bluuebunny/crossref_metadata_2025_split huggingface dataset:
The ontogeny of purinoceptors in rat urinary bladder and duodenum
Authors: Nicholls J. , Hourani S.M.O. , Kitchen I. 
Published: July 2012

The ontogeny of responses to purines and analogues of smooth muscle preparations was studied in rat duodenum and rat urinary bladder.
Responses to adenosine and to adenosine 5′‐triphosphate (ATP) mediated by P1‐ and P2‐purinoceptors respectively were present as early as postnatal day 2, the earliest day studied.
In rat bladder, adenosine was inhibitory and ATP and adenosine 5′‐(β,γ‐methylene) triphosphonate (AMP‐PCP) were excitatory, acting on the P2X subtype of P2‐purinoceptors. Adenosine was more potent in the neonate than in the adult, while the potency of the nucleotides initially increased with age but then declined, being highest between postnatal days 10 and 25.
In rat duodenum also, adenosine was inhibitory, its potency being less than the adult before day 15.
ATP at low concentrations was inhibitory in rat duodenum at every age studied and its potency increased with age, but higher concentrations of ATP (3 μm and above) were excitatory until day 15. Both relaxations and contractions were mediated by the P2Y subtype of P2‐purinoceptors. These ATP‐induced contractions were not inhibited by indomethacin (25 μm) or by tetrodotoxin (1 μm) and are therefore not due to prostaglandin synthesis or to ATP‐induced release of transmitter substances from nerves.
These results show that responses to adenosine and to adenine nucleotides are present from birth and vary with age, and that the changes seen indicate a differential development for P1, P2X‐ and P2Y‐purinoceptors.
Electrophysiological effects of AFD‐21 and AFD‐19, new antiarrythmic compounds on papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts
Authors: Kodama Itsuo , Kamiya Kaichiro , Kawamura Takashi , Suzuki Ryoko , Toyama Junji 
Published: July 2012

The effects of AFD‐21, a newly synthesized antiarrhythmic compound, and AFD‐19, its active metabolite, on transmembrane action potentials were examined in right ventricular papillary muscles and single ventricular myocytes isolated from guinea‐pig hearts.
In papillary muscles, AFD‐21 10−5 m caused a slight prolongation of action potential duration (APD), while AFD‐19 above 10−6 m shortened APD in a dose‐dependent manner.
Both AFD‐21 and AFD‐19 above 10−6 m caused a significant and dose‐dependent decrease in the maximum upstroke velocity () of the action potential without affecting the resting membrane potential.
In the presence of AFD‐21 or AFD‐19, trains of stimuli at rates ≥ 0.2 Hz led to an exponential decline in . This use‐dependent block was enhanced at higher stimulation frequencies. A time constant for the recovery of from the use‐dependent block was 2.9 s for AFD‐21 and 3.6 s for AFD‐19.
The curves relating membrane potential and were shifted by AFD‐21 (10−5 m) or AFD‐19 (10−5 m) to the direction of more negative potentials by 5.3 mV and 5.1 mV respectively.
In single ventricular myocytes treated with AFD‐21 (10−5 m) or AFD‐19 (10−5 m), of test action potentials preceded by conditioning clamp pulses to 0 mV was decreased progressively as the clamp pulse duration was prolonged.
These findings suggest that both AFD‐21 and AFD‐19 have use‐ and voltage‐dependent inhibitory action on the sodium channel by binding to the channel during its inactivated state, and that the unbinding rate is comparable to that of Class I antiarrhythmic drugs with intermediate kinetics.
Effects of cyclic AMP‐affecting agents on contractile reactivity of isolated mesenteric and renal resistance arteries of the rat
Authors: Heesen Bart‐Jeroen , DE Mey Jo G.R. 
Published: July 2012

