bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of intravenous μ and κ opioid receptor agonists on sensory responses of convergent neurones in the dorsal horn of spinalized rats
Authors: Dong Xiao‐wei , Parsons Chris G. , Headley P. Max 
Published: July 2012

Electrophysiological experiments have been performed to assess the effects of intravenously administered μ and κ opioid agonists on the responses to noxious thermal and mechanical and non‐noxious tactile stimuli of single convergent neurones in laminae III‐VI of the dorsal horn of spinalized rats anaesthetized with α‐chloralose.
The μ receptor agonists tested were fentanyl (1–16 μg kg−1) and morphine (0.5–16 mg kg−1) and the κ‐receptor agonists U‐50,488 (1–16 mg kg−1) and tifluadom (0.1–1.6 mg kg−1). Multiple drug tests were made on each cell so that compounds could be compared under closely comparable conditions.
In one protocol, thermal and mechanical nociceptive responses of matched amplitudes were elicited alternately. Both μ and κ agonists dose‐dependently reduce the neuronal responses. Thermal nociceptive responses were as sensitive to the κ agents as were the mechanical nociceptive responses; the μ agonists similarly reduced both types of response in parallel.
In another protocol, nociceptive and non‐nociceptive responses were elicited alternately to permit the degree of selective antinociception to be assessed. The μ agonists were scarcely selective, fentanyl reducing nociceptive only slightly (but significantly at 4–16 μg kg−1) more than non‐nociceptive responses. The κ‐opioid agonist U50,488 reduced tactile responses somewhat more than nociceptive responses.
The spontaneous discharge of these cells with ongoing activity was reduced to a significantly greater degree than the evoked responses; this is likely to have contributed to the non‐selectivity of the reduction of the evoked responses.
The results are discussed with respect firstly to previous reports that κ opioids are ineffective in tests of thermal nociception, and secondly to the likely spinal mechanisms by which opioid receptor agonists mediate antinociception.
Haemodynamic effects of human α‐calcitonin gene‐related peptide following administration of endothelin‐1 or NG‐nitro‐l‐arginine methyl ester in conscious rats
Authors: Gardiner S.M. , Compton A.M. , Kemp P.A. , Bennett T. , Foulkes R. , Hughes B. 
Published: July 2012

We investigated the peripheral haemodynamic effects of human α‐calcitonin gene‐related peptide (CGRP) following administration of endothelin‐1 or NG‐nitro‐l‐arginine methyl ester (l‐NAME), an inhibitor of nitric oxide production, in conscious, chronically‐instrumented, Long Evans rats.
Infusion of endothelin‐1 (3 nmol kg−1 h−1) caused hypertension, bradycardia and renal, mesenteric and hindquarters vasoconstrictions. Co‐infusion of human α‐CGRP (1.5 nmol kg−1 h−1) reduced the hypertension and abolished the hindquarters vasoconstriction caused by endothelin‐1 but the renal and mesenteric vasoconstrictor actions of endothelin‐1 were not affected.
Infusion of human α‐CGRP (15 nmol kg−1 h−1) in the presence of endothelin‐1 caused hypotension and hyperaemic vasodilatation in the hindquarters; the mesenteric vasoconstrictor effects of endothelin‐1 were diminished, but there was only a transient reversal of the renal vasoconstrictor effects of endothelin‐1.
Pretreatment with the non‐peptide angiotensin II receptor antagonist, DuP 753 (10 mg kg−1), caused slight hypotension associated with renal, mesenteric and hindquarters vasodilatations, but DuP 753 did not affect responses to endothelin‐1 infusion. However, under these conditions co‐infusion of human α‐CGRP (15 nmol kg−1 h−1) caused a sustained reversal of the renal vasoconstrictor effects of endothelin‐1.
These results indicate that the failure of human α‐CGRP to cause sustained reversal of the renal vasoconstrictor effects of endothelin‐1 in the absence of DuP 753 was due to activation of the renin‐angiotensin system (possibly as a consequence of the hypotension).
In the second experiment, l‐NAME (10 mg kg−1) caused renal, mesenteric and hindquarters vasoconstrictions similar to those seen in the presence of endothelin‐1. However, the renal vasoconstrictor effects of l‐NAME were reversed completely by human α‐CGRP (15 nmol kg−1 h−1), even though the latter caused hypotension comparable to that seen in the presence of endothelin‐1. These results are consistent with a lack of functional activation of the renin‐angiotensin system by human α‐CGRP in the presence of l‐NAME.
The vasoconstrictor effects of l‐NAME on the hindquarters were completely reversed by infusion of human α‐CGRP, but hindquarters flow and vascular conductance did not rise above baseline levels. Hence these results indicate the hindquarters hyperaemic vasodilator effects of human α‐CGRP seen in the presence of endothelin‐1 were contributed to by nitric oxide‐mediated mechanisms.
Block of ATP‐regulated potassium channels by phentolamine and other α‐adrenoceptor antagonists
Authors: Dunne M.J. 
Published: July 2012

