bluuebunny/crossref_metadata_2025_split huggingface dataset:
Endothelial 5‐HT receptors mediate relaxation of porcine pulmonary arteries in response to ergotamine and dihydroergotamine
Authors: Glusa E. , Roos A. 
Published: July 2012

The aim of the present study was to investigate whether antimigraine ergot compounds may act at endothelial 5‐hydroxytryptamine (5‐HT) receptors which trigger the release of endothelium‐derived relaxing factor (EDRF). Changes in tone of porcine isolated pulmonary arteries were measured isometrically. The integrity of the endothelium was assessed by the bradykinin‐induced relaxation of prostaglandin F2α (PGF2α, 3 μm)‐precontracted vessels.
The ergot derivatives ergotamine, dihydroergotamine (DHE) and dihydroergocristine, as well as 5‐HT and (±)‐α‐methyl‐5‐HT, elicited a reversible endothelium‐dependent relaxation of PGF2α‐precontracted arterial ring segments. The relaxation to both ergotamine and 5‐HT was associated with an increase in cyclic GMP. After pretreatment of the vessels with NG‐nitro‐L‐arginine methyl ester (200 μm), or removal of endothelium by mechanical rubbing, the relaxant responses were abolished.
The mean pEC50 values for relaxant responses followed the order: (±)‐α‐methyl‐5‐HT (8.80) > 5‐HT (8.75) > ergotamine (8.17) > DHE (7.70) > 5‐carboxamidotryptamine (7.62) > dihydroergocristine (7.17).
The relaxant effects of both ergotamine and dihydroergotamine were resistant to block by indomethacin (3 μm), prazosin (1 μm) and ketanserin (1 μm). However, the ergotamine‐induced relaxation was highly susceptible to block by pizotifen (pA2 = 8.23), norclozapine (pA2 = 8.20), methiothepin (‐log IC50 = 7.26), rauwolscine (pA2 = 7.24) and mesulergine (pA2 = 6.64). Each antagonist inhibited the relaxant responses to (±)‐α‐methyl‐5‐HT in the same manner with similar potency as that determined against ergotamine.
Recently, mRNA transcripts for 5‐HT1Dβ and 5‐HT2B receptors have been demonstrated in porcine pulmonary arteries. The rank order of potencies of agonists and antagonists in the present study suggests that the relaxant responses to 5‐HT and ergot derivatives are mediated through activation of endothelial 5‐HT receptors which are similar to the 5‐HT2B receptor subtypes.
Role of bradykinin receptors in the renal effects of inhibition of angiotensin converting enzyme and endopeptidases 24.11 and 24.15 in conscious rabbits
Authors: Tomoda Fumihiro , Lew Rebecca A. , Smith A. Ian , Madden Anna C. , Evans Roger G. 
Published: July 2012

