bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acceleration by chronic treatment with clorgyline of the turnover of brain α2‐adrenoceptors in normotensive but not in spontaneously hypertensive rats
Authors: Ribas Catalina , Miralles Antonio , García‐Sevilla Jesús A. 
Published: July 2012

The aim of this study was to quantitate and compare the turnover of α2‐adrenoceptors in the cerebral cortex of normotensive Wistar‐Kyoto (WKY) and spontaneously hypertensive (SHR) rats, and its modulation during chronic treatment with the monoamine oxidase (MAO) inhibitor, clorgyline.
In SHR, the specific binding of the agonist [3H]‐UK 14304 and of the antagonist [3H]‐RX 821002 was significantly reduced in the brain (Bmax 15–19% lower) as compared to that in sex‐ and age‐matched WKY rats. In contrast, no significant changes in the Kd values for both radioligands were found between WKY and SHR rats. Therefore, SHR rats offer a genetic model with a lower density of α2‐adrenoceptors in the brain.
Chronic treatment (21–35 days) with clorgyline (1 mg kg−1, i.p.) markedly decreased the density of brain α2‐adrenoceptors ([3H]‐UK 14304 binding) in Sprague‐Dawley (Bmax reduced by 50%) and in WKY (Bmax reduced by 30%) rats without any apparent change in the affinity of the radioligand. In contrast, the density of brain α2‐adrenoceptors in SHR was not down‐regulated by chronic clorgyline treatment.
The recovery of [3H]‐UK 14304 binding after irreversible inactivation by N‐ethoxycarbonyl‐2‐ethoxy‐1,2‐dihydroquinoline (EEDQ; 1.6 mg kg−1) (an alkylating agent for the α2‐adrenoceptor) was assessed in control and clorgyline‐treated (1 mg kg−1; i.p. for 7–21 days) WKY and SHR rats to study the process of α2‐adrenoceptor repopulation and to calculate receptor turnover parameters.
The simultaneous analysis of receptor recovery curves revealed that the turnover of brain α2‐adrenoceptors in SHR rats was accelerated (k = 0.141 day−1; t1/2 = 4.9 days; r/k = 40 fmol mg−1 protein) compared to that in WKY rats (k = 0.085 day−1; t1/2 = 8.1 days; r/k = 54 fmol mg−1 protein) and that the reduced density of cortical α2‐adrenoceptors (Bmax or r/k values) in SHR was probably due to an abnormal higher receptor degradation (Δk = 66%) and not to a decreased receptor synthesis which in fact showed a slight increase (Δr = 24%).
Treatment with clorgyline (1 mg kg−1, i.p. for 21 days) accelerated the turnover of brain α2‐adrenoceptors in WKY rats (k = 0.328 days−1; t1/2 = 2.1 days; r/k = 29 fmol mg−1 protein) and the greater increase in receptor degradation (Δk = 286%) over receptor synthesis (Δr = 109%) led to down‐regulation of receptor density (r/k = 46% lower). In contrast, treatment with clorgyline did not modify significantly the turnover of brain α2‐adrenoceptors in SHR (k = 0.192 days−1; t1/2 = 3.6 days; r/k = 39 fmol mg−1 protein), indicating that in this genetic model of hypertension, the desensitized α2‐adrenoceptors cannot be further down‐regulated by clorgyline treatment and that they lack the expected adaptative increase in receptor synthesis.
Leukotriene D4‐ and prostaglandin F2α‐induced airflow obstruction and airway plasma exudation in guinea‐pig: role of thromboxane and its receptor
Authors: Arakawa Hirokazu , Lötvall Jan , Kawikova Ivana , Löfdahl Claes‐Göran , Skoogh Bengt‐Eric 
Published: July 2012