The patch clamp technique has been used to characterize the effects of phentolamine, an unselective blocker of α1 and α2‐adrenoceptors, on the electrical activity of isolated RINm5F insulin‐secreting cells and the gating of ATP‐regulated potassium (K+ATP) channels.
Current‐clamp experiments carried out by use of both conventional whole‐cell recordings and nystatin‐perforated cells, have demonstrated that phentolamine (5–20 μm) in the complete absence of α‐adrenoceptor agonists, caused a sharp depolarization of the cell membrane from approximately −66 mV to −42 mV. This depolarization was associated with the generation of calcium action potential‐like spikes. In the continued presence of phentolamine, diazoxide (100 μm) reversed these effects by causing a hyperpolarization of the cell, thereby preventing Ca2+ spikes.
Unitary current events from K+ATP channels were recorded from both outside‐out membrane patches and saponin permeabilized or open‐cells. When added to either the inside or the outside of the plasma membrane, phentolamine (0.1–100 μm) blocked openings from these channels. The effects of phentolamine were rapid, sustained and fully reversible. Phentolamine was apparently a more effective blocker of channels from the inside than the outside of the membrane.
The K1 value, corresponding to 50% inhibition of channels was estimated to be approximately 0.7 μm when phentolamine was added to the inside of the membrane and the Hill coefficient approximately 1.
Yohimbine (1–10 μm) and the chemically 2‐substituted imidazoline α‐adrenoceptor antagonists, antazoline (25 μm) and tolazoline (25 μm) were also found to block K+ATP channels in isolated patches of membrane.
In conclusion the present study demonstrates that phentolamine and other imidazoline adrenoceptor antagonists have effects upon ATP‐sensitive K+ channels that are not associated with stimulation of the adrenoceptor.
Kinin receptors of the central nervous system of spontaneously hypertensive rats related to the pressor response to bradykinin
Authors: Martins D.T.O. , Fior D.R. , Nakaie C.R. , Lindsey C.J. 
Published: July 2012

Kinin analogues bradykinin (BK), T‐kinin, Met‐Lys‐BK, Lys‐Lys‐BK, Des‐Arg9‐BK with agonist activity and d‐Arg0‐Hyp3‐Thi5,8‐d‐Phe7‐BK (DAHTDBK) and Arg9‐Leu8‐BK with antagonist activity were injected into the posterior portion of the fourth cerebral ventricle of unanaesthetized rats implanted with permanent cannulae and arterial pressure was measured directly from the abdominal aorta.
The spontaneously hypertensive rats (SHR) were more sensitive than normotensive Wistar rats (NWR) to the pressor effect of BK and other kinin analogues. The SHR did not differ in sensitivity of the pressor response to centrally administered angiotensin II or endothelin‐1.
Experiments with selective kinin agonists and antagonists revealed that in the SHR, as in the NWR, the receptors which mediated the central pressor response are of the BK2 subtype.
Measurements of the pressor activity of kinins with different degrees of susceptibility to degradation, as well as experiments with kininase inhibitors, enalaprilat and CPP‐Ala‐Ala‐Phe‐pAB, suggest that the kininase activity in the central nervous system of SHR is reduced in comparison to that of NWR.
The SHR also showed increased sensitivity to BK and Lys‐Lys‐BK, compared with the NWR, when the kinins were injected following the administration of a mixture of the kininase inhibitors, suggesting that mechanisms other than kininase activity may play a role in the increased sensitivity of the SHR to the central pressor action of kinins.
An in vivo characterization of the kinin receptors which mediate the central pressor response showed that the interaction with DAHTDBK was reversible and of competitive nature. The pA2 in vivo estimated for the kinin receptors of the SHR was 0.7 logarithm units larger than that obtained in the NWR.
The kinin receptors which mediate the central BK pressor effect in the SHR are of the BK2 subtype and are similar to receptors in the NWR. The increased sensitivity to kinins in the SHR may be explained, at least in part, by their decreased kininase activity. At present it is impossible to conclude whether the difference observed in the pA2 represents an increased affinity of the kinin receptors or can be attributed to differences amongst strains in the enzymatic degradation of the antagonist.
Mechanisms controlling caffeine‐induced relaxation of coronary artery of the pig
Authors: van der Bent Vincent , Bény Jean‐Louis 
Published: July 2012