Effects of adenosine 3′:5′‐cyclic monophosphate (cyclic AMP)‐affecting agents were compared in mesenteric and renal resistance arteries that had been isolated from 20 week old Wistar‐Kyoto rats, chemically sympathectomized, stretched to their optimal diameter for mechanical performance and made to contract in response to 30 mm potassium.
In mesenteric resistance arteries, isoprenaline, dopamine, NaF, forskolin, isobutyl‐methylxanthine, milrinone and dibutyryl‐cyclic AMP induced relaxation. Clonidine induced further increases in tension that could be reduced by pertussis toxin and prazosin but not by yohimbine. Clonidine also reduced relaxant responses to isoprenaline.
In renal resistance arteries, isoprenaline and dopamine failed to induce relaxation. Compared to mesenteric resistance arteries, renal vessels were less sensitive to the relaxant effect of NaF, forskolin and isobutyl‐methylxanthine. Relaxant responses to dibutyryl‐cyclic AMP did not differ between the two resistance arteries.
Indirect evidence thus suggests that in mesenteric resistance arteries, adenylate cyclase is susceptible to pharmacological activation and inhibition and is functionally coupled to relaxation. The refractory nature of renal resistance arteries to the relaxant effects of isoprenaline and dopamine could be due primarily to absence of appropriate receptors and to a relatively low activity of adenylate cyclase.
The antinociceptive activity of paracetamol in zymosan‐induced peritonitis in mice: the role of prostacyclin and reactive oxygen species
Authors: Doherty N.S. , Beaver T.H. , Chan K.Y. , Dinerstein R.J. , Diekema K.A. 
Published: July 2012

Oral administration of high doses of paracetamol (600 mg kg−1 or more) resulted in inhibition of the writhing and reduced the levels of prostacyclin (PGI2, measured as 6‐keto‐PGF1α) induced by intraperitoneal administration of zymosan in mice. The high oral doses of paracetamol required were accompanied by behavioural toxicity which may have contributed to the inhibition of writhing.
The number of writhes per mouse and the proportion of mice writhing at least once correlated significantly with the levels of 6‐keto‐PGF1α. However, inhibition of writhing by paracetamol occurred at higher levels of 6‐keto‐PGF1α than was previously observed with acidic non‐steroidal anti‐inflammatory agents.
When injected i.p., PGI2, carbacyclin and iloprost (agonists at the PGI2 receptor) induced writhing. Intraperitoneal injection of PGI2 reversed the inhibition of writhing induced by indomethacin (1 mg kg−1, p.o.) but not that induced by oral administration of paracetamol.
Paracetamol at 800 mg kg−1, p.o., inhibited carbacyclin‐induced writhing but indomethacin at 1 mg kg−1 p.o. did not. Paracetamol administered i.p. at 100 mg kg−1 reduced the peritoneal levels of 6‐keto‐PGF1α and inhibited zymosan‐induced but not carbacyclin‐induced writhing and did not produce behavioural toxicity.
The in vitro potency of paracetamol as a prostaglandin synthesis inhibitor is known to be reduced by the presence of lipid peroxides. However, no lipid peroxides, measured as thiobarbituric acid reactive material, were detected in the peritoneal lavage fluid of zymosan‐injected mice.
Intraperitoneal administration of a mixture of superoxide dismutase and catalase reduced detectable superoxide anion by 98% without inhibiting the writhing response to zymosan or the antinociceptive potency of paracetamol.
The data are consistent with the suggestion that inhibition of PGI2 synthesis in the peritoneal cavity by paracetamol is responsible for only a part of its antinociceptive activity in this test. However, extremely high oral doses of paracetamol were required which produced behavioural toxicity which clearly contributed to the inhibition of writhing. The low potency of paracetamol in this model cannot be attributed to the generation of lipid peroxides via the oxidative burst.
Non‐adrenergic, non‐cholinergic contractions in the electrically field stimulated guinea‐pig trachea
Authors: Ellis James L. , Undem Bradley J. 
Published: July 2012

