bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atriopeptin, sodium azide and cyclic GMP reduce secretion of aqueous humour and inhibit intracellular calcium release in bovine cultured ciliary epithelium
Authors: Shahidullah Mohammad , Wilson William S 
Published: January 2005

This study examined the involvement of cyclic GMP, protein kinase G and intracellular Ca2+ movements in the modulation of aqueous humour formation.
Using the bovine arterially‐perfused eye preparation, drug effects on intraocular pressure and aqueous humour formation rate were measured by manometry and fluorescein dilution, respectively. Drug effects on intracellular [Ca2+] were determined by fura‐2 fluorescence ratio technique in non‐transformed, cultured ciliary epithelium.
Intra‐arterial injection of atriopeptin (50 pmol) or sodium azide (10 nmol) produced significant reduction in aqueous humour formation (>38%). This was blocked by selective inhibition (KT‐5823) of protein kinase G, but not by selective inhibition (KT‐5720) of protein kinase A. Reductions of intraocular pressure produced by atriopeptin or azide were almost completely blocked by KT‐5823.
ATP (100 μM) caused rapid, transient increase in intracellular Ca2+ followed by a slow decline and prolonged plateau. This response showed concentration‐dependent inhibition by atriopeptin, azide or 8‐bromo cyclic GMP, and this inhibition of the rapid (peak) Ca2+ increase was enhanced by zaprinast (100 μM; phosphodiesterase inhibitor). KT‐5823 blocked the suppression of the peak Ca2+ response but not suppression of the plateau.
Arterial perfusion of ATP (0.1–100 μM) produced a concentration‐dependent decrease in aqueous humour formation.
Aqueous humour formation in the bovine eye can be manipulated through cyclic GMP, operating via protein kinase G. Close parallels appear when Ca2+ movements are modified by similar manipulations of cyclic GMP, suggesting that Ca2+ transients may play an important role in aqueous humour formation and that interplay occurs between cyclic GMP and Ca2+.

British Journal of Pharmacology (1999) 127, 1438–1446; doi:10.1038/sj.bjp.0702681
Spinal effect of a neuropeptide FF analogue on hyperalgesia and morphine‐induced analgesia in mononeuropathic and diabetic rats
Authors: Courteix Christine , Coudoré‐Civiale Marie‐Ange , Privat Anne‐Marie , Zajac Jean‐Marie , Eschalier Alain , Fialip Joseph 
Published: January 2005

1DMe, a neuropeptide FF (NPFF) analogue, has been shown to produce antinociception and to enhance morphine analgesia in rats after intrathecal administration. To determine whether 1DMe could correct hyperalgesia and restore morphine efficacy in mononeuropathic (MN) and diabetic (D) rats we examined the spinal effect of 1DMe in MN and D rats without and after spinal blockade of μ‐ and δ‐opioid receptors with CTOP and naltrindole, respectively. The influence of 1DMe on morphine‐induced antinociception was assessed in the two models using isobolographic analysis.
Whereas 1DMe intrathecally injected (0.1, 1, 7.5 μg rat−1) was ineffective in normal (N) rats, it suppressed mechanical hyperalgesia (decrease in paw pressure‐induced vocalisation thresholds) in both MN and D rats. This effect was completely cancelled by CTOP (10 μg rat−1) and naltrindole (1 μg rat−1) suggesting that it requires the simultaneous availability of μ‐ and δ‐opioid receptors.
The combinations of morphine : 1DMe (80.6 : 19.4% and 99.8 : 0.2%, in MN and D rats, respectively) followed by isobolographic analysis, showed a superadditive interaction, relative to the antinociceptive effect of single doses, in D rats only. In N rats, the combination of morphine : 1DMe (0.5 mg kg−1, i.v.: 1 μg rat−1, i.t., ineffective doses) resulted in a weak short‐lasting antinociceptive effect.
These results show a different efficacy of 1DMe according to the pain model used, suggesting that the pro‐opioid effects of the NPFF in neuropathic pain are only weak, which should contribute to hyperalgesia and to the impaired efficacy of morphine.