We studied the effects of caffeine on coronary artery smooth muscle of the pig by measuring changes in isometric tension, cytosolic free Ca2+ concentration ([Ca2+]i) and transmembrane potential.
In the absence of tone, caffeine induced a concentration‐dependent transient contraction of coronary artery strips, followed by sustained relaxation. Simultaneously with the relaxation, caffeine, 25 mm, hyperpolarized the smooth muscle cells by 7.7 ± 0.9 mV.
Caffeine caused a concentration‐dependent relaxation of strips precontracted with 10−5 m acetylcholine (ACh). A supramaximal relaxing concentration of 25 mm caffeine produced an additional transient increase in [Ca2+]i on the Ca2+ plateau of ACh tonic contraction, which was followed by a decrease in [Ca2+]i to a level slightly below the basal concentration. This relaxation was accompanied by a hyperpolarization of 7.3 ± 0.9 mV.
KCl 120 mm (high K+) contracted the strips with a concomitant depolarization of 38.6 ± 1.6 mV and sustained increase in [Ca2+]i. Caffeine caused a concentration‐dependent relaxation of high K+‐induced contraction. Caffeine, 25 mm, decreased the Ca2+ plateau to a level that remained above the basal concentration of Ca2+ but did not change the membrane potential.
When strips were placed in a Ca2+‐free medium with EGTA 2 mm and, in addition, ACh was applied successively three times, both intracellular and extracellular mobilizable Ca2+ pools were depleted. In these conditions, phorbol 12,13 dibutyrate (PDBu) 10−7 m and prostaglandin F2α (PGF2α) 10−5 m contracted the strips. Caffeine (25 mm) inhibited these contractions with no change in [Ca2+]i.
Forskolin, 3 × 10−7 m, inhibited ACh induced‐contraction but did not affect those induced by PDBu.
In conclusion, these results show that caffeine has multiple cellular effects. During caffeine‐induced relaxation, [Ca2+]i, adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) content and membrane potential are modified. The findings suggest, however, that these effects are secondary, and that caffeine acts mainly by another unknown mechanism, possibly involving a direct inhibition of the contractile apparatus.
Characterization of a novel, hydrophilic dihydropyridine, NKY‐722, as a Ca2+ antagonist in bovine cultured adrenal chromaffin cells
Authors: Ohue Tetsuya , Lee Ken , Koshimura Kunio , Miwa Soichi 
Published: July 2012

To characterize NKY‐722, a novel hydrophilic dihydropyridine derivative, as a Ca2+ antagonist, we examined its effects on 45Ca2+ influx, intracellular free Ca2+ concentrations ([Ca2+]i), and release of noradrenaline and adrenaline in bovine cultured adrenal chromaffin cells.
NKY‐722 had little effect on basal 45Ca2+ influx into the resting cells, but inhibited high K+ (35.9 mm)‐evoked 45Ca2+ influx in a concentration‐dependent manner with an IC50 value of 5.2 nm.
NKY‐722 inhibited high K+‐evoked increases in [Ca2+]i in a concentration‐dependent manner without effect on the resting [Ca2+]i.
NKY‐722 had little effect on basal release of noradrenaline and adrenaline but inhibited high K+‐evoked release of noradrenaline and adrenaline in a concentration‐dependent manner with IC50 values of 5.0 nm and 4.8 nm, respectively.
Nicardipine, a prototype of NKY‐722, also inhibited high K+‐evoked 45Ca2+ influx and release of noradrenaline and adrenaline in a concentration‐dependent manner: the IC50 value for high K+‐evoked 45Ca2+ influx was 51 nm, and the values for high K+‐evoked release of noradrenaline and adrenaline were 52 nm and 50 nm, respectively.
These results show that NKY‐722 is a hydrophilic Ca2+ antagonist ten times more potent than nicardipine.
Thrombin‐activated platelets promote leukotriene B4 synthesis in polymorphonuclear leucocytes stimulated by physiological agonists
Authors: Palmantier Rémi , Borgeat Pierre 
Published: July 2012