The effects of drugs and altering stimulus parameters on neurogenic responses to electrical field stimulation (EFS) have been investigated in distal and proximal portions of the guinea‐pig trachea.
In the presence of indomethacin (3 μm) and propranolol (1 μm) two contractile phases were evident in both the proximal and distal trachea. The first rapid phase was abolished by atropine (0.1 μm), whereas the prolonged, second phase was abolished by capsaicin (10 μm) pretreatment. Tetrodotoxin (3 μm) abolished the initial response and greatly inhibited the second phase. In proximal trachea this second phase was evident only in 9 of 22 preparations. The addition of the peptidase inhibitor thiorphan (10 μm) however, caused a second phase to be seen in all the proximal tissues examined.
The two phases of the contractions to EFS were differentially sensitive to the pulse duration applied. The initial, cholinergic contractions were evident at lower pulse durations than were the prolonged capsaicin‐sensitive contractions, with the first phase being approximately 10 fold more sensitive than the second phase.
The magnitude of the capsaicin‐sensitive contraction to EFS was significantly greater in the distal trachea than in the proximal trachea. This difference prevailed in the presence of thiorphan, an inhibitor of neutral endopeptidase. In contrast, concentration‐response curves to capsaicin were similar in segments of proximal and distal trachea.
The non‐adrenergic non‐cholinergic (NANC) relaxant responses were studied in tissues in which excitatory neurogenic responses were pharmacologically abolished by capsaicin and atropine treatment. The NANC relaxant responses in the proximal trachea were evident at lower pulse frequencies and were of greater magnitude compared with NANC relaxant responses in the distal trachea.
These results indicate that, by pharmacologically manipulating the trachea and by selecting optimum stimulation parameters, a NANC contractile response to EFS can be seen throughout the length of the guinea‐pig trachea. This NANC response is most likely to be due to the release of tachykinins from capsaicin‐sensitive sensory fibres. It is suggested that NANC relaxant responses mask NANC contractile responses especially in the proximal trachea where NANC relaxant responses predominate.
Prostanoid stimulation of anion secretion in guinea‐pig gastric and ileal muscosa is mediated by different receptors
Authors: Bunce K.T. , Spraggs C.F. 
Published: July 2012

The receptors that mediate stimulation of anion secretion by prostanoids in isolated preparations of guinea‐pig gastric and ileal mucosa have been compared by use of selective prostanoid agonists and antagonists.
In gastric mucosa, the relative potency of agonists suggested that the control of anion secretion in this tissue was complex and may be mediated by EP2, EP3, and TP receptors. A role for TP receptors was confirmed with the TP‐selective antagonist AH23848 which inhibited short circuit current responses to the TP receptor agonist U‐46619 with a pA2 value of 8.44 but was without effect on responses to prostaglandin E2 (PGE2) or the EP selective agonist, sulprostone.
In ileal mucosa, the relative potency of agonists differed from that observed in gastric mucosa and was consistent with the view that anion secretion in this region of intestine was controlled by DP and EP2 receptors.
These studies suggest that anion secretion in gastric and ileal mucosa is controlled by different prostanoid receptor subtypes and so provide important informtion for the design of prostanoids which may protect gastric mucosa and that are free from side effects such as diarrhoea.
Effects of several potassium channel openers and glibenclamide on the uterus of the rat
Authors: Piper Ian , Minshall Eleanor , Downing Sandra J. , Hollingsworth Michael , Sadraei Hassan 
Published: July 2012

