bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparative study of the cardiovascular and biochemical actions of the imidazo [4,5b] pyridine sulmazole and an imidazo [4,5c] pyridine analogue, BW A746C
Authors: Allan G. , Cambridge D. , Follenfant M.J. , Stone D. , Whiting M.V. 
Published: July 2012

BW A746C is a chemical analogue of the imidazo [4,5b] pyridine, sulmazole (AR‐L115 BS). Like sulmazole, BW A746C possesses positive inotropic and vasodilator activity in vivo.
In anaesthetized guinea‐pigs, dogs and primates, a bolus i.v. injection of BW A746C, (0.001‐1.0 mg kg−1) caused a significant, dose‐related increase in ventricular dP/dt, and reduction in diastolic blood pressure, with small increases in heart rate. In these species, a significantly higher dose of BW A746C was required to lower blood pressure by 30% from basal, than was needed to raise ventricular dP/dt by 50% over basal.
In anaesthetized guinea‐pigs and dogs, bolus i.v. injections of sulmazole (0.1–10.0 mg kg−1) caused similar effects to those observed with BW A746C. In these species, however, there was no significant difference between the dose of sulmazole required to lower blood pressure by 30% from basal and that required to raise ventricular dP/dt by 50%.
In conscious dogs, i.v. infusion of BW A746C (to a total dose of 0.3 mg kg−1) caused a significant increase in ventricular dP/dt, but no significant change in either diastolic blood pressure or heart rate.
In cell‐free biochemical assays, there were no clear differences between the observed activities of BW A746C and sulmazole. Both compounds are cyclic nucleotide phosphodiesterase inhibitors with similar potencies and selectivities for the Type III enzyme (IC50 BW A746C = 3.0 ± 0.5 × 10−5 m, sulmazole 5.0 ± 1.9 × 10−5 m). The compounds had little or no effects on sarcolemmal Na+/K+‐ATPase, Ca2+ ATPase or Na+/Ca2+ exchange, and sulmazole, but not BW A746C, had a small, stimulatory effect on myofibrillar ATPase.
In anaesthetized guinea‐pigs and dogs, BW A746C was significantly more potent as a positive inotrope than sulmazole. In contrast with sulmazole, BW A746C produced its inotropic effects at significantly lower doses than those required to reduce diastolic blood pressure. This was also apparent from the results obtained in the anaesthetised primates and the conscious dogs. It was therefore concluded that the inotropic/vasodilator profile of BW A746C favours its positive inotrope activity. This profile cannot be explained on the basis of any biochemical differences from sulmazole.
4‐Hydroxy‐2‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydroisoquinoline (PI‐OH): a new potentiator of sympathomimetic amines on the rat anococcygeus muscle
Authors: Ishida Y. , Koga N. , Nanbu T. , Kihara M. , Kobayashi S. 
Published: July 2012

The potentiating effects of racemic 4‐hydroxy‐2‐methyl‐4‐phenyl‐1,2,3,4‐tetrahydroisoquinoline (PI‐OH), cocaine, desipramine and nomifensine on the concentration‐response curves of the rat anococcygeus muscle to noradrenaline (NA) and field stimulation were examined.
PI‐OH and cocaine concentration‐dependently potentiated the responses of anococcygeus muscle to NA and field stimulation, but the activity of PI‐OH was stronger than that of cocaine on both responses.
At high concentrations the potentiating activities of desipramine and nomifensine were less, a fact that was explained by their postsynaptic inhibitory properties; the actions of nomifensine and desipramine as antagonists against NA were competitive and non‐competitive, respectively.
It is concluded that PI‐OH may be an ideal potentiator of the response to NA in adrenergically‐innervated tissues because it has no side effects such as postsynaptic inhibition.
The involvement of afferent nerve terminals in the stimulation of ion transport by bradykinin in rat isolated colon
Authors: Perkins M.N. , Forster P.L. , Dray A. 
Published: July 2012

