bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence that A2 purinoceptors are involved in endothelium‐dependent relaxation of the rat thoracic aorta
Authors: Rose'Meyer R.B. , Hope W. 
Published: July 2012

The effect of adenosine and some adenosine analogues on the isolated thoracic aorta from rats was compared with the effect of adenosine 5′‐triphosphate (ATP) and adenosine 5′‐diphosphate (ADP).
Both ATP and adenosine analogues caused relaxation of the noradrenaline (30 nm)‐contracted thoracic aorta.
The order of potency for adenosine analogues was 5′‐(N‐ethyl) carboxamidoadenosine (NECA) > l‐N6‐phenylisopropyladenosine (l‐PIA), adenosine 5′‐monophosphate (AMP), adenosine indicating the presence of adenosine A2 receptors.
Removal of the endothelium or prior treatment with haemoglobin (10 μm) attenuated relaxant responses to both ATP and NECA, attenuation being greater for ATP than NECA.
8‐Phenyltheophylline (10 μm) reduced relaxant responses to NECA but not to ATP in the intact tissue.
These results provide evidence that there are two components to relaxation of the rat thoracic aorta induced by purinoceptor agonists. The first is an endothelium‐dependent mechanism involving release of endothelium‐derived relaxant factor (EDRF) and the second is due to a direct effect on smooth muscle.
Competitive antagonists discriminate between NK2 tachykinin receptor subtypes
Authors: Maggi Carlo Alberto , Patacchini Riccardo , Giuliani Sandro , Rovero Paolo , Dion Stephane , Regoli Domenico , Giachetti Antonio , Meli Alberto 
Published: July 2012

We have compared the ability of various tachykinins and selective tachykinin receptor agonists to induce contraction of the endothelium‐denuded rabbit pulmonary artery (RPA) and hamster trachea (HT) and have estimated the affinity of some newly developed NK2 selective antagonists in the same tissues.
In confirmation of previous findings, experiments with the agonists indicated that NK2 receptors are the main if not the sole mediators of the response to tachykinins in both RPA and HT. No evidence for significant degradation of neurokinin A (NKA) was found in either tissue when experiments were repeated in the presence of a mixture of peptidase inhibitors (thiorphan, captopril and bestatin, 1 μm each).
The peptide antagonists tested were: Peptide I = [Tyr5, d‐Trp6,8,9, Arg10]‐NKA(4–10); Peptide II = [Tyr5, d‐Trp6,8,9, Arg10]‐NKA(3–10); Peptide III = Ac‐Leu‐Asp‐Gln‐Trp‐Phe‐Gly‐NH2. The three peptides produced a concentration‐dependent rightward shift of the concentration‐response curve to NKA in both RPA and HT with no significant depression of the maximal response attainable. The slopes of the Schild plots were not significantly different from unity, indicating a competitive antagonism. Peptides I and II were about 100 times more potent in the RPA than in the HT, while Peptide III was about 100 times more potent in the HT than RPA.
The pA2 values obtained in these two tissues with the three antagonists were not significantly different when tested in the absence or presence of peptidase inhibitors, or when a selective NK2 receptor agonist, [βAla8]‐NKA(4–10) was used instead of NKA. Similar pA2 values were obtained after 15 or 90 min of incubation with the antagonists. Peptides I, II and III had no inhibitory effect on contractions produced by noradrenaline in the RPA or by carbachol in the HT.
Peptides I, II and III showed weak or no antagonistic activity toward the vasodilatator effect of substance P in the dog carotid artery (NK1 receptor‐mediated) or toward the contractile effect of neurokinin B in the rat portal vein (NK3 receptor‐mediated).
These results provide pharmacological evidence for heterogeneity of NK2 receptors in the RPA and HT. The NK2 receptors present in these tissues are not discriminated by natural tachykinins or selective agonists, but are recognized with very different affinity by NK2 receptor antagonists.
Increase in calcium channel current by β‐adrenoceptor agonists in single smooth muscle cells isolated from porcine coronary artery
Authors: Fukumitsu T. , Hayashi H. , Tokuno H. , Tomita T. 
Published: July 2012