The ability of several potassium (K+) channel openers to inhibit spasm of the uterus of the nonpregnant rat and their susceptibility to antagonism by glibenclamide was assessed in vitro and in vivo.
In the isolated uterus exposed to oxytocin (0.2 nm), cromakalim, RP 49356 and pinacidil were of similar potency (mean pD2 = 6.4, 6.0 and 6.2 respectively) while minoxidil sulphate was of lower potency (pD2 = 4.7). Glibenclamide antagonized cromakalim and RP 49356 with the interactions consistent with competitive antagonism (mean pA2 of 6.57 and 7.00 respectively). Glibenclamide also antagonized pinacidil (pA2 = 6.22) but the slope of the Schild plot was significantly greater than −1. Neither salbutamol nor minoxidil sulphate was antagonized by glibenclamide (10 μm).
Cromakalim (1 and 10 μm), RP 49356 (1 and 10 μm), pinacidil (1 μm) and minoxidil sulphate (100 μm) suppressed spasm evoked by low (< 40 mm) but not high (≥ 40 mm) KCl concentrations. Glibenclamide (10 μm) prevented cromakalim (10 μm)‐, RP 49356 (10 μm)‐ and pinacidil (10 μm)‐induced suppression of KCl (20 mm)‐evoked spasm. Pinacidil (10 and 100 μm), cromakalim (100 μm) and salbutamol (0.01–1 μm) inhibited spasm evoked by all concentrations of KCl (10–80 mm). Suppression of spasm evoked by KCl (10–80 mm) by cromakalim (100 μm) and pinacidil (100 μm) was insensitive to glibenclamide (10 μm).
Cromakalim (0.1 mg kg−1) and RP 49356 (0.1 mg kg−1), given by i.v. bolus injection, inhibited uterine contractions, produced a fall in blood pressure and a slight tachycardia in the conscious ovariectomized rat. Glibenclamide (20 mg kg−1), given by i.v. infusion, antagonized the vascular and uterine smooth muscle relaxant properties of cromakalim and RP 49356.
Several K+ channel openers are uterine relaxants. The antagonism of cromakalim, RP 49356 and pinacidil, at low concentrations, by glibenclamide suggests their actions may involve an ATP‐sensitive K+ channel. High concentrations of pinacidil (10 and 100 μm) and cromakalim (100 μm) may exert an additional action in the uterus. The low potency of minoxidil sulphate and its insensitivity to glibenclamide in the isolated uterus suggests that its mechanism of action may differ from that of the other K+ channel openers.
Effects of putative neurotransmitters and related drugs on withdrawal contractures of guinea‐pig isolated ileum following brief contact with [Met5] enkephalin
Authors: Chahl Loris A. 
Published: July 2012

Brief exposure for 2 min of guinea‐pig isolated ileum to [Met5]enkephalin (MEnk) and noradrenaline has been shown previously to produce withdrawal contractures on washout of the agonist or addition of naloxone (MEnk) or phentolamine (noradrenaline).
The present study was undertaken to investigate firstly, whether other putative neurotransmitters and/or related drugs which inhibit transmitter release also produced withdrawal responses following 2 min contact with the ileum and secondly, whether they affected the opioid withdrawal response.
Adenosine (1–5 μm), but not U‐50,488H (1–5 μm), somatostatin (0.01–5 μm), ocreotide (1–5 μm), baclofen (1–25 μm) or dopamine (5, 50 μm), produced a contracture on washout following 2 min contact with the ileum. The adenosine (5 μm) washout contracture, in common with MEnk and noradrenaline washout contractures, was inhibited by the substance P antagonist, spantide (10 μm).
Added 30 s before washout at a concentration of 5 μm, noradrenaline, U‐50,488H, adenosine, somatostatin and ocreotide significantly inhibited the washout withdrawal response following 2 min contact of the ileum with MEnk, 1 μm. A higher concentration of baclofen, 250 μm, also inhibited this response.
The naloxone (1 μm)‐precipitated withdrawal response following contact of the ileum with MEnk, 1 μm, for 2 min, was inhibited only by noradrenaline (5 μm) and U‐50,488H (5 μm).
It is concluded that during naloxone‐precipitated opioid withdrawal an additional population of enteric motor neurones is recruited which is not involved in the washout withdrawal response and these neurones have less diversity of presynaptic receptors mediating inhibition of transmitter release than cholinergic motor neurones.
Philanthotoxin blocks quisqualate‐, AMPA‐ and kainate‐, but not NMDA‐, induced excitation of rat brainstem neurones in vivo
Authors: Jones M.G. , Anis N.A. , Lodge D. 
Published: July 2012

