bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of α‐adrenoceptors in the vasculature of the canine nasal mucosa
Authors: Berridge T.L. , Roach A.G. 
Published: July 2012

α‐Adrenoceptors present in the vasculature of the nasal mucosa in β‐adrenoceptor blocked dogs have been characterized pharmacologically using selective α1‐ and α2‐adrenoceptor agonists and antagonists.
In pentobarbitone‐anaesthetized dogs, intra‐arterial (i.a.) administration of the selective α1‐agonists cirazoline and phenylephrine, the selective α2‐agonist UK‐14,304 and the mixed α1/α2‐agonists adrenaline, noradrenaline and oxymetazoline produced dose‐related nasal vasoconstrictor responses (as measured by decreases in nasal cavity pressure). The rank order of agonist potency was adrenaline > oxymetazoline = UK‐14,304 > noradrenaline > cirazoline > phenylephrine.
The nasal response to cirazoline was inhibited by the selective α1‐adrenoceptor antagonist prazosin but not by the new, potent selective α2‐adrenoceptor antagonist RX 811059. In contrast, UK‐14,304 was inhibited only by RX 811059. Either prazosin or RX 811059 reduced the effect of the mixed agonist adrenaline.
In spinal dogs, the noradrenaline‐evoked fall in nasal cavity pressure was reduced by either prazosin or RX 811059. Prazosin attenuated markedly the nasal vasoconstrictor response to electrical stimulation of postganglionic fibres emerging from the superior cervical ganglion (SNS) whereas RX 811059 was ineffective. Administration of the neuronal re‐uptake inhibitor cocaine potentiated the effect of i.a. noradrenaline but reduced marginally the maximal response to SNS. After cocaine, RX 811059 enhanced the effect of SNS and attenuated the response to noradrenaline. Prazosin reduced effectively the responses to both SNS and noradrenaline after cocaine. Pretreatment with the α2‐agonist UK‐14,304 did not affect the response to noradrenaline in the nasal cavity but evoked a persistent (up to 2 h) reduction in the response to SNS. RX 811059 antagonized the inhibitory effect of UK‐14,304.
These results demonstrate that both postjunctional α1‐ and α2‐adrenoceptors mediating vasoconstriction are present in the canine nasal mucosa. In addition, sympathetic neurones innervating the nasal mucosa are characterized by a very efficient re‐uptake process and contain prejunctional α2‐adrenoceptors.
A study in the rat of the renal actions of nitrendipine and diltiazem on the adrenergic regulation of calcium and sodium reabsorption
Authors: Johns Edward J. , Manitius Jacek 
Published: July 2012

In pentobarbitone‐anaesthetized rats, intravenous administration of diltiazem at 5 μg kg−1min−1did not change blood pressure or renal blood flow but increased glomerular filtration rate by approximately 16%, urine flow by 85%, calcium excretion by 151% and absolute and fractional sodium excretions by 100% and 69%, respectively. A similar pattern of responses was obtained in renally denervated animals, except that calcium excretion did not change statistically. Diltiazem given at 20 μg kg−1min−1into renally innervated and denervated groups of animals depressed blood pressure between 15–17 mmHg but had no effect on renal haemodynamic or tubular function.Nitrendipine administered at 0.5 μg kg−1min−1to renally innervated and denervated animals significantly depressed blood pressure in intact animals by 6 mmHg and in both groups did not change renal haemodynamics but caused similar increases in urine flow of between 79–98%, calcium excretion of between 87 and 125%, absolute sodium excretion of between 108 and 140% and fractional sodium excretion of between 83 and 170%. Infusion of nitrendipine at 1.0 μg kg−1min−1into intact or renally denervated animals decreased blood pressure by 18–20 mmHg and increased urine flow by 84–111%, calcium excretion by 85%, absolute sodium excretion by 81–137% and fractional sodium excretion by 52–102%.Stimulation of the renal nerves at low frequencies (0.8 to 1.5 Hz) caused minimal changes in renal haemodynamics but decreased urine flow by 27%, calcium excretion by 35%, absolute and fractional sodium excretions 32% and 36%, respectively. In different groups of animals given either diltiazem at 20 μg kg−1min−1or nitrendipine at 0.5 μg kg−1min−1or l.0 μg kg−1min−1, a similar degree of renal nerve stimulation caused an identical pattern of excretory responses of similar magnitude to those obtained in the absence of drug.The calciuretic, diuretic and natriuretic activities of diltiazem and nitrendipine were not dependent on renal nerves and probably represented a direct action on the tubular reabsorptive processes of these ions. The renal nerve‐induced increases in tubular calcium and sodium reabsorption indicate that these α‐adrenoceptor‐mediated responses are not dependent on the inward movement of calcium
Effects of calcium channel antagonists on action potential conduction and transmitter release in the guinea‐pig vas deferens
Authors: Beattie D.T. , Cunnane T.C. , Muir T.C. 
Published: July 2012