The action of catecholamines (isoprenaline and noradrenaline) and forskolin on membrane currents was studied in single cells freshly dispersed from the pig coronary artery by use of the whole‐cell clamp method, usually with electrodes containing CsCl.
In normal Krebs solution, with and without 30 mm tetraethylammonium (TEA) and 0.5 mm 4‐aminopyridine, isoprenaline (1–5 μm) clearly increased the inward currents elicited by membrane depolarization, without affecting the holding current at −80 mV. The same effect was observed when the external Cl− was replaced with isethionate. The outward current recorded with K+‐containing electrodes was not significantly affected by isoprenaline.
In the presence of 67 mm Ba2+ and 30 mm TEA, the maximum inward current recorded with CsCl containing electrodes was 119 ± 7pA (the mean ± s.e.mean, n = 90) in cells where the current was larger than 30 pA. The L‐type Ca2+ channel was considered to be responsible for these currents, based on the threshold voltage, the slow time course of decay, the large depolarization necessary to produce inactivation, and the high susceptibility to the Ca2+ channel antagonist, nicardipine.
Isoprenaline and noradrenaline increased the amplitude of inward currents evoked by depolarizing pulses. The maximum inward current was potentiated by 43 ± 7% (n = 12) by isoprenaline and 39 ± 10% by noradrenaline (n = 6) at a concentration of 1 μm. These effects were strongly inhibited by propranolol, but not phentolamine. Forskolin (10 μm) also potentiated the currents to a similar degree.
It is suggested that stimulation of β‐adrenoceptors increases the amplitude of inward currents through L‐type Ca2+ channels in the pig coronary artery and that intracellular cyclic adenosine monophosphate is likely to be inolved in this action.
Evidence for the involvement of imidazoline receptors in the central hypotensive effect of rilmenidine in the rabbit
Authors: Feldman J. , Tibiriça E. , Bricca G. , Dontenwill M. , Belcourt A. , Bousquet P. 
Published: July 2012

Rilmenidine has recently been introduced as a new centrally‐acting antihypertensive agent. We examined its cardiovascular effects after intracerebral injection to anaesthetized rabbits. Cumulative doses of rilmenidine injected intracisternally (1 to 300 μg kg−1) led to dose‐dependent decreases in arterial blood pressure and heart rate. The effective doses of rilmenidine were lower when injected centrally than when injected intravenously.
Pretreatment with the same dose of yohimbine or idazoxan shifted the rilmenidine dose‐response curves for its hypotensive and bradycardic effects to the right. Idazoxan, which has an imidazoline structure, proved to be a more active antagonist than yohimbine of rilmenidine centrally‐mediated cardiovascular effects.
The dose‐response curve for the central hypotensive effect of rilmenidine was also shifted to the right after pretreatment with a bovine brain extract. This extract contains the endogenous ligand of the imidazoline‐preferring receptors which is not a catecholamine.
Rilmenidine, like clonidine, proved to be active when micro‐injected into the rabbit nucleus reticularis lateralis region.
In conclusion, rilmenidine exhibited in the rabbit a central hypotensive effect which originated in the same area as where clonidine acts. Specific imidazoline‐preferring receptors appear to be involved in this hypotensive effect.
Modulation of fluoroaluminate‐induced inositol phosphate formation by increases in tissue cyclic AMP content in bovine tracheal smooth muscle
Authors: Hall I.P. , Donaldson J. , Hill S.J. 
Published: July 2012