The actions of bradykinin (Bk) were investigated on rat colon epithelium preparations that had been stripped of the muscle layers. The electrogenic ion flux was monitored by measuring changes in the short circuit current (SCC) produced by addition of drugs. Bk, administered to the basolateral side, but not apical side, of the epithelium evoked an increase in SCC which was separable into two distinct components, both of which were mediated mainly by chloride efflux.
The early component was robust, reproducible and exhibited clear concentration‐dependency with an EC50 of 6.2 nm. The second phase of the response exhibited a much slower time course than the first phase and diminished amplitude with repeated applications of Bk.
In preparations of unstripped epithelium, bradykinin (Bk) evoked mainly a slow neurogenic response which was attenuated or abolished by tetrodotoxin (TTX). When the epithelium was stripped off, TTX had little effect either on the baseline SCC or on responses to Bk.
Perfusion with zero calcium solution did not affect the early phase but abolished the late phase of the Bk response. Verapamil (20 μm), but not nifedipine (20 μm), also attenuated the later phase of the response.
Capsaicin (20 μm) administered to the basolateral, but not the apical, side produced an increase in SCC. Following desensitization to capsaicin the second phase of the response to Bk was abolished with little effect on the initial response to Bk.
The data suggest that Bk increases the efflux of chloride ions across the colonic epithelium in at least two ways: (a) by an action on the epithelial cells and (b) by an action on neuronal elements within the epithelium. This latter effect of Bk is due to stimulation of capsaicin‐sensitive nerve terminals within the mucosa of the colon epithelium causing the release of a mediator which is responsible for the second phase of the response to Bk.
Phospholipase A2 induced airway hyperreactivity to cooling and acetylcholine in rat trachea: pharmacological modulation
Authors: Chand N. , Diamantis W. , Mahoney T.P. , Sofia R.D. 
Published: July 2012

Rat isolated tracheal smooth muscle preparations respond to phospholipase A2 (PLA2) and phospholipase C (PLC) with contractile responses of highly variable magnitudes. Rat tracheae exposed to PLA2 or PLC for a period of 10–30 min, exhibit airway hyperreactivity (AH) to cooling (10°C), i.e., respond with strong contractile responses. Phospholipase D neither contracted rat tracheae nor induced AH to cooling.
PLA2‐induced AH to cooling was dependent on the presence of extracellular Ca2+ in the physiological solution.
Verapamil, azelastine, diltiazem and TMB‐8 (each 10 μm) significantly attenuated PLA2‐induced AH. This effect was not shared by nifedipine (10 μm).
Bepridil (10 μm), a Ca2+ and calmodulin antagonist, also significantly attenuated AH induced by PLA2.
Indomethacin (a cyclo‐oxygenase inhibitor), AA‐861 (a selective 5‐lipoxygenase inhibitor), FPL 55712 (a leukotriene receptor antagonist), methysergide (a 5‐hydroxytryptamine D‐receptor antagonist) and pyrilamine (a histamine H1‐receptor antagonist) exerted little or no effect on PLA2‐induced AH to cooling.
Atropine significantly attenuated PLA2‐induced AH suggesting the participation of acetylcholine.
Nordihydroguaiaretic acid (an antioxidant; 5‐lipoxygenase inhibitor) and BW 755C (an antioxidant; a dual inhibitor of cyclo‐oxygenase and 5‐lipoxygenase) significantly attenuated PLA2‐induced AH to cooling.
In conclusion, these data show that PLA2 (an enzyme involved in the synthesis of Paf‐acether, prostaglandins, thromboxanes, leukotrienes, diacylglycerol, superoxide free radicals and lipid peroxides, etc.) induces AH to cooling and acetylcholine in rat trachea. The induction of AH to cooling is dependent on the presence of extracellular Ca2+ and is significantly attenuated by verapamil, diltiazem, bepridil, atropine and azelastine (an antiallergic/antiasthmatic drug).
Responses to 5‐hydroxytryptamine evoked in the hemisected spinal cord of the neonate rat
Authors: Connell L.A. , Wallis D.I. 
Published: July 2012