We tested the effects on systemic haemodynamics and renal function, of inhibition of endopeptidase (EP) 24.15 (E.C. 3.4.24.15), in conscious uninephrectomized rabbits in which the activities of angiotensin converting enzyme (ACE, E.C. 3.4.15.1) and neutral endopeptidase (EP 24.11, E.C. 3.4.24.11) were already inhibited. To test the role of bradykinin B2‐receptors in mediating the effects following inhibition of these enzymes, the antagonist Hoe 140 was used.
Hoe 140 (0.1 mg kg−1, i.v.) did not affect resting mean arterial pressure or heart rate, but antagonized the depressor effect of right atrial administration of bradykinin. The dose‐response curve for bradykinin was shifted more than 1000 fold to the right for more than 4 h. Hoe 140 approximately doubled resting urine flow and increased fractional Na+ excretion from 4.2 to 6.0%; consistent with the hypothesis that it exerts a partial agonist effect on the kidney.
Combined inhibition of ACE (captopril; 0.25 mg kg−1 plus 0.2 mg kg−1h−1) and EP 24.11 (SCH 39370; 3 mg kg−1 plus 3 mg kg−1h−1) was followed by a sustained reduction in arterial pressure (−6 ± 2 mmHg) and increase in heart rate (35 ± 7 beats min−1). There was a small increase in renal blood flow (by 6.5 ± 3.2% relative to vehicle‐treatment) without a change in glomerular filtration rate, and about a 150% increase in Na+ excretion. Hoe 140 (0.1 mg kg−1, i.v.) pretreatment did not influence the renal effects of captopril and SCH 39370, although it did appear to blunt their hypotensive and tachycardic effects.
When EP 24.15 was inhibited with N‐[1‐(R,S)‐carboxy‐3‐phenylpropyl]‐Ala‐Ala‐Tyr‐p‐aminobenzoate (cFP‐AAY‐pAB; 5 mg kg−1 plus 3 mg kg−1h−1, i.v.) in rabbits pretreated with captopril and SCH 39370, no changes in systemic haemodynamics or renal function were observed.
We concluded that in conscious uninephrectomized rabbits, EP 24.15 does not play a major role in modulating renal function, at least under conditions where ACE and EP 24.11 are already inhibited. In contrast, ACE and/or EP 24.11 do modulate renal function in this model, but their influences are mediated chiefly through metabolism of peptides other than bradykinin.
Different subtypes of α1A‐adrenoceptor mediating contraction of rat epididymal vas deferens, rat hepatic portal vein and human prostate distinguished by the antagonist RS 17053
Authors: Marshall Ian , Burt Richard P. , Green G. Mark , Hussain Monira B. , Chapple Christopher R. 
Published: July 2012

The α1‐adrenoceptor subtype mediating contraction of the rat hepatic portal vein to phenylephrine was characterized by use of competitive antagonists previously shown to have selectivity between the expressed α1‐subtype clones. Prazosin competitively antagonized the phenylephrine contractions with a pA2 value of 9.2, as did WB 4101 (pA2 9.4), 5‐methyl urapidil (pA2 8.6), indoramin (pA2 8.4) and BMY 7378 (pA2 6.5).
The pA2 values on the rat portal vein correlated highly with their previously published pA2 values for the α1A‐adrenoceptors mediating contraction of the rat epididymal vas deferens and human prostate and poorly with those for the α1B‐ and α1D‐adrenoceptors mediating contraction of the rat spleen and aorta, respectively. The antagonist pA2 values on the rat portal vein correlated highly with their previously published pK1 values for the expressed α1a‐clone and poorly with those for the expressed α1b‐ and α1d‐clones. Therefore the results show that contraction of the rat portal vein to phenylephrine is mediated by α1A‐adrenoceptors.
The novel α1‐adrenoceptor antagonist RS 17053 had a relatively high affinity for the α1A‐adrenoceptors mediating contraction of the rat epididymal vas deferens (pA2 9.5) compared with the α1B‐adrenoceptors in the rat spleen (pA2 7.2) or the α1D‐adrenoceptors in the rat aorta (pKB 7.1), in agreement with its selectivity for the expressed α1a‐clone. However, RS 17053 had over 100 fold lower affinity for the α1A‐adrenoceptors mediating contraction of the rat portal vein (pKB 7.1) and human prostate (pKB 7.1) compared with its affinity for the α1A‐adrenoceptors in the rat epididymal vas deferens or the expressed α1a‐clone.
The difference in affinity of RS 17053 between the rat epididymal vas deferens and rat portal vein cannot be explained by a species difference in the receptor. Therefore RS 17053 may distinguish between subtypes of the α1a‐adrenoceptor in the rat portal vein and human prostate compared with those in the rat epididymal vas deferens or the expressed α1a‐clone.
Inhibition of nicotinic responses of bovine adrenal chromaffin cells by the protein kinase C inhibitor, Ro 31–8220
Authors: Marley Philip D. , Thomson Kerrie A. 
Published: July 2012

