bluuebunny/crossref_metadata_2025_split huggingface dataset:
Adenosine A1‐receptor stimulation of inositol phospholipid hydrolysis and calcium mobilisation in DDT1 MF‐2 cells
Authors: White Teresa E. , Dickenson John M. , Alexander Stephen P.H. , Hill Stephen J. 
Published: July 2012

. The effect of adenosine receptor‐stimulation on inositol phospholipid hydrolysis and calcium mobilization has been investigated in the hamster vas deferens smooth muscle cell line DDT1 MF‐2.
. Adenosine receptor stimulation increased the accumulation of total [3H]‐inositol phosphates in DDT1 MF‐2 cells prelabelled with [3H]‐myo‐inositol. The rank order of agonist potencies was N6‐cyclo‐pentyladenosine > 5′‐N‐ethylcarboxamidoadenosine > 2‐chloroadenosine > adenosine.
. The response to 2‐chloroadenosine was antagonized by the antagonists 8‐cyclopentyl‐1,3‐dipropylxanthine (KD 1.2 nm), PD 115,199 (KD 39 nm) and 8‐phenyltheophylline (KD 31 nm).
. The inositol phosphate response to 2‐chloradenosine (10 μm) was not significantly altered when the extracellular Ca2+ ion concentration was reduced from 2.4 mm to 1.2 mm or 0.6 mm. Under calcium‐free conditions, however, a reduced but still significant response to 2‐chloroadenosine was evident (39 ± 10% of the response in calcium‐containing medium).
. The 5‐lipoxygenase inhibitor AA861 (10 and 100 μm) inhibited the inositol phosphate response to 2‐chloroadenosine by 40 ± 9% and 60 ± 4% respectively. The cyclo‐oxygenase inhibitor, indomethacin, however, was without significant effect at 1 μm.
. 2‐Chloroadenosine stimulated an increase in intracellular free Ca2+ ion concentration in fura‐2 loaded DDT1 MF‐2 cells in calcium‐free medium containing 0.1 mm EGTA, which could be inhibited by the adenosine A1‐receptor antagonist 8‐cyclopentyl‐1,3‐dipropylxanthine (0.1 μm).
. These data suggest that adenosine A1‐receptor stimulation results in inositol phospholipid hydrolysis and calcium mobilization from intracellular stores in DDT1 MF‐2 cells.
Pituitary adenylate cyclase activating polypeptide is a potent vasodilator and oedema potentiator in rabbit skin in vivo
Authors: Warren J.B. , Larkin S.W. , Coughlan M. , Kajekar R. , Williams T.J. 
Published: July 2012

The effects of pituitary adenylate cyclase activating polypeptide (PACAP) on microvascular blood flow and plasma protein leakage were investigated in rabbit skin in vivo.
Intradermal injection of PACAP38, the 38 amino acid form of the peptide, caused a dose‐dependent increase in blood flow measured by a 133Xe clearance technique. An equivalent increase in blood flow was induced by 10−12 mol per site of PACAP38, 10−12 mol per site of human α‐calcitonin gene‐related peptide (CGRP) and 10−10 mol per site of vasoactive intestinal polypeptide (VIP).
The vasodilator activity of PACAP38 was not significantly different from that of the 27 amino acid form of the peptide, PACAP27, when measured with a laser Doppler flow meter, causing a 104 ± 14% compared with 110 ± 18% increase above basal blood flow at 10−12 mol per site respectively.
At 10−12 mol per site the effect of PACAP38 was longer lasting than that of CGRP. Blood flow remained significantly increased above control at 2 h with PACAP38 (P < 0.05) whereas blood flow after intradermal CGRP had returned to control values by this time.
PACAP38 injected alone had no significant effect on microvascular leakage of 125I‐labelled albumin. However, PACAP38 significantly potentiated bradykinin‐induced oedema where it was approximately 100 fold more potent than VIP.
Oedema potentiation induced by PACAP38 was not inhibited by indomethacin at a dose which did inhibit potentiation of bradykinin‐induced oedema by arachidonic acid.
PACAP38 is at least as potent as other peptides which have been postulated to be involved in the inflammatory response when tested in rabbit skin in vivo. PACAP may contribute to both the hyperaemia and oedema components of inflammation.
Effects of Hoe 140, a bradykinin B2‐receptor antagonist, on renal function in conscious normotensive rats
Authors: Madeddu Paolo , Anania Vittorio , Demontis Maria Piera , Varoni Maria Vittoria , Pisanu Gavino , Troffa Chiara , Tonolo Giancarlo , Glorioso Nicola , Parpaglia Paolo Pinna 
Published: July 2012