The effect of electrophoretic ejection of philanthotoxin (the polyamine toxin, from the Egyptian digger wasp) was tested on responses of brainstem and spinal neurones in the pentobarbitone‐anaesthetized rat to excitatory amino acids.
Philanthotoxin caused a dose‐dependent reduction of responses to quisqualate, α‐amino‐3‐hydroxy‐5‐phenyl‐4‐isoxazolepropionate (AMPA) and kainate with little effect on those to N‐methyl‐d‐aspartate (NMDA).
The time‐course of this antagonist action was slow. In particular the rate of recovery was dependent on frequency of ejection of the agonist. This agonist‐dependent recovery suggests that philanthotoxin has a channel blocking mode of action on mammalian central neurones.
Pharmacological characterization of polycation‐induced rat hind‐paw oedema
Authors: Antunes Edson , Mariano Mário , Cirino Giuseppe , Levi Silvio , DE Nucci Gilberto 
Published: July 2012

The inflammatory response induced by poly‐l‐arginine in the rat hind‐paw was studied both by measuring paw oedema and histologically.
The paw volume was measured with a hydroplethysmometer at 0.5, 1, 2, 4, 6 and 18 h after the subplantar injection of the polycation. Protein extravasation was evaluated with Evans' blue and the histology studied by light microscopy.
Poly‐l‐arginine (12, 24, 43 and 115 kD) caused dose‐ and molecular weight‐dependent oedema which had a rapid onset and long duration. Evans' blue extravasation paralleled the oedema induced by poly‐l‐arginine. Microscopic examination of the paws at early stages of oedema formation showed exuberant liquid exudate with no inflammatory cells. After 18 h, a cellular infiltrate was present, consisting mainly of mononuclear cells.
Indomethacin, dexamethasone, BW755c or the PAF‐antagonist WEB 2086 caused no significant inhibition of the poly‐l‐arginine‐induced oedema. Cyproheptadine had inhibitory effects only on the early stages of the polycation‐induced oedema. Similar results were observed with rats depleted of histamine and 5‐hydroxytryptamine.
Heparin, a polyanion, injected in the rat paw caused a marked inhibition of the polycation‐induced oedema. NG‐monomethyl‐l‐arginine (LNMMA), an inhibitor of EDRF synthesis, injected locally also produced a marked inhibition, but this inhibition was reversed by iloprost.
These results suggest that the oedema induced by polycations was due to their cationic charge. The inhibitory effect of LNMMA is probably due to a decrease in vascular flow rather than a decrease in vascular permeability.
Tachykinin receptors in the circular muscle of the guinea‐pig ileum
Authors: Maggi Carlo Alberto , Patacchini Riccardo , Giachetti Antonio , Meli Alberto 
Published: July 2012

We have studied the mechanical response of circular strips of the guinea‐pig ileum to tachykinins and characterized the receptors involved by means of receptor‐selective agonists.
The strips responded to both substance P (SP) and neurokinin A (NKA), as well as to [Pro9]‐SP sulphone (selective NK1‐receptor agonist), [βAla8]‐NKA(4–10) (selective NK2‐receptor agonist) and [MePhe7]‐neurokinin B (selective NK3‐receptor agonist). The ED50s of the various peptides (calculated as the concentration of agonist which produced 50% of the response to 10 μm carbachol) were similar, in the range of 40–200 nm, i.e. no clearcut rank order of potency was evident.
The response to a submaximal (10 nm) concentration of SP or NKA was unaffected in the presence of peptidase inhibitors (thiorphan, captopril and bestatin, 1 μm each).
The response to the NK1‐agonist was totally atropine‐resistant, but was reduced (about 30% inhibition) by tetrodotoxin. The response to the NK3‐receptor agonist was halved by atropine and abolished by tetrodotoxin. The response to the NK2‐agonist was unaffected by either atropine or tetrodotoxin.
The response to the selective NK2‐agonist was unchanged after desensitization of NK1‐ or NK3‐receptors.
The response to the NK2‐selective agonist was strongly inhibited by [Tyr5, d‐Trp6,8,9, Arg10]‐NKA(4–10) (MEN 10,207) a selective NK2‐receptor antagonist which did not modify the response to the NK1‐selective agonist.
Our findings indicate that all the three known types of tachykinin receptors mediate the contractile response of the circular muscle of the guinea‐pig ileum to peptides of this family. The response to activation of NK3‐receptors is totally neurogenic and partially mediated by endogenous acetylcholine, the response to activation of NK1‐receptors is partly neurogenic and largely myogenic and the response to activation of NK2‐receptors is totally myogenic.
Effects of hypomagnesia on transmitter actions in neocortical slices
Authors: El‐Beheiry H. , Puil E. 
Published: July 2012

