bluuebunny/crossref_metadata_2025_split huggingface dataset:
The effects of N‐(cyclopropylmethyl)‐19‐isopentyl‐nororvinol (M320), a potent agonist at k‐ and μ‐ opiate receptors, on urine excretion of rats
Authors: Abrahams J.M. , Boura A.L.A. , Evans R.G. , Johnston C.I. , Olley J.E. 
Published: July 2012

The effects of N‐(cyclopropylmethyl)‐19‐isopentylnororvinol hydrochloride (M320) on urine excretion by rats were investigated. Further studies, using rabbit isolated vas deferens, investigated its interactions with k‐opiate receptors.
The output of urine for a 2 h period after M320, administered subcutaneously to normally hydrated Long Evans rats, showed a bell‐shaped dose‐response relationship, the maximum effect occurring after 10 μg kg−1. Urinary retention contributed to but did not fully account for the weaker diuresis after high doses. Attenuation of the ascending portion of the dose‐response curve to M320 occurred after 1 and 10 mg kg−1 but not 0.1 mg kg−1 of naltrexone intraperitoneally.
M320 in low doses (3–10 μg kg−1) caused a small but significant increase in sodium excretion. M320 (30 μg kg−1) reduced both sodium and potassium excretion.
M320 (10 μg kg−1 s.c.) did not increase the volume of urine voided in 2 h by Brattleboro rats showing diabetes insipidus, even when urine excretion was reduced to normal by 1 week of vasopressin replacement.
The volume of urine voided in 4 h by Brattleboro rats was progressively reduced to zero by M320 (10–100 μg kg−1 s.c). Urinary retention contributed to but did not account for this reduction.
Plasma levels of immunoreactive arginine vasopressin (ir‐AVP) were reduced in both normal and dehydrated Long Evans rats after doses greater than 1 μg kg−1 M320 s.c.
In vitro, M320 caused persistent inhibition of twitches of the electrically stimulated rabbit vas deferens (IC50 1.7 nM).
These data suggest that M320 has potent opioid agonist activity at k‐receptors and at higher concentrations stimulates μ‐ receptors. In the rat, its activity on k‐receptors is associated with diuresis and suppression of plasma vasopressin levels. The antidiuresis seen after high doses may be due to its activity on μ‐receptors, possibly at a central site.
Influence of the vascular endothelium on agonist‐induced contractions and relaxations in rat aorta
Authors: Bullock Gillian R. , Taylor S.G. , Weston A.H. 
Published: July 2012

The influence of the vascular endothelium on agonist‐induced contractions and relaxations has been measured using intact segments of rat aorta. Contiguous rubbed segments were used as controls.
Angiotensin II, histamine, noradrenaline, U46619 and UK 14304 contracted both rubbed and intact tissues. The threshold spasmogenic concentrations of these agonists were lower in rubbed tissues than in intact preparations.
The sensitivity and responsiveness of tissues to angiotensin II, histamine, noradrenaline and UK 14304 were greater in rubbed than in intact tissues.
Acetylcholine and histamine relaxed the established spasms of intact tissues but not those of rubbed preparations, These relaxant effects of acetylcholine were abolished by pre‐incubation with haemoglobin.
In the presence of prazosin, noradrenaline or UK 14304 relaxed established contractions in intact tissues. These effects were antagonized by idazoxan or by pre‐incubation with haemoglobin.
In intact preparations, idazoxan had no effect on the spasmogenic sensitivity and responsiveness to UK 14304.
Pre‐incubation with haemoglobin augmented the spasmogenic actions of noradrenaline, U46619 or UK 14304 in intact tissues, but had no effect on these responses in rubbed preparations.
Tissue concentrations of cyclic GMP were greater in intact than in rubbed tissues. A concentration of acetylcholine (10 μM) evoking just maximal mechanical inhibition produced a significant increase in cyclic GMP concentration in intact preparations. However, no detectable changes in cyclic GMP concentration were produced by UK 14304 (10 μM) or by acetylcholine (30 nM), concentrations which were equi‐effective in inhibiting mechanical activity.
In the presence of threshold spasmogenic concentrations of noradrenaline, the contractile effects of angiotensin II were augmented and became comparable to those observed in rubbed preparations. In the presence of greater concentrations of noradrenaline, angiotensin II always produced an additional contraction.
It is concluded that the presence of the vascular endothelium limits the spasmogenic action of a variety of agonists. Although spasmogens like noradrenaline and UK 14304 can stimulate the release of endothelium‐derived relaxing factor (EDRF) via α2‐adrenoceptors, the inhibitory effects of EDRF largely result from the spontaneous release of this substance.
Muscarinic and nicotinic mechanisms in the responses of the adrenal medulla of the dog and cat to reflex stimuli and to cholinomimetic drugs
Authors: Critchley J.A.J.H. , Ellis P. , Henderson C.G. , Ungar A. , West Christine P. 
Published: July 2012

