bluuebunny/crossref_metadata_2025_split huggingface dataset:
Blockade of porcine carotid vascular responses to sumatriptan by GR127935, a selective 5‐HT1D receptor antagonist
Authors: De Vries Peter , Heiligers Jan P.C. , Villalón Carlos M. , Saxena Pramod R. 
Published: July 2012

. It has previously been shown that the antimigraine drug, sumatriptan, a putative 5‐HT1D receptor agonist, decreases porcine common carotid and arteriovenous anastomotic blood flows, but slightly increases the arteriolar (capillary) blood flow to the skin and ears. Interestingly, such responses, being mediated by 5‐HT1‐like receptors, are resistant to blockade by metergoline, which, in addition to displaying a very high affinity for (and occasionally intrinsic efficacy at) the 5‐HT1D receptor subtypes, blocks (with lower potency than methiothepin) some 5‐HT1D receptor‐mediated vascular responses. These findings raise doubts whether sumatriptan‐sensitive 5‐HT1‐like receptors mediating changes in the distribution of porcine carotid blood flow are identical to cloned 5‐HT1D receptors. With the recent advent of the potent and selective 5‐HT1D receptor antagonist, GR127935, we have examined in the present study whether the carotid vascular effects of sumatriptan in the pig are amenable to blockade by GR127935.
. In animals pretreated with saline, sumatriptan (30, 100 and 300 μm kg−1, i.v.) reduced the total carotid and arteriovenous anastomotic blood flows in a dose dependent manner. In contrast, sumatriptan increased blood flow to the skin, ears and fat, although the total capillary fraction was not significantly affected.
. While GR127935 pretreatment (0.25 and 0.5 mg kg−1) itself slightly reduced the total carotid and arteriovenous anastomotic blood flows, carotid vasoconstrictor responses to sumatriptan were either partly (0.25 mg kg−1) or completely (0.5 mg kg−1) blocked by the compound. In GR127935 pretreated animals, the sumatriptan‐induced increases in blood flow to the skin, ears and fat were also attenuated.
. Taken together, the results suggest that arteriovenous anastomotic constriction and, possibly, arteriolar dilatation in the skin, ears and fat by sumatriptan are mediated by 5‐HT1D receptors. Therefore, vascular 5‐HT1‐like receptors in the porcine carotid bed appear to be identical to 5‐HT1D receptors.
Baroreflex resetting but no vascular tolerance in response to transdermal glyceryl trinitrate in conscious rabbits
Authors: Serone Adrian P. , Angus James A. , Wright Christine E. 
Published: July 2012

. We investigated whether acute (5 h) and chronic (3 days) transdermal glyceryl trinitrate (GTN) patches could cause the development of tolerance in terms of haemodynamics and vascular reactivity in the conscious rabbit. The effects of haemodynamic tolerance were assessed on arterial pressure, heart rate and the baroreflex control of heart rate, while hindquarter vascular reactivity in response to dilator and constrictor drugs and reactive hyperaemia were used to assess vascular tolerance.. Seven days prior to experiments, an inflatable cuff, a pulsed Doppler flow probe and an indwelling intra‐aortic catheter (for i.a. agonist infusions) were implanted around the lower abdominal aorta.. In acute experiments, the effects of 0–5 h treatment with transdermal GTN (0 Sham), 10 or 20 mg 24 h−1) on MAP, HR and the baroreflex were examined. Chronic experiments were performed on three separate days (days 0 ‐ before, 4 ‐ with GTN patch and 8 ‐ recovery). On each day, the baroreflex, reactive hyperaemic responses and hindquarter vascular dose‐response curves to i.a. GTN, adenosine, acetylcholine, S‐nitroso‐N‐acetylpenicillamine (SNAP) and methoxamine were assessed. On days 1–4, GTN was administered transdermally via a patch(es) (10 mg 24 h−1(low dose) or 20 mg 24 h−1(high dose); renewed every 24 h).. Acute treatment with 20 mg GTN 24 h−1, but not with 0 (n= 4) or 10 mg GTN 24 h−1(n= 4), caused a significant fall in MAP (−8±1 mmHg;n= 4) and resetting of the baroreflex by 5 h. Chronic GTN caused a significant fall in MAP of 8±2 and 8±2 mmHg on day 4 with low (n= 8) and high dose (n= 8), respectively, with no change in HR. There was no significant change to hindquarter vascular reactivity to i.a. infusion of GTN, nor were there any significant differences in the reactivity to i.a. adenosine, acetylcholine, SNAP or methoxamine with either low or high doses of GTN.. Chronic GTN treatment with low and high dose patches caused a parallel leftward shift (‘resetting’) of the baroreflex on day 4. By day 8, the baroreflex had still not recovered from this leftward shift.. In the rabbit, chronic exposure to clinical nitrate patches caused haemodynamic compensation and baroreflex resetting but no evidence of vascular reactivity tolerance. Novel NO donor drugs and delivery regimens which provide intermittent dosing may prevent the development of haemodynamic resetting rather than preventing vascular tolerance, a commonly perceived difficulty in chronic nitrate therapy.
Inhibition of nitrergic relaxations by a selective inhibitor of the soluble guanylate cyclase
Authors: Cellek Selim , Kasakov Lubomir , Moncada Salvador 
Published: July 2012

