bluuebunny/crossref_metadata_2025_split huggingface dataset:
Nitric oxide‐dependent and ‐independent hyperaemia due to calcitonin gene‐related peptide in the rat stomach
Authors: Holzer P. , Lippe I.Th. , Jocic̆ M. , Wachter Ch. , Erb R. , Heinemann A. 
Published: July 2012

Calcitonin gene‐related peptide (CGRP) potently enhances mucosal blood flow in the rat stomach. The aim of this study was to examine whether CGRP also dilates extramural arteries supplying the stomach and whether the vasodilator action of CGRP involves nitric oxide (NO).
Rat CGRP‐α (0.03–1 nmol kg−1, i.v.) produced a dose‐dependent increase in blood flow through the left gastric artery (LGA) as determined by an ultrasonic transit time technique in urethane‐anaesthetized rats. Blockade of NO synthesis by NG‐nitro‐l‐arginine methyl ester (l‐NAME, 20 and 60 μmol kg−1, i.v.) significantly reduced basal blood flow (BF) in the LGA and attenuated the hyperaemic activity of CGRP by a factor of 2.8–4. d‐NAME tended to enhance basal BF in the LGA but had no influence on the dilator activity of CGRP. The ability of vasoactive intestinal polypeptide to increase left gastric arterial blood flow remained unaltered by l‐NAME.
l‐NAME (20 and 60 μmol kg−1, i.v.) evoked a prompt and sustained rise of mean arterial blood pressure (MAP) and caused a slight decrease in the hypotensive activity of CGRP. In contrast, d‐NAME induced a delayed and moderate increase in MAP and did not influence the hypotensive activity of CGRP.
Rat CGRP‐α dilated the isolated perfused bed of the rat LGA precontracted with methoxamine and was 3 times more potent in this respect than rat CGRP‐β. The dilator action of rat CGRP‐α in this preparation was not affected by l‐NAME or d‐NAME (40 μm).
L‐NAME (60 μmol kg−1, i.v.) reduced gastric mucosal blood flow as assessed by laser Doppler flowmetry and diminished the hyperaemic activity of rat CGRP‐α in the gastric mucosa by a factor of 4.5, whereas d‐NAME was without effect.
These data show that CGRP is a potent dilator of mucosal and extramural resistance vessels in the rat stomach. Its dilator action involves both NO‐dependent and NO‐independent mechanisms.
E‐type prostaglandins enhance local oedema formation and neutrophil accumulation but suppress eosinophil accumulation in guinea‐pig skin
Authors: Teixeira M.M. , Williams T.J. , Hellewell P.G. 
Published: July 2012

Prostaglandins possess both pro‐ and anti‐inflammatory actions depending on their route of administration and the experimental model used. In this study, we have investigated the effect of locally injected prostaglandins on oedema formation, neutrophil accumulation and eosinophil accumulation in inflammatory responses in guinea‐pig skin.
Prostaglandin E1 (PGE1) significantly enhanced local oedema formation induced by zymosan‐activated plasma (ZAP), bradykinin and in a passive cutaneous anaphylatic (PCA) reaction. The accumulation of ZAP‐induced 111In‐labelled neutrophils was also significantly enhanced by PGE1. In addition, the prostacyclin analogue, iloprost, enhanced ZAP‐induced responses.
In contrast PGE1 decreased the accumulation of 111In‐labelled eosinophils in skin sites. This was demonstrated on eosinophil accumulation and local eodema formation induced by PAF, compound 48/80 and in the PCA reaction. PGE2 also suppressed eosinophil accumulation while iloprost had no detectable effect.
Isoprenaline inhibited eosinophil accumulation in a dose‐dependent manner with no effect on local oedema formation, except in the case of responses to ZAP where suppression was observed.
The vasodilator neuropeptide, calcitonin gene‐related peptide (CGRP), enhanced local oedema formation but had no detectable effect on eosinophil accumulation.
In conclusion, the magnitude of a given response to an inflammatory mediator in vivo depends on the net effect of stimulation of several cell types e.g. arteriolar smooth muscle cells, microvascular endothelial cells, mast cells and accumulating leukocytes. In this study, we have demonstrated that different components of the inflammatory response in guinea‐pig skin can be differentially modulated by E‐type prostaglandins and isoprenaline, suggesting that cyclic AMP has an important regulatory role.
Cyclopiazonic acid, an inhibitor of Ca2+‐ATPase in sarcoplasmic reticulum, increases excitability in ileal smooth muscle
Authors: Uyama Yoshiaki , Imaizumi Yuji , Watanabe Minoru 
Published: July 2012