. The present study was designed to determine if endogenous kinins are involved in the regulation of arterial blood pressure and renal function in conscious rats given deoxycorticosterone enantate (DOC, 25 mg kg−1, s.c., weekly) or vehicle for two weeks.
. The bradykinin B2‐receptor antagonist, d‐Arg[Hyp3,Thi5,d‐Tic7,Oic8]‐bradykinin (Hoe 140), at a dose of 300 μg kg−1, s.c., blocked the hypotensive effect of 300 ng kg−1 bradykinin i.a., but it did not alter the blood pressure lowering action of 300 ng kg−1 acetylcholine or prostaglandin E2. Inhibition of the response to bradykinin persisted up to 6 h after the administration of Hoe 140.
. Administration of 300 μg kg−1 Hoe 140 s.c. four times a day did not alter mean blood pressure, renal blood flow, or renal function in rats given DOC‐vehicle. However, it decreased urinary volume by 70% (from 48.2 ± 3.8 to 14.3 ± 3.7 ml 24 h−1, P < 0.01) and urinary secretion of sodium by 54% (from 1.02 ± 0.05 to 0.47 ± 0.16 mmol 24 h−1, P < 0.01) and potassium by 30% (from 2.93 ± 0.15 to 2.04 ± 0.15 mmol 24 h−1, P < 0.05) in DOC‐treated rats. Mean blood pressure, glomerular filtration rate and total renal blood flow remained unchanged.
. Our results suggest that endogenous kinins play a role in the regulation of renal excretion of water and sodium in the presence of elevated levels of DOC.
Synergistic anti‐nociceptive effect of l‐NG‐nitro arginine methyl ester (l‐NAME) and flurbiprofen in the mouse
Authors: Morgan C.V.J. , Babbedge R.C. , Gaffen Z. , Wallace P. , Hart S.L. , Moore P.K. 
Published: July 2012

l‐NG‐nitro arginine methyl ester (l‐NAME) administered i.p. produces anti‐nociception in the mouse assessed by the formalin‐induced paw licking and acetic acid‐induced abdominal constriction models. The non‐steroidal anti‐inflammatory drug (NSAID), flurbiprofen, was similarly anti‐nociceptive in both models.
Combination of a sub‐threshold dose of l‐NAME (10 mg kg−1) with increasing doses of flurbiprofen (25‐ 75 mg kg−1) or a sub‐threshold dose of flurbiprofen (50 mg kg−1) with increasing doses of l‐NAME (10‐ 100 mg kg−1) resulted in potentiated anti‐nociception in the formalin model. Combined therapy with sub‐threshold doses of l‐NAME (10 mg kg−1) and indomethacin (10 mg kg−1) also resulted in significant anti‐nociception. In addition, combining sub‐threshold doses of l‐NAME (12.5 mg kg−1) and flurbiprofen (2 mg kg−1) significantly reduced acetic acid‐induced abdominal constriction.
l‐NAME (10 mg kg−1) administered i.p. caused a significant (approximately 35%) increase in MAP in the urethane‐anaesthetized mouse. Flurbiprofen (50 mg kg−1) was inactive. Combination treatment with l‐NAME (10 mg kg−1) and flurbiprofen (50 mg kg−1) failed to elevate MAP above that observed with l‐NAME alone. Neither l‐NAME (10 mg kg−1) nor flurbiprofen (50 mg kg−1) either alone or in combination significantly altered mouse locomotor activity.
These results suggest that l‐NAME and flurbiprofen/indomethacin act synergistically in their antinociceptive action in the mouse. Combination therapy with l‐NAME and flurbiprofen and a similar NSAID may provide an alternative to the clinical control of pain in man.
Ramiprilat increases bradykinin outflow from isolated hearts of rat
Authors: Baumgarten Claus R. , Linz Wolfgang , Kunkel Gert , Schölkens Bernward A. , Wiemer Gabriele 
Published: July 2012