The effects of the protein kinase C inhibitor, Ro 31–8220, on the responses of cultured bovine adrenal chromaffin cells to nicotine, phorbol 12,13‐dibutyrate (PDBu) and K+ have been investigated.
Tyrosine hydroxylase activity was measured in situ in intact cells by measuring 14CO2 evolved following the hydroxylation and rapid decarboxylation of [14C]‐tyrosine offered to the cells. Secretion of endogenous adrenaline and noradrenaline was measured by use of h.p.1.c. with electrochemical detection. Cyclic AMP levels were measured in cell extracts by RIA.
Ro 31–8220 produced a concentration‐dependent inhibition of 300 nM PDBu‐stimulated tyrosine hydroxylase activity with an IC50 of < 2 μm and complete inhibition at 10 μm. It had no effect on the responses to forskolin.
Ro 31–8220 produced a concentration‐dependent inhibition of 5 μm nicotine‐stimulated tyrosine hydroxylase activity, adrenaline and noradrenaline secretion and cellular cyclic AMP levels, with an IC50 of about 3 μm and complete inhibition by 10 μm. At concentrations up to 10 μm, Ro 31–8220 had little or no effect on the corresponding responses to 50 mM K+.
A structural analogue of Ro 31–8220, bisindolylmaleimide V, that lacks activity as a protein kinase C inhibitor, had no effect up to 10 μm on PDBu‐stimulated tyrosine hydroxylase activity or on nicotine‐stimulated cyclic AMP levels or noradrenaline secretion and only marginal inhibitory effects on nicotine‐stimulated tyrosine hydroxylase activity and adrenaline secretion.
A structurally related protein kinase C inhibitor, bisindolylmaleimide I, inhibited PDBu‐stimulated tyrosine hydroxylase activity with an IC50 of < 1 μm and complete inhibition by 3 μm, but had essentially no effect on nicotine stimulated tyrosine hydroxylase activity or catecholamine secretion.
The results suggest that Ro 31–8220 is not only a protein kinase C inhibitor but is also a potent inhibitor of nicotinic receptor responses in adrenal chromaffin cells by a mechanism unrelated to protein kinase C inhibition. The results are consistent with Ro 31–8220 being a nicotinic receptor antagonist.
P2x‐purinoceptors of myenteric neurones from the guinea‐pig ileum and their unusual pharmacological properties
Authors: Barajas‐López Carlos , Huizinga Jan D. , Collins Stephen M. , Gerzanich Vladimir , Espinosa‐Luna Rosa , Peres Andrea L. 
Published: July 2012

Whole‐cell and outside‐out patch clamp recordings were used to characterize the physiological and pharmacological properties of the P2x‐purinoceptors of myenteric neurones from the guinea‐pig ileum.
Adenosine 5′‐triphosphate (ATP) and analogues (1–3000μm) evoked a rapid inward current in > 90% of all recorded neurones. The reversal potential of this current was dependent on the extracellular sodium concentration, at +14 ± 1.9, 0 ± 1.6 and −12 ± 1 mV for 166, 83 and 42 mM of sodium, respectively. The fast activation and inactivation of this current occurred even when guanosine 5′‐triphosphate (GTP) was omitted from the pipette solution or substituted with an equimolar concentration of guanosine 5′‐o‐[2‐thiotriphosphate] (GTP‐γ‐S). Single channel currents were observed when these outside‐out membrane patches were exposed to ATP (10–30 μm). These channels have a unitary conductance of about 17 picosiemens.
The rank‐order of potency of the agonists used to induce the whole‐cell currents was: ATP‐γ‐S = ATP = 2‐methylthio‐ATP (2‐Me‐S‐ATP) > > α,β‐methylene ATP = β,γ‐methylene ATP; adenosine and uridine 5′‐triphosphate (UTP) (up to 1 mM) were inactive.
Pyridoxalphosphate‐6‐azophenyl‐2′,4′‐disulphonic acid (PPADS) (1–30μm) antagonized the effects of ATP (1 mM) with an IC50 of 4 μm. α,β‐Methylene ATP (100 μm) did not affect the ATP (30 μm)‐induced current. Cibacron Blue 3GA increased the ATP activated cationic current whereas Basilen Blue E‐3G had a very weak antagonistic effect (IC50 μ 3 mM). Suramin potentiated the currents induced by ATP through a mechanism that was independent of its inhibitory effect on ectonucleotidase activity, as suramin also potentiated the effect of α,β‐methylene ATP (an ATP analogue that is resistant to nucleotidases).
In conclusion, the myenteric P2x‐purinoceptor shares some properties with other purinoceptors in particular with the P2times4‐ and P2X6‐purinoceptors. This receptor has also some unusual pharmacological properties suggesting that myenteric neurones express a novel subtype of P2x‐purinoceptors. The properties of this receptor, however, might be a result of the combination of two or more of the homomeric purinoceptors so far characterized.
Effects of competitive and noncompetitive antagonists of the N‐methyl‐D‐aspartate receptor on the analgesic action of δ1‐ and δ2‐opioid receptor agonists in mice
Authors: Bhargava Hemendra N. , Zhao Guo‐Min 
Published: July 2012