The effects of the Ca2+ channel antagonists amlodipine, cobalt, diltiazem, nifedipine and verapamil and the local anaesthetic lignocaine were investigated on action potential conduction in and on evoked transmitter release from sympathetic nerves in the guinea‐pig isolated vas deferens. Transmitter release was investigated by measurement of (a) evoked (trains of pulses at 1 and 2 Hz, 0.1‐0.5 ms supramaximal voltage) excitatory junction potentials (e.j.ps) using microelectrodes; tension was recorded simultaneously; (b) tritium (3H) overflow from vasa preincubated (37°C, 30 min) in Krebs solution containing either [3H]‐noradrenaline (NA, 25 μCi ml−1, 2 × 10−6 M NA) or [3H]‐adenosine (50 μCi ml−1, 1 × 10−6 M adenosine).
Amlodipine (0.5–2 × 10−4 M), verapamil (0.5‐2 × 10−4 M), diltiazem (1–8 × 10−4 M), lignocaine (0.1–2 × 10−3 M) and cobalt (2–6 × 10−2 M) in descending order of potency, but not nifedipine (1–5 × 10−3 M), increased the latency and inhibited, then abolished, the amplitude and number of action potentials in a concentration‐dependent manner.
Amlodipine (0.5–1 × 10−4 M), verapamil (1–2 × 10−4 M), diltiazem (1–5 × 10−4 M) and cobalt (1 × 10−3 M), in descending order of potency, but not nifedipine (5 × 10−4 M), inhibited then abolished evoked e.j.ps in a concentration‐dependent manner. Cobalt inhibited e.j.ps at a lower concentration than that (2–6 × 10−2 M) required to block action potential conduction.
In unstimulated tissues, the resting 3H overflow following preincubation with [3H]‐NA consisted largely of 4‐hydroxy 3‐methoxymandelic acid (VMA), 4‐hydroxy 3‐methoxy phenylglycol (MOPEG), 3,4 dihydroxyphenylglycol (DOPEG) and NA; stimulated tissues (300 pulses at 20 Hz, 0.5 ms supramaximal voltage) released mainly NA. Verapamil (0.1–1 × 10−4 M), amlodipine (0.05–1 × 10−4 M) and nifedipine (1–5 × 10−4 M), but not cobalt (2 × 10−3 M), increased, significantly, the resting overflow of 3H comprising mainly DOPEG. Cobalt (2 × 10−3 M) inhibited, significantly, the stimulation‐evoked overflow of 3H.
Verapamil (1 × 10−4 M) had little effect on the resting overflow of 3H following preincubation with [3H]‐adenosine. Diltiazem (5 × 10−4 M) and cobalt (2 × 10−3 M) both inhibited evoked 3H overflow. Nifedipine (5 × 10−4 M) was ineffective.
The effectiveness of Ca2+ channel antagonists at pre‐ and postjunctional sites differ; the results are discussed in terms of the selectivity of these drugs for each site and their differential effects on transmitter release.
Regional differences of reactivity to stimulants in the dog portal tree
Authors: Fujii Kazutoshi , Fujiwara Motohatsu , Kumada Kaoru , Kurahashi Kazuyoshi , Usui Hachiro 
Published: July 2012