. The actions of 1H‐[1,2,4]oxadiazolo[4,3,‐a]quinoxalin‐1‐one (ODQ), a specific inhibitor of the soluble guanylate cyclase (SGC), were investigated in the rabbit anococcygeus muscle.
. ODQ (1 nM‐1 μm) inhibited in a concentration‐dependent manner the relaxations induced by electrical field stimulation (EFS; 50 V, 0.3 ms duration, 1 Hz, for 5 s, every 120 s).
. ODQ (1 μm) also inhibited the relaxations elicited by EFS (50 V, 0.3 ms duration, 1, 2.5, 5, 10 Hz, for 5 s) and sodium nitroprusside (SNP; 1 μm) without affecting those induced by isoprenaline (1 μm), atrial natriuretic peptide (ANP; 100 nM) or an analogue of cyclic GMP (8‐pCPT‐cyclic GMP; 500 μm).
. ODQ (1 μm) inhibited the elevations in the concentration of cyclic GMP induced by SNP or EFS, but not by ANP. ODQ did not affect the concentrations of cyclic AMP.
. Nitrergic relaxation in this tissue appears, therefore, to be mediated via activation of SGC.
Nitric oxide as a mediator of cocaine‐induced penile erection in the rat
Authors: Chan Julie Y.H. , Huang Chian‐Ling , Chan Samuel H.H. 
Published: July 2012

. The effect of local application of cocaine to the corpus cavemosum on intracavemous pressure (ICP), an experimental index for penile erection, was examined in Sprague‐Dawley rats anaesthetized with chloral hydrate. The potential involvement of dopamine, noradrenaline or nitric oxide as the chemical mediator in this process, and the pharmacological action of cocaine as a local anaesthetic in the induced increase in ICP, were also investigated.
. Intracavemous (i.e.) administration of cocaine (40, 80 or 160 μg) to the corpus cavemosum resulted in a dose‐related increase in both amplitude and duration of ICP.
. The elevation in ICP induced by cocaine (160 μg, i.e.) was not significantly influenced by prior injection into the corpus cavemosum of either the D1 or D2 dopamine receptor antagonist, R‐(+)‐SCH 23390 (250 pmol) or (—)‐sulpiride (250 pmol).
. Similarly, penile erection promoted by cocaine (160 μg, i.e.) was not appreciably affected by i.e. pretreatment with the α1, α2‐, or β‐adrenoceptor antagonist, prazosin (50 pmol), yohimbine (50 pmol) or propranolol (5 nmol).
. Whereas lignocaine (4 μmol, i.e.) depressed penile erection induced by papaverine (400 μg, i.e.), local application of cocaine (160 μg) into the corpus cavemosum still elicited significant elevation in ICP in the presence of lignocaine or papaverine.
. The increase in ICP induced by cocaine (160 μg, i.e.) was attenuated dose‐dependently by prior cavemosal administration of the NO synthase inhibitor, Nω‐nitro‐L‐arginine methyl ester (1‐NAME, 0.5, 1 or 5 pmol) or NG‐monomethyl‐L‐arginine (L‐NMMA, 2.5, 5 or 10 pmol). The blunting effect of L‐NAME or L‐NMMA was reversed by co‐administration of the NO precursor, L‐arginine (1 nmol, i.e.).
. Pretreatment by local application into the corpus cavemosum of methylene blue (2.5 μmol), an inhibitor of cytosolic guanylyl cyclase, antagonized cocaine‐induced penile erection.
. Direct i.e. administration of a NO donor, nitroglycerin (10 or 20 nmol), mimicked the local action of cocaine by promoting a significant increase in ICP.
. It is concluded that cocaine may induce penile erection by increasing ICP via a local action on the corpus cavemosum. This process did not appear to involve either dopamine or noradrenaline as the chemical mediator, nor the pharmacological action of cocaine as a local anaesthetic. On the other hand, it is likely that initiation and maintenance of penile erection elicited by cavemosal application of cocaine engaged an active participation of NO and subsequent activation of guanylyl cyclase in the corpus cavemosum.
Deficient nitric oxide responsible for reduced nerve blood flow in diabetic rats: effects of L‐NAME, L‐arginine, sodium nitroprusside and evening primrose oil
Authors: Omawari Nagashige , Dewhurst Mark , Vo Phuong , Mahmood Salina , Stevens Elizabeth , Tomlinson David R. 
Published: July 2012