The effect of fluoroaluminate complexes (AlCl3 plus NaF) upon smooth muscle tone, [3H]‐inositol phosphate accumulation and [3H]‐cyclic AMP accumulation has been investigated in slices of bovine tracheal smooth muscle.
Fluoroaluminate (10 μm AlCl3 + various concentrations of NaF) elicited concentration‐dependent contractions of bovine tracheal smooth muscle strips at concentrations of NaF in the range 1–10 mm. The resultant contractile response was reversed by isoprenaline (50 nm) and was preserved in calcium‐free medium.
Fluoroaluminate stimulated [3H]‐inositol phosphate formation at concentrations of NaF over 1 mm. The response to 20 mm NaF + 10 μm AlCl3 was 164 ± 29% of the response to 1 mm histamine. Fluoroaluminate also increased the incorporation of [3H]‐myo‐inositol into membrane phospholipids.
Fluoroaluminate produced a small rise in [3H]‐cyclic AMP levels (2.1 fold increase over basal with 20 mm NaF). The response to forskolin (1 μm, 8.6 fold over basal) was reduced by fluoroaluminate in a concentration‐dependent manner, but still remained significantly (P < 0.05) elevated over the response to fluoroaluminate alone.
The [3H]‐inositol phosphate response to fluoroaluminate was inhibited by salbutamol (maximum inhibition 60%, IC50 = 0.08 μm), forskolin (1 μm, 46% inhibition) and isobutylmethylxanthine (1 mm, 73% inhibition).
These data suggest that inhibition of agonist‐induced inositol phospholipid turnover by cyclic AMP in this tissue can occur at the post‐receptor level.
Bradykinin‐induced depolarization of primary afferent nerve terminals in the neonatal rat spinal cord in vitro
Authors: Dunn P.M. , Rang H.P. 
Published: July 2012

Application of bradykinin (BK) to the spinal cord of the neonatal rat evoked depolarizations which could be recorded via either the dorsal or ventral roots. However, responses recorded via the ventral root were abolished by removal of extracellular Ca2+ or the addition of Cd2+, while responses recorded via the dorsal root were unaffected.
The response recorded via the ventral root was inhibited by the substance P antagonist spantide, while responses recorded via the dorsal root were unaffected.
Depolarizations recorded via the dorsal root were concentration‐dependent with an EC50 of 30 nm. These responses were not antagonized by the BK1 selective antagonist Leu8des‐Arg9BK, but were antagonized by d‐Arg0Hyp3Thi5,8D‐Phe7BK with a pA2 of 6.8 ± 0.6, which is similar to the values determined for other BK2‐mediated responses.
Application of phorbol dibutyrate (PDBu) to the spinal cord also evoked a depolarization with respect to the dorsal root. This response to PDBu was enhanced by removal of extracellular Ca2+, while the response to BK was unaffected.
The potent protein kinase inhibitor staurosporine reduced the response to PDBu, but did not affect the response to BK.
These results suggest that BK by acting on BK2 receptors can depolarize the central terminals of primary afferent nerve fibres. This response to BK does not appear to be mediated via the activation of protein kinase C. The depolarization to BK recorded via the ventral root of the spinal cord is indirect and may be secondary to the action of BK on the primary afferent terminals.
Effects of NG‐nitro‐l‐arginine methyl ester or indomethacin on differential regional and cardiac haemodynamic actions of arginine vasopressin and lysine vasopressin in conscious rats
Authors: Gardiner Sheila M. , Compton Alix M. , Kemp Philip A. , Bennett Terence 
Published: July 2012