The effects of MK‐801, a noncompetitive antagonist of the N‐methyl‐D‐aspartate (NMDA) receptor and LY 235959, a competitive antagonist of the NMDA receptor on the analgesic actions of [D‐Pen2, D‐Pen5]enkephalin (DPDPE) and [D‐Ala2, Glu4] deltorphin II (deltorphin II), the putative δ1‐ and δ2‐opioid receptor agonists, respectively, were determined in the male Swiss‐Webster mice.
Intracerebroventricular administration of DPDPE or deltorphin II produced analgesia. MK‐801 administered intraperitoneally 10 min before the injection of DPDPE or deltorphin II, dose‐dependently antagonized the analgesic actions of both drugs.
LY 235959 also dose‐dependently antagonized the analgesic actions of DPDPE and deltorphin II.
The effects of MK‐801 and LY 235959 on the binding of [3H]‐DPDPE to mouse brain membranes were also determined. Neither of the NMDA receptor antagonists had any effect on the binding of [3H]‐DPDPE.
It is concluded that competitive and noncompetitive antagonists of the NMDA receptor antagonize the analgesic action of δ1‐ and δ2‐opioid receptor agonists and that such effects are not mediated via a direct interaction with brain δ‐opioid receptors.
Nociceptin receptor coupling to a potassium conductance in rat locus coeruleus neurones in vitro
Authors: Connor Mark , Vaughan Christopher W. , Chieng Billy , Christie Macdonald J. 
Published: July 2012

In this study we have examined the effects of nociceptin, an endogenous ligand for the opioid‐like receptor ORL1, on the membrane properties of rat locus coeruleus (LC) neurones in vitro, using intracellular and whole cell patch clamp recording.
When locus coeruleus neurones were voltage clamped to −60 mV, application of nociceptin caused an outward current in all cells examined (n = 49), with an EC50 of 90 nM. Neither the potency nor the maximal effect of nociceptin was altered in the presence of the peptidase inhibitors, bestatin (20 μm) or thiorphan (2 μm).
The outward currents caused by nociceptin in 2.5 mM extracellular K+ reversed polarity at −123 mV, more negative than the predicted K+ reversal potential of −105 mV. Increasing extracellular K+ to 6.5 mM resulted in a shift of the reversal potential of +25 mV, a shift consistent with a K+ conductance. The conductance activated by nociceptin showed mild inward rectification.
Application of a high concentration of nociceptin (3 μm) occluded the current produced by simultaneous application of high concentrations of Met‐enkephalin (10 μm), (3 μm) somatostatin and UK 14304 (3 μm), indicating that nociceptin activated the same conductance as μ‐opioid and somatostatin receptors and α2‐adrenoceptors.
The actions of nociceptin were weakly antagonized by the opioid antagonist, naloxone, with pKb′s estimated from 2 cells of −4.23 and −4.33. The μ‐opioid antagonist, CTAP (D‐Phe‐Cys‐Tyr‐D‐Trp‐Arg‐Pen‐Thr‐NH2, 1 μm), the opioid antagonist, nalorphine (30 μm), or the somatostatin antagonist, CPP (cyclo(7‐aminoheptanoyl‐Phe‐D‐Tip‐Lys‐Thr[Bzl]) 3 μm) did not affect the nociceptin‐induced current.
Dynorphin A (3 μm), another putative endogenous ligand for ORL1, caused a robust outward current in locus coeruleus neurones that was, however, completely antagonized by moderate concentrations of naloxone (300 nM‐1 μm).
Continuous application of nociceptin (3 μm) resulted in a decrease of the outward current to a steady level of 70% of the maximum response with a t1/2 of 120s. Desensitization was largely homologous because simultaneous application of Met‐enkephalin (30 μm) during the desensitized period of the nociceptin response resulted in an outward current that was 92% of control responses to Met‐enkephalin in the same cells. Conversely, continuous application of Met‐enkephalin (30 μm) resulted in a decrease of Met‐enkephalin current to a steady level that was 54% of the initial current. During this desensitized period application of nociceptin (3 μm) resulted in a current that was 78% of the control responses to nociceptin in the same cells.
Thus nociceptin potently activates an inwardly rectifying K+ conductance in locus coeruleus neurones, with a pharmacological profile consistent with activation of the ORL1 receptor. Dynorphin A does not appear to be a ligand for ORL1 in rat locus coeruleus neurones.
Inhibition of cortical acetylcholine release and cognitive performance by histamine H3 receptor activation in rats
Authors: Blandina P. , Giorgetti M. , Bartolini L. , Cecchi M. , Timmerman H. , Leurs R. , Pepeu G. , Giovannini M.G. 
Published: July 2012