To establish that bradykinin is formed in the heart we measured bradykinin in the venous effluent from rat isolated hearts perfused with Krebs‐Henseleit buffer. In addition, we examined the effect on bradykinin outflow of the angiotensin converting enzyme (ACE) inhibitor, ramiprilat. From rat isolated normoxic hearts a bradykinin outflow of 0.85 ± 0.1 ng ml−1 perfusate g−1 wet weight was measured. Perfusion with ramiprilat increased the bradykinin concentration to 2.8 ± 0.3 ng ml−1 perfusate g−1 wet weight. During ischaemia bradykinin outflow maximally increased 8.2 fold to 7.0 ± 0.5 ng ml−1 perfusate g−1, and in ramiprilat‐perfused hearts 5.8 fold to 16.0 ± 1.8 ng ml−1 perfusate g−1. In the reperfusion period bradykinin outflow normalized to values measured in the respective pre‐ischaemic period.The presents data show that bradykinin is continuously formed in the rat isolated heart. Ischaemia increases bradykinin outflow from the heart. Presumably by inhibiting degradation of kinins, ACE inhibition significantly increased the bradykinin concentration during normoxia, ischaemia and reperfusion.
Chloroethylclonidine: an irreversible agonist at prejunctional α2‐adrenoceptors in rat vas deferens
Authors: Bültmann Ralph , Starke Klaus 
Published: July 2012

The possibility that chloroethylclonidine (CEC) activates prejunctional α2‐adrenoceptors was studied in the isolated vas deferens of the rat. Tissues were stimulated electrically and both the stimulation‐evoked overflow of tritium (after preincubation with [3H]‐noradrenaline) and the purinergic contraction component (isolated by prazosin 0.3 μm) were measured.
CEC (0.1–3 μm) concentration‐dependently reduced the overflow of tritium evoked by trains of 6 pulses/100 Hz. The inhibition by CEC was not altered by prazosin (0.3 μm) but was prevented by pre‐exposure to rauwolscine (0.3 μm). The inhibition, once established, did not fade upon washout of CEC, even when the washout fluid contained rauwolscine (0.3 μm).
CEC (0.1–3 μm) concentration‐dependently reduced the purinergic component of contractions elicited by single pulses. The inhibition, again, was prevented by pre‐exposure to rauwolscine (0.3 μm) and once established, did not fade upon washout of CEC, even when the washout fluid contained rauwolscine (0.3 μm).
CEC (3 μm) reduced the overflow of tritium evoked by 20 pulses/10 Hz, did not alter the overflow evoked by 100 pulses/10 Hz and increased the overflow evoked by 500 pulses/10 Hz.
CEC (3 μm) reduced the early peak, but increased the late plateau phase, of purinergic contractions elicited by 100 pulses/10 Hz.
It is concluded that CEC reduces the release of noradrenaline and a purinergic co‐transmitter by irreversible activation of prejunctional α2‐adrenoceptors. CEC seems to be a partial α2‐agonist with an efficacy lower than that of noradrenaline. The prejunctional inhibitory effect limits the suitability of CEC for the characterization of postjunctional α1‐adrenoceptors mediating responses to sympathetic nerve stimulation.
Lymphocyte β2‐adrenoceptors and adenosine 3′:5′‐cyclic monophosphate during and after normal pregnancy
Authors: von Mandach Ursula , Gubler Hans Peter , Engel Günther , Huch Renate , Huch Albert 
Published: July 2012