In isolated perfused adrenal glands of the cat, muscarinic and nicotinic agonists selectively released adrenaline and noradrenaline respectively.
In isolated perfused adrenal glands of the dog, the output of adrenaline and noradrenaline remained in a fixed ratio at rest and when stimulated by muscarinic or by nicotinic agonists.
In the anaesthetized dog, a combination of muscarinic and nicotinic antagonists was needed to block reflex responses of the adrenal medulla. A nicotinic antagonist was more effective in blocking the baroreceptor reflex response than the chemoreceptor reflex response.
Vascular responses to leukotriene B4, C4 and D4 following FPL 55712, indomethacin, saralasin, phentolamine and verapamil in the conscious rat
Authors: Filep János , Földes‐Filep Éva , Frölich Jürgen C. 
Published: July 2012

The pressor and vascular permeability effects of leukotrienes B4 (LTB4), C4 and D4 were investigated in conscious unrestrained rats.
Leukotrienes C4 and D4 (3.2–51 nmol kg−1 i.v.) caused an acute dose‐dependent elevation of the mean arterial pressure, which was maximal after 2 min and returned to control levels within 14 min. Heart rate was significantly reduced by the higher doses of LTC4 and LTD4. LTB4 (up to a dose of 51 nmol kg−1) was essentially inactive.
These effects of LTC4 and LTD4 were abolished by FPL 55712, a putative antagonist of sulphidopeptide leukotrienes and by verapamil, a calcium channel blocker.
Indomethacin, phentolamine or saralasin pretreatment failed to modify the pressor response to LTC4 and LTD4.
LTC4 and LTD4 furthermore caused an increase in haematocrit values, which was significantly attenuated by FPL 55712, indomethacin and verapamil.
The present findings show that the pressor effect of LTC4 and LTD4 is not related to prostanoid release and can be reversed by calcium channel blockade; whereas the effect on vascular permeability seems to require the presence of both cyclo‐oxygenase product(s) and calcium.
Inhibition of myocardial Ca2+ channels by three dihydropyridines with different structural features: potential‐dependent blockade by Ro 18–3981
Authors: Holck Mark , Osterrieder Wolfgang 
Published: July 2012