We studied the effects of a thromboxane A2 receptor (TP receptor) antagonist, ICI‐192,605 (0.5 mg kg−1, i.v.) and a selective thromboxane (Tx) synthetase inhibitor, OKY‐046 (30 mg kg−1, i.v.), on airway responses induced by leukotriene D4 (LTD4; 0.2 nmol) or prostaglandin F2α (PGF2α; 20 nmol) instilled via the airways route to anaesthetized guinea‐pigs. For a comparison, airway responses to a TxA2‐mimetic, U‐46619 (0.02 nmol) were also studied. We measured both lung resistance (RL) to monitor airflow obstruction, and extravasation of Evans Blue dye to quantify airway plasma exudation.
Instilled LTD4 into the tracheal lumen induced an immediate peak and subsequently persistent increase in RL and produced a large amount of extravasation of Evans Blue dye at all airway levels. Both ICI‐192,605 and OKY‐046 significantly attenuated the persistent increase in RL following the immediate response and reduced LTD4‐induced extravasation of Evans Blue dye in the trachea and proximal intrapulmonary airway. Instilled LTD4 produced significant increases in immunoreactive TxB2 in bronchoalveolar lavage fluid obtained 1.5 min after instillation of LTD4.
Instilled PGF2α into the tracheal lumen induced an immediate increase in RL which peaked at approximately 15 s. We also observed a delayed sustained increase in RL, reaching a second peak at approximately 4 min. PGF2α produced small but significant increases in the amount of Evans Blue dye at all airway levels. As with PGF2α, instillation of U‐46619 produced a biphasic increase in RL and extravasation of Evans Blue dye. The potency of PGF2α in inducing these airway responses was about 1000 times less than U‐46619. ICI‐192,605 abolished both the immediate and the delayed increase in RL after PGF2α, and also blocked PGF2α‐induced extravasation of Evans Blue dye. However, OKY‐046 had no inhibitory effects on these responses.
We conclude that airflow obstruction and airway plasma exudation induced by instilled LTD4 is, in part, mediated via TxA2 generation and subsequent activation of TP‐receptors. On the other hand, instilled PGF2α, while inducing similar responses, does so primarily by direct activation of TP receptors, rather than via TxA2 generation.
Kinetics of rate‐dependent slowing of intraventricular conduction by the class Ib antiarrhythmic agent tocainide in vivo
Authors: Todt Hannes , Zojer Niklas , Raberger Gerhard 
Published: July 2012

The effects of the class I antiarrhythmic agent, tocainide, on intraventricular conduction were assessed in guinea‐pigs, anaesthetized with pentobarbitone sodium 60 mg kg−1, i.p.
After electrical ablation of the sinus node, heart rate was controlled by atrial pacing. His bundle electrograms were recorded by means of an epicardial bipolar electrode.
During continuous stimulation, comparison of HV intervals measured at a cycle length of 475 ms, with HV intervals measured at a cycle length of 250 ms yielded the following results: 25.26 ± 0.64 ms versus 25.02 ± 0.70 ms (NS), at baseline, 26.65 ± 0.80 ms versus 29.881 1.13 ms (P < 0.001) after i.v. administration of 30 mg kg−1 tocainide, and 28.04 ± 0.64 ms versus 36.24 ± 1.31 ms (P < 0.001), after addition of 20 mg kg−1 tocainide. Thus, tocainide caused HV intervals to increase in a strictly rate‐dependent fashion.
In order to characterize the rate‐dependent class I activity of tocainide in terms of its binding kinetics to sodium channels, fractional sodium channel block was estimated from drug induced reductions of intraventricular conduction velocity (Δθ). On abruptly changing the drive cycle length from 500 ms to 250 ms, Δθ reached a new steady state with rate constants of 1.23 ± 0.09 beat−1 and 1.28 ± 0.09 beat−1, after administration of 30 mg kg−1 and addition of 20 mg kg−1 tocainide, respectively. At a basic drive cycle length of 250 ms Δθ recovered with time constants of 250.29 ± 23.32 ms and 183.04 ± 8.03 ms after administration of 30 mg kg−1 and addition of 20 mg kg−1 tocainide, respectively.
The experimentally determined kinetic parameters were implemented into a mathematical model that assumes drug binding to sodium channels in terms of a periodical two‐state process. Rate‐dependent reductions in conduction velocity during continuous stimulation after administration of tocainide were closely approximated by steady state reductions in sodium channel availability as calculated on the basis of the aforementioned model.
In agreement with previously published in vitro studies, our data, obtained in vivo, confirm the classification of tocainide as a class I antiarrhythmic agent with fast onset and offset kinetics. The kinetic parameters obtained in vivo can be used in order to predict steady state reductions in conduction velocity at a wide range of frequencies.
Evidence for participation of B1 and B2 kinin receptors in formalin‐induced nociceptive response in the mouse
Authors: Corrêa Clóvis R. , Calixto João B. 
Published: July 2012