. This study examined the potential role of impaired nitric oxide production and response in the development of endoneurial ischaemia in experimental diabetes. Rats were anaesthetized (Na pentobarbitone 45 mg kg−1, diazepam 2 mg kg−1) for measurement of sciatic nerve laser Doppler flux and systemic arterial pressure. Drugs were administered into the sciatic endoneurium via a microinjector attached to a glass micropipette.
. In two separate studies comparing diabetic rats (streptozotocin‐induced; 8–10 wk duration) with controls, nerve Doppler flux in diabetic rats (Study 1, 116.6±40.4 and Study 2, 90.1±34.7 (s.d.) in arbitrary units) was about half that measured in controls (219.6±52.4 and 212.8±95.5 respectively; P<0.005 for both). There were no significant differences between the two in systemic arterial pressure.
. Inhibition of nitric oxide production by microinjection of 1 nmol L‐NAME into the endoneurium halved flux in controls (to 126.3±41.3 in Study 1 and 102.1±38.9 in Study 2; both P<0.001), with no significant effect in diabetic rats, indicating markedly diminished tonic nitric oxide production in the latter. D‐NAME was without effect on nerve Doppler flux.
. L‐Arginine (100 nmol), injected after L‐NAME, markedly increased flux in controls (by 65.8% (P<0.03) and 97.8% (P<0.01) in the two studies) and by proportionally similar amounts in diabetic rats [75.8% (P<0.001) and 60.2% (P<0.02)]. The nitro‐donor, sodium nitroprusside (SNP; 10 nmol) had similar effects to L‐arginine in both groups (increases of 66.0% in controls and 77.5% in diabetics; both P<0.002).
. A second diabetic group, treated with evening primrose oil performed exactly like control rats in respect of responses to L‐NAME, L‐arginine and SNP.
. These findings implicate deficient nitric oxide in nerve ischaemia of diabetes and suggest correction thereof as a mechanism of action of evening primrose oil.
Effects of the endothelin receptor antagonist, SB 209670, on circulatory failure and organ injury in endotoxic shock in the anaesthetized rat
Authors: Ruetten Hartmut , Thiemermann Christoph , Vane John R. 
Published: July 2012