We studied the regional differences both of reactivity to various stimulants and of neurogenic responses elicited by transmural stimulation in the longitudinal and circular muscles of the truncal portal vein, mesenteric vein, splenic vein and gastric vein of the dog portal tree.
Strong spontaneous activity appeared in the longitudinal muscle of the truncal portal vein (96% of preparations tested). Weak spontaneous activity sometimes appeared in the circular muscle of the truncal portal vein (41%) and rarely in the longitudinal muscle of the mesenteric vein (12%). It did not appear in other segments.
The splenic vein and the gastric vein showed similar patterns in the relationship between resting tension and response to noradrenaline; that is, the responsiveness of either longitudinal or circular muscle of these two veins increased and then decreased almost parallel as resting tension increased and reached a maximum under the same resting tension.
The longitudinal muscle of both the truncal portal vein and the mesenteric vein was more responsive to noradrenaline, acetylcholine, histamine and KCl than the circular muscle; for example 2.02 and 1.44 times more responsive to noradrenaline, respectively. On the other hand, the longitudinal muscle of the splenic vein and the gastric vein responded less well than the circular muscle; for example 0.36 and 0.16 times as responsive to noradrenaline, respectively.
Acetylcholine and histamine caused marked contractions which were comparable to those elicited by noradrenaline in the longitudinal muscle of the truncal portal vein. Acetylcholine also elicited similar contractions in the longitudinal muscle of the mesenteric vein but the responses induced in preparations of other segments were small.
The longitudinal muscle of the truncal portal vein responded well even to low‐frequency stimulation of 2 Hz, while the circular muscles of the truncal portal and splenic veins gave marked responses only to high‐frequency stimulation of 10 or 20 Hz or more. These contractile responses were attenuated by phentolamine (10−6 m) or atropine (10−6 m). The longitudinal muscle of the splenic vein showed no significant response to stimuli of any frequency.
It seems that the portal tree receives not only adrenergic but also cholinergic innervation. In addition, the longitudinal muscle of the truncal portal vein may receive non‐adrenergic, non‐cholinergic innervation as well.
The longitudinal muscle of the portal vein may be crucial to venous return in assisting movement of the blood it contains. If this is the case in man, then the regional differences in the portal tree demonstrated in this study may explain why varicose changes during portal hypertension occur preferentially in the oesophagogastric region and rarely in other regions, as blood stasis may occur more readily in the regions of the gastric and splenic veins where the longitudinal muscle is not very active.
The effects of the stable thromboxane A2‐mimetic, U46619, on gastric mucosal damage and gastric non‐parietal secretion in the rat
Authors: Bunce K.T. , Clayton N.M. 
Published: July 2012

The effects of the thromboxane A2‐mimetic, U46619, and the thromboxane receptor antagonist, AH23848, on ethanol‐induced gastric mucosal damage and gastric non‐parietal secretion have been examined in the rat.
Oral dosing with U46619 or AH23848 produced a dose‐related inhibition of ethanol‐induced gastric mucosal damage in the conscious rat, and these effects were partially blocked by indomethacin treatment.
Intragastric application of U46619 or AH23848 to the stomach of the anaesthetized rat stimulated the gastric secretion of a juice which consisted principally of Na+ and Cl− ions. These secretagogue effects of both compounds were blocked by indomethacin treatment.
These results show that U46619 and AH23848 induce secretory and protective effects in the stomach of the rat, although these responses probably do not involve thromboxane receptors and are mediated, at least in part, by endogenous prostaglandins.
The results are discussed in relation to the role of endogenous thromboxane A2 in gastric mucosal protection, and of the possible protective function of non‐parietal secretion in the stomach.
Kinin antagonist activity of compounds from Mandevilla velutina in the rat isolated uterus
Authors: Calixto João B. , Nicolau Mauro , Pizzolatti Moacir G. , Yunes Rosendo A. 
Published: July 2012

