be involved in the regulation of monoamine metabolism.
Effects of U46619 on contractions to 5‐HT, sumatriptan and methysergide in canine coronary artery and saphenous vein in vitro
Authors: Kemp B.K. , Cocks T.M. 
Published: July 2012

The aim of this study was to investigate the mechanism of enhanced reactivity to 5‐hydroxytryptamine (5‐HT) and sumatriptan previously observed in human isolated coronary arteries when active force was raised with the thromboxane A2‐mimetic, U46619.
Ring segments of dog isolated coronary artery and saphenous vein were suspended in organ baths and cumulative concentration‐contraction curves to 5‐HT, sumatriptan and methysergide were constructed in the absence and presence of low concentrations of U46619.
In both endothelium‐intact and endothelium‐denuded rings of coronary artery, precontraction with U46619 to low (<10% Fmax; the contraction to a maximum depolarizing 125 mM KCl Krebs solution; KPSS) levels of active force had no effect on either the maximum contraction or sensitivity (pEC50) to 5‐HT, sumatriptan and methysergide.
Ketanserin (1 μm) had no effect on contractions to sumatriptan and methysergide in endothelium‐denuded coronary artery rings, but reduced the maximum contraction to 5‐HT by z 90% to a value (5% Fmax) similar to that for sumatriptan and methysergide. Under these conditions, U46619 precontraction had no effect on either pEC50 or maximum for 5‐HT, sumatriptan or methysergide. 5 In rings of saphenous vein with endothelium and treated with ketanserin (1 μm), 5‐HT and sumatriptan caused equal maximum responses of 65% Fmax which were approximately double that of methysergide (32% Fmax). The maximum responses and sensitivity to 5‐HT, sumatriptan, methysergide and noradrenaline were unaffected by precontraction with U46619.
Pretreatment of the saphenous vein with sodium nitroprusside (SNP; 10 μm) caused a small sustained relaxation and significantly depressed the maximal contraction to 5‐HT without affecting sensitivity and abolished the contraction curve to sumatriptan and methysergide. When the relaxation response to SNP was reversed with U46619 (1–4 nM), the contraction curves to 5‐HT, sumatriptan and methysergide were similar to those obtained prior to relaxation with SNP. In contrast, the same treatment with SNP had little affect on the contraction curve to noradrenaline.
In conclusion, the pattern of U46619‐enhanced reactivity of 5‐HT, sumatriptan and methysergide in SNP‐treated dog saphenous vein, highlights the importance of functional antagonism when assessing reactivity to contractile agonists in isolated blood vessels.
Possible role of Na+‐K+‐ATPase in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide
Authors: Gupta Sandeep , Moreland Robert B. , Munarriz Ricardo , Daley Jennifer , Goldstein Irwin , de Tejada Iñigo Saenz 
Published: July 2012

This study was designed to determine the role of sodium‐potassium adenosine triphosphatase (Na+‐K+‐ATPase) in the regulation of human corpus cavernosum smooth muscle contractility by nitric oxide (NO). In addition, we determined if the modulation of Na+‐K+‐ATPase activity by NO is dependent on the increases in intracellular cyclic GMP concentration.
The effect of NO donors, sodium‐nitroprusside (SNP) and S‐nitroso‐glutathione (S‐NO‐Glu), and a permeable cyclic GMP analogue, 8‐bromo‐cyclic GMP, on Na+‐K+‐ATPase activity (measured as ouabain‐sensitive 86Rb‐uptake) was studied in human cultured corpus cavernosum smooth muscle cells (HCCSMC). In addition, the effect of the cyclic GMP lowering agent, methylene blue, on NO‐induced increase in Na+‐K+‐ATPase activity was studied.
SNP (1 μm) caused time‐dependent increases in ouabain‐sensitive Rb‐uptake (33–72%) over 2–20 min in HCCSMC. The stimulation of ouabain‐sensitive Rb‐uptake by SNP was concentration‐dependent (30 and 102% with 0.1 and 1 μm SNP, respectively). Similarly, significant increases in ouabain‐sensitive Rb‐uptake were obtained with 1 and 10 μm S‐NO‐Glu. In contrast, incubation of HCCSMC with 8‐bromo‐cyclic GMP (100 μm) did not increase ouabain‐sensitive Rb‐uptake.
S‐NO‐Glu induced‐increase in intracellular cyclic GMP synthesis, but not the increase in ouabain‐sensitive Rb‐uptake, was completely inhibited by methylene blue in HCCSMC.
The Na+‐K+‐ATPase inhibitor, ouabain, caused a concentration‐dependent increase in tension (0.5 to 2 fold) in tissues contracted with 15 mM KCL. SNP and S‐NO‐Glu caused a concentration‐dependent relaxation (concentration required to cause half maximal relaxation (ED50) = 0.04 and 0.2 μm, respectively) of HCC strips contracted with 15 mM K+. Ouabain (0.1 to 10 μm) inhibited the response to SNP and S‐NO‐Glu by shifting the concentration‐response curves to the right and preventing full smooth muscle relaxation.
These results indicate that the activity of Na+‐K+‐ATPase modulates the contractility of HCC smooth muscle, and that NO stimulates Na+‐K+‐ATPase activity in HCCSMC independently of its ability to increase the intracellular cyclic GMP concentration. They also suggest that stimulation of Na+‐K+‐ATPase activity plays an important role in NO‐induced relaxation of HCC smooth muscle
Electrical activity in rat tail artery during asynchronous activation of postganglionic nerve terminals by ciguatoxin‐1
Authors: Brock James A. , McLachlan Elspeth M. , Jobling P. , Lewis R.J. 
Published: July 2012