British Journal of Pharmacology (1999) 127, 1454–1462; doi:10.1038/sj.bjp.0702682
Involvement of 5‐HT1B receptors in collar‐induced hypersensitivity to 5‐hydroxytryptamine of the rabbit carotid artery
Authors: Geerts Inge S , Matthys Katelijne E , Herman Arnold G , Bult Hidde 
Published: January 2005

In humans intimal thickening is a prerequisite of atherosclerosis. Application of a silicone collar around the rabbit carotid artery induces an intimal thickening but in addition it increases the sensitivity to the vasoconstrictor action of serotonin (5‐hydroxytryptamine, 5‐HT). The 5‐HT receptors involved in collar‐induced hypersensitivity to 5‐HT were investigated using several agonists and antagonists.
One week after placement of collars around both carotid arteries of anaesthetized rabbits, rings (2 mm width) from inside (=collar) and outside (=sham) the collars were mounted in organ baths (10 ml) for isometric force measurements at 6 g loading tension.
Collared rings were more sensitive to the contractile effect of 5‐HT (7.6 fold) and 5‐carboxamidotryptamine (31 fold, 5‐CT, 5‐HT1 agonist) in cumulative concentration response curves. Sumatriptan (5‐HT1B/1D agonist) caused concentration‐dependent constrictions in collared rings only.
Collar placement did not significantly alter pA2 values (Schild regression) or apparent pKb values (non‐linear regression) of spiperone and methysergide (mixed 5‐HT2A/5‐HT1 antagonists) or ketanserin and ritanserin (5‐HT2A antagonists), indicating unchanged binding characteristics of the 5‐HT2A receptor. However, the reduced slope of the Schild regression pointed to a heterogeneous receptor population in collared rings.
In contrast, the apparent pKb value of methiothepin (5‐HT1B antagonist) was significantly reduced by collar placement, and its antagonism shifted from non‐surmountable in sham rings to surmountable in collared segments.
Taken together, this study demonstrates that the serotonergic receptor involved in the hypersensitivity to 5‐HT of rabbit collared carotid artery is a 5‐HT1B receptor subtype.

British Journal of Pharmacology (1999) 127, 1327–1336; doi:10.1038/sj.bjp.0702684
Antagonist activities of mecamylamine and nicotine show reciprocal dependence on beta subunit sequence in the second transmembrane domain
Authors: Webster J Christopher , Francis Michael M , Porter Julia K , Robinson Gillian , Stokes Clare , Horenstein Ben , Papke Roger L 
Published: January 2005

We show that a portion of the TM2 domain regulates the sensitivity of beta subunit‐containing rat neuronal nicotinic AChR to the ganglionic blocker mecamylamine, such that the substitution of 4 amino acids of the muscle beta subunit sequence into the neuronal beta4 sequence decreases the potency of mecamylamine by a factor of 200 and eliminates any long‐term effects of this drug on receptor function.
The same exchange of sequence that decreases inhibition by mecamylamine produces a comparable potentiation of long‐term inhibition by nicotine.
Inhibition by mecamylamine is voltage‐dependent, suggesting a direct interaction of mecamylamine with sequence elements within the membrane field. We have previously shown that sensitivity to TMP (tetramethylpiperidine) inhibitors is controlled by the same sequence elements that determine mecamylamine sensitivity. However, inhibition by bis‐TMP compounds is independent of voltage.
Our experiments did not show any influence of voltage on the inhibition of chimeric receptors by nicotine, suggesting that the inhibitory effects of nicotine are mediated by binding to a site outside the membrane's electric field.
An analysis of point mutations indicates that the residues at the 6′ position within the beta subunit TM2 domain may be important for determining the effects of both mecamylamine and nicotine in a reciprocal manner. Single mutations at the 10′ position are not sufficient to produce effects, but 6′ 10′ double mutants show more effect than do the 6′ single mutants.