Effects of cyclopiazonic acid (CPA), a specific inhibitor of Ca2+‐ATPase in endo‐ and sarcoplasmic reticulum (ER/SR), on contractile responses, cytosolic Ca2+ concentration and spontaneous electrical activity were examined in ileal longitudinal smooth muscle strips.
After intracellular stored Ca2+ in intact ileal strips was depleted by application of 25 mm caffeine in Ca2+‐free solution, Ca2+‐loading was performed in the absence or presence of 10 μm CPA in a standard solution containing 2.2 mm Ca2+. Subsequent application of caffeine in Ca2+‐free solution induced a phasic contraction which was significantly smaller in the strip pretreated with CPA than that in the control.
Spontaneous and 20 mm K+‐induced contractions in the presence of 1 μm atropine were markedly enhanced by 1–30 μm CPA, whereas that induced by 80 mm K+ was not. The magnitude of repetitive transient elevation of cytosolic Ca2+ concentration ([Ca2+]i) and concomitant phasic contractions were markedly enhanced by CPA. The effects were abolished by 10 μm verapamil and restored by 10 μm Bay K 8644.
Application of 10 μm CPA depolarized the cell by about 5 mV, decreased the action potential (AP) afterhyperpolarization and markedly increased the frequency of spontaneous AP. These effects were mimicked by 100 nm charybdotoxin.
The rate of decay of [Ca2+]i and tension after the bathing solution was changed from one containing 140 mm K+ and 2.2 mm Ca2+ to one containing 5.9 mm K+ and 0 mm Ca2+ was significantly slowed when 10 μm CPA was added to the latter solution.
These results indicate that CPA enhances ileal smooth muscle excitability and increases Ca2+‐influx through voltage‐dependent Ca2+ channels. The effect may be consistent with the hypothesis that CPA‐induced decrease in stored Ca due to Ca‐pump inhibition reduces the Ca2+‐dependent K+ current and indirectly enhances Ca2+‐influx through membrane activity resulting from the increased excitability. Direct evidence for the regulation of Ca2+ channel activity by intracellular Ca storage sites was not obtained in the present study.
Protection by oestradiol against the development of cardiovascular changes associated with monocrotaline pulmonary hypertension in rats
Authors: Farhat Michel Y. , Chen Ming‐Fong , Bhatti Tahira , Iqbal Azhar , Cathapermal Seedabarum , Ramwell Peter W. 
Published: July 2012

We studied the effects of oestradiol 17β on the development of pulmonary vascular changes and right ventricular (RV) hypertrophy in response to monocrotaline in male Sprague‐Dawley rats.
Rats were treated with either placebo or oestradiol 17β (10 mg) in the form of slow release pellets implanted subcutaneously 48 h before monocrotaline administration. Rats were injected with either saline or a single dose of monocrotaline (60 mg kg−1, i.m.). Pulmonary vascular changes and RV hypertrophy were studied at 4 weeks following monocrotaline administration.
Monocrotaline induced a significant increase in the ratio of right ventricle (RV) to left ventricle‐plus‐septum (LV + S) weights. Monocrotaline‐treated rats also showed significant myointimal proliferation in small pulmonary arteries, decrease of arterial numbers and increase in the number of abnormal alveolar macrophages.
Oestradiol 17β attenuated myointimal hyperplasia in pulmonary vessels, decreased the RV/(LV + S) ratio in monocrotaline‐treated rats. Oestradiol 17β had no significant effect on control animals.
Oestradiol treatment prevented the increase in lung wet to dry weight ratio, observed 7 days post monocrotaline administration.
These results suggest that oestradiol 17β protects against the pulmonary vascular remodelling and RV hypertrophy associated with monocrotaline‐induced pulmonary hypertension in the rat. Oestradiol also protects against microvascular leak observed in the early days of lesion.
Pharmacological activity of (−)‐discretamine, a novel vascular α‐adrenoceptor and 5‐hydroxytryptamine receptor antagonist, isolated from Fissistigma glaucescens
Authors: Ko Feng‐Nien , Yu Sheu‐Meei , Su Ming‐Jai , Wu Yang‐Chang , Teng Che‐Ming 
Published: July 2012