. This study investigates the effects of the non‐selective ETA/ETB receptor antagonist, SB 209670, on systemic haemodynamics, renal function, liver function, acid‐base balance and survival in a rat model of endotoxic shock.
. Injection of E. coli lipopolysaccharide (LPS, 10 mg kg−1, i.v.) resulted in increases in the serum levels of tumour necrosis factor‐α (TNF‐α, maximum 60 min after LPS), endothelin‐1 (ET‐1; maximum 120 min after LPS), and interferon‐γ (IFN‐γ, maximum 180 min after LPS).
. Injection of LPS also resulted in a fall in blood pressure from 113 ± 3 mmHg (time = 0) to 84 ± 4 mmHg at 360 min (n = 15) as well as a hyporeactivity to the vasoconstrictor responses elicited by noradrenaline (NA, 1 μg kg−1, i.v.). Pretreatment of rats with a continuous infusion of SB 209670 (3 mg kg−1, i.v. bolus + 100 μg kg−1, i.v. infusion commencing 15 min prior to LPS) significantly augmented the hypotension as well as the vascular hyporeactivity to NA caused by endotoxaemia.
. Pretreatment of LPS‐rats with SB 209670 (3 mg kg−1, i.v. bolus given 15 min prior to LPS) or infusion of SB 209670 (bolus dose and infusion as above) resulted in a reduction in 6 h‐survival from 71% (control) to 30% and 13%, respectively.
. Endotoxaemia for 4 h resulted in rises in the serum levels of urea and creatinine (indicators of renal failure), but not in the serum levels of bilirubin, GPT and GOT (indicators of liver dysfunction and/or hepatocellular injury). Pretreatment of LPS‐rats with SB 209670 (3 mg kg−1, i.v. bolus 15 min prior to LPS) significantly augmented the serum levels of creatinine, bilirubin, GPT and GOT caused by endotoxin. In addition, endotoxaemia caused, within 15 min, an acute metabolic acidosis (falls in pH, HCO3− and base excess) which was compensated by hyperventilation (fall in Paco2). Pretreatment of LPS‐rats with SB 209670 (3 mg kg−1, i.v. bolus) significantly augmented the metabolic acidosis caused by LPS.
. Thus, the non‐selective ETA/ETB receptor antagonist, SB 209670, augments the degree of (i) hypotension, (ii) vascular hyporeactivity to noradrenaline, (iii) renal dysfunction and (iv) metabolic acidosis caused by endotoxin in the anaesthetized rat. In contrast to rats treated with LPS alone, LPS‐rats treated with SB 209670 exhibited liver dysfunction and hepatocellular injury. We propose that the release of endogenous ET‐1 serves to maintain blood pressure and subsequently organ perfusion in septic shock.
Functional correlation between allopregnanolone and [35S]‐TBPS binding in the brain of rats exposed to isoniazid, pentylenetetrazol or stress
Authors: Concas Alessandra , Mostallino Maria Cristina , Perra Chiara , Lener Raffaela , Roscetti Gianna , Barbaccia Maria Luisa , Purdy Robert H. , Biggio Giovanni 
Published: July 2012

The relation between changes in the cerebral cortical concentration of allopregnanolone and γ‐aminobutyric acid (GABA) type A receptor function after intracerebroventricular injection of this neurosteroid was investigated in male rats.
Intracerebroventricular administration of allopregnanolone (1.25 to 15 μg) produced a maximal increase (100 fold at the highest dose) in cortical allopregnanolone concentration within 5 min; the concentration remained significantly increased at 15 and 30 min, before returning to control values by 60 min.
The same treatment induced a rapid and dose‐dependent decrease in the binding of t‐[35S]‐butylbicyclophosphorothionate ([35S]‐TBPS) to cerebral cortical membranes measured ex vivo, an effect mimicked by the benzodiazepine midazolam but not by the 3β‐hydroxyepimer of allopregnanolone. The time course of changes in [35S]‐TBPS binding paralleled that of brain allopregnanolone concentration.
In a dose‐dependent manner, allopregnanolone both delayed the onset of convulsions and inhibited the increase in [35S]‐TBPS binding to cortical membranes induced by isoniazid. The potency of allopregnanolone in inhibiting [35S]‐TBPS binding in isoniazid‐treated rats was approximately four times that in control animals.
The ability of allopregnanolone to decrease [35S]‐TBPS binding in isoniazid‐treated rats also correlated with its anticonvulsant activity against pentylenetetrazol‐induced seizures as well as its inhibitory effect on the increase in [35S]‐TBPS binding induced by foot shock.
The results indicate that the in vivo administration of allopregnanolone enhances the function of GABAA receptors in rat cerebral cortex and antagonizes the inhibitory action of stress and drugs that reduce GABAergic transmission.
Effects of cyclopiazonic acid and thapsigargin on electromechanical activities and intracellular Ca2+ in smooth muscle of carotid artery of hypertensive rats
Authors: Sekiguchi F. , Shimamura K. , Akashi M. , Sunano S. 
Published: July 2012

