bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impairment of relaxations to acetylcholine and nitric oxide by a phorbol ester in rat isolated aorta
Authors: Morrison Keith J. , Pollock David 
Published: July 2012

This study compared the abilities of acetylcholine (ACh) (endothelium‐dependent) and nitric oxide (NO) (endothelium‐independent and which may be the active component of the endothelium‐derived relaxing factor) to relax rat isolated aortic rings contracted with equi‐effective concentrations of noradrenaline (NA) or phorbol 12‐myristate 13‐acetate (PMA).
ACh and NO induced concentration‐dependent relaxations of aortic rings contracted with NA (EC70 value: 0.2 μm). However, relaxations to both ACh and NO were markedly reduced in rings contracted with PMA (EC80 value: 0.5 μm). NO‐induced relaxations of tissues were not affected by removal of the endothelium, but ACh‐induced relaxations were confirmed to be endothelium‐dependent.
ACh (10 μm) induced a 10 fold increase in guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) levels above control values in aortic rings contracted with NA (0.2 μm), but did not affect cyclic GMP levels in rings contracted with PMA (0.5 μm).
NO (3 μm) induced a 100 fold increase in cyclic GMP levels above control values in aortic rings contracted with NA (0.2 μm), but only an 11 fold increase in tissues contracted with PMA (0.5 μm).
It is concluded that the action (s) of EDRF (NO) are impaired in the presence of PMA by a mechanism that may involve the stimulation of protein kinase C in vascular smooth muscle cells.
Distinct antinociceptive actions mediated by different opioid receptors in the region of lamina I and laminae III‐V of the dorsal horn of the rat
Authors: Hope P.J. , Fleetwood‐Walker S.M. , Mitchell R. 
Published: July 2012

In view of the presence of μ, δ and κ opioid receptors in the spinal dorsal horn and their apparent involvement in behavioural analgesia, the present experiments addressed the action of selective agonists ionophoresed in the vicinity of rat dorsal horn neurones which were located either in lamina I or in laminae III‐V.
In laminae III‐V, κ agonists (U50488H and dynorphin A) caused a selective inhibition of the nociceptive responses of multireceptive cells, whilst μ and δ agonists ([d‐Ala2,MePhe4,Gry‐ol]enkephalin and [d‐Pen2,d‐Pen5]enkephalin respectively) failed to alter either the spontaneous activity or the responses to noxious and innocuous cutaneous stimuli and to d,l‐homocysteic acid or glutamate. Nocispecific neurones were encountered too rarely in laminae III‐V to study their properties.
In lamina I, agonists had no effects on either nocispecific or multireceptive neurones. In contrast, the μ agonist [d‐Ala2,MePhe4,Gly‐ol]enkephalin consistently inhibited nociceptive responses of both multireceptive and nocispecific lamina I cells. The δ agonist [d‐Pen2,d‐Pen5]enkephalin consistently caused selective inhibition of the nociceptive responses of multireceptive cells but had a mixed profile of action on nocispecific cells.
These results suggest that μ, δ and κ opioid receptors mediate different antinociceptive actions in both laminae III‐V and lamina I. The study reveals a distinct physiological role for δ receptors in modulating nociceptive inputs to lamina I neurones. In contrast to μ and κ receptor actions, δ receptors heterogeneously influence subpopulations of neurones.
The anti‐adrenergic effect of adenosine and its blockade by pertussus toxin: a comparative study in myocytes isolated from guinea‐pig, rat and failing human hearts
Authors: Brown L.A. , Humphrey S.M. , Harding S.E. 
Published: July 2012