The pharmacological activity of (−)‐discretamine, isolated from Fissistigma glaucescens, was determined in rat isolated thoracic aorta, cardiac tissues and ventricular myocytes and guinea‐pig isolated trachea.
(−)‐Discretamine was found to be an α1‐adrenoceptor blocking agent in rat thoracic aorta as revealed by its competitive antagonism of noradrenaline (pA2 = 7.20 ± 0.10)‐ or phenylephrine (pA2 = 7.60 ± 0.09)‐induced vasoconstriction. It was as potent as phentolamine (pA2 = 7.51 ± 0.10), but was more potent than yohimbine (pA2 = 6.18 ± 0.06). Removal of endothelium significantly increased the antagonistic potency of (−)‐discretamine on noradrenaline (pA2 = 7.52 ± 0.09)‐ or phenylephrine (pA2 = 7.90 ± 0.09)‐induced vasoconstriction.
(−)‐Discretamine was also an α2‐adrenoceptor blocking agent (pA2 = 6.30 ± 0.15) and a 5‐hydroxytryptamine antagonist (pA2 = 6.87 ± 0.06), both in rat aorta denuded of endothelium.
(−)‐Discretamine protected α‐adrenoceptors from alkylation by the irreversible blocking agent, phenoxybenzamine.
[3H]‐inositol monophosphate formation caused by noradrenaline (3 μm) in rat thoracic aorta was suppressed by (−)‐discretamine (10 and 30 μm) and prazosin (3 μm).
A high concentration of (−)‐discretamine (30 μm) did not affect the contraction induced by the thromboxane receptor agonist U‐46619, prostaglandin F2α (PGF2α), angiotensin II, high K+ or endothelin in rat aorta denuded of endothelium. Neither cyclic AMP nor cyclic GMP content of rat thoracic aorta was changed by (−)‐discretamine.
Contraction of guinea‐pig trachea caused by histamine, leukotriene C4 or carbachol was not affected by (−)‐discretamine (30 μm). (−)‐Discretamine also did not block β1 or β2‐adrenoceptor‐mediated responses induced by isoprenaline in rat right atria and guinea‐pig trachea.
A voltage clamp study in rat ventricular single myocytes revealed that sodium inward current, slow inward Ca2+ current or transient (Ito) and steady state (I800) outward current was not affected by (−)‐discretamine (30 μm).
It is concluded that (−)‐discretamine is a selective α‐adrenoceptor and 5‐HT receptor antagonist in vascular smooth muscle.
Solubilization and characterization of GABABreceptor binding sites from porcine brain synaptic membranes
Authors: Facklam M. , Bowery N.G. 
Published: July 2012

The characteristics of membrane bound GABABreceptors in pig brain are similar to those in rat brain as judged byin vitrobinding experiments and sensitivity to GTP. The rank order of affinity of GABABreceptor ligands was CGP 54626 > GABA ∼(−)‐baclofen >> CGP 35348 = CGP 36742 > (+)‐baclofen in membranes from both species.For solubilization of GABABreceptors from pig brain, washed membranes were preincubated with 5 mmMgSO4and subsequently incubated with various detergents. 3‐[(3‐Cholamidopropyl)dimethyl‐ammoniol]‐1‐propane sulphonate (CHAPS) (0.5%) proved to be the most successful, solubilizing 22.7 ± 4.7% (mean ± s.e.mean,n= 6) of GABABreceptors.Binding of [3H]‐GABA to GABABreceptors solubilized with 0.5% CHAPS exhibited similar characteristics to the binding at membrane bound receptors since, firstly, theKdandBmaxvalues (around 30 nmand 450 fmol mg−1protein, respectively) were comparable; secondly, stereospecific binding for baclofen was obtained in both forms; thirdly, the affinity for the agonists GABA and (−)‐baclofen and the antagonists CGP 35348, CGP 36742 and CGP 54626 were the same; fourthly, comparable sensitivity to Ca2+(2.5 mm) was observed and finally, a similar sensitivity to GTP was apparent.Saturation experiments performed with the GABABantagonist, [3H]‐CGP 54626, indicated a higherKdvalue and a lowerBmaxvalue for solubilized (7.7 ± 2.6 nmand 1033 ± 41 fmol mg−1protein, mean ± s.e.mean,n= 3) than for membrane bound receptors (1.35 ± 0.08 nm, 1171 ± 20 fmol mg−1protein,n= 3).
Protection by scoparone against the alterations of plasma lipoproteins, vascular morphology and vascular reactivity in hyperlipidaemic diabetic rabbit
Authors: Huang Huei‐Chen , Weng Yu‐I , Lee Chai‐Rong , Jan Tong‐Rong , Chen Yuh‐Lien , Lee Yuan‐Teh 
Published: July 2012