This study was designed to investigate the role of bradykinin (BK), as well as the subtype of BK receptors involved, in formalin‐induced hindpaw pain in the mouse by use of selective B1 and B2 receptor antagonists. In addition, we have analysed whether or not BK may be involved in formalin‐induced hindpaw oedema in the mouse.
The pretreatment of animals with captopril (2 and 5 mg kg−1, s.c.) significantly increase the first and the second phases of formalin‐induced pain.
Co‐injection of the selective B1 receptor antagonist des‐Arg9[Leu8]‐BK (0.2–0.4 nmol/paw), together with formalin, caused graded and similar inhibitions of both phases of formalin‐induced pain. Similar results were obtained with the B2 antagonists NPC 349 (d‐Arg[Hyp3,Thi5,8‐d‐Phe7]‐BK) and NPC 567 (d‐Arg[Hyp3, d‐Phe7]‐BK) (0.2 and 0.6 nmol/paw). Higher concentrations of these antagonists (1 nmol/paw) failed to antagonize formalin‐induced pain.
The new potent and selective B2 receptor antagonists, Hoe 140 (d‐Arg[Hyp3,Thi5,d‐Tic7,Oic8]‐BK), NPC 17731 (d‐Arg[Hyp3, trans‐4‐propoxy‐d‐proline (transpropyl)7, Oic8]‐BK), and NPC 17761 (d‐Arg[Hyp3, trans‐4‐propoxy‐d‐proline (trans thiophenyl)7, Oic8]‐BK) (0.02 to 1.0 nmol/paw), also caused significant inhibitions of both phases of formalin‐induced pain. When Hoe 140 was injected subcutaneously 30 min before formalin injection (9.9 and 99 nmol kg−1), it significantly attenuated both phases of formalin‐induced pain. The putative non‐peptide BK antagonist, MV 8612 (1.6 to 9.6 nmol/paw), but not MV 8608 (5.5 to 33 nmol/paw), caused a graded inhibition of both phases of formalin‐induced pain, being, however, more active against the first phase.
The pretreatment of animals with morphine (2.6 to 13μmol kg−1, s.c.) caused dose‐dependent and equipotent inhibitions of both phases of formalin‐induced pain. In contrast, indomethacin (2.7 to 27 μmol kg−1) antagonized only the second phase of formalin‐induced pain.
The B2 receptor antagonists, Hoe 140, NPC 17731, NPC 17761, NPC 349 and NPC 567, all caused a significant inhibition of formalin‐induced hindpaw oedema. A similar inhibition was also observed with indomethacin but not with captopril or morphine.
Our results provide strong evidence for the important role of endogenous BK, acting through both B1 and B2 receptors, in the genesis of both phases of formalin‐induced persistent pain in the mouse. In addition, the current results also demonstrate that the inflammatory oedema associated with the later phase of formalin‐induced pain seems to be mediated by endogenous BK, via activation of B2 receptors.
Interaction of nitric oxide and salivary gland epidermal growth factor in the modulation of rat gastric mucosal integrity
Authors: Tepperman B.L. , Soper B.D. 
Published: July 2012

The interaction between endogenous nitric oxide (NO) and factors from the rat submandibular salivary gland such as epidermal growth factor (EGF) on gastric mucosal integrity in the rat has been investigated.
Bolus administration of the NO synthase inhibitor, NG nitro‐l‐arginine methyl ester (l‐NAME; 6.25–50 mg kg−1, i.v.) to animals treated intraluminally with 0.15 n HCl resulted in a significant increase in the area of mucosal haemorrhagic damage at doses 12.5 and 50 mg kg−1. Concurrent administration of indomethacin (5 mg kg−1, i.v.) resulted in a significant haemorrhagic mucosal damage in response to l‐NAME (12.5–50 mg kg−1). Administration of the highest dose of l‐NAME resulted in an increase in histological damage to the rat gastric mucosa.
When compared to control animals, the extent of damage produced by l‐NAME or l‐NAME in combination with indomethacin was significantly exacerbated in rats which had been sialoadenectomized (SALX) by removal of the submandibular salivary glands. The mucosal damage in SALX rats was ameliorated by treatment with EGF (5 and 10 μg kg−1, i.v.).
l‐NAME administration resulted in a small reduction of gastric mucosal blood flow as assessed by laser Doppler flowmetry (LDF). The reduction in LDF by 25 and 50 mg kg−1 l‐NAME was significantly greater in SALX rats than in rats with intact salivary glands. Pretreatment of SALX rats with indomethacin did not augment this large decrease in LDF suggesting that endogenous prostanoids do not interact with NO and salivary factors in regulating mucosal microcirculation.
Mucosal NO biosynthesis as assessed by [14C]‐citrulline formation was reduced in SALX rats when compared to control animals. Pretreatment of SALX animals with parenterally‐administered EGF (10 μg kg−1) was associated with an increase in [14C]‐citrulline formation in the gastric mucosa to levels observed in control SALX rats.
These data suggest that factors which originate from the salivary gland such as EGF interact with NO in the maintenance of mucosal integrity. The effects may be mediated at least in part by changes in gastric mucosal blood flow. Salivary glands and EGF may mediate these effects to some extent via changes in mucosal NO biosynthesis.
Eicosanoid‐dependence of responses of pre‐ but not postglomerular vessels to noradrenaline in rat isolated kidneys
Authors: Zhang Bei‐Li , Sassard Jean 
Published: July 2012