In intact ventricular preparations, adenosine has been shown to reduce the β‐adrenoceptor‐induced increase in contraction (the anti‐adrenergic effect). In the present study we have investigated this effect of adenosine on isolated ventricular myocytes from failing human heart and normal guinea‐pig and rat heart.
Adenosine in the absence of β‐adrenoceptor‐mediated stimulation had no effect on contraction in human and guinea‐pig myocytes but produced a variable effect in rat myocytes.
8‐Cyclopentyl 1,3‐dipropylxanthine (CPX), a selective A1‐receptor antagonist, antagonised the anti‐adrenergic effect of adenosine in guinea‐pig myocytes.
The anti‐adrenergic effect of adenosine was greater in guinea‐pig than rat myocytes and even more pronounced in cells isolated from failing human heart.
Pertussis toxin‐pretreatment at 35°C of guinea‐pig and human myocytes abolished the anti‐adrenergic effect of adenosine. Longer exposure to higher concentrations of pertussis toxin was required for complete abolition in human compared to guinea‐pig cells.
These results support the suggestion that the adenosine receptors mediating the anti‐adrenergic effect of adenosine are of the A1 subtype and are coupled to the inhibitory guanine nucleotide binding protein, Gi/Go.
Pertussis toxin pretreatment increased the sensitivity of guinea‐pig myocytes to isoprenaline in the absence of adenosine; the EC50 value was decreased by a factor of 10. This suggests that Gi may exert a tonic inhibitory effect on the β‐adrenoceptor/adenylate cyclase interaction in normal myocardium.
α‐Methyldopa induces a naltrexone‐insensitive antinociception and hypomotility in rats
Authors: van Giersberge Paul L.M. , van Duinkerken Elizabeth , Sweep C.G.J. (Fred) , Wiegant Victor M. , van Ree Jan M. , de Jong Wybren 
Published: July 2012

This study served to investigate whether endogenous opioid peptides play a role in the putative antinociceptive and the sedative actions of α‐methyldopa.
In conscious normotensive rats, α‐methyldopa induced hypotension, starting around 1 h and reaching a maximum 3–4 h after administration. Pretreatment with naltrexone resulted in an inhibition of α‐methyldopa‐induced hypotension.
α‐Methyldopa dose‐dependently increased hot plate latency which became evident after a 4 h lag period and reaching a maximum effect at 6 h. The antinociceptive effect of α‐methyldopa was not affected by naltrexone.
In a small open field, α‐methyldopa dose‐dependently suppressed locomotion and sniffing behaviour. These effects of α‐methyldopa were apparent 1 h after administration and were naltrexone‐insensitive.
No changes in the level of β‐endorphin‐like immunoreactivity in plasma and cerebrospinal fluid were observed after administration of α‐methyldopa.
The results indicate that endogenous opioid peptides are involved in the hypotensive action of α‐methyldopa but not in α‐methyldopa‐induced hypomotility and antinociception.
Heterogeneity of α2‐adrenoceptors in rat cortex but not human platelets can be defined by 8‐OH‐DPAT, RU 24969 and methysergide
Authors: Brown C.M. , MacKinnon A.C. , McGrath J.C. , Spedding M. , Kilpatrick A.T. 
Published: July 2012

Saturation experiments indicated that [3H]‐yohimbine binding was specific, saturable and labelled a single population of sites in rat cerebral cortex (Kd 5.3 ± 0.9 nm, Bmax 121 ± 10 fmol mg−1 protein) and human platelets (Kd 0.7 ± 0.1 nm, Bmax 152 ± 10 fmol mg−1 protein).
The α2‐adrenoceptor antagonists, yohimbine, rauwolscine, WY 26703, idazoxan and BDF 6143 displaced [3H]‐yohimbine binding to each tissue in a simple manner, with high affinity and Hill slopes close to unity.
The α1‐adrenoceptor agonist, oxymetazoline and the antagonist prazosin inhibited the binding of [3H]‐yohimbine to rat cortex in a complex manner consistent with an interaction at more than one site. However, indoramin and WB 4101 only appeared to interact with one site. In contrast, in human platelets, all antagonists gave rise to monophasic displacement curves with Hill slopes close to unity suggesting a single site of interaction.
The 5‐hydroxytryptamine (5‐HT) receptor ligands, 8‐hydroxy‐2‐(di‐n‐propylamino)‐tetralin (8‐OH‐DPAT), RU 24969, and methysergide inhibited the binding of [3H]‐yohimbine to rat cortex with high and low affinity, consistent with an interaction with two populations of binding sites. However, inhibition of [3H]‐yohimbine binding to human platelets suggested a single site of interaction. The low affinity of 5‐HT, 5‐carboxyamidotryptamine (5‐CT) and dipropyl‐5‐CT indicated that [3H]‐yohimbine was not labelling a 5‐HT1‐like site in rat cortex.
The ability of 8‐OH‐DPAT, RU 24969 and methysergide in addition to prazosin and oxymetazoline to differentiate [3H]‐yohimbine binding provides additional pharmacological evidence for heterogeneity within rat cortical α2‐adrenoceptors. However, if the two sites in rat cortex that are differentiated by the 5‐HT ligands represent α2A‐ and α2B‐adrenoceptor subtypes as defined by prazosin and oxymetazoline, then they do not correspond to the population of sites in human platelets. As receptor classification should be linked to affinity of drugs rather than tissue distribution, the current classification of α2‐adrenoceptor subtypes does not appear to be satisfactory.
Effects of pinacidil, RP 49356 and nicorandil on ATP‐sensitive potassium channels in insulin‐secreting cells
Authors: Dunne M.J. 
Published: July 2012