The effects of hypomagnesia on the neuronal responses induced by iontophoretically applied acetylcholine, glutamate, N‐methylaspartate (NMDA) and γ‐aminobutyric acid (GABA) were investigated using intracellular recording techniques in in vitro slices of sensorimotor cortex (guinea‐pigs).
Perfusion with Mg‐free media, with or without tetrodotoxin (TTX), induced a small hyperpolarization (∼4mV) and a small decrease (∼10%) in the input resistance of neurones. During TTX‐blockade of Na‐spike genesis, spontaneous depolarizing waves of low frequencies were observed in neurones of slices under Mg‐free conditions.
The effects of acetylcholine and to a lesser extent, GABA actions, were depressed in a dose‐dependent, reversible manner by decreases in the [Mg2+] of the perfusing media. In neurones of slices that had been incubated in Mg‐free artificial cerebrospinal fluid to ensure a maximal depletion, the responses to these transmitters were potentiated by each sequentially administered increase in extracellular [Mg2+]. The actions of NMDA were potentiated during perfusion of Mg‐free media. However, the responses to glutamate, which may activate receptors for NMDA, were either depressed or unchanged under these conditions.
A regulatory role for external Mg cations in the responses of neocortical neurones to the transmitter substances, acetylcholine and GABA, can be inferred from these investigations which simulate hypomagnesemia. The dose‐dependent depression of GABA actions by low extracellular [Mg2+] additionally provides a plausible mechanism that may contribute to the neuronal hyperexcitability that is observed during conditions of hypomagnesemia.
The effects of cromakalim on ATP‐sensitive potassium channels in insulin‐secreting cells
Authors: Dunne M.J. , Aspinall R.J. , Petersen O.H. 
Published: July 2012

The single‐channel current recording technique has been used to investigate the effects of cromakalim, diazoxide and ATP, separately and combined, on the opening of ATP‐sensitive potassium channels in the insulin‐secreting cell‐line RINm5F. The actions of these drugs have been studied using the permeabilized open‐cell variation of the patch‐clamp technique.
In the absence of internal ATP, cromakalim (80–200 μm) was unable to open ATP‐sensitive K+ channels but when ATP was present both cromakalim and diazoxide caused channel openings.
Interactions between ATP and cromakalim seemed competitive. Concentrations of cromakalim in the range 80–200 μm readily activated channels inhibited by 0.1 mm ATP, but had no effects when the concentration of ATP was increased to 0.5–2 mm. Only when the concentration of cromakalim was increased to 400–800 μm could opening of 0.5–2 mm ATP‐inhibited channels be regularly observed. In the continued presence of cromakalim (400–800 μm), an increase in the internal concentration of ATP from either 0.25 to 0.5 mm or 1 to 2 mm, inhibited cromakalim‐activated K+ channels.
Activation of ATP‐inhibited K+ channels was abolished by replacing ATP with ATPγS and cromakalim had no effects on ATPγS‐inhibited channels. This suggests that cromakalim may open KATP channels in insulin‐secreting cells by a mechanism which involves protein phosphorylation.