The effects of cyclopiazonic acid (CPA) and thapsigargin (TG), both of which are known to inhibit sarcoplasmic reticular Ca2+‐ATPase, on the mechanical activities, intracellular Ca2+ level and electrical activities of smooth muscle of the carotid artery of stroke‐prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY) were compared.
Both CPA and TG induced elevation of tension of the smooth muscle, which was composed of a phasic and a tonic component. The level of tension attained, especially the tonic component, was greater in the preparation from SHRSP.
The elevation of tension was associated with an increased intracellular Ca2+ level. Both the elevation of tension and the increase in intracellular Ca2+ were diminished by the removal of extracellular Ca2+ or by the application of verapamil.
The resting membrane potential of the preparations from SHRSP were depolarized to a greater extent than those from WKY. CPA depolarized the smooth muscle from both SHRSP and WKY, and the final level was also more depolarized in the preparation from SHRSP.
These results indicate that the elevation of tension induced by these drugs is mainly due to increased Ca2+ influx through voltage‐dependent Ca2+ channels, and the difference in the action between the preparation from SHRSP and that from WKY can be explained mainly by the changes in the channels.
Thus, differences in the action of these drugs on the tension of smooth muscle between preparations from WKY and SHRSP can mainly be explained by the difference in the membrane potential which is related to the difference in voltage‐dependent Ca2+ influx.
Nitric oxide, a possible mediator of 1,4‐dihydropyridine‐induced photorelaxation of vascular smooth muscle
Authors: Lovren Fina , O'Neill Sean K. , Bieger Detlef , Igbal Nadeem , Knaus Ed E. , Triggle Chris R. 
Published: July 2012

In rat aortic tissues pre‐contracted with phenylephrine, certain 1,4‐dihydropyridines (DHPs) such as Bay K 8644 (0.1 μm), PN 202791 (1 μm), RK 30 (1 μm), NI 104 (1 μm) and NI 105 (1 μm) enhanced photoactivated relaxations (photorelaxation or PR) whereas NI 72, NI 85, NI 99, NI 102, amlodipine, felodipine, nifedipine and nimodipine were inactive.
The PR inducing effects of Bay K 8644 were mimicked by the diabetogenic agent, streptozotocin (STZ).
Solutions of Bay K 8644 which had been irradiated for various periods of time initiated light independent transient relaxations followed by contractile responses in aortic tissue partially contracted with phenylephrine. With exposure times to light of 30 to 120 min, the intensity of the relaxation response to irradiated Bay K 8644 increased from 26±3.3 to 71±3.7% of the maximum contractile response to phenylephrine (n = 5). Conversely the contractile responses decreased, from 84.2±4.1 to 19.8±10.4% of the maximum contractile response to phenylephrine (n = 5).
Superoxide ions, generated by incubation of xanthine (2 mM) plus xanthine oxidase (10 mu ml−1) in physiological saline solution (PSS) NaCl 118, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 12.5 and glucose 11.1 (mM) for 1 h, reduced the PR induced by DHPs, STZ, and also NO‐induced relaxations of rat aortic preparations.
Direct measurements of NO indicate that, following exposure to a polychromatic light source, equimolar concentrations (0.1 mM) of the DHP compounds that enhance PR, as well as STZ, photodegrade to release NO (25±2‐40.3±5.9 nmol min−1, n = 6).
Structure‐activity studies indicate that a nitro group at the −3 position of the dihydropyridine ring is essential for DHPs to support PR.
These data suggest that the photodegradation of DHPs and STZ leading to the release of NO provides the primary cellular process underlying the PR response.
Involvement of nitric oxide and eicosanoids in platelet‐activating factor‐induced haemodynamic and haematological effects in dogs
Authors: Noguchi Katsuhiko , Matsuzaki Toshihiro , Shiroma Noboru , Ojiri Yoshihiko , Sakanashi Matao 
Published: July 2012