The effects of ciguatoxin‐1 (CTX‐1) on the membrane potential of smooth muscle cells have been examined in rat proximal tail arteries isolated in vitro.
CTX‐1 (≥ 10 pM) increased the frequency of spontaneous excitatory junction potentials (s.ej.ps). At 100–400 pM, there was also a marked and maintained depolarization (19.7 ± 1.4 mV, n=14, at 400 pM).
In 20–400 pM CTX‐1, perivascular stimuli evoked excitatory junction potentials (s.e.j.ps) which were prolonged in time course relative to control.
Although threshold and latency of the e.j.p. were not affected by CTX‐1 (≤400 pM), propagated impulses were blocked at ≥ 100 pM.
The spontaneous activity and the depolarization produced by CTX‐1 were reduced in the presence of Ca2+ (0.1 mM)/Mg2+ (25 mM), ω‐conotoxin (0.1 μm) or Cd2+ (50–100 μm)
All effects of CTX‐1 were abolished by tetrodotoxin (0.3 μm).
Raised Ca2+ (6 mM) reduced the depolarization and spontaneous activity produced by CTX‐1.
In 400 pM CTX‐1, the membrane repolarized (17 ± 3.2 mV, n=4) following the addition of phentolamine (1 μm). S.e.j.ps and e.j.ps were selectively abolished by suramin (1 mM), and the membrane repolarized by 1.3±1.6 mV (n=4).
We conclude that CTX‐1 releases noradrenaline and ATP by initiating asynchronous discharge of postganglionic perivascular axons. In 100–400 pM CTX‐1, the smooth muscle was depolarized to levels resembling those recorded in this artery during ongoing vasoconstrictor discharge in vivo.
Lack of involvement of bradykinin in the vascular sympathoinhibitory effects of angiotensin converting enzyme inhibitors in spontaneously hypertensive rats
Authors: Chauvin Bénédicte , Richer Christine , Giudicelli Jean‐François 
Published: July 2012

The aim of this study was to investigate the contribution of endogenous bradykinin to the vascular sympathoinhibitory effects exerted by angiotensin I converting enzyme inhibitors (ACEIs) in the spontaneously hypertensive rat (SHR).
Adult SHRs were treated daily for 8 days with either perindopril (3 mg kg−1), or a selective angiotensin II AT1 receptor antagonist, losartan (10 mg kg−1) both given orally ‐ these two doses being equipotent in inhibiting angiotensin I (AI)‐induced vascular responses ‐ or distilled water (controls). After pithing, the animals were instrumented for determination of blood pressure, heart rate, cardiac output, regional (renal, mesenteric, hindlimb) blood flows (pulsed Doppler technique) and corresponding vascular resistances. Afterwards, half of the animals of each group were given the selective bradykinin B2 receptor antagonist, icatibant, used in a dose (10 μg kg−1, i.v.) that achieved B2 receptor blockade, the other half received saline (10 μl kg−1, i.v.). Haemodynamic responses to increasing frequencies of spinal cord stimulation were then measured.
Pressor and vasoconstrictor responses to AI were significantly and similarly reduced in both perindopril‐ and losartan‐treated groups. Perindopril and losartan both decreased to a similar extent the pressor and vasoconstrictor responses to electrical stimulation of the spinal cord.
In the dose used, icatibant did not affect any of the investigated haemodynamic parameters in any of the experimental groups. Furthermore, icatibant did not affect the stimulation frequency‐response curves in the control animals and did not modify the vascular sympathoinhibitory effects exerted by perindopril and by losartan.
Taken together, these results demonstrate that endogenous bradykinin does not, through B2 receptor activation, contribute to the vascular sympathoinhibitory effects of ACEIs in SHRs.
Mediation by CCKB receptors of the CCK‐evoked hyperaemia in rat gastric mucosa
Authors: Heinemann Akos , Jociĉ Milana , Holzer‐Petsche Ulrike , Pethö Gábor , Peskar Brigitta M. , Horwell David C. , Holzer Peter 
Published: July 2012