The effect of four semi‐purified compounds obtained from Mandevilla velutina crude extract by silica gel chromatography fractionization were analysed for their inhibitory effects on uterine contractions induced by bradykinin (BK), lysylbradykinin (L‐BK), acetylcholine (ACh) and oxytocin, in vitro.
None of the compounds tested affected uterine tone. Pre‐incubation for 20 min with fraction 12 (20 to 80 μg ml−1), isolated from M. velutina produced a parallel and concentration‐dependent displacement to the right of the concentration‐response curves for BK and L‐BK (1 to 1000 nM). Schild plots of these data were linear (correlation close to unity), and yielded a nominal pA2 value (as g ml−1) of 5.1 and 4.9, respectively, and the values of the slopes were not significantly different from unity. Fraction 11 (10 to 40 μg ml−1) also produced a parallel and concentration‐dependent displacement to the right of the BK concentration‐response curve. The Schild plot gave a mean pA2 value (g ml−1) of 5.4 and a slope not significantly different from unity.
Fraction 12 did not influence the uterine contractile responses induced by ACh (0.1 to 100 μm) and oxytocin (0.01 to 30 miu ml−1) at concentrations less than 80 μg ml−1.
Fraction 16 (20 to 80 μg ml−1) antagonized the action of BK only at concentrations greater than 40 μg ml−1, whereas fraction 5 (20 to 80 μg ml−1) was completely inactive against BK‐induced responses.
As observed previously with the crude extract, the onset of the BK antagonistic action of these compounds was rapid and completely reversible following intermittent washing of the preparation for 30–60 min.
These results indicate the existence of at least two compounds in the crude extract of Mandevilla velutina that act as competitive and selective kinin antagonists on the isolated uterus of the rat.
Antinociception induced by systemic administration of local anaesthetics depends on a central cholinergic mechanism
Authors: Bartolini A. , Galli A. , Ghelardini C. , Giotti A. , Malcangio M. , Malmberg‐Aiello P. , Zucchi P.L. 
Published: July 2012

The antinociceptive effects of systemically‐administered procaine, lignocaine and bupivacaine were examined in mice and rats by using the hot‐plate, writhing and tail flick tests.
In both species all three local anaesthetics produced significant antinociception which was prevented by atropine (5 mg kg−1, i.p.) and by hemicholinium‐3 (1 μg per mouse, i.c.v.), but not by naloxone (3 mg kg−1, i.p.), α‐methyl‐p‐tyrosine (100 mg kg−1, s.c.), reserpine (2 mg kg−1, i.p.) or atropine methylbromide (5.5 mg kg−1, i.p.).
Atropine (5 mg kg−1, i.p.) which totally antagonized oxotremorine (40 μg kg−1, s.c.) antinociception did not modify morphine (5 mg kg−1, s.c.) or baclofen (4 mg kg−1, s.c.) antinociception. On the other hand, hemicholinium, which antagonized local anaesthetic antinociception, did not prevent oxotremorine, morphine or baclofen antinociception.
Intracerebroventricular injection in mice of procaine (200 μg), lignocaine (150 μg) and bupivacaine (25 μg), doses which were largely ineffective by parenteral routes, induced an antinociception whose intensity equalled that obtainable subcutaneously. Moreover, the i.c.v. injection of antinociceptive doses did not impair performance on the rota‐rod test.
Concentrations below 10−10 m of procaine, lignocaine and bupivacaine did not evoke any response on the isolated longitudinal muscle strip of guinea‐pig ileum, or modify acetylcholine (ACh)‐induced contractions. On the other hand, they always increased electrically‐evoked twitches.
The same concentrations of local anaesthetics which induced antinociception did not inhibit acetylcholinesterase (AChE) in vitro.
On the basis of the above findings and the existing literature, a facilitation of cholinergic transmission by the local anaesthetics is postulated; this could be due to blockade of presynaptic muscarinic receptors.
Direct binding studies on ileal and cardiac muscarinic receptors
Authors: Michel Anton D. , Whiting Roger L. 
Published: July 2012