The whole‐cell patch‐clamp technique has been used to investigate the effects of pinacidil, RP 49356 and nicorandil on membrane potential and adenosine 5′‐triphosphate (ATP)‐sensitive K+ channel currents in the insulin‐secreting cell line RINm5F. Interactions between pinacidil, RP 49356, nicorandil, diazoxide and ATP have been studied in excised outside‐out membrane patches and open‐cells.
In RINm5F whole‐cells (current‐clamp mode) continually exposed to glucose, pinacidil, RP 49356 and nicorandil, at concentrations greater than 100 μm, consistently reversed the effects of the sugar by repolarizing the membrane and terminating voltage‐gated Ca2+ spike‐potentials.
The actions of pinacidil, RP 49356 and nicorandil on membrane potential may be explained by their effects on the opening of ATP‐sensitive K+ channels, since all three compounds activated channels in whole‐cells (voltage‐clamp mode), excised outside‐out membrane patches and open‐cells, at concentrations greater than 100 μm. Below 100 μm the actions of pinacidil, RP 49356 and nicorandil were weak and inconsistent.
The mechanism of channel activation appears to depend on the presence of cytosolic ATP, since in its absence, pinacidil, RP 49356 and nicorandil (> 100 μm) had either no effects or inhibited K+ channels.
Pinacidil, nicorandil and RP 49356 (200–500 μm) also appeared to open K+ channels inhibited by quasi‐physiological concentrations of ATP (4 mm) and ADP (1 mm). However, in comparison to diazoxide their effects were weak.
Since pinacidil, RP 49356 and nicorandil have been shown to have effects on smooth muscle preparations at concentrations of 30 μm and below, the data presented in this study may have important implications for any prospective therapeutic application of the drugs, since at the concentrations required to relax smooth muscle cells, hyperglycaemia will be avoided.
Opioid receptor ligands in the neonatal rat spinal cord: binding and in vitro depression of the nociceptive responses
Authors: James I.F. , Bettaney J. , Perkins M.N. , Ketchum S.B. , Dray A. 
Published: July 2012