Inhibition of myocardial Ca2+ channels was investigated for three dihydropyridines with different structural features: Ro 18–3981, darodipine (PY 108‐068) and nifedipine. Ro 18–3981 contains a sulphamoyl acetyl side‐chain.
In voltage‐clamp experiments with isolated cardiac myocytes of guinea‐pig, Ro 18‐3981 caused a concentration‐dependent inhibition of the Ca2+ current, which was influenced by the membrane holding potential. A markedly greater inhibition by Ro 18‐3981 was observed when myocytes were depolarized (to + 10 mV) from a holding potential (Vh) of −20 mV (IC50 = 2.3 nm) than at −50 mV (IC50 = 100 nm).
The three dihydropyridines caused a concentration‐dependent reduction in contractile force of isolated, electrically‐stimulated left atria of the guinea‐pig. Elevation of the extracellular K+ concentration from 5.9 to 24 mm resulted in a significant reduction in negative inotropic IC50 values for Ro 18‐3981 (137 fold), darodipine (8 fold) and nifedipine (20 fold).
The affinity of these drugs for the high‐affinity (+)‐[3H]‐PN 200‐110 binding site was determined in guinea‐pig cardiac membranes. The KD value of Ro 18‐3981 (1.0 nm) was similar to the IC50 value for blockade of ICa at a Vh of − 20 mV (2.3 nm), i.e. at a level of near‐maximal depolarization.
Thus, structurally‐different dihydropyridines exert potential‐dependent inhibition of myocardial Ca2+ channel activity consistent with the modulated receptor hypothesis. These results demonstrate that blockade of myocardial excitation‐contraction coupling by Ca2+ entry blockers is also potential‐dependent.
The role of calcium in the cyclic AMP response to histamine in rabbit cerebral cortical slices
Authors: Al‐Gadi M. , Hill S.J. 
Published: July 2012

The effect of calcium on the H1‐and H2‐receptor components of the cyclic AMP response to histamine in rabbit cerebral cortical slices has been investigated.
Removal of calcium ions from the incubation medium during the preparation, preincubation and final incubation of brain slices significantly reduced the cyclic AMP responses to adenosine, histamine and the H2‐selective agonist, impromidine.
Removal of calcium ions from the incubation medium during only the final incubation with agonists did not influence the responses to adenosine, histamine, impromidine and the H1‐selective agonist, 2‐thiazolylethylamine.
Final incubation of rabbit cerebral cortical slices in calcium‐free buffer containing EGTA (1 mm) however, selectively reduced the cyclic AMP responses to the H1‐agonists histamine and 2‐thiazolylethylamine without affecting the response to impromidine or adenosine.
These latter incubation conditions significantly reduced the maximal extent of the augmentation of impromidine‐or adenosine‐stimulated cyclic AMP accumulation produced by H1‐receptor stimulation, without affecting the EC50 values of the H1‐agonists. Calcium‐free/EGTA conditions did not, however, alter the dose‐response parameters for the response to the H2‐agonist, impromidine.
These data provide further evidence that the two histamine receptor systems affect cyclic AMP accumulation in rabbit cerebral cortical slices by different mechanisms.
Human calcitonin gene‐related peptide activates adenylate cyclase and releases prostacyclin from human umbilical vein endothelial cells
Authors: Crossman D. , McEwan J. , MacDermot J. , MacIntyre I. , Dollery C.T. 
Published: July 2012

Endothelial cells of human umbilical vein were isolated and cultured in vitro.
In these cells there was a concentration‐dependent release of prostacyclin and activation of adenylate cyclase by human calcitonin gene‐related peptide (hCGRP). The concentration of hCGRP for half‐maximum activation of adenylate cyclase (Kact) by hCGRP was 190 nm.
Bradykinin induced a ten fold greater release of prostacyclin than CGRP, but did not activate adenylate cyclase.
hCGRP may exert its potent vasodilator properties by stimulating release of vasorelaxant substances, including prostacyclin from endothelial cells.
Pharmacological analysis of the calcium‐dependence of μ‐receptor agonism
Authors: Dougall I.G. , Leff P. 
Published: July 2012