The β2‐sympathomimetics, used to inhibit preterm labour, bind predominantly to β2‐adrenoceptors, activating adenylate cyclase to form adenosine 3′:5′‐cyclic monophosphate (cyclic AMP), a messenger substance which inhibits the enzyme cascade triggering smooth muscle contraction. β2‐Adrenoceptor density and cyclic AMP formation can be used as markers of β2‐adrenergic effect.
The present study addresses the influence of pregnancy on the β‐adrenoceptor system. β2‐Adrenoceptor density and cyclic AMP concentrations (basal and evoked by isoprenaline) in circulating lymphocytes were determined at three points in gestation (16, 29 and 37 weeks) and 9 weeks post partum in 22 normal pregnancies. (−)‐[125Iodo]‐cyanopindolol was used as the ligand to identify a homogeneous population of β2‐adrenoceptors on lymphocytes. B‐ and T‐cell fractions were estimated from the same samples.
β2‐Adrenoceptor density decreased significantly during gestation until week 37 (P < 0.01), then increased post partum (P < 0.005). Cyclic AMP concentrations (basal and evoked by isoprenaline) were significantly lower after 16 weeks of gestation than post partum (P<0.05).
The results, which cannot be explained in terms of a shift in the lymphocyte (B‐ and T‐cell) ratio, indicate that β‐adrenoceptor density and function are reduced in normal pregnancy and only return to normal post partum. These findings may be of significance in devising future tocolytic therapy with β2‐adrenoceptor agonists.
NK2 receptors mediate plasma extravasation in guinea‐pig lower airways
Authors: Tousignant Christine , Chan Chi‐Chung , Guevremont Diane , Brideau Christine , Hale Jeffrey J. , MacCoss Malcolm , Rodger Ian W. 
Published: July 2012

Neurokinin (NK) receptor‐mediated extravasation has been examined in guinea‐pig airways by use of a recently described marker for microvascular protein leakage, 125I‐labelled human fibrinogen.
Neurokinin A (NKA) caused a dose‐dependent increase in plasma [125I]‐fibrinogen extravasation in trachea, main bronchi, secondary bronchi and intraparenchymal airways. In contrast, the NK2 selective agonist [β‐Ala8]NKA(4–10) only caused extravasation in the secondary and intraparenchymal airways.
The NK2 selective antagonist, SR 48968, caused a dose‐dependent inhibition of NKA and [β‐Ala8]NKA(4–10)‐induced extravasation of fibrinogen in guinea‐pig secondary bronchi and intraparenchymal airways. SR 48968 was without effect on the NKA‐induced extravasation in trachea and main bronchi.
NKA‐ or [β‐Ala8]NKA(4–10)‐induced plasma extravasation was not modified by pretreatment with histamine H1‐ or H2‐receptor antagonists.
It is concluded that NK2 receptors mediate plasma [125I]‐fibrinogen extravasation in guinea‐pig secondary bronchi and intraparenchymal airways. This effect is direct and does not depend upon histamine released from mast cells.
α‐Sialyl cholesterol reverses AF64A‐induced deficit in passive avoidance response and depletion of hippocampal acetylcholine in mice
Authors: Abe Eiichi , Murai Shigeo , Masuda Yoshikatsu , Saito Hiroko , Itoh Tadanobu 
Published: July 2012

The effect of α‐sialyl cholesterol (α‐SC; α‐d‐N‐acethylneuraminyl cholesterol) on disturbances of the central cholinergic system induced by ethylcholine mustard aziridinium ion (AF64A) and by scopolamine were studied by means of a step‐down passive avoidance response and locomotor activities in mice. The levels of acetylcholine (ACh) in certain regions of the brain were measured to assess the neurochemical recovery promoted by α‐SC.
Treatment with AF64A (2.5, 5 and 10 nmol, i.c.v.) impaired the 24 h retention latencies of animals in a dose‐dependent manner, and scopolamine (0.5 mg kg−1, i.p.) also impaired the retention performance. Administration of α‐SC (1 and 4 mg kg−1, p.o.) once daily for 13 days improved the retention performance in AF64A‐treated animals in a dose‐dependent manner, but not in the scopolamine‐treated animals.
Treatment with AF64A (2.5, 5 and 10 nmol, i.c.v.) and scopolamine (0.5 mg kg−1, i.p.) increased vertical and horizontal locomotor activities. α‐SC dose‐dependently attenuated the increase in locomotor activies induced by 2.5 nmol of AF64A, but not the locomotor activities caused by 5 or 10 nmol of AF64A, or scopolamine (0.5 mg kg−1, i.p.).
The deficit retention performance of AF64A‐treated animals was associated with depletion of ACh levels in the hippocampus, but not in the septum or cerebral cortex. Administration of α‐SC to AF64A‐treated animals dose‐dependently reversed the depletion of ACh levels in the hippocampus.
The results indicate that α‐SC had significant effects after oral administration of AF64A‐treated animals. The behavioural recovery promoted by α‐SC may be based on the reversal of ACh depletion in the hippocampus.
Acetylcholine‐induced relaxation in bovine isolated mesenteric arteries is suppressed by polymorphonuclear leukocytes
Authors: De Kimpe Sjef J. , Van Heuven‐Nolsen Dicky , Nijkamp Frans P. 
Published: July 2012