We investigated the role of nitric oxide (NO) and of vasoactive eicosanoids in the control of renal vascular resistance (RVR) and glomerular filtration rate (GFR) and of their responses to noradrenaline (NA). This study was conducted in single‐pass perfused, isolated kidney preparations of the rat.
NA (63, 110 and 160 nm) dose‐dependently increased RVR and to a lesser degree GFR.
In baseline conditions, Nω‐nitro‐l‐arginine methylester (l‐NAME, 100 μm) increased GFR more than RVR, thus demonstrating a basal release of NO which predominates in postglomerular vessels.
In kidneys stimulated with NA, l‐NAME potentiated the increases in RVR but not in GFR. Indomethacin (1.5, 150 nm and 15 μm) did not alter GFR but markedly and dose‐dependently reduced the NA‐induced increase in RVR. Similar results were obtained with GR 32191B (10 and 100 μm), a prostaglandin H2/thromboxane A2 (PGH2/TxA2) receptor antagonist.
Indomethacin (15 μm) suppressed the enhancing effects of l‐NAME on RVR responses to NA but did not affect those on GFR.
It is concluded that the mechanisms of the response to NA differ among pre‐ and postglomerular vessels. In preglomerular vessels the vasoconstrictor action and the NO release depend upon the activation of PGH2/TxA2 receptors, while both are eicosanoid‐independent in the postglomerular vessels.
Mechanical and electrophysiological studies on the positive inotropic effect of 2‐phenyl‐4‐oxo‐hydroquinoline in rat cardiac tissues
Authors: Su Ming Jai , Chang Gwo Jyh , Kuo Sheng Chu 
Published: July 2012

The pharmacological and electrophysiological effect of 2‐phenyl‐4‐oxo‐hydroquinoline (YT‐1), a new synthetic agent, were determined in rat isolated cardiac tissues and ventricular myocytes.
YT‐1 was found to have a positive inotropic effect in both atria and ventricular muscles but did not cause significant increases in the spontaneously beating rate of right atria.
The positive inotropic effect of YT‐1 was antagonized neither by β‐nor by α‐adrenoceptor antagonists but was partially antagonized by a Ca2+ channel blocker (verapamil) and a K+ channel blocker (4‐AP).
The action potential duration and amplitude of ventricular cells were progressively increased as the concentration of YT‐1 was increased from 3 to 30 μm.
A voltage clamp study revealed that the prolongation of action potential duration by YT‐1 was associated with a prominent inhibition of 4‐AP‐sensitive transient outward current (Ito). At potentials negative to the reversal potential of K1‐channels, the inward current through these channels was partially reduced by YT‐1. At potentials positive to the reversal potential, the outward current through these channels was affected very little.
Although YT‐1 blocked the amplitude of Ito, the voltage‐dependence of the steady‐state inactivation of Ito, was unaffected.
Apart from the inhibition of K+ currents, YT‐1 also inhibited the sodium inward current.
The evidence suggests that YT‐1 increases the slow inward Ca2+ current (ICa) significantly.
It is concluded that the positive inotropic effect of YT‐1 is due predominantly to the increase of ICa and inhibition of Ito.
Effect of endopeptidase‐24.11 inhibition and of atrial natriuretic peptide clearance receptor ligand on the response to rat brain natriuretic peptide in the conscious rat
Authors: Kirk Jane E. , Wilkins M.R. 
Published: July 2012

The present studies examined the effect of (a) a specific endopeptidase‐24.11 (E‐24.11) inhibitor (candoxatrilat) and (b) a ligand for the atrial natriuretic peptide (ANP) clearance receptor (SC 46542) on the renal and blood pressure response to brain natriuretic peptide (BNP) in conscious rats.
Infusion of BNP 200 ng kg−1 min−1 for 60 min produced a small rise in urinary sodium and guanosine 3′:5′‐cyclic monophosphate (cyclic GMP) excretion with a non‐significant fall in mean arterial blood pressure.
Candoxatrilat (3 mg kg−1) alone had no significant effect on sodium excretion or blood pressure but markedly potentiated the natriuretic response to BNP.
Similarly SC 46542 (68 μg kg−1; 6.8 μg kg−1 min−1) which produced no significant effect on its own, potentiated the natriuresis‐induced by BNP, although the effect was of shorter duration compared to that of candoxatrilat.
The data indicate two approaches to the potentiation of the renal activity of BNP and suggest that BNP may mediate some of the activity of E‐24.11 inhibitors reported in cardiac failure.
The interaction of the NK1 receptor antagonist CP‐96,345 with L‐type calcium channels and its functional consequences
Authors: Guard S. , Boyle S.J. , Tang K.‐W. , Watling K.J. , McKnight A.T. , Woodruff G.N. 
Published: July 2012