The addition of 2 × 108 human platelets to 8 × 106 polymorphonuclear leucocytes (PMNL) incubated in presence of 2.5 u ml−1 thrombin and 0.1 μm N‐formyl‐Met‐Leu‐Phe (FMLP) (or C5a or PAF) led to enhancement of leukotriene B4 (LTB4) synthesis by the PMNL (measured by h.p.l.c. as 20‐hydroxy‐ and 20‐carboxy‐LTB4) from 4 ± 1 pmol (in absence of platelets) to 26 ± 4 pmol (mean ± s.e.mean, n = 9). Platelets and thrombin were both essential for the enhancement of LTB4 synthesis.
Platelets also caused enhancement of LTB4 synthesis from (30 ± 12 to 134 ± 25 pmol, n = 6) when PMNL pretreated with granulocyte‐macrophage colony‐stimulating factor were used in similar experiments.
Enhancement of LTB4 synthesis was also observed (from 5 ± 1.5 to 26.5 ± 5 pmol, n = 9) when the supernatants of thrombin‐activated platelet suspensions were added to FMLP‐stimulated PMNL.
Supernatants of platelet suspensions activated by thrombin in presence of cyclo‐oxygenase and 12‐lipoxygenase inhibitors led to greater enhancement (from 5 ± 3 to 153.5 ± 27.5 pmol, n = 3) of LTB4 synthesis by FMLP‐stimulated PMNL, suggesting that arachidonic acid itself, rather than its metabolites was responsible for the effects of platelets.
Addition of arachidonic acid to FMLP‐stimulated PMNL at a concentration comparable to that measured in thrombin‐activated platelet supernatants (0.2 ± 0.025 μm, n = 6) mimicked the effect of platelets or platelet supernatants on LTB4 synthesis in FMLP‐activated PMNL.
The present data indicate that under conditions of cell activation by physiological agonists, platelets can significantly increase the formation of the proinflammatory compound LTB4 in PMNL by providing arachidonic acid. These data lend support to the concept that platelet‐PMNL interactions could modulate the inflammatory process.
Inotropic and electrophysiological effects of BDF 9148, a congener of DPI 201–106, in guinea‐pig atria and papillary muscles
Authors: Brasch Helmut , Iven Heiko 
Published: July 2012

BDF 9148 is a newly synthesized congener of DPI 201–106 in which the piperazidinyl moiety has been replaced by an azetidine‐3‐oxy‐moiety. The inotropic effect of both drugs was studied as well as their influence on the action potential, by use of standard microelectrode techniques.
BDF 9148 increased the contractile force of guinea‐pig atria and papillary muscles. The EC50 was 1.32 × 10−7mol l−1 and 0.7 × 10−6 mol l−1 respectively. DPI 201–106 was effective in a similar concentration‐range, the EC50 being 2.6 × 10−7mol l−1 for atria and 2.8 × 10−7 mol l−1 for papillary muscles.
Both drugs caused a concentration‐dependent prolongation of the relaxation time of the isometric contraction curve. With 10−6 mol l−1 BDF 9148, the mean increase was 39.1 ± 4.4 ms in atria and 39.4 ± 7.5 ms in papillary muscles while 10−6 mol l−1 DPI 201–106 caused increases of 56.7 ± 2.5 ms and 79.3 ± 11.7 ms, respectively. The effect of BDF 9148 was not prevented by propranolol, but was reversed by 3 × 10−6 mol l−1 tetrodotoxin. Pretreatment of atria with 3 × 10−8 mol l−1 BDF shifted the concentration‐response curve of ouabain to the left and reduced the EC50 of the glycoside from 3.21 × 10−7 mol l−1 to 2 × 10−7 mol l−1.
BDF 9148 and DPI 201–106 concentration‐dependently increased the action potential duration of papillary muscles and their functional refractory period. The drugs did not modify the resting potential, the action potential amplitude or the maximum depolarization velocity.
All effects of BDF 9148 persisted after washout. The lipophilic drug accumulated in the tissues and the tissue drug concentration was little reduced by washout of BDF 9148 from the organ bath.
In contrast to DPI 201–106, which had a prominent negative chronotropic effect in right atria, BDF 9148 caused only a slight reduction of the beating frequency with the largest (3 × 10−5 mol l−1) concentration.
The results are consistent with BDF 9148 being a sodium channel activator with much weaker influence on the beating frequency than the parent compound DPI 201–106.
Desensitization and functional antagonism by β‐adrenoceptor and muscarinic receptor agonists, respectively: a comparison with receptor alkylation for calculation of apparent agonist affinity
Authors: Eglen R.M. , Montgomery W.W. , Whiting R.L. 
Published: July 2012