The effects of histamine and agents acting at histamine receptors on spontaneous and 100 mM K+‐evoked release of acetylcholine, measured by microdialysis from the cortex of freely moving rats, and on cognitive tests are described.
Local administration of histamine (0.1–100 μm) failed to affect spontaneous but inhibited 100 mM K+‐stimulated release of acetylcholine up to about 50%. The H3 receptor agonists (R)‐α‐methylhistamine (RAMH) (0.1–10 μm), imetit (0.01–10 μm) and immepip (0.01–10 μm) mimicked the effect of histamine.
Neither 2‐thiazolylethylamine (TEA), an agonist showing some selectivity for H1 receptors, nor the H2 receptor agonist, dimaprit, modified 100 mM K+‐evoked release of acetylcholine.
The inhibitory effect of 100 μm histamine was completely prevented by the highly selective histamine H3 receptor antagonist, clobenpropit but was resistant to antagonism by triprolidine and cimetidine, antagonists at histamine H1 and H2 but not H3 receptors.
The H3 receptor‐induced inhibition of K+‐evoked release of acetylcholine was fully sensitive to tetrodotoxin (TTX).
The effects of intraperitoneal (i.p.) injection of imetit (5 mg kg−1) and RAMH (5 mg kg−1) were tested on acetylcholine release and short term memory paradigms. Both drugs reduced 100 mM K+‐evoked release of cortical acetylcholine, and impaired object recognition and a passive avoidance response.
These observations provide the first evidence of a regulatory role of histamine H3 receptors on cortical acetylcholine release in vivo. Moreover, they suggest a role for histamine in learning and memory and may have implications for the treatment of degenerative disorders associated with impaired cholinergic function.
A New Transcutaneous Bidirectional Communication for Monitoring Implanted Artificial Heart Using the Human Body as a Conductive Medium
Authors: Okamoto Eiji , Kato Yoshikuni , Seino Kazuyuki , Miura Hidekazu , Shiraishi Yasuyuki , Yambe Tomoyuki , Mitamura Yoshinori 
Published: July 2012