British Journal of Pharmacology (1999) 127, 1337–1348; doi:10.1038/sj.bjp.0702686
Mutation at the putative GABAA ion‐channel gate reveals changes in allosteric modulation
Authors: Thompson Sally‐Anne , Smith Maria Z , Wingrove Peter B , Whiting Paul J , Wafford Keith A 
Published: January 2005

We have mutated a conserved leucine in the putative membrane‐spanning domain to serine in human GABAA β2 and investigated the actions of a number of GABAA agonists, antagonists and modulators on human α1β2ΔL259Sγ2s compared to wild type α1β2γ2s GABAA receptors, expressed in Xenopus oocytes.
The mutation resulted in smaller maximum currents to γ‐aminobutyric acid (GABA) compared to α1β2γ2s receptors, and large leak currents resulting from spontaneous channel opening. As reported, this mutation significantly decreased the GABA EC50 (110 fold), and reduced desensitization. Muscimol and the partial agonists 4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol (THIP) and piperidine‐4‐sulphonic acid (P4S) also displayed a decrease in EC50.
In addition to competitively shifting GABA concentration response curves, the antagonists bicuculline and SR95531 both inhibited the spontaneous channel activity on α1β2ΔL259Sγ2s receptors, with different degrees of maximum inhibition.
The effects of a range of allosteric modulators, including benzodiazepines and anaesthetics were examined on a submaximal GABA concentration (EC20). Compared to wild type, none of these modulators potentiated the EC20 response of α1β2ΔL259Sγ2s receptors, however they all directly activated the receptor in the absence of GABA.
To conclude, the above mutation resulted in receptors which exhibit a degree of spontaneous activity, and are more sensitive to agonists. Benzodiazepines and other agents modulate constitutive activity, but positive modulation of GABA is lost. The competitive antagonists bicuculline and SR95531 can also act as allosteric channel modulators through the same GABA binding site.

British Journal of Pharmacology (1999) 127, 1349–1358; doi:10.1038/sj.bjp.0702687
Involvement of thromboxane A2 in the endothelium‐dependent contractions induced by myricetin in rat isolated aorta
Authors: Jiménez Rosario , Andriambeloson Emile , Duarte Juan , Andriantsitohaina Ramaroson , Jiménez José , Pérez‐Vizcaino Francisco , Zarzuelo Antonio , Tamargo Juan 
Published: January 2005

The present study was undertaken to analyse the mechanism of the contractile response induced by the bioflavonoid myricetin in isolated rat aortic rings.
Myricetin induced endothelium‐dependent contractile responses (maximal value=21±2% of the response induced by 80 mM KCl and pD2=5.12±0.03). This effect developed slowly, reached a peak within 6 min and then declined progressively.
Myricetin‐induced contractions were almost abolished by the phospholipase A2 (PLA2) inhibitor, quinacrine (10 μM), the cyclo‐oxygenase inhibitor, indomethacin (10 μM), the thromboxane synthase inhibitor, dazoxiben (100 μM), the putative thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor antagonist, ifetroban (3 μM). These contractions were abolished in Ca2+‐free medium but were not affected by the Ca2+ channel blocker verapamil (10 μM).
In cultured bovine endothelial cells (BAEC), myricetin (50 μM) produced an increase in cytosolic free calcium ([Ca2+]i) which peaked within 1 min and remained sustained for 6 min, as determined by the fluorescent probe fura 2. This rise in [Ca2+]i was abolished after removal of extracellular Ca2+ in the medium.
Myricetin (50 μM) significantly increased TXB2 production both in aortic rings with and without endothelium and in BAEC. These increases were abolished both by Ca2+‐free media and by indomethacin.
Taken together, these results suggests that myricetin stimulates Ca2+ influx and subsequently triggers the activation of the PLA2 and cyclo‐oxygenase pathways releasing TXA2 from the endothelium to contract rat aortic rings. The latter response occurs via the activation of Tp receptors on vascular smooth muscle cells.