The endothelium plays a critical role in maintaining vascular tone via generation of potent vasoconstrictor and dilator substances. We examined the effect of bovine purified polymorphonuclear leukocytes (PMN) on the endothelium‐dependent relaxation to acetylcholine in isolated mesenteric arteries.
In the presence of PMN (2.5 × 106 cells ml−1) the maximal relaxation to acetylcholine was decreased from 76.1 ± 2.4% to 44.9 ± 7.4% of the precontraction (P < 0.001). This effect was inhibited by superoxide dismutase and NG‐mono‐methyl‐l‐arginine, but not by catalase or indomethacin.
PMN were not able to influence significantly the endothelium‐independent relaxation to nitroprusside.
Removal of PMN after preincubation and prior to precontraction and relaxation did not influence the acetylcholine‐induced relaxation, indicating that no irreversible vascular damage had occurred.
Superoxide anion production by unstimulated PMN was less than 10% compared to phorbol myristate acetate‐activated PMN, measured by chemiluminescence and reduction of ferricytochrome c.
We conclude that small amounts of superoxide anions produced by unstimulated PMN contribute to a decrease in relaxation to acetylcholine by interfering with endothelium‐derived nitric oxide.
Withdrawal contractures of guinea‐pig isolated ileum after acute activation of κ‐opioid receptors
Authors: Morrone L.A. , Romanelli L. , Amico M.C. , Valeri P. 
Published: July 2012

The present study was undertaken to investigate firstly whether a brief exposure for 5 min of guinea‐pig isolated ileum to the κ‐opioid agonist, U‐50,488H produced a withdrawal contracture on addition of naloxone and secondly to ascertain whether the response was due to the activation of κ‐opioid receptors.
Naloxone (10−6 m) did not elicit a response in preparations exposed to U‐50,488H (5 × 10−7 M‐2 × 10−6 m). However, after exposure to U‐50,488H (5 × 10−7 m), naloxone (10−6 m) produced a strong contracture if the agonist was washed out 1 min before the addition of the antagonist.
The addition of naloxone (10−6 m) to the ileum preparation exposed to U‐50,488H (10−7 m or lower) caused a response of similar intensity irrespective of whether the agonist had been washed out.
The selective κ‐opioid antagonist, nor‐binaltorphimine (2.7 × 10−9 m and 2.7 × 10−7 m), injected before the opioid agonists, prevented the naloxone‐induced contracture after exposure to U‐50,488H (8 × 10−8 m) but did not affect the contracture after exposure to morphine (5 × 10−7 m).
Nor‐binaltorphimine (2.7 × 10−9 m) caused a contraction of the ileum preparation when injected
min after exposure to U‐50,488H (8 × 10−8 m) but not after morphine (5 × 10−7 m).
The α2‐adrenoceptor agonist, clonidine (3 × 10−8 m) and the calcium channel blocker, nifedipine (3 × 10−8 m), injected 1 min before naloxone, blocked the ileum contraction to naloxone after exposure to U‐50,488H (8 × 10−8 m). The results demonstrate that the stimulation of K‐opioid receptors can induce a similar dependence in guinea‐pig ileum to that produced by activation of μ receptors.
Functional characterization of muscarinic receptors in murine airways
Authors: Garssen J. , Van Loveren H. , Gierveld C.M. , Van Der Vliet H. , Nijkamp F.P. 
Published: July 2012