The in vivo pharmacological effects of scoparone (6,7‐dimethoxycoumarin) in a hyperlipidaemic diabetic rabbit model were investigated.
Three groups of rabbits were studied: (1) normal, (2) hyperlipidaemic and diabetic‐untreated and (3) hyperlipidaemic and diabetic‐scoparone treated. The hyperlipidaemic diabetic rabbits were fed with 1% cholesterol and treated with alloxan, a diabetogenic agent. The plasma levels of total cholesterol, total triglyceride, very low‐density lipoprotein (VLDL) cholesterol, low density lipoprotein (LDL) cholesterol and high‐density lipoprotein (HDL) cholesterol were markedly increased as soon as the rabbit became diabetic at the second week. Scoparone‐treatment (5 mg kg−1 day−1, s.c.) significantly reduced the plasma lipid and lipoprotein cholesterol levels of the hyperlipidaemic diabetic rabbit to 73.3% of total cholesterol, 48.3% of total triglyceride, 66.0% of VLDL cholesterol, 55.7% of LDL cholesterol and 79.5% of HDL cholesterol.
Six weeks after cholesterol‐feeding, the aortic arch and thoracic aorta were dissected for morphological and functional studies. In vascular rings from the untreated hyperlipidaemic diabetic rabbit, there was intimal thickening with accumulation of fatty streaks, foam cells and migration of smooth muscle cells to the intima. In the rabbits treated with scoparone, there were fewer pathological morphology changes found in vascular segments than in the untreated hyperlipidaemic diabetic rabbits.
In the vascular reactivity experiments, the phenylephrine‐induced contraction and nitroprusside‐induced dilatation did not differ significantly among the three rabbit groups, except that the contraction was enhanced in the thoracic aorta of hyperlipidaemic diabetic rabbits either untreated or treated with scoparone, as compared to the normal group, and the sensitivity to nitroprusside was increased in the thoracic aorta of the scoparone‐treated group as compared to the untreated group.
The endothelium‐dependent dilatation induced by acetylcholine was significantly attenuated in both the aortic arch and thoracic aorta from the hyperlipidaemic diabetic rabbits as compared to the normal rabbits. This attenuation was partially prevented, when scoparone (5 mg kg−1) was administered daily.
These results suggest that scoparone protects against some alterations of plasma lipoproteins, vascular morphology and vascular reactivity in the hyperlipidaemic diabetic rabbit. These protective effects of scoparone may be partly related to its free radical scavenging property.
Different pathways of calcium sensitization activated by receptor agonists and phorbol esters in vascular smooth muscle
Authors: Hori Masatoshi , Sato Koichi , Miyamoto Shigeki , Ozaki Hiroshi , Karaki Hideaki 
Published: July 2012