Measurements of changes in renal, mesenteric and hindquarters haemodynamics or cardiac haemodynamics in response to i.v. bolus doses of arginine vasopressin (AVP) or lysine vasopressin (LVP, 0.7 and 7.0 pmol) were made in conscious, chronically‐instrumented Long Evans rats.
In some experiments AVP and LVP were administered during an infusion of NG‐nitro‐l‐arginine methyl ester (l‐NAME; 1.0 or 0.3 mg kg−1 h−1) to determine whether or not inhibition of nitric oxide production influenced the cardiovascular effects of the peptides. In other experiments, indomethacin (bolus dose of 5 mg kg−1 followed by infusion at 5 mg kg−1 h−1) was given to determine the possible involvement of cyclo‐oxygenase products in the responses to AVP and LVP.
Under control conditions, the lower dose of LVP had significantly greater effects than AVP on heart rate, mean arterial blood pressure, renal, mesenteric and hindquarters conductances, total peripheral conductance, cardiac index, peak aortic flow and + dF/dtmax. The higher dose of LVP had significantly greater effects than AVP on all variables (i.e. including stroke index and central venous pressure).
In the presence of l‐NAME (1 mg kg−1 h−1) there was a sustained increase in mean arterial blood pressure (+ 23 ± 3 mmHg) and reductions in mesenteric (– 38 ± 4%) and hindquarters (–30 ± 6%) vascular conductances. Under these conditions the difference in the pressor effects of AVP and LVP was abolished, but their differential effects on regional and cardiac haemodynamics persisted. This dose of l‐NAME did not change cardiac baroreflex sensitivity.
During infusion of l‐NAME at a lower rate (0.3 mg kg−1 h−1), baseline cardiovascular status was unchanged and regional haemodynamic effects of AVP and LVP were enhanced, but the differences in the regional vasoconstrictor responses to the two peptides persisted.
Indomethacin (5 mg kg−1 bolus, then 5 mg kg−1 h−1 infusion) augmented the renal vasoconstrictor responses to AVP and LVP, but abolished the difference in the hindquarters vasoconstrictor responses to the two peptides. However, the differences in the pressor and the renal and mesenteric vasoconstrictor effects of AVP and LVP still occurred in the presence of indomethacin.
The results indicate that AVP normally has lesser cardiovascular effects than LVP but this difference does not seem to be due to more effective stimulation of nitric oxide‐mediated or cyclo‐oxygenase‐dependent vasodilator mechanisms by AVP than LVP.
Effect of endothelium removal on the vasoconstrictor response to neuronally released 5‐hydroxytryptamine and noradrenaline in the rat isolated mesenteric and femoral arteries
Authors: Urabe Masanobu , Kawasaki Hiromu , Takasaki Koichiro 
Published: July 2012

The role of the vascular endothelium in the vasoconstrictor response to transmural nerve stimulation (TNS) was studied in isolated ring segments of rat mesenteric and femoral arteries.
In both types of artery, TNS (1 to 16 Hz) produced frequency‐dependent vasoconstriction, which was abolished by 100 nm tetrodotoxin, 10 μm guanethidine or 10 nm prazosin, indicating that the response was mediated by endogenous noradrenaline (NA) released from noradrenergic nerves. NA‐mediated vasoconstriction in response to TNS was significantly potentiated by removal of the endothelium.
In the presence of 10 nm prazosin, the reduced vasoconstriction in response to TNS was restored by incubation with 10 μm 5‐hydroxytryptamine (5‐HT) for 20 min. Restoration of the response to TNS was markedly attenuated by treatment with 10 nm ketanserin, 100 nm tetrodotoxin, or 10 μm guanethidine, indicating that the restored response was mediated by 5‐HT released from noradrenergic nerves. Vasoconstriction mediated by 5‐HT in response to TNS was not modified by removal of the endothelium.
In both types of artery with intact endothelium, treatment with 3μm methylene blue potentiated the NA‐mediated contractile response to TNS, but did not potentiate the 5‐HT‐mediated response to TNS.
In both types of artery, the contractile responses to exogenous NA and 5‐HT were potentiated by removal of the endothelium.
These results suggest that endothelial cells regulate neurogenic vasoconstriction by releasing endothelium‐derived relaxing factor. Furthermore, it appears likely that the response to neuronally released 5‐HT is not affected by the endothelium.
Further characterization, by use of tryptamine and benzamide derivatives, of the putative 5‐HT4 receptor mediating tachycardia in the pig
Authors: Villalón Carlos M. , den Boer Marien O. , Heiligers Jan P.C. , Saxena Pramod R. 
Published: July 2012