A number of studies in isolated tissues have shown that μ‐opioid‐receptor‐mediated agonism can be augmented or potentiated with reduction in extracellular calcium concentration ([Ca2+]o). These effects have been ascribed to alterations in post‐receptor coupling but the nature of the changes involved have not been quantitatively elucidated.
In this paper, logistic curve‐fitting and operational model‐fitting (Black & Leff, 1983) were used to analyse the effects of variations in [Ca2+]o on the μ‐receptor‐mediated effects of [d‐Ala2, MePhe4, Glyol5]enkephalin (DAGOL) in the isolated, coaxially‐stimulated ileum of the guinea‐pig. At each value of [Ca2+]o, the effects of irreversible receptor alkylation by β‐chlornaltrexamine (β‐CNA) were also investigated.
From these analyses it is concluded that with reduction in [Ca2+]o the efficacy of DAGOL in this system is increased and the sensitivity of the transducer relation is also enhanced, the latter indicating a trend towards positive co‐operativity. Reduction of [Ca2+]o also appeared to produce a reduction in agonist affinity.
Experimental manipulation of [Ca2+]o may provide a useful means of enhancing μ‐agonist efficacy, allowing detection of agonism in compounds with low intrinsic efficacies. However, the accompanying change in co‐operativity of the transducer relation must be considered when quantifying agonism under these conditions.
Effects of theophylline, choleragen and loperamide on rabbit ileal fluid and electrolyte transport in vitro
Authors: Ahsan M.A. , Ilundain Ana , Naftalin R.J. , Sandhu Bhupinda K. , Smith P.M. 
Published: July 2012

The effects of theophylline and cholera toxin on water and anion movements across rabbit ileum in vitro and the reversal of these effects by the opiate action of loperamide have been investigated. Water movement across the mucosal and serosal surfaces of the tissue was measured continuously by a high resolution method.
Theophylline caused an increase in short circuit current and reversed the direction of net Cl− movement, due mainly to a decrease in mucosal‐serosal flux. It also caused a rapid, but transient, reversal in the direction of fluid movement across the mucosal surface. Fluid outflow across the serosal surface was decreased but not reversed. Cholera toxin caused a slow inhibition of water movement across both mucosal and serosal surfaces.
Theophylline increased the exit rate of 77Br across the mucosal surface and decreased the exit rate of 77Br across the serosal surface. Theophylline increased the exit rate of 3H‐labelled mannitol across the mucosal surface.
Loperamide reversed the effects of theophylline and cholera toxin on water flow across the mucosal and serosal surfaces and on net transepithelial Cl− flux; it also increased the rate of 77Br exit across the serosal surface of theophylline‐treated tissue. These effects of loperamide could be reversed by naloxone.
The hydraulic conductivity, Lp of the serosal surface was measured directly by determining the osmotic flow generated by low concentrations of polyethylene glycol (mol. wt. 20000 and 90000). Theophylline reduced the Lp by 57%. Loperamide added to theophylline‐treated tissues increased the Lp by 340%. This effect was reversed by naloxone.
These results indicate that modulation of intestinal smooth muscle tone affects transepithelial ion and water flows in vitro. The increase in tone induced by secretagogues increases ion and water reflux via wide shunt channels in the mucosa and thereby reduces net absorption. The increased net fluid and electrolyte absorption induced by loperamide results from the opiate‐dependent inhibition of acetylcholine release from intrinsic ganglia which reduces smooth muscle tone and thereby enhances the fluid and electrolyte conductance of the submucosal layers.
Sensory neuropeptide effects in human skin
Authors: Fuller R.W. , Conradson T.‐B. , Dixon C.M.S. , Crossman D.C. , Barnes P.J. 
Published: July 2012