Platelet‐activating factor (PAF) is a phospholipid mediator with potent cardiovascular and haematological actions. But its mechanisms of action in vivo have not been fully elucidated, probably due to difficulties arising from previous findings that the effects of PAF are largely mediated by the release of a variety of other autacoids. In the present study, the roles of nitric oxide and eicosanoids in the effects of PAF (0.01‐0.25 μg kg−1 i.v.) on systemic and pulmonary vasculatures and circulating blood cell count were pharmacologically evaluated in anaesthetized dogs.
Higher doses of PAF (>0.1 μg kg−1) produced a biphasic systemic hypotension. The first hypotension seen 30 s after the injection was accompanied by a decrease in systemic vascular resistance, thrombocytopenia and leukopenia, while the second hypotension seen 1–2 min after PAF was accompanied by a marked rise in pulmonary vascular resistance and decreases in aortic blood flow and cardiac contractility. Lower doses of PAF (0.01‐0.05 μg kg−1) caused only the first responses in a dose‐dependent manner.
Pretreatment with indomethacin inhibited the second responses to PAF without affecting the first responses. The thromboxane A2/prostaglandin H2 (TP)‐receptor antagonist vapiprost blocked the PAF‐induced rise in pulmonary vascular resistance. AA‐861, a 5‐lipoxygenase inhibitor, attenuated the PAF‐induced cardiac depression. The nitric oxide synthase inhibitor NG‐nitro‐l‐arginine methyl ester inhibited the PAF‐induced early decrease in systemic vascular resistance.
All observed changes in haemodynamics and blood cell count after PAF were almost abolished by TCV‐309, a PAF‐receptor antagonist.
Reproducible hypotension and thrombocytopenia produced by a lower dose of PAF (0.05 μg kg−1) were respectively attenuated and potentiated by pretreatment with NG‐nitro‐l‐arginine, another nitric oxide synthase inhibitor. Administration of l‐arginine reversed the effects of the nitric oxide synthase inhibitor.
These results indicate that PAF‐receptor‐mediated production of not only eicosanoids but also nitric oxide may contribute to the cardiovascular and haematological responses to PAF in the dog.
Electrophysiological actions of GABAB agonists and antagonists in rat dorso‐lateral septal neurones in vitro
Authors: Bon Christelle , Galvan Martin 
Published: July 2012

The actions of GABAB‐receptor agonists and antagonists on rat dorso‐lateral septal neurones in vitro were recorded with intracellular microelectrodes.
In the presence of 1 μm tetrodotoxin to prevent indirect neuronal effects caused by action potential‐dependent neurotransmitter release, bath application of baclofen (0.1–30 μm) or SK&F 97541 (0.01–3 μm) evoked concentration‐dependent hyperpolarizations which reversed close to the potassium equilibrium potential; the EC50s were 0.55 and 0.05 μm, respectively. No significant desensitization was observed during prolonged agonist exposure (≤ 10 min).
Hyperpolarizations induced by baclofen were antagonized in a competitive manner by the following GABAB‐receptors antagonists (calculated pA2 values in parentheses): CGP 36742 (4.0), 2‐OH saclofen (4.2), CGP 35348 (4.5), CGP 52432 (6.7) and CGP 55845A (8.3). Responses to SK&F 97541 were also antagonized by CGP 55845A (pA2 = 8.4).
The amplitude of the late, GABAB receptor‐mediated inhibitory postsynaptic potential (i.p.s.p.) was reduced by the GABAB antagonists as follows (means ± s.e.mean): CGP 55845A (1 μm) 91 ± 5%, CGP 52432 (1 μm) 64 ± 5%, CGP 35348 (100 μm) 82 ± 5%, CGP 36742 (100 μm) 76 ± 8%, and 2‐OH saclofen (100 μm) 68 ± 3%.
It is concluded that neurones in the rat dorso‐lateral septal nucleus express conventional GABAB receptors, which are involved in the generation of slow inhibitory postsynaptic potentials. CGP 55845A is the most potent GABAB receptor antagonist described in this brain area.