British Journal of Pharmacology (1999) 127, 1539–1544; doi:10.1038/sj.bjp.0702694
Effects of exercise training on responsiveness of the mesenteric arterial bed to phenylephrine and KCl in male rats
Authors: Jansakul C , Hirunpan P 
Published: January 2005

We aimed to determine whether there are any changes in responsiveness of the mesenteric arterial beds to phenylephrine (Phe) and KCl in exercise‐trained rats, and whether vascular endothelium and/or vascular smooth muscle play a role in these changes.
Adult male rats were subjected to a swimming schedule every day for 28–33 days. Studies were performed in vitro using Krebs perfused mesenteric arterial beds.
Maximum perfusion pressure responses to KCl and Phe of the mesenteric arterial beds from exercise‐trained rats were significantly lower than those from sedentary controls. However, these differences disappeared after blocking the nitric oxide synthase by NG‐nitro‐L‐arginine (L‐NOARG).
3‐[(3‐cholamidopropyl)‐dimethylammonio]‐1‐propanesulphonate (CHAPS, 3 mg ml−1, 2 min infusion) caused a significant increase in maximum perfusion pressure responses to KCl to the same extent in both exercise‐trained and sedentary control rats. CHAPS caused about a 4.5 fold leftward shift of the curve with no change in maximum response to Phe for the mesenteric arterial beds from sedentary control rats, but not for those obtained from exercise‐trained rats. However, these differences were abolished in the presence of L‐NOARG.
Indomethacin did not alter the dose‐response curves to KCl or Phe in either swimming or control groups.
These results suggest that there was a lower vascular responsiveness to KCl and Phe in exercise‐trained rats at rest. The decrease in reactivities to KCl or decrease in sensitivity to Phe after having endothelium impairment by CHAPS of the mesenteric arterial beds of exercise‐trained rats were due to an increase in both spontaneous release and upregulation of phenylephrine‐stimulated release of nitric oxide from both the vascular endothelium and the vascular smooth muscle cells, and may not be a consequence of an increase in vasodilator prostaglandins by the vascular bed.

British Journal of Pharmacology (1999) 127, 1559–1566; doi:10.1038/sj.bjp.0702697
Nociceptin‐induced scratching, biting and licking in mice: involvement of spinal NK1 receptors
Authors: Sakurada Tsukasa , Katsuyama Sou , Sakurada Shinobu , Inoue Makoto , Tan‐No Koichi , Kisara Kensuke , Sakurada Chikai , Ueda Hiroshi , Sasaki Jun 
Published: January 2005

Intrathecal (i.t.) injection of nociceptin at small doses (fmol order) elicited a behavioural response consisting of scratching, biting and licking in conscious mice. Here we have examined the involvement of substance P‐containing neurons by using i.t. injection of tachykinin neurokinin (NK)1 receptor antagonists and substance P (SP) antiserum.
Nociceptin‐induced behavioural response was evoked significantly 5–10 min after i.t. injection and reached a maximum at 10–15 min. Dose‐dependency of the induced response showed a bell‐shaped pattern from 0.375–30.0 fmol, and the maximum effect was observed at 3.0 fmol.
The behavioural response elicited by nociceptin (3.0 fmol) was dose‐dependently inhibited by intraperitoneal (i.p.) administration of morphine.
The NK1 receptor antagonists, CP‐96,345, CP‐99,994 and sendide, inhibited nociceptin‐induced behavioural response in a dose‐dependent manner. A significant antagonistic effect of [D‐Phe7, D‐His9]SP (6–11), a selective antagonist for SP receptors, was observed against nociceptin‐induced response. The NK2 receptor antagonist, MEN‐10376, had no effect on the response elicited by nociceptin.
Pretreatment with SP antiserum resulted in a significant reduction of the response to nociceptin. No significant reduction of nociceptin‐induced response was detected in mice pretreated with NKA antiserum.
The N‐methyl‐D‐aspartate (NMDA) receptor antagonists, dizocilpine (MK‐801) and D(−)‐2‐amino‐5‐phosphonovaleric acid (APV) (D‐APV), and L‐NG‐nitro arginine methyl ester (L‐NAME), a nitric oxide (NO) synthase inhibitor, failed to inhibit nociceptin‐induced behavioural response.
The present results suggest that SP‐containing neurons in the mouse spinal cord may be involved in elicitation of scratching, biting and licking behaviour following i.t. injection of nociceptin.