It has been shown that receptor agonists and activators of protein kinase C, phorbol esters, increase Ca2+ sensitivity of contractile elements in vascular smooth muscle. To discover if protein kinase C is involved in the agonist‐mediated Ca2+ sensitization, we examined the effects of receptor agonists in the rat isolated aorta in which protein kinase C activity had been diminished by pretreatment with phorbol 12‐myristate 13‐acetate for 24 h.
In the aorta with protein kinase C activity, a high concentration (1 μm) of 12‐deoxyphorbol 13‐isobutyrate induced contraction and a low concentration (100 nm) potentiated high K+‐induced contraction. In addition, prostaglandin F2α induced greater contractions than high K+ at a given cytosolic Ca2+ level. The maximally effective concentrations of noradrenaline and endothelin‐1 also induced greater contraction than high K+. In the aorta without protein kinase C activity, the contraction induced by 12‐deoxyphorbol 13‐isobutyrate and its potentiation of the high K+‐induced contraction were abolished. However, prostaglandin F2α, noradrenaline and endothelin‐1 still induced a greater contraction than high K+.
In the aorta without protein kinase C activity, noradrenaline, endothelin‐1 and prostaglandin F2α, but not 12‐deoxyphorbol 13‐isobutyrate, induced contractions in the presence of the Ca2+ channel blocker, verapamil, or in the absence of external Ca2+, by increasing Ca2+ sensitivity.
In the permeabilized preparations, inhibition of protein kinase C activity abolished the effect of potentiation of the Ca2+‐induced contraction by 12‐deoxyphorbol 13‐isobutyrate although the potentiation of the contraction by prostaglandin F2α did not change.
These results suggest that there are two pathways for Ca2+ sensitization in rat aorta; a protein kinase C‐dependent pathway which is activated by phorbol esters, and a protein kinase C‐independent pathway which is activated by receptor agonists.
GABAB receptors modulate catecholamine secretion in chromaffin cells by a mechanism involving cyclic AMP formation
Authors: Oset‐Gasque M.J. , Parramón M. , González M.P. 
Published: July 2012

The function of γ‐aminobutyric acidB (GABAB) receptors in modulation of catecholamine secretion by chromaffin cells and the possible mechanism involved in this action have been examined.
The GABAB agonists (−)‐baclofen and 3‐aminopropylphosphinic acid (3‐APPA) were found to induce a dose‐dependent increase of basal catecholamine secretion. The EC50s were 151 ± 35 μm and 225 ± 58 μm for baclofen and 3‐APPA, respectively. This stimulatory effect was specific since it could be blocked by 0.5 mm of the specific GABAB antagonist CGP‐35348.
In contrast, preincubation of chromaffin cells with the GABAB agonists was found to inhibit, in a dose‐dependent manner, the catecholamine secretion evoked by 10 μm nicotine and 200 μm muscimol.
The effects of GABAB agonists on both basal and evoked catecholamine secretion were found to be accompanied by parallel changes in intracellular calcium concentration ([Ca2+]i). GABAB agonists produced a dose‐dependent increase in [Ca2+]i which was partially blocked by CGP 35348, but they produced a strong inhibition of the [Ca2+]i increase induced by nicotine and muscimol.
The GABAB agonists also produced a dose‐dependent increase in intracellular cyclic AMP levels, there being a direct correlation between both increase in catecholamine secretion and in intracellular cyclic AMP levels.
The pretreatment of chromaffin cells with pertussis toxin doubled the catecholamine secretion and increased by four times the intracellular cyclic AMP levels evoked by GABAB agonists.
The possible involvement of adenylate cyclase in the mechanism of GABAB receptor modulation of catecholamine secretion is discussed.
Binding kinetics and antiplatelet activities of picotamide, a thromboxane A2 receptor antagonist
Authors: Modesti Pietro Amedeo , Cecioni Ilaria , Colella Andrea , Costoli Alessandro , Paniccia Rita , Serneri Gian Gastone Neri 
Published: July 2012