Superfusion of isolated hemisected spinal cord from neonate rats with 5‐hydroxytryptamine (5‐HT) (10−6 to 10−3 m) evoked concentration‐related depolarizations. The maximal depolarization elicited by a concentration of 10−4 m was 1.0 ± 0.1 mV (mean ± s.e.mean, n = 30). Noradrenaline in a similar range of concentrations also elicited depolarizations.
The depolarizations probably originate in motoneurones as a result of direct interaction of the amines with these cells, since responses were unaltered by tetrodotoxin (10−7 m) or Ca2+‐free/Mg2+‐rich medium.
5‐Carboxamidotryptamine (5‐CT), S(+)−α‐methyl‐5‐hydroxytryptamine (α‐Me5‐HT) and 5‐methoxytryptamine (5‐MeOT) evoked similar depolarizations to 5‐HT. Tryptamine evoked depolarizations of smaller maximal amplitude. 5‐Hydroxytryptophan, 2‐methyl‐5‐hydroxytryptamine, 8‐hydroxy‐2‐(di‐N‐propylamino) tetralin hydrobromide (8‐OH‐DPAT) and 5‐methoxy‐3‐[1,2,3,6‐tetrahydro‐4‐pyridinyl]‐1‐H‐indole succinate (RU 24969) had no depolarizing action.
Concentration‐response (CR) curves were determined for 5‐HT, 5‐CT, α‐Me5‐HT, 5‐MeOT and tryptamine. The ED50 value for 5‐HT was 20.5 ± 1.2 μm. The equipotent molar ratios (EPMRs) for 5‐CT and α‐Me5‐HT were close to unity, while 5‐MeOT was approximately 3 times and tryptamine 13 to 14 times less potent than 5‐HT.
The relative agonist potency of 5‐HT with respect to other tryptamine analogues capable of depolarizing motoneurones was increased when 5‐HT uptake was blocked by citalopram (10−7 m). In the presence of citalopram, 5‐HT was 2.7 times more potent than α‐Me5‐HT and 16.9 times more potent than 5‐CT. The apparent order of potency was 5‐HT > α‐Me5‐HT > 5‐CT (> 5‐MeOT > tryptamine).
The monoamine oxidase inhibitor, pargyline (5 × 10−4 m), had no effect on depolarizations to 5‐HT, 5‐CT or α‐Me5‐HT.
Methiothepin, 1αH, 3α, 5H‐tropan‐3‐yl‐3,5‐dichlorobenzoate methanesulphonate (MDL 72222) and [3α‐tropanyl]‐1H‐indole‐3‐carboxylic acid ester hydrochloride (ICS 205–930) had no effect on 5‐HT depolarizations elicited in motoneurones. Ketanserin (0.75 × 10−7 m to 10−6 m) showed modest antagonistic action and depressed maximal response amplitude; the pIC50 was 6.5.
Methysergide (10−8 to 10−7 m) was a potent antagonist of responses to 5‐HT. CR curves were displaced to the right and flattened in the presence of the antagonist. The pIC50 assessed from the effect on depolarizations evoked by 5‐HT 10−4 m was 7.5.
It is concluded that 5‐HT acts directly to depolarize mammalian spinal motoneurones through receptors that are also activated by 5‐CT, α‐Me5‐HT and 5‐MeOT and are blocked by methysergide. The receptor profile, although not 5‐HT3‐like, does not clearly coincide with that for either 5‐HT1‐like or 5‐HT2 receptors.
Effects of REV 5901, a 5‐lipoxygenase inhibitor and leukotriene antagonist, on pulmonary responses to platelet activating factor in the guinea‐pig
Authors: Anderson Gary , Fennessy Max 
Published: July 2012

The effects of REV 5901 on the platelet activating factor (Paf)‐induced (a) bronchoconstriction, (b) contraction of lung parenchymal strips and (c) increased airways responsiveness to histamine, were assessed in the guinea‐pig. REV 5901 is a 5‐lipoxygenase inhibitor and competitive peptidoleukotriene antagonist which does not inhibit multiple forms of phosphodiesterase.
In urethane/pentobarbitone anaesthetized animals, REV 5901 (10 or 30 mg kg−1 i.v.) substantially inhibited the bronchoconstriction, measured as changes in airways resistance (RL) and dynamic lung compliance (Cdyn), induced by leukotriene D4 (2.5 μg kg−1, i.v.) but did not attenuate that induced by Paf (50 ng kg−l, i.v.).
Paf contracted the lung parenchymal strip in a concentration‐dependent manner. REV 5901 (25 μm) neither altered the magnitude of the contractions nor the tissue sensitivity to Paf. The sustained contraction induced by Paf was not affected when REV 5901 was added after the response had reached a plateau.
Contractions of parenchymal strips to Paf (50 nm) were prevented by pretreatment with the competitive Paf antagonists, SRI 63441 and WEB 2086. Also WEB 2086, but not SRI 63441, reversed established Paf‐induced contractions and relaxed parenchymal strips from intrinsic tone in the absence of Paf.
Paf (20 ng kg−1, i.v.) caused an acute increase in airways responsiveness to histamine (4–12 μg kg−1, i.v.) which was attenuated by REV 5901 at 10 mg kg−1, i.v. and abolished by 30 mg kg−1, i.v.
These data suggest that leukotrienes do not participate in Paf‐induced bronchoconstriction or contraction of the lung parenchymal strip, but may play a role in the increased responsiveness of the airways to histamine observed after Paf challenge in the guinea‐pig.
Gastric motor responses elicited by vagal stimulation and purine compounds in the atropine‐treated rabbit
Authors: Beck K. , Calamai F. , Staderini G. , Susini T. 
Published: July 2012