British Journal of Pharmacology (1999) 127, 1712–1718; doi:10.1038/sj.bjp.0702698
Anisatin modulation of the γ‐aminobutyric acid receptor‐channel in rat dorsal root ganglion neurons
Authors: Ikeda Tomoko , Ozoe Yoshihisa , Okuyama Emi , Nagata Keiichi , Honda Hiroshi , Shono Toshio , Narahashi Toshio 
Published: January 2005

Anisatin, a toxic, insecticidally active component of Sikimi plant, is known to act on the GABA system. In order to elucidate the mechanism of anisatin interaction with the GABA system, whole‐cell and single‐channel patch clamp experiments were performed with rat dorsal root ganglion neurons in primary culture.
Repeated co‐applications of GABA and anisatin suppressed GABA‐induced whole‐cell currents with an EC50 of 1.10 μM. No recovery of currents was observed after washout with anisatin‐free solution.
However, pre‐application of anisatin through the bath had no effect on GABA‐induced currents. The decay phase of currents was accelerated by anisatin. These results indicate that anisatin suppression of GABA‐induced currents requires opening of the channels and is use‐dependent.
Anisatin suppression of GABA‐induced currents was not voltage dependent.
Picrotoxinin attenuated anisatin suppression of GABA‐induced currents. [3H]‐EBOB binding to rat brain membranes was competitively inhibited by anisatin. These data indicated that anisatin bound to the picrotoxinin site.
At the single‐channel level, anisatin did not alter the open time but prolonged the closed time. The burst duration was reduced and channel openings per burst were decreased indicating that anisatin decreased the probability of openings.

British Journal of Pharmacology (1999) 127, 1567–1576; doi:10.1038/sj.bjp.0702700
Effects of propranolol treatment on left ventricular function and intracellular calcium regulation in rats with postinfarction heart failure
Authors: Litwin Sheldon E , Katz Sarah E , Morgan James P , Douglas Pamela S 
Published: January 2005

Chronic treatment with beta‐adrenergic blocking agents can improve survival in patients with heart failure. The mechanisms underlying the beneficial effects and whether these effects are generalizable to ischaemic heart failure are unresolved.
We performed echocardiographic‐Doppler examinations in rats (n=28) 1 and 6 weeks after myocardial infarction (MI) or sham surgery. Rats were randomized to no treatment or propranolol (500 mg/l in drinking water) after the first echocardiogram. Isometric contractions and intracellular Ca transients were recorded simultaneously in noninfarcted left ventricular (LV) papillary muscles.
Untreated MI rats had significant LV dilatation (10.6±0.4* vs 8.9±0.3 mm, MI vs control), impaired systolic function (fractional shortening=11±2* vs 38±2%), and a restrictive LV diastolic filling pattern. MI rats receiving propranolol had similar LV chamber sizes (10.6±0.5 mm) and systolic function (13±2%). The propranolol treated animals had higher LV end‐diastolic pressures (27±2* vs 20±3 mmHg) and a more restricted LV diastolic filling pattern (increased ratio of early to late filling velocities and more rapid E wave deceleration rate). Contractility of papillary muscles from untreated MI rats was depressed (1.6±0.3 vs 2.4±0.5 g mm−2). In addition, Ca transients were prolonged and the inotropic response to isoproterenol was blunted. Propranolol treatment did not improve force development (1.6±0.3 g mm−2) or the duration of Ca transients during isoproterenol stimulation.
Chronic propranolol treatment in rats with postinfarction heart failure did not improve LV remodeling or systolic function. LV diastolic pressures and filling patterns were worsened by propranolol. Treatment also did not produce appreciable improvement in contractility, intracellular Ca regulation or beta‐adrenergic responsiveness in the noninfarcted myocardium.