Cholecystokinin octapeptide (CCK‐8) and gastrin‐17 augment gastric mucosal blood flow in the rat. The present study examined whether the gastric vasodilator effect of these peptides is mediated by CCKA or CCKB receptors.
Intravenous injection of CAM‐1481 (1 mg kg−1), a dipeptoid antagonist of CCKA receptors, or CAM‐1028, a dipeptoid CCKB receptor antagonist (1 mg kg−1), had no effect on basal gastric mucosal blood flow as determined by the clearance of hydrogen in urethane‐anaesthetized rats.
Intravenous infusion of CCK‐8 or gastrin‐17 (8–200 pmol min−1) increased gastric mucosal blood flow in a dose‐dependent fashion. The CCKB receptor antagonist, CAM‐1028, significantly attenuated the hyperaemic response to CCK‐8 and gastrin‐17 whereas the CCKA receptor antagonist, CAM‐1481, did not antagonize CCK‐8 but caused a slight attenuation of the vasodilator response to gastrin‐17.
The selectivity of the two antagonists was proved by the findings that CAM‐1028, but not CAM‐1481, inhibited gastric acid secretion evoked by CCK‐8 or gastrin‐17 (CCKB receptor assay) while CAM‐1481, but not CAM‐1028, inhibited the CCK‐8‐induced contraction of guinea‐pig isolated gall bladder strips (CCKA receptor assay).
These data show that the actions of CCK‐8 and gastrin‐17 to increase mucosal blood flow in the rat stomach are primarily mediated by CCKB receptors.
Effects of 5‐HT and 5‐HT1Areceptor agonists and antagonists on dorsal vagal preganglionic neurones in anaesthetized rats: an ionophoretic study
Authors: Wang Yun , Jones James F.X. , Ramage Andrew G. , Jordan David 
Published: July 2012

Effects of ionophoretic administration of 5‐hydroxytryptamine (5‐HT) and selective 5‐HT1Areceptor agonists and antagonists on identified dorsal vagal preganglionic and dorsal raphe neurones were studied in pentobarbitone sodium or chloral hydrate‐anaesthetized rats, respectively.Extracellular recordings were made from 176 preganglionic neurones in the dorsal vagal nucleus (DVN). Application of 5‐HT at low currents (<10nA) increased the activity of these neurones. However, at increased currents (10–60 nA), it had a predominantly depressant effect. Application of selective 5‐HT1Areceptor antagonists, (±)‐pindolol or WAY‐100635, attenuated the excitatory responses evoked by 5‐HT.Ionophoresis of the 5‐HT1Areceptor agonist, 8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (8‐OH‐DPAT) (5–30 nA) increased the firing rate of 19 and decreased that of 67 of the 104 vagal neurones tested. Other 5‐HT1Areceptor agonists, flesinoxan and N, N‐di‐n‐propyl‐5‐carboxamidotryptamine (DP‐5‐CT) also had predominantly depressant effects.(±)‐Pindolol attenuated excitations but not inhibitions evoked by 8‐OH‐DPAT. Surprisingly, WAY‐100635 and 8‐OH‐DPAT produced the same effect on these neurones and when applied together, WAY‐100635 failed to attenuate the 8‐OH‐DPAT responses.Dorsal raphe neurones were identified by their low, regular firing rate and their subsequent histological localization. 8‐OH‐DPAT reversibly reduced the activity in all 7 neurones tested and this was antagonized by WAY‐100635 in all 3 neurones tested.In conclusion, 5‐HT applied to vagal preganglionic neurones evokes excitatory and inhibitory responses. The excitatory, but not the inhibitory responses may be mediated, at least in part, by activation of 5‐HT1Areceptors.
Endothelium‐dependent relaxations in sheep pulmonary arteries and veins: resistance to block by NG‐nitro‐L‐arginine in pulmonary hypertension
Authors: Kemp B.K. , Smolich J.J. , Ritchie B.C. , Cocks T.M. 
Published: July 2012