The effects of vagal inhibitory stimulation and of purine compounds were studied in the rabbit stomach.
Gastric motility was assessed by the balloon method. Vagal nerves were electrically stimulated at the neck. Purine compounds were injected intra‐arterially.
In the atropine‐treated rabbit, vagal stimulation caused relaxant motor responses followed by a rebound contraction.
Among the purine compounds, only ADP and ATP caused relaxant motor responses similar to the effects of vagal inhibitory stimulation. However, the relaxation produced by ATP was more powerful than that due to ADP, especially at lower infusion rates.
Vagal inhibitory responses were recorded during and after infusion of ATP. When relaxation by ATP was fully developed, vagal inhibitory stimulation was ineffective. At the highest infusion rates of ATP, a depression of the vagal inhibitory motility was also observed after cessation of the infusion.
Relaxant responses to ATP and vagal inhibitory stimulation were not influenced by theophylline, scarcely affected by α,β‐methylene ATP, but were reduced or blocked by reactive blue 2.
The results are consistent with ATP being an inhibitory neurotransmitter in the stomach of the rabbit.
Methylflavonolamine hydrochloride inhibits contractions induced by noradrenaline, calcium and potassium in rabbit isolated aortic strips
Authors: Zhang Ming‐Sheng , Zhou Er‐Feng 
Published: July 2012

The effects of methylflavonolamine hydrochloride (4′‐methyl‐7‐(2‐hydroxy‐3‐isopropylaminopropoxy)‐flavone hydrochloride, MFA) were investigated and compared with verapamil and papaverine on rabbit isolated aortic strips, which were contracted by noradrenaline, calcium and potassium.
Pre‐incubation for 25 min with either MFA (0.03 to 0.2 mm) or papaverine (0.03 to 0.2 mm) induced non‐parallel and concentration‐dependent rightward displacements of the curves to noradrenaline (0.00001 to 0.1 mm) with the maximal response depressed. The calculated pD′2 values (mean ± s.d.) were 3.89 ± 0.15 for MFA and 3.93 ± 0.05 for papaverine, respectively. Verapamil (0.03 to 0.2 mm) inhibited the contraction induced by noradrenaline in a competitive manner with a pA2 value of 5.91 ± 0.83.
In depolarized aortic strips of the rabbit, prior exposure to MFA (0.03 to 0.3 mm) and papaverine (0.03 to 0.2 mm) shifted the cumulative curves to Ca2+ (0.003 to 100 mm) parallel to the right with the maximal responses depressed, pD′2 values being 3.88 ± 0.05 and 3.89 ± 0.13, respectively. Verapamil produced comparable inhibition of the contraction at much lower concentrations (30 to 300 nm).
MFA (0.03 and 0.1 mm) inhibited the contraction elicited by graded depolarization at a constant Ca2+ concentration with a pD′2 value of 4.09 ± 0.07.
The present results show that MFA has some actions consistent with a calcium antagonist. It resembles papaverine more closely than verapamil.
The lack of involvement of cyclic nucleotides in the smooth muscle relaxant action of BRL 34915
Authors: Gillespie John S. , Sheng Hong 
Published: July 2012

The relaxant effect of BRL 34915 has been examined on four isolated preparations, the bovine retractor penis (BRP), guinea‐pig taenia coli, guinea‐pig trachea and rabbit aortic strip contracted by either histamine, carbachol, noradrenaline or 10 mM KCl. Even though the probability of the involvement of external calcium entering through voltage‐operated channels in these tissues varied, there was little corresponding variation in sensitivity to BRL 34915.
The relaxant effect of BRL 34915 on the BRP and guinea‐pig taenia coli was unaffected by haemoglobin 3.3 μm or Apamin 0.5 μm, concentrations which blocked completely the relaxant effect of non‐adrenergic, non‐cholinergic (NANC) nerve stimulation in these tissues.
BRL 34915 in doses causing maximum relaxation did not increase the levels of either cyclic AMP or cyclic GMP in the BRP, although the appropriate enzymes were present and could be stimulated by forskolin or sodium nitroprusside.
In the BRP isoprenaline 30 μm acting through β‐receptors caused maximum relaxation but did not raise the levels of cyclic AMP, even though lower doses of 2 μm did raise the levels of this nucleotide in the rabbit uterus.
These results provide some indirect evidence that membrane hyperpolarization may not be the only cause of the smooth muscle relaxation induced by BRL 34915. However, neither a rise in cyclic AMP nor cyclic GMP are satisfactory alternative mechanisms.
Characterization of receptors for platelet‐activating factor on platelets, polymorphonuclear leukocytes and macrophages
Authors: Stewart A.G. , Dusting G.J. 
Published: July 2012