British Journal of Pharmacology (1999) 127, 1671–1679; doi:10.1038/sj.bjp.0702701
Pharmacological characterization of β‐adrenoceptors mediating relaxation of the rat urinary bladder in vitro
Authors: Longhurst Penelope A , Levendusky Mark 
Published: January 2005

Isoproterenol relaxed KCl‐precontracted rat bladder strips with a pD2 of 7.21 leaving a residual contractile response of 3.2% after 30 μM. The selective β1‐agonist, T‐0509 (pD2 : 6.24, 10.1% residual contraction after 100 μM), β2‐agonist, terbutaline (pD2 : 5.43, 13.7% residual contraction after 100 μM), and β3‐agonists, BRL 37344A (pD2 : 6.60, 17.3% residual contraction after 100 μM), and SR 58611A (pD2 : 5.15, 34.0% residual contraction after 100 μM), also relaxed bladder strips.
The relaxant response to isoproterenol was weakly but significantly antagonized by 1 μM propranolol which produced a 3 fold shift of the concentration‐response curve to the right, and significantly antagonized by the β1‐selective antagonist, metoprolol (10 μM, 3 fold shift), and the β2‐selective antagonist, butoxamine (100 μM, 6 fold shift). A combination of 10 μM metoprolol and 100 μM butoxamine caused a 15 fold shift of the concentration‐response curve for isoproterenol to the right. Incubation with the β3‐antagonist, SR 59230A (1 μM), caused a 6 fold shift of the concentration response curve for isoproterenol to the right.
The non‐conventional partial agonist, CGP 12177A, weakly relaxed KCl‐precontracted bladder strips (pD2 : 3.31, 51.3% residual contraction after 300 μM); the relaxation was resistant to blockade by 1 or 10 μM propranolol.
In the presence of 200 μM propranolol, CGP 12177A (20 μM) or SR 59230A (10 μM) antagonized surmountably the relaxant effects of BRL 37344A.
The data suggest that rat urinary bladder body contains β1, β2, and β3‐adrenoceptors, all of which mediate relaxation.

British Journal of Pharmacology (1999) 127, 1744–1750; doi:10.1038/sj.bjp.0702709
Effects of nociceptin and nocistatin on antidromic vasodilatation in hairless skin of the rat hindlimb in vivo
Authors: Häbler H ‐J , Timmermann L , Stegmann J ‐U , Jänig W 
Published: January 2005

We tested whether nociceptin (NCE), the endogenous ligand of the opioid receptor‐like 1 (ORL1) receptor, and nocistatin (NST), which reverses central NCE effects when applied intrathecally (i.t.), affect small‐diameter afferent fibre‐mediated vasodilatation in rat hairless skin.
Female Wistar rats were vagotomized. Ongoing sympathetic vasoconstrictor activity was abolished by bilateral section of the lumbar sympathetic trunk between ganglia L2 and L3. Sensory axons were selectively stimulated in the dorsal root L5 by 20 electrical impulses supramaximal for activating C‐fibres at 1 Hz. Blood flow was measured on the plantar skin of the left hind paw in the L5 dermatome using laser Doppler flowmetry.
NCE injected intravenously (i.v.) as single boluses (1, 10 and 100 nmol kg−1) 7–8 min before dorsal root stimulation (n=6) dose‐dependently decreased blood pressure and local vascular resistance and suppressed antidromic vasodilatation maximally by 47% (P<0.01). When NCE was injected 2 min before stimulation (n=3), antidromic vasodilatation was reduced by 64% after NCE (1 nmol kg−1) and totally, or almost totally, abolished after the two higher doses.
NST (1–100 nmol kg−1 i.v., n=6) was without significant effect on blood pressure and cutaneous vascular resistance. Applied 5 (n=6) or 2 min (n=3) before stimulation it also did not affect antidromic vasodilatation. NST (100 nmol kg−1 i.v.) applied shortly before an equimolar dose of NCE did not antagonize NCE effects on vascular resistance, blood pressure and antidromic vasodilatation (n=4).
In conclusion, NCE inhibits antidromic vasodilatation, a component of neurogenic inflammation, in rat skin while NST is without effect. NST, at the small‐diameter sensory ending, is not an effective antagonist of NCE.

British Journal of Pharmacology (1999) 127, 1719–1727; doi:10.1038/sj.bjp.0702712