Neuropeptides released from sensory nerves may account for cutaneous flare and wheal following local trauma. In 28 normal subjects we have studied the effects of four sensory neuropeptides given by intradermal injection on the forearm or back.
All peptides caused a flare distant from the site of injection, presumably due to an axon reflex. Substance P (SP) was the most potent (geometric mean dose causing 50% of maximum flare, 4.2 pmol). Neurokinin A (NKA) was the next most potent with neurokinin B (NKB) and calcitonin gene‐related peptide (CGRP) the least. The distant flare response to SP, NKA and NKB was maximal at 5 min and disappeared within 2 h.
CGRP caused a local erythema over the site of injection at doses above 0.5 pmol which at higher doses lasted for up to 12 h.
SP, NKA and NKB caused wheals at doses above 5 pmol with SP and NKB being the most potent. CGRP (up to 250 pmol) did not consistently cause wheal formation. There was no significant effect of coinjection of CGRP upon the response to SP although there was a tendency for an enhancement of the wheal response.
The H1‐histamine antagonist terfenadine (60 mg orally) significantly inhibited the wheal and distant flare response to histamine (5 nmol) and NKA, but not that caused by NKB. The distant flare of CGRP was also reduced but the local erythema was unaltered.
Aspirin (600 mg orally) significantly inhibited the distant flare response to SP, NKA and CGRP, but not that caused by NKB or histamine; the local erythema induced by CGRP was unaffected by aspirin. Aspirin also inhibited the wheal formed by NKA but not the wheal induced by the other substances.
These results suggest that tachykinins cause a distant flare response partially via the release of histamine and cyclo‐oxygenase products, but cause a wheal by a direct effect on the skin microvasculature. The order of potency SP > NKB > NKA suggests that an SPp or NKl receptor is involved in the wheal response. CGRP by contrast has a direct vasodilator effect which is very prolonged.
Inhibition by quinine of endothelium‐dependent relaxation of rabbit aortic strips
Authors: Gebremedhin D. , Hadházy P. , Magyar K. 
Published: July 2012

The effects of quinine sulphate, tetramethylammonium chloride (TMA) and tetraethylammonium chloride (TEA) (all blockers of the Ca2+‐activated K+ channels) on the relaxations induced by acetylcholine (ACh), calcium ionophore A23187 and sodium nitrite were studied in helical strips of rabbit aorta.
The strips were contracted to a moderate stable tone with phenylephrine (10−7 m). ACh (4 × 10−9 to 10−6 m) as well as A23187 (10−8 to 3 × 10−7 m) reduced this tone in a concentration‐and endothelium‐dependent manner.
Pretreatment of the tissues with quinine (2.5 × 10−5 to 10−4 m) for 60 min produced a concentration‐dependent inhibition of the relaxation induced by ACh. Also 90 min incubation of the strips with TMA (3 × 10−3 to 6.5 × 10−2 m) or TEA (10−3 to 3 × 10−2 m) inhibited the ACh‐evoked relaxation in a manner similar to quinine.
Quinine (10−4 m, 60 min), TMA (6.5 × 10−2 m, 90 min) or TEA (3 × 10−2 m, 90 min) produced 5 to 10 fold reductions in the relaxant EC50 values of A23187 and ACh and depressed (by 40 to 95%) the maximal relaxations to the ionophore and ACh.
On a molar basis, quinine was more effective than the two tetraalkylammonium ions in reducing the endothelium‐dependent relaxations of the aortic strips induced by ACh or A23187. The inhibitory actions were reversible after 60 to 90 min washout.
Exposure of the strips to either quinine (10−4 m, 60 min), TMA (6.5 × 10−2 m, 90 min) or TEA (3 × 10−2 m, 90 min), however, did not influence significantly the relaxations evoked by sodium nitrite, a direct smooth muscle relaxant.
These results suggest that stimulation of the Ca2+‐activated K+ channels could be, at least partially, responsible for the endothelium‐dependent relaxations induced by ACh or A23187. Their activation might not be required for the endothelium‐independent relaxant effects of sodium nitrite.
The inhibition of release of endothelium‐derived relaxant factor by manoalide, a potent inhibitor of phospholipase A2
Authors: Long Clive J. , Sarau Henry M. , Berkowitz Barry A. 
Published: July 2012