It has recently been shown that the tachycardic response to 5‐hydroxytryptamine (5‐HT) in the anaesthetized pig, being mimicked by 5‐methoxytryptamine and renzapride and blocked by high doses of ICS 205–930, is mediated by the putative 5‐HT4 receptor. In the present investigation we have further characterized this receptor.
Intravenous bolus injections of the tryptamine derivatives, 5‐HT (3, 10 and 30 μg kg−1), 5‐methoxytryptamine (3, 10 and 30 μg kg−1) and α‐methyl‐5‐hydroxytryptamine (α‐methyl‐5‐HT; 3, 10, 30 and 100 μg kg−1), resulted in dose‐dependent increases in heart rate of, respectively, 25 ± 2, 48 + 3 and 68 ± 3 beats min−1 (5‐HT; n = 35); 15 ± 1, 32 ± 2 and 57 ± 3 beats min−1 (5‐methoxytryptamine; n = 30); 6 ± 4, 18 ± 6, 34 ± 6 and 64 ± 11 beats min−1 (α‐methyl‐5‐HT; n = 3).
The increases in heart rate following i.v. administration of certain substituted benzamide derivatives were genereally less marked and not dose‐dependent: 1 ± 5, 11 ± 3 and 10 ± 5 beats min−1 after 300, 1000 and 3000 μg kg−1 of metoclopramide, respectively, (n = 8); 21 ± 4, 19 ± 2 and 2 ± 2 beats min−1 after 100, 300 and 1000 μg kg−1 of cisapride, respectively, (n = 5); 6 ± 2, 14 ± 2, 37 ± 6, 43 ± 8 and 34 ± 10 beats min−1 after 10, 30, 100, 300 and 1000 μg kg−1 of zacopride, respectively, (n = 6); and 1 ± 1, 2 ± 1 and 5 ± 2 beats min−1 after 300, 1000 and 3000 μg kg−1 of dazopride, respectively, (n = 4). These drugs behaved as partial agonists, antagonizing the responses to 5‐HT and 5‐methoxytryptamine dose‐dependently.
The 5‐HT3 receptor agonist 1‐phenyl‐biguanide (100, 300 and 1000 μg kg−1) induced only slight increases in heart rate of 1 ± 1, 6 ± 2 and 11 + 1 beats min−1, respectively, (n = 3). These effects were not antagonized by the selective 5‐HT3 receptor antagonist granisetron (3 mg kg−1). In addition, 1‐phenyl‐biguanide (1000 μg kg−1) did not modify the tachycardia induced by either 5‐HT‐ or 5‐methoxytryptamine.
High doses (3 mg kg−1) of ICS 205–930, a 5‐HT3 receptor antagonist with an indole group and devoid of effects on porcine heart rate per se, antagonized the stimulatory effects of 5‐HT, 5‐methoxytryptamine, α‐Me‐5‐HT, metoclopramide, cisapride, zacopride, dazopride and 1‐phenyl‐biguanide. However, the 5‐HT2 receptor antagonist ketanserin (0.5 mg kg−1), the 5‐HT3 receptor antagonists granisetron (3 mg kg−1) and MDL 72222 (3 mg kg−1) and the dopamine D2 receptor antagonist domperidone (3 mg kg−1) had no antagonist activity.
The above results support our contention that 5‐HT, 5‐methoxytryptamine, α‐Me‐5‐HT and the substituted benzamide derivatives increase porcine heart rate by a direct action on the cardiac pacemaker, via the activation of a putative 5‐HT4 receptor. The pharmacological profile of this novel 5‐HT receptor is similar (neurones from mouse brain colliculi and human heart) or, perhaps, even identical (guinea‐pig cholinergic neurones) to other putative 5‐HT4 receptors.
Effects of glibenclamide on cytosolic calcium concentrations and on contraction of the rabbit aorta
Authors: Yoshitake Kiyonobu , Hirano Katsuya , Kanaide Hideo 
Published: July 2012