Picotamide was shown to inhibit platelet binding of thromboxane A2 (TxA2)‐mimetics and to cause a reduction of TxA2 platelet receptors after in vivo administration. The present study aimed to investigate directly [3H]‐picotamide binding to human platelets and in particular the relationship between binding kinetics and antiaggregating properties.
[3H]‐picotamide time‐dependently bound to a single class of platelet TxA2 receptors with a KD of 325 nmol l−1 at equilibrium. The binding was displaceable by TxA2 analogues U46619 and ONO11120 (Ki 19 and 28 nmol l−1 respectively) but not by prostacyclin (PGI2), prostaglandin E2 (PGE2) and TxB2. Antiaggregating activity and TxA2 formation inhibition paralleled with binding kinetics.
By prolonging the incubation time from 30 to 120 min, picotamide showed a progressively increasing non‐displaceable binding, whereas specific displaceable binding decreased in comparison to the values reached at 30 min. Non displaceable binding was specific, temperature‐dependent, saturable and followed a Michaelis‐Menten kinetic (Vmaxapp = 130 fmol per 108 platelets h−1, KMapp = 330 nmol l−1). Picotamide progressively underwent a specific stable interaction with its platelet receptor.
In conclusion, after an initial reversible binding, a progressive stabilization of picotamide binding takes place resulting in a progressively more stable interaction with platelets.
The effect of nitric oxide synthase inhibition on the plasma fibrinolytic system in septic shock in rats
Authors: Korbut Richard , Warner Tim D. , Gryglewski Richard J. , Vane John R. 
Published: July 2012

We have investigated the effect of pretreatment of rats with nitric oxide (NO) synthase inhibitor, NG‐nitro‐l‐arginine methyl ester (l‐NAME) on the E. coli lipopolysaccharide (LPS)‐induced changes in the plasma fibrinolytic system, platelet count, fibrinogen level, as well as in gross and microscopic pathophysiological changes indicative of disseminated intravascular coagulation (DIC) in rats.
E. coli LPS (6 mg kg−1, i.p.) produced a decrease in the levels of plasma fibrinogen and a drop in the blood platelet count 6 h after administration. The decrease in fibrinogen but not the drop in platelet count was reversed by pretreatment with l‐NAME (30 mg kg−1, i.p., 24 h and 15 min before administration of LPS).
Pretreatment with l‐NAME antagonized the LPS‐induced activation of fibrinolysis as measured by changes in the euglobulin clot lysis time (ECLT) and enhanced the LPS‐induced rise in the plasma level of plasminogen activator inhibitor (PAI). In animals pretreated with l‐NAME there was also a marked reduction in the histological changes indicative of DIC.
We propose that l‐NAME can act as a protective agent in LPS‐induced DIC, and this protection is due to an increased generation of PAI following inhibition of NO synthase.
Comparison of the ability of nicardipine, theophylline and zaprinast to restore cardiovascular haemodynamics following inhibition of nitric oxide synthesis
Authors: Herity N.A. , Allen J.D. , Silke B. , Adgey A.A.J. 
Published: July 2012

The use of pharmacological inhibitors of nitric oxide (NO) synthesis to treat patients with septic shock is limited by the observation that they cause a fall in cardiac output in some subjects. The aim of this work was to investigate this fall and to test whether it was reversible by subsequent administration of nicardipine, theophylline or the cyclic GMP‐selective phosphodiesterase inhibitor, zaprinast (M&B 22948).
In pentobarbitone‐anaesthetized pigs, haemodynamic indices were measured before and after intravenous administration of NG‐nitro‐l‐arginine methyl ester (l‐NAME) in a dose‐response protocol (0.2–20 mg kg−1; n = 6) and as a single bolus of 10 mg kg−1 either alone or followed by increasing doses of nicardipine, theophylline or zaprinast (n = 8 in each group).
l‐NAME caused a dose‐dependent rise in systemic vascular resistance and mean systemic arterial pressure and a dose‐dependent fall in cardiac output. A single bolus of l‐NAME (10 mg kg−1) produced these effects within 15 min.
Subsequent administration of nicardipine (0.05–0.2 mg kg−1) caused complete reversal of systemic vasoconstriction and hypertension and in doing so completely restored cardiac output. Theophylline (7.5–10 mg kg−1) partially reversed the rise in systemic vascular resistance and partially restored cardiac output but the effect was small compared to that of nicardipine. Zaprinast (1–5 mg kg−1) had no significant effect on any of these variables.
These results suggest that reduced cardiac output following inhibition of NO synthesis is an effect of increased afterload on the heart and is reversible by nicardipine and to a lesser extent by theophylline. These findings may have potential value for those using NO synthase inhibitors to treat patients with septic shock.