We investigated the effects of the non‐peptide NK1 receptor antagonist, CP‐96,345, its inactive enantiomer CP‐96,344, and the racemic mixture (±)‐CP‐96,345, on the binding of [3H]‐nimodipine and [3H]‐diltiazem to L‐type calcium channels in rat cerebral cortex membranes. In isolated peripheral tissues containing tachykinin receptors, the effects of (±)‐CP‐96,345 have been compared with those of diltiazem.
In guinea‐pig trachea, (±)‐CP‐96,345 produced antagonism of responses to the selective NK1 agonists [Sar9, Met(O2)11]SP and substance P‐methyl ester that was apparently competitive in nature (pKB 7.0–7.5), while in guinea‐pig ileum the antagonism was not surmountable.
The reduction of maximum responses by (±)‐CP‐96,345 in the guinea‐pig ileum was not selective; it was obtained with muscarinic agonists and other agents, and was also observed in the portal vein of the rat where NK1 receptors are not present.
The tissue‐specific reduction of maximum responses by (±)‐CP‐96,345 in ileum was reproduced by diltiazem.
(±)‐CP‐96,345 produced a concentration‐dependent enhancement of [3H]‐nimodipine binding to rat cerebral cortex membranes with a maximal stimulation of 186 ± 29% above control (EC50 83.2 nm). Scatchard analysis revealed that (±)‐CP‐96,345 increased the affinity of [3H]‐nimodipine for its binding sites without affecting Bmax (control: KD = 0.32 nm; with 100 nm (±)‐CP‐96,345: KD = 0.074 nm).
CP‐96,345, CP‐96,344, and the racemate all inhibited [3H]‐diltiazem binding in rat cerebral cortex membranes with Ki values of 22.5 nm, 34.5 nm and 29.9 nm respectively; a similar value was obtained for diltiazem itself (33.6 nm). In comparison, CP‐96,345 and (±)‐CP‐96,345 inhibited the binding of [125I]‐Bolton‐Hunter‐conjugated substance P in this tissue with Ki values of 59.6 nm and 82.0 nm respectively, while CP‐96,344 had no measurable affinity (IC50 > 10 μm).
Substance P and a range of ligands selective for NK1, NK2, or NK3 receptors had no significant effect at 10 μm on either [3H]‐diltiazem or [3H]‐nimodipine binding.
The results indicate that in addition to possessing affinity for the NK1 receptor, the non‐peptide antagonist, CP‐96,345, displays high affinity for [3H]‐diltiazem binding sites on L‐type calcium channels. The functional effect that may be observed in integrated models will be a consequence of either property, or be a composite effect of NK1 receptor antagonism and L‐channel blockade.
Effect of trimebutine on voltage‐activated calcium current in rabbit ileal smooth muscle cells
Authors: Nagasaki Masaaki , Komori Seiichi , Ohashi Hidenori 
Published: July 2012

The effect of trimebutine on the voltage‐dependent inward Ca2+ current was investigated by the whole‐cell voltage‐clamp technique in single smooth muscle cells from rabbit ileum.
Trimebutine (3–100 μm) reduced the Ca2+ current in a concentration‐dependent manner. The inhibitory effect on the Ca2+ current was also dependent on the holding potential. The Ca2+ current after a low holding potential was inhibited to a greater extent than that after a high membrane potential: the IC50 values were 7 μm and 36 μm at holding potentials of −40 mV and −60 mV, respectively. The Ca2+ current elicited from a holding potential of −80 mV could not be reduced by as much as 50% of the control by trimebutine at concentrations as high as 100 μm.
Trimebutine (30 μm) shifted the voltage‐dependent inactivation curve for the Ca2+ current by 18 mV in the negative direction. The affinity of the drug for Ca2+ channels was calculated to be 36 times higher in the inactivated state than in the closed‐available state.
Blockade of the Ca2+ current by trimebutine, unlike verapamil, was not use‐dependent.
The results suggest that trimebutine inhibits the voltage‐dependent inward Ca2+ current through a preferential binding to Ca2+ channels in the inactivated state in the smooth muscle cell from rabbit ileum. The inhibitory effect of trimebutine on gastrointestinal motility is discussed in the light of the present findings.