Using fluorometry of fura‐2 and rabbit aortic strips, we studied the effects of glibenclamide (GLB), a sulphonylurea anti‐diabetic drug and an inhibitor of opening of K+ channels, on cytosolic calcium concentrations ([Ca2+]i) and on force development.
Both high K+‐depolarization and noradrenaline (NA) increased [Ca2+]i and force, in a concentration‐dependent manner, in the presence of extracellular Ca2+ (1.25 mm). However, force development in relation to [Ca2+]i ([Ca2+]i‐force relationship) observed with NA was much greater than that observed with K+‐depolarization.
Pretreatment with GLB (10−6–10−4 m) for 10 min partially inhibited, in a concentration‐dependent manner, both [Ca2+]i elevation and the force development induced by 118 mm K+‐depolarization or NA 10−5 m in the presence of extracellular Ca2+. The [Ca2+]i‐force relationship induced by both 118 mm K+ physiological salt solutions and by NA 10−5 m in the GLB‐treated strips overlapped that obtained in the non‐treated strips, thereby suggesting that GLB has no effect on the Ca2+‐sensitivity of the intracellular contractile apparatus. Only high concentrations (10−4 m) of GLB decreased [Ca2+]i and the force, when applied after the force induced by 118 mm K+ PSS or NA 10−5 m reached the maximum level.
In the absence of extracellular Ca2+, NA induced a transient increase in [Ca2+]i and in the force and these increases were inhibited when the vascular strips were pretreated with GLB for 10 min. The [Ca2+]i‐force relationship obtained in the GLB‐treated strips overlapped that in the non‐treated ones.
An ATP‐sensitive K+ channel opener, cromakalim (10−5 m) reduced the increased [Ca2+]i and force induced by 25 mm K+‐depolarization and NA 10−5 m. Subsequent application of GLB concentration‐dependently reversed this relaxant effect of cromakalim on the NA‐induced contraction (IC50 = 2 × 10−7 m). Complete reversal of the effect was observed with 10−5 m GLB.
We suggest that GLB inhibits both high K+‐depolarization‐ and NA‐induced contraction of the rabbit aorta, by decreasing [Ca2+]i and with no effect on the [Ca2+]i‐force relationship. However, when NA‐induced contractions were inhibited by a K+‐channel opener, GLB reversed this inhibitory effect by inhibiting K+‐channel opening and increasing [Ca2+]i.
l‐NG‐nitro arginine methyl ester exhibits antinociceptive activity in the mouse
Authors: Moore P.K. , Oluyomi A.O. , Babbedge R.C. , Wallace P. , Hart S.L. 
Published: July 2012

l‐NG‐nitro arginine methyl ester (l‐NAME, 1–75 mg kg−1) administered intraperitoneally (i.p.) elicits dose‐related antinociception in the mouse assessed by the formalin‐induced paw licking procedure. Antinociceptive activity is still present 24 h after injection. l‐NAME (75 mg kg−1, i.p.) is also antinociceptive in the acetic acid‐induced abdominal constriction and hot plate procedures.
l‐NAME additionally produces a dose‐related inhibition of formalin‐induced paw licking following intracerebroventricular (i.c.v., 0.1–100 μg per mouse) and oral (p.o., 75–150 mg kg−1) administration.
l‐Arginine (600 mg kg−1, i.p.) but not d‐arginine (600 mg kg−1) or naloxone (5 mg kg−1) reverses the antinociceptive effect of l‐NAME in the formalin test.
High doses of l‐NAME (37.5–600 mg kg−1) but not d‐NAME (75 mg kg−1) administered i.p. produce dose‐related increases in blood pressure of the urethane‐anaesthetized mouse whilst i.c.v. injected l‐NAME (0.1 and 100 μg per mouse) is inactive.
l‐NAME (75 mg kg−1, i.p.) did not inhibit oedema formation in the formalin‐injected mouse hindpaw.
l‐NAME (75 mg kg−1) did not produce any overt behavioural changes in treated mice and failed to influence locomotor activity or the incidence of dipping, crossing, rearing or circling behaviour assessed by a modified ‘head‐dipping’ board procedure. A high dose of l‐NAME (600 mg kg−1) reduced dipping behaviour and locomotor activity suggesting a possible sedative effect. d‐NAME (600 mg kg−1) was inactive.
These results suggest that l‐NAME produces an opioid‐independent and long‐lasting antinociception in the mouse most probably by a direct effect within the central nervous system.