Functional studies have indicated that muscarinic receptors in cardiac tissue differ from those in the ileum. In the present study ileal and cardiac muscarinic receptors identified by [3H]‐N‐methyl scopolamine ([3H]‐NMS) were characterized and the selectivity of currently available ileal and atrial selective antagonists determined.
In terms of the current functional classification of muscarinic receptors both ileal and cardiac muscarinic receptors were of the M2 subtype based upon their low affinity for pirenzepine.
Cyclohexylphenyl(2‐piperidinoethyl)silanol (CPPS), a highly ileal selective antagonist in functional studies, was unable to distinguish between ileal and atrial muscarinic receptors identified in binding studies. Furthermore, although AF‐DX 116 and dicyclomine were able to differentiate atrial and ileal muscarinic receptors, neither compound was more than 2 fold selective. These data indicate that it is not possible to subclassify ileal and atrial muscarinic receptors using direct ligand binding studies with these antagonists.
In circular ileal smooth muscle, apparent heterogeneity of the M2 muscarinic receptor population was observed. Thus AF‐DX 116 identified two populations of sites with affinities differing by 30 fold. These two populations of M2 muscarinic receptors may represent the typical M2 muscarinic receptors identified in cardiac tissue and the more recently discovered ‘gland type’ M2 muscarinic receptors.
The circular ileal smooth muscle tissue homogenate was able to decrease dramatically the apparent affinity of adiphenine. This activity, which appeared to result from a phenylmethylsulphonylfluoride (PMSF) sensitive protease effect, should be considered when conducting studies using this tissue preparation and compounds of similar structure to adiphenine.
Actions of amiloride analogues on prostacyclin synthesis by rat aortic rings
Authors: Ritter J.M. , Aksoy A. , Cragoe E.J. , Taylor G.W. 
Published: July 2012

Fresh rat aortic rings were incubated in HEPES‐buffered salt solutions (pH 8.0) in the presence or absence of amiloride analogues. The effect of these drugs on prostacyclin (PGI2) synthesis was determined by radioimmunoassay of the stable hydrolysis product 6‐oxo‐prostaglandin (PG)F1α.
Amiloride and phenamil (potent inhibitors of epithelial Na+ transport) had no significant effect on basal or Ca2+‐stimulated PGI2 synthesis.
Several analogues previously reported to inhibit Na+/Ca2+ exchange caused a dose‐related increase in 6‐oxo‐PGF1α production in media containing NaCl 120 mm and CaCl2 2.5 mm. 2′,3′‐Benzobenzamil was the most potent analogue with a maximum stimulation of 4.51 ± 0.89 fold, and an EC50 of 3 × 10−5 m.
Amiloride analogues bearing substituents on the 5‐amino group of the pyrazine ring have been reported to inhibit Na+/H+ exchange more potently than Na+/Ca2+ exchange. Three of these compounds inhibited Ca2+‐stimulated 6‐oxo‐PGF1α production at concentrations that did not significantly influence basal 6‐oxo‐PGF1α production.
Metabolic requirements for release of endogenous noradrenaline during myocardial ischaemia and anoxia
Authors: Dart A.M. , Riemersma R.A. , Schömig A. , Ungar A. 
Published: July 2012