The effects of muscarinic receptor antagonists considered to be selective for M1 receptors (pirenzepine; PZ), M2 receptors (AFDX‐116), and for M3 receptors (4‐diphenyl acetoxy N‐methylpiperidine (4‐DAMP)) were used to investigate the existence of muscarinic receptor subtypes in murine airways. Atropine was used as a nonselective antagonist. The effects of these antagonists were studied upon tracheal contractions induced either by EFS (electric field stimulation) or by application of an exogenous cholinoceptor agonist (arecoline).
The muscarinic receptor antagonists tested inhibited arecoline‐induced tracheal contractions with the following rank order of potency: 4‐DAMP = atropine > pirenzepine = AFDX‐116. The rank order of potency of the muscarinic antagonists used in inhibiting EFS‐induced tracheal contractions was: 4‐DAMP = atropine > PZ > AFDX‐116. The pA2 values for these antagonists were similar when compared to the pA2 values determined in guinea‐pig and bovine airway smooth muscle.
In addition to in vitro studies, the effects of inhalation of the different muscarinic antagonists on lung function parameters in vivo were investigated. Inhalation of 4‐DAMP induced a decrease in airway resistance and an increase in lung compliance. In contrast, inhalation of AFDX‐116 induced an increase in airway resistance and almost no change in lung compliance. Apart from some minor effects of atropine on airway resistance, atropine, PZ, and pilocarpine failed to induce changes in lung mechanics as determined by in vivo lung function measurements.
The results provide evidence for the existence of M3 receptors on murine tracheae that are involved in the contraction of tracheal smooth muscle. This is in agreement with other animal species such as the guinea‐pig and bovine. In vivo experiments also demonstrated that in the mouse, M3 receptors play an important role in bronchial smooth muscle contraction and thus in bronchoconstriction. Interestingly we have also demonstrated that M2 receptors can play a role in bronchodilatation. Inhalation of an M2 receptor antagonist induced an increase in airway resistance whereas inhalation of an M3 receptor antagonist induced a decrease in airway resistance. It is therefore likely that an M3/M2 receptor balance plays an important role in the regulation of airway function.
Effects of MS‐551, a new class III antiarrhythmic drug, on action potential and membrane currents in rabbit ventricular myocytes
Authors: Nakaya Haruaki , Tohse Noritsugu , Takeda Youji , Kanno Morio 
Published: July 2012

Electrophysiological effects of MS‐551, a new class III antiarrhythmic drug, were examined and compared with those of (+)‐sotalol in rabbit ventricular cells.
In rabbit ventricular muscles stimulated at 1.0 Hz, MS‐551 (0.1–10 μm) and (+)‐sotalol (3–100 μm) prolonged action potential duration (APD) and effective refractory period without affecting the maximum upstroke velocity of phase 0 depolarization . The class III effect of MS‐551 was approximately 30 times more potent than that of (+)‐sotalol.
Class III effects of MS‐551 and (+)‐sotalol showed reverse use‐dependence, i.e., a greater prolongation of APD at a longer cycle length.
In rabbit isolated ventricular cells, 3 μm MS‐551 and 100 μm sotalol inhibited the delayed rectifier potassium current (IK) which was activated at more positive potentials than −50 mV and saturated around + 20 mV.
MS‐551 at a higher concentration of 10 μm decreased the transient outward current (Ito) and the inward rectifier potassium current (IK1) although 100 μm sotalol failed to inhibit these currents.
MS‐551 is a non‐specific class III drug which can inhibit three voltage‐gated K+ channels in rabbit ventricular cells.
Effects of propafenone on calcium currents in single ventricular myocytes of guinea‐pig
Authors: Fei Lü , Gill Jaswinder S. , McKenna William J. , Camm A. John 
Published: July 2012

The effects of propafenone on the inward calcium current (ICa) were investigated in isolated single ventricular myocytes of the guinea‐pig by the whole‐cell clamp method. Propafenone inhibited ICa in a dose‐dependent manner at concentrations of propafenone ranging from 1 × 10−8 to 1 × 10−3 m and half maximal block of ICa occurred at a propafenone concentration of 1.5 × 10−6 m. Propafenone did not change the current‐voltage relation of ICa other than a reduction in amplitude and showed no clear use‐ or frequency‐dependent effects upon ICa (stimulation frequencies from 0.03 to 2 Hz). Propafenone did not alter the steady‐state inactivation process: the half maximal activation potentials were 18.5 ± 2.2 mV in the control state and 20.9 ± 5.0 mV in the presence of 1×10−6 m propafenone (n = 12, NS). Propafenone (1 × 10−6 m) increased the half‐time of reactivation by 73.9% (n = 6, 212.3 ± 1.2 ms vs 369.2 ± 1.5 ms, P < 0.05).
We conclude that propafenone blocks ICa in a concentration‐dependent and a channel state‐, use‐ or frequency‐independent manner. The ICa, blockade elicited by propafenone at clinically therapeutic plasma concentration is significant and may be involved in its anti‐arrhythmic effects.