Opioid receptors in the neonatal rat spinal cord have been characterized by measurements of ligand binding to crude membrane fractions and by functional tests on the nociceptive spinal response in a spinal cord‐tail preparation in vitro.
There were high affinity binding sites for [3H]‐[d‐Ala2, MePhe4, Gly(ol)5]enkephalin (DAGOL), [3H]‐U69593, and [3H]‐ethylketocyclazocine (EKC) on spinal cord membranes from neonatal rats. Hill slopes for binding of [3H]‐DAGOL and [3H]‐U69593 were close to unity. The Hill slope for binding of [3H]‐EKC was less than unity, even after its interactions at μ‐receptors had been blocked with 100 nm unlabelled DAGOL. Binding sites for [3H]‐[d‐Pen2, d‐Pen5]enkephalin (DPDPE) could not be detected.
In competition assays U50488 was as potent as PD117302 and U69593 in competition for either [3H]‐U69593 or [3H]‐EKC binding sites. Hill slopes for a range of competing ligands at [3H]‐DAGOL or [3H]‐U69593 sites were close to unity. Hill slopes for competition at [3H]‐EKC sites were less than one.
In the spinal cord‐tail preparation from neonatal rats, opioid receptor agonists depressed spinal nociceptive responses evoked by application of capsaicin or heat to the tail. The order of potency was DAGOL > U69593 = PD117302 > morphine > U50488 = [d‐Pen2, l‐Pen5]enkephalin (DPLPE).
The antagonist naloxone was about equally potent against DAGOL, morphine and DPLPE, and about ten times less potent against U69593 and PD117302. The effects of U50488 were much less sensitive to blockade by naloxone than the effects of PD11703 or U69593. The κ antagonist, nor‐binaltorphimine was equipotent against all three κ agonists.
The absence of δ‐binding sites, and the low potency and relatively high sensitivity to naloxone suggest that DPLPE could be working at μ‐receptors in the neonatal rat spinal cord.
The binding assays show that U50488 has the same affinity as PD117302 and U69593 for κ‐receptors, yet it was less effective in the depression of nociceptive responses. This may be because U50488 has a relatively low efficacy at κ‐receptors. It is possible that at high concentrations U50488 activates receptors not affected by other κ‐ligands. These additional receptors may be non‐opioid receptors (hence the insensitivity to naloxone), or they could be a subtype of κ‐opioid receptor.
Effects of B‐HT 920 on nigrostriatal and mesolimbic dopamine systems in normosensitive and supersensitive rats
Authors: Clarke Paul B.S. , Wyder Kathleen J. , Jakubovic Alexander , Fibiger Hans C. 
Published: July 2012

B‐HT 920, a D2 dopamine receptor agonist, was tested for its ability to exert presynaptic actions in normosensitive rats, and for possible postsynaptic actions in rats made ‘supersensitive’ to apomorphine.
In normosensitive rats, B‐HT 920 (0.01–0.3 mg kg−1, i.p.) increased dopamine concentrations and lowered metabolite levels to a similar extent in all four terminal regions examined (medial prefrontal cortex, olfactory tubercle, nucleus accumbens, caudate‐putamen). Analogous effects were seen for 5‐hydroxytryptamine and its metabolite 5‐hydroxyindoleacetic acid.
Rats which received bilateral 6‐hydroxydopamine (6‐OHDA) infusions into the caudate‐putamen showed signs of postsynaptic dopamine receptor activation (stereotyped behaviour) in response to B‐HT 920 (0.1 and 1.0 mg kg−1, i.p.) and to apomorphine (0.2 mg kg−1, s.c.). Similarly, B‐HT 920 (0.1 mg kg−1) induced contralateral circling in rats that had received unilateral 6‐OHDA infusions into the medial forebrain bundle; the rate of circling increased gradually over several weeks.
In contrast, bilateral 6‐OHDA infusions into the nucleus accumbens resulted in a supersensitive (locomotor stimulant) response to a low dose of apomorphine (0.1 mg kg−1, s.c.), but not to B‐HT 920 (0.01 and 0.1 mg kg−1).
In intact rats, withdrawal of chronic haloperidol treatment induced behavioural supersensitivity to apomorphine but not to B‐HT 920.
The involvement of 5‐hydroxytryptaminergic and dopaminergic mechanisms in the eating induced by buspirone, gepirone and ipsapirone
Authors: Fletcher Paul J. , Davies Michael 
Published: July 2012