The metabolic conditions required for noradrenaline (NA) release from ischaemic and anoxic perfused hearts of the rat were studied.
Forty minutes of flow reduction to approximately 0.25 ml g−1 min−1 did not elicit enhanced noradrenaline overflow from the isolated heart perfused with normoxic perfusate even in the absence of added substrate. Enhanced overflow did occur when substrate‐free ischaemia was induced after a 60 min period of substrate‐free perfusion.
Noradrenaline overflow was enhanced by perfusion at normal flow rates with an anoxic (PO2<1 mmHg) perfusate containing no substrate. Such enhanced overflow occurred in the absence of calcium in the perfusate and was almost completely abolished by the addition of 11 mm glucose.
Enhanced noradrenaline overflow occurring either during low flow ischaemia after substrate deprivation or during anoxic substrate‐free perfusion at normal flow rates was markedly suppressed by desipramine.
Exocytotic noradrenaline overflow induced by electrical stimulation of the left cervico‐thoracic ganglion continued unchanged during 60 min of anoxia if the perfusate contained 11 mm glucose. In the absence of added substrate there was a decline in the overflow induced by such stimulation which was more rapid with anoxic than normoxic perfusate.
Re‐introduction of calcium, oxygen and substrate after 10, 20 or 30 min of calcium‐free, substrate‐free, anoxic perfusion was associated with a massive overflow of the intracellular enzyme lactate dehydrogenase. At 10 min there was an associated transient minor increase in NA overflow but at 20 and 30 min the overflow of NA, elevated as a result of anoxic perfusion, returned to pre‐anoxic levels on the re‐introduction of substrate and oxygen.
These studies demonstrate a central role for the metabolic status of the sympathetic nerve terminal in determining the magnitude of exocytotic and nerve‐impulse independent noradrenaline release from the heart. During the course of myocardial ischaemia in vivo nerve‐impulse independent release would be expected to occur only in regions of severe flow reduction. This may produce heterogeneous stimulation of the myocardium.
Triazolodiazepines: dissociation of their Paf (platelet activating factor) antagonistic and CNS activity
Authors: Casals‐Stenzel J. , Weber K.H. 
Published: July 2012

The relationship between the activity of thieno‐ or benzo‐triazolodiazepines on platelet‐activating factor (Paf)‐induced effects and on the CNS (central nervous system) was studied in vitro and in vivo.
Brotizolam and triazolam inhibited Paf‐induced human platelet aggregation. The IC50 ‐ values were 0.54 and 7.6 μm, respectively. This inhibitory effect was not blocked by the specific central‐type benzodiazepine (BDZ) antagonist, Ro 15–1788, or the specific peripheral‐type BDZ ligand, Ro 5–4846. These BDZ ligands also showed an inhibitory effect on Paf‐induced platelet aggregation (IC50 = 200 and 560 μm, respectively). Ro 15–1788 or Ro 5–4846 in combination with brotizolam or triazolam enhanced the Paf inhibitory effect of these triazolodiazepines.
In guinea‐pigs, Ro 15–1788, 100 mg kg‐1p.o. and 10 mg kg‐1 i.v. completely inhibited the hypnogenic effect of 10 mg kg−1 p.o. and 1 mg kg−1 i.v. of brotizolam, respectively. Similar results were obtained with triazolam but at higher doses.
In anaesthetized guinea‐pigs, a dose of 100 mg kg‐1 p.o. of Ro 15–1788 did not inhibit bronchoconstriction and hypotension caused by Paf (30 ngkg−1 min−1 i.v.). The combination of brotizolam (10 mg kg−1 p.o.) or triazolam (200 mg kg−1 p.o.) with this BDZ antagonist (100 and 400 mg kg‐1 p.o., respectively) did not affect the Paf inhibitory activity of these triazolodiazepines.
These results show that the Paf antagonistic properties of the triazolodiazepines can be dissociated from their CNS activity. It is conceivable that compounds of this structural type could be the forerunners of a novel series of potent Paf antagonists.