Apparent affinity constants (KD) for prenalterol, an agonist of low intrinsic efficacy at β1‐adrenoceptors in rat left atria, have been determined by use of receptor desensitization and functional antagonism induced by isoprenaline and carbachol, respectively. The values obtained have been compared to those values estimated with the irreversible β‐adrenoceptor antagonist, bromoacetylalprenololmenthane (BAAM).
The −log KD values for prenalterol estimated by desensitization or irreversible antagonism ranged from 6.8–7.1 and 6.2–7.1, respectively.
Carbachol produced functional antagonism of the response to prenalterol even though it was removed before addition of prenalterol. This effect was mediated by M2‐muscarinic receptors. Pretreatment of animals with pertussis toxin did not affect the functional antagonism elicited by carbachol. The apparent KD value obtained after pre‐exposure to carbachol (6.8) was similar to those estimated by use of either alkylation with BAAM or desensitization with isoprenaline (see above).
It is concluded that acute desensitization or functional antagonism of responses to agonists of low intrinsic efficacy provides a means to estimate apparent KD constants. This approach could be useful to characterize receptors for which an irreversible antagonist may not be available.
Modulation of gastric contractions in response to tachykinins and bethanechol by extrinsic nerves
Authors: Holzer‐Petsche Ulrike 
Published: July 2012

Extrinsic reflexes elicited by changes in gastric wall tension play an important role in regulating gastric tone. The present study investigated whether such reflexes modulate gastric contractions induced by close arterially administered neurokinin A (NKA), substance P (SP), SP‐methylester and bethanechol in anaesthetized rats.
Reflex pathways were acutely interrupted by either subdiaphragmatic vagotomy or prevertebral ganglionectomy. C‐fibre afferent nerve activity was abolished by pretreating rats with capsaicin 10 to 16 days before the experiments.
The order of potency in inducing gastric contractions was NKA > SP > bethanechol. SP‐methylester was markedly less effective than SP and its effects did not fit sigmoid dose‐response curves (DRCs). The maximal responses to NKA, SP, and bethanechol were similar, whilst the DRC for SP was significantly flatter than those for NKA or bethanechol. Pretreatment of the rats with the peptidase inhibitors phosphoramidon or captopril did not increase the contractile response to SP.
Prevertebral ganglionectomy had no significant effect on the DRCs for SP and NKA, whereas vagotomy shifted the DRCs for all three test substances to the left.
Capsaicin pretreatment did not change the DRC for NKA in rats with intact vagus but shifted that for bethanechol to the left. The leftward shift of the DRC for NKA caused by vagotomy was prevented in capsaicin‐pretreated rats whereas the vagotomy‐induced shift of the DRC for bethanechol remained unaltered. The shift of the DRC for SP seen in response to vagotomy was only slightly reduced by capsaicin pretreatment.
These data may be interpreted as demonstrating two neuronal mechanisms for modulating drug‐induced gastric contractions. First, the contractions themselves activate a vago‐vagal negative feedback involving capsaicin‐sensitive afferents. Second, NKA, and to a lesser degree SP, seem to induce a non‐vagal non‐splanchnic mechanism which via capsaicin‐sensitive afferent neurones reinforces tachykinin‐induced gastric contractions.
A receptor that is highly specific for extracellular ATP in developing chick skeletal muscle in vitro
Authors: Thomas Steven A. , Zawisa Mark J. , Lin Xi , Hume Richard I. 
Published: July 2012

Extracellular adenosine 5′‐triphosphate (ATP) activated an early excitatory conductance followed by a late potassium conductance in developing chick skeletal muscle. A series of ATP analogues were tested for their ability to activate these two conductances. All compounds tested were either agonists for both responses or for neither. Furthermore, the potency of agonists was similar for the two responses.
The order of potency for agonists was ATP ≅ adenosine 5′‐O‐(3‐thio triphosphate) (ATP‐γ‐S) ≅ 2‐methylthio‐ATP (2‐CH3S‐ATP) > 2′‐deoxy‐ATP ≅ 3′‐deoxy‐ATP > adenosine 5′‐tetraphosphate (ATP‐OPO3) ≅ adenosine 5′‐diphosphate (ADP). Many other ATP analogues were not agonists.
Activation of the excitatory response did not require divalent cations. Furthermore, the concentration‐response relation of the excitatory response was similar when ATP was applied as the free anion of ATP (ATP4‐) or complexed with a divalent cation (M · ATP2‐).
Three antagonists of the ATP response were characterized. 8‐Br‐ATP was a weak antagonist, while 2′,3′‐dialdehyde‐ATP and DIDS (4,4′‐diisocyanatostilbene‐2,2′‐disulphonic acid) were potent irreversible inhibitors. The two conductances were equally affected by these antagonists.
These results suggest that both ATP responses are activated through the same receptor type, or two very similar receptors.