The roles of 5‐hydroxytryptamine (5‐HT) and dopamine systems in mediating the increased feeding induced by buspirone, gepirone and ipsapirone were investigated.
All three compounds induced dose‐dependent increases in food intake when administered subcutaneously to free feeding rats. Buspirone was effective over a narrower dose range than either gepirone or ipsapirone, and the maximal effect observed was smaller than the effects elicited by gepirone and ipsapirone.
Depletion of brain 5‐HT with parachlorophenylalanine (PCPA) prevented the effects of equi‐effective doses of gepirone (2.5 mg kg−1) and ipsapirone (2.5 mg kg−1), but failed to prevent buspirone (1 mg kg−1)‐induced eating. Thus buspirone does not appear to interact with 5‐HT systems to elicit feeding.
Gepirone (0.2 μg) and ipsapirone (0.04 and 0.2 μg) increased food intake when injected into the dorsal raphé nucleus (DRN), presumably by inhibiting the activity of DRN 5‐hydroxytryptaminergic afferents. Buspirone (0.04–5 μg) was ineffective when injected into the DRN.
Pretreatment with haloperidol (0.1 mg kg−1, 30 min) significantly attenuated the effects of equi‐effective doses of buspirone, gepirone and ipsapirone, indicating that these drugs interact with dopaminergic systems to increase feeding.
Previously it has been shown that each of these drugs increases striatal dopamine activity. Increased dopaminergic neurotransmission in the striatum induces a general behavioural activation, which under certain conditions facilitates feeding. It is possible that this mechanism underlies the behavioural effects of buspirone, gepirone and ipsapirone. The effects of gepirone and ipsapirone probably involve an indirect action to inhibit the activity of DRN 5‐hydroxytryptaminergic afferents, whereas buspirone interacts directly with dopaminergic systems.
Release of a neutrophil‐derived vascoconstrictor agent which augments platelet‐induced contractions of blood vessels in vitro
Authors: Sessa William C. , Mullane Kevin M. 
Published: July 2012

The effects of neutrophil‐derived products on vascular tone in vitro were examined by adding purified rabbit neutrophils to siliconized organ baths containing rings of rabbit thoracic aorta.
Neutrophil‐derived products induced a concentration‐dependent contraction of the blood vessels generating 3.9 ± 0.2 g of tension at a cell concentration of 2 × 106 ml−1. This contractile response was not dependent on an intact endothelium and was not ameliorated by treatment of the neutrophils with inhibitors of lipoxygenase or cyclo‐oxygenase enzymes, by free radical scavengers or by the use of end organ antagonists to angiotensin II, desArg9‐bradykinin, histamine, catecholamines or acetylcholine.
Neutrophils stimulated with phorbol myristate acetate, formyl methionyl‐leucyl‐phenylalanine or calcium ionophore A23187 released a contractile factor into the supernatant which produced qualitatively similar contractions compared to those elicited by incubation with intact unstimulated neutrophils.
Ten to twenty times more platelets were required to evoke equivalent contractions to those observed with neutrophils. However, neutrophil supernates significantly augmented platelet‐mediated contractions (P < 0.001).
Contractions elicited by neutrophils and supernates derived from activated neutrophils were partially antagonized by 5‐hydroxytryptamine (5‐HT) receptor antagonists, methysergide and ketanserin. However, the inhibition of exogenous 5‐HT‐induced contractions on rabbit aorta and rat stomach strips by both antagonists was greater than the inhibition of contractions produced by neutrophils and neutrophil‐derived supernates.
Extraction of the biologically active material from supernatants of activated neutrophils into acetone, but not chloroform‐methanol or ethyl acetate, suggests the contractile factor may be a protein/peptide. Partial purification on a Sephadex G100 column yields a contractile factor with a molecular weight of less than 4,000 daltons.
This factor may augment vascular tone, either directly or by interactions with platelets, in pathophysiological states associated with neutrophil activation and accumulation.
Alterations of responsiveness to adrenoceptor agonists and calcium of non‐infarcted hypertrophied muscles from rats with chronic myocardial infarction
Authors: Itaya Takehiko , Hashimoto Hisakuni , Uematsu Toshihiko , Nakashima Mitsuyoshi 
Published: July 2012