The effect of the nitric oxide synthase inhibitor, NG‐nitro‐L‐arginine (L‐NOARG), on endothelium‐dependent relaxation to a receptor‐independent agent, ionomycin, was examined in isolated pulmonary arteries and veins from control, short‐term and chronic pulmonary hypertensive sheep. All vessel segments were contracted to optimal levels of active force with endothelin‐1 to record endothelium‐dependent relaxation.
Pulmonary hypertension was induced by continuous pulmonary artery air embolization for 1 day (short‐term) and 14 days (chronic) and was associated with a 2 and 3 fold increase in pulmonary vascular resistance respectively.
L‐NOARG (0.1 mM) reduced the maximum relaxation (Rmax) to ionomycin in large and medium‐sized pulmonary arteries from control sheep by approximately 70%. By contrast, L‐NOARG (0.1 mM) did not inhibit the Rmax to ionomycin in matched vessels from short‐term and chronic pulmonary hypertensive sheep.
Resistance of ionomycin‐induced relaxations to inhibition by L‐NOARG, was confined to the arterial vasculature in chronic pulmonary hypertensive animals, as relaxations to ionomycin in large and medium‐sized chronic pulmonary hypertensive veins were, like those in control veins, abolished by L‐NOARG. Both large and medium‐sized pulmonary veins from short‐term pulmonary hypertensive sheep, however, were resistant to block by L‐NOARG.
Neither sensitivity (pEC50) nor Rmax, to ionomycin in large, short‐term pulmonary hypertensive arteries was affected when the extracellular concentration of K+ was increased isotonically to 30 mM. Nifedipine (0.3 μm) was present throughout to prevent high K+‐induced smooth muscle contraction. In the presence of this high extracellular K+, however, L‐NOARG (0.1 mM) caused complete inhibition of the relaxation to ionomycin, whereas in normal extracellular K+ (4.7 mM), L‐NOARG only weakly inhibited ionomycin relaxations.
In conclusion, the onset of pulmonary hypertension in sheep following air embolization, is associated with the development of resistance of endothelium‐dependent relaxations to block by L‐NOARG. The mechanism of L‐NOARG resistance appears to be due to the up‐regulation of a K+ channel‐mediated backup vasodilator mechanism which can compensate for the loss of nitric oxide (NO)‐mediated relaxation. Although this mechanism remains functionally ‘silent’ in the presence of NO it is able to maintain adequate endothelium‐dependent vasodilatation during pulmonary hypertension if NO synthesis is compromised.
Lack of effect of TNF antibodies on the cardiovascular sequelae of lipopolysaccharide infusion in conscious rats
Authors: Waller John , Gardiner Sheila M. , Jose Joby , Bennett Terence 
Published: July 2012

The aims of the present study were to determine the profile of tumour necrosis factor (TNF) release, and the effect of monoclonal antibodies to TNF, on the changes in regional haemodynamics and the responses to vasodilator and vasoconstrictor challenges, during a continuous 24 h low dose infusion of lipopolysaccharide (LPS) in conscious rats.
Male Long Evans rats were chronically instrumented for measurement of regional haemodynamics (renal, superior mesenteric and hindquarters) and were challenged with 3 min infusions of acetylcholine (22 nmol min−1), methoxamine (120 nmol min−1), salbutamol (0.83 nmol min−1) and bradykinin (14.4 nmol min−1). The rats were given either saline, or the TNF antibodies, TN3gl or TN3g2a, 1 h before the start of a continuous infusion of LPS (150 μg kg−1 h−1) and were subsequently re‐tested with the vasodilator and vasoconstrictor challenges 2, 6 and 24 h after the start of the LPS infusion.
Prior to infusion of LPS, TNF was not detectable in the plasma. During continuous infusion of LPS there was a transient elevation in plasma TNF levels, reaching a maximum (∼2300 pg ml−1) after approximately 1 h, and returning to undetectable levels after approximately 3 h of LPS infusion.
In the saline pretreated group, after 1–2 h of LPS infusion, there was a small hypotension and a marked renal vasodilatation; 6 h after the start of LPS infusion there was a minor elevation in MAP above control levels, renal vasodilatation was maintained and a hindquarters vasoconstriction occurred; after 24 h of LPS infusion, there was a hypotension and renal and hindquarters vasodilatation. There were significant reductions in the tachycardic and renal vasodilator responses and an enhanced depressor response to acetylcholine after 24 h of LPS infusion. LPS infusion also caused a generalized hyporesponsiveness to the cardiovascular effects of methoxamine and salbutamol. The major changes in response to bradykinin were reduced tachycardic and enhanced depressor responses throughout the LPS infusion, a biphasic decrease and increase in renal conductance and enhanced hindquarters vasodilatation at 24 h.
Pretreatment with either TN3gl or TN3g2a antibodies had no major effects on the changes in resting haemodynamics, or on the changes in response to methoxamine, salbutamol or bradykinin challenges during LPS infusion. However, the tachycardic responses to acetylcholine were generally preserved, and its hypotensive effect after 24 h of LPS infusion was not enhanced after TN3gl or TN3g2a pretreatment. Thus, despite substantial, but transient, elevation of plasma TNF levels during continuous LPS infusion, it appears that the majority of cardiovascular changes were dependent on factors other than plasma TNF.