The inhibitory action of manoalide on vascular relaxation was characterized. Manoalide was a potent inhibitor of endothelium‐dependent relaxations in the isolated aorta of the rabbit. Responses to acetylcholine (ACh), A23187 and substance P were reduced by manoalide in a dose‐dependent manner whilst those to nitroglycerin were unaffected.
Repeated washing of manoalide‐treated tissues did not restore the relaxant response to ACh, indicating an irreversible action of manoalide. Scanning electron microscopic studies revealed that the endothelium remained intact on manoalide‐treated tissues.
Rabbit aortae from which the endothelium had been removed relaxed in response to perfusion with ACh when delivered via an upstream endothelium‐bearing tissue, indicating release of an endothelium‐derived relaxant factor (EDRF). Incubation of the tissue without endothelium with manoalide (100 nm; 30 min) or inclusion of manoalide in the superfusate at a point just distal to the endothelium bearing tissue did not reduce the relaxant potency of EDRF.
Contractile responses of the guinea‐pig isolated ileum to ACh were not affected by manoalide and, furthermore, binding of [3H]‐quinuclidinyl benzilate to striatal membranes was not reduced by manoalide except at very high concentrations.
Manoalide therefore appears to inhibit vascular relaxation with a selectivity directed towards that mediated by EDRF. A direct antagonism of neither cholinoceptors nor EDRF receptors occurs and it is suggested that manoalide acts at a site within the endothelium to inhibit the synthesis and/or release of EDRF. Based upon these and previous data the possibility that EDRF is lipid‐like or controlled by an arachidonic acid metabolite must continue to be considered.
The effect of apomorphine on exocytosis and metabolic burst of polymorphonuclear leukocytes
Authors: Elferink Jan G.R. 
Published: July 2012

In rabbit polymorphonuclear leukocytes (PMNLs) apomorphine at 10–100 μm inhibits fMet‐Leu‐Phe and A23187‐induced exocytosis, and the phorbol myristate acetate‐and fMet‐Leu‐Phe‐induced activation of the metabolic burst. The secretory response was not restored by washing the cells after pretreatment with apomorphine.
The inhibitory effect of apomorphine was not prevented by the dopamine receptor antagonists haloperidol and pimozide, nor did dopamine itself inhibit fMet‐Leu‐Phe‐induced exocytosis. It therefore seems unlikely that effects are mediated via dopamine receptors. However, sulphydryl reagents reduced the inhibitory effect of apomorphine, suggesting that it may depend upon interaction with susceptible sulphydryl groups, the intactness of which is required for exocytosis and other functions of PMNLs.
Dopamine receptor‐mediated spinal antinociception in the normal and haloperidol pretreated rat: effects of sulpiride and SCH 23390
Authors: Barasi S. , Ben‐Sreti M.M. , Clatworthy A.L. , Duggal K.N. , Gonzalez J.P. , Robertson J. , Rooney K.F. , Sewell R.D.E. 
Published: July 2012

Nociceptive tail flick latencies (TFL) were recorded in response to noxious thermal stimuli applied to lightly anaesthetized rats. The effects of intrathecally administered dopamine receptor agonists alone and combined with dopamine receptor antagonists were examined upon the TFL. Experiments were repeated on animals made supersensitive to dopamine following withdrawal from 28 day administration of haloperidol.
In untreated animals the D2‐receptor agonist LY171555 and apomorphine produced an increase in TFL. In contrast, the D1‐receptor agonist SKF 38393 had no significant effect on TFL.
Following haloperidol‐induced dopamine‐supersensitivity, SKF 38393 produced an increase in TFL. In contrast, LY 171555 and apomorphine had minimal effects on TFL in this preparation.
In animals not treated with haloperidol, the dopamine receptor antagonists SCH 23390 and (±)‐sulpiride both blocked the increase in TFL produced by the D2‐agonists.
SCH 23390 and (±)‐sulpiride also blocked the increase in TFL produced by SKF 38393 in haloperidol‐supersensitized animals.
The antinociceptive action of intrathecally administered dopamine agonists appears to be mediated via D2‐receptors. Whether the antinociception produced by SKF 38393 is exclusively contingent upon the activation of D1‐receptors in the dopamine‐supersensitive animal is as yet unresolved.