The responsiveness of hypertrophied right ventricular muscle from rats with chronic myocardial infarction (MI) was examined. Myocardial infarction was produced by ligating the left coronary artery. The positive inotropic effects of α‐ and β‐adrenoceptor agonists and calcium on the isolated non‐ischaemic muscles were determined at one and four weeks after ligation, and were compared with those in sham‐operated (SO) rats.
The contractile force of electrically‐driven right ventricular papillary muscles was measured isometrically. We also determined the change of beating rate of the right atrium in response to a β‐adrenoceptor agonist.
Basal contractile force increased at four weeks after ligation.
The pEC50 values of the α1‐adrenoceptor agonist, methoxamine, and calcium increased at four weeks after ligation, but the pEC50 values of the β‐adrenoceptor agonist, dobutamine did not change.
Maximal contractile force did not change with these agonists at either one and four weeks after ligation.
Tissues from rats four weeks after MI exhibited slight increases in the Bmax of α‐ but not β‐receptors, without any changes of affinity.
The increases in the sensitivity to an α1‐adrenoceptor agonist and calcium may be compensatory mechanisms of non‐infarcted ventricular tissue which has undergone hypertrophy in chronic MI.
Somatostatin decreases the calcium inward current in guinea‐pig atria
Authors: Ohmura Tsuyoshi , Nishio Matomo , Kigoshi Shigeru , Muramatsu Ikunobu 
Published: July 2012

The effects of somatostatin on mechanical and electrophysiological responses were studied in guinea‐pig atrial muscle preparations and single cells.
Somatostatin (≥ 10−8 m) decreased the twitch contraction in a concentration‐dependent manner in electrically driven left atria and spontaneously beating right atria. However, the beating rate was not affected.
The negative inotropic effect of somatostatin was transient. Desensitization to this agent developed slowly during continuous exposure to the peptide.
In single atrial cells, somatostatin significantly shortened the action potential duration, but the resting potential and action potential amplitude were not affected.
Under whole cell voltage‐clamp conditions, somatostatin decreased the calcium inward current without affecting the sodium and potassium currents.
These results suggest that somatostatin selectively acts on the calcium channel of guinea‐pig atrial cells to reduce the calcium inward current, which in turn gives rise to the negative inotropic effect.
The β1 and β2‐adrenoceptor affinity and β1‐blocking potency of S‐ and R‐metoprolol
Authors: Wahlund Göran , Nerme Viveca , Abrahamsson Tommy , Sjöquist Per‐Ove 
Published: July 2012

The β‐adrenoceptor affinity and blocking potency of the two enantiomers and the racemate of metoprolol were investigated in vitro, by use of a receptor‐binding technique, and in vivo in the anaesthetized cat.
The enantiomeric purity of the S‐ and R‐form was: >99.2% and >99.9%, respectively.
The β1‐ and β2‐adrenoceptor affinity (–log equilibrium dissociation constant) of the enantiomers was determined from competition binding experiments (radioligand: [125I]‐(S)‐pindolol) performed in membranes prepared from the guinea‐pig left ventricular free wall (predominantly β1) and soleus muscle (β2). The β1‐adrenoceptor affinity was (means ± s.d.): 7.73 ± 0.10 and 5.00 ± 0.06 for the S‐ and R‐form of metoprolol, respectively. The corresponding values for β2‐adrenoceptors were 6.28 ± 0.06 (S) and 4.52 ± 0.09 (R). Thus, the difference in affinity for the two enantiomers was greater on β1 (about 500) than on β2‐adrenoceptors (about 50). The β1‐adrenoceptor selectivity of the S‐form (about 30) was similar to that of the racemic metoprolol, while the R‐form was almost non‐selective (3 fold β1‐selective).
In the anaesthetized cat, the (–log) intravenous doses (μmol kg−1) of S‐ and R‐metoprolol causing a 50% reduction (ED50) in the heart rate response to sympathetic nerve stimulation were determined. The doses inducing a 25% depression (DD25) of the basal myocardial contractility were also estimated. For the two enantiomers, the β1‐blocking potency (‐log ED50) was 7.04 ± 0.16 (S) and 4.65 ± 0.16 (R). A significant cardiodepressive effect was observed at high doses (‐log DD25): 4.18 ± 0.20 (S) and 4.08 ± 0.10 (R).
It is concluded that the binding of metoprolol to β1‐adrenoceptors has a stricter steric requirement than that for the binding of this β‐blocker to β2‐adrenoceptors. Furthermore, the non‐specific cardiodepressive effect of metoprolol was observed at equally high doses for the two enantiomers.