AbstractA transcutaneous communication system (TCS) is a key technology for monitoring and controlling artificial hearts and other artificial organs in the body. In this study, we developed a new TCS that uses the human body as a conductive medium. Direct data exchange provides a higher level of communication security compared to that of wireless methods without physical constraints such as an external wire. The external and internal units of the new TCS each consist mainly of a data transmitter and a data receiver. The data transmitter has an amplitude shift keying (ASK) modulator (carrier frequencies: 4 and 10 MHz) and an electrode. The ASK‐modulated data current is led into the body through the electrode, and it flows back to the energy source through the body, the data receiver, and the earth ground that includes all conductors and dielectrics in the environment that are in close proximity to the patient. Performance of the TCS was evaluated by a communication test on the surface of the human body and in an animal experiment using a goat. The TCS was able to transmit data concurrently for 4 weeks between everywhere on the surface of the body and everywhere inside the body under full‐duplex communication at a transmission rate of 115 kbps. The power consumption of each TCS unit was 125 mW with an ASK‐modulated current of 7 mA (root‐mean‐square). While further study is required to secure its safety, the newly developed TCS has promise to be a next‐generation transcutaneous communication device.
Quality of life in young adults who underwent resective surgery for epilepsy in childhood
Authors: Elliott Irene , Kadis Darren S. , Lach Lucyna , Olds Janet , McCleary Lynn , Whiting Sharon , Snyder Thomas , Smith Mary Lou 
Published: July 2012

SummaryPurpose:  This study investigated quality of life (QOL) in young adults who had undergone epilepsy surgery before the age of 16 years. The contribution to QOL of seizure status in the prior year, sex, number of antiepileptic drugs, and mood were evaluated.Methods:  Sixty‐nine young adults who had undergone surgery were subdivided into those who were seizure‐free in the past year (n = 38) and those who had seizures (n = 31) in that time. A nonsurgical comparison group of young adults (n = 29) with childhood‐onset medically intractable epilepsy was also studied. All groups completed measures of QOL and mood.Key Findings:  After accounting for mood, sex, and number of antiepileptic drugs, the seizure‐free group reported better cognitive and physical function and overall QOL, experienced less seizure worry, and had better self‐perception. Mood was the most consistently predictive covariate, and was independently predictive of many aspects of QOL.Significance:  Seizure freedom associated with surgery in childhood is associated with improved QOL in certain domains. Findings highlight the importance of mood in determining self‐perception of QOL.
Steady‐state plasma and cerebrospinal fluid pharmacokinetics and tolerability of eslicarbazepine acetate and oxcarbazepine in healthy volunteers
Authors: Nunes Teresa , Rocha José Francisco , Falcão Amílcar , Almeida Luis , Soares‐da‐Silva Patrício 
Published: July 2012

SummaryPurpose:  To evaluate the pharmacokinetics and tolerability of once‐daily eslicarbazepine acetate (ESL) and twice‐daily oxcarbazepine (OXC) and their metabolites in cerebrospinal fluid (CSF) and plasma following repeated oral administration.Methods:  Single‐center, open‐label, randomized, parallel‐group study in healthy volunteers. Volunteers in ESL group (n = 7) received 600 mg on days 1–3 and 1,200 mg on days 4–9, once daily. Volunteers in the OXC group (n = 7) received 300 mg on days 1–3 and 600 mg on days 4–9, twice daily. Plasma and CSF sampling was performed following the last dose.Key Findings:  Eslicarbazepine was the major drug entity in plasma and CSF, accounting for, respectively, 93.84% and 91.96% of total exposure in the ESL group and 78.06% and 76.42% in the OXC group. The extent of exposure to drug entities R‐licarbazepine and oxcarbazepine was approximately four‐fold higher with OXC as compared with ESL. There was relatively little fluctuation from peak‐to‐trough (ratio) in the CSF for both eslicarbazepine (ESL = 1.5; OXC = 1.2) and R‐licarbazepine (ESL = 1.2; OXC = 1.2). In contrast, oxcarbazepine showed larger differences between peak and trough (ESL = 3.1; OXC = 6.4). A total of 84 and 24 treatment‐emergent adverse events (TEAEs) were reported with OXC and ESL, respectively.Significance:  In comparison to OXC, administration of ESL resulted in more eslicarbazepine, less R‐licarbazepine, and less oxcarbazepine in plasma and CSF, which may correlate with the tolerability profile reported with ESL. The smaller peak‐to‐trough fluctuation of eslicarbazepine in CSF (a measure of sustained delivery to the brain) than in plasma supports once‐daily dosing of ESL.