We have compared the potency of the putative platelet‐activating factor (Paf) receptor antagonists (WEB 2086, L‐652,731 and BN 52021) against Paf‐induced aggregation of rabbit and guinea‐pig platelets, aggregation of rabbit polymorphonuclear leukocytes (PMNLs) and prostacyclin generation by guinea‐pig resident peritoneal macrophages.On rabbit washed platelets and PMNLs WEB 2086, L‐652,731 and BN 52021 each antagonized competitively Paf‐induced aggregation. The rank order of potency was WEB 2086 ⋍ L‐652, 731 > BN 52021 and was the same for the two cell types.The pA2values for each of the three antagonists were similar on rabbit washed platelets and PMNLs. Moreover, the pA2for WEB 2086 on rabbit platelets (7.58) did not differ significantly from that on guinea‐pig platelets (7.69).On guinea‐pig resident peritoneal macrophages WEB 2086 was 10 fold less potent for receptors mediating increased generation of 6‐oxo‐prostaglandin F1α(6‐oxo‐PGF1α) than for those mediating platelet aggregation.The potencies of L‐652,731 and BN 52021 were also markedly less (2 log units) for the macrophage receptors than for platelet or PMNL receptors and BN 52021 was more potent than L‐652, 731 in the macrophages.WEB 2086 and L‐652,731 significantly reduced basal 6‐oxo‐PGF1αproduced by macrophages, but none of the antagonists affected 6‐oxo‐PGF1αproduction during stimulation by A23187.These data raise the possibility that there may be a Paf receptor‐subtype mediating prostacyclin generation in macrophages that is different from that on the platelet and PMNL. Hence, the potency of Paf antagonists against platelet aggregation would not be a good predictor of antagonist potency in disorders involving macrophages.
Dicyclomine discriminates between M1‐ and M2‐muscarinic receptors in the guinea‐pig ileum
Authors: Kilbinger H. , Stein A. 
Published: July 2012

The affinity of the antagonist dicyclomine for subtypes of muscarinic receptors has been assessed in the myenteric plexus‐longitudinal muscle preparation of the guinea‐pig.
Dicyclomine had a high affinity (pA2 9.13) for the neuronal M1‐receptor whose activation by pilocarpine causes an increase in acetylcholine release. Dicyclomine had a low affinity for both the prejunctional M2‐receptor (pA2 7.61) mediating inhibition of the electrically‐evoked acetylcholine release and the postjunctional M2‐receptor (pA2 7.21).
It is concluded that dicyclomine distinguishes between M1‐ and M2‐muscarinic receptors in functional experiments.
Antagonism of PGD2 vasodepressor responses in the rat in vivo by the novel, selective antagonist, BW A868C
Authors: Hamid‐Bloomfield S. , Whittle B.J.R. 
Published: July 2012

Bolus intravenous injection of prostaglandin D2 (PGD2, 1–160μg kg−1), the hydantoin prostanoid BW245C (0.25–160 μg kg−1) or prostacyclin (PGI2, 0.05–0.5 μg kg−1) caused a dose‐dependent fall in systemic arterial blood pressure (BP) in the anaesthetized rat, lasting 2–4 min.
Intravenous infusion of the novel 3‐benzyl substituted hydantoin, BW A868C (1–10 μg kg−1 min−1), in doses that had no direct effect on BP, dose‐dependently reduced the vasodepressor action of PGD2.
Bolus injection of BW A868C (30 and 100 μg kg−1, i.v.) likewise dose‐dependently antagonized the vasodepressor responses to PGD2, causing a 3.4 and 13.2 fold rightward shift of the dose‐response curve.
The thromboxane‐receptor antagonist, BM 13.177 (2.5 mg kg−1 i.v.) had little effect on the PGD2 vasodepressor responses, suggesting minimal contribution of a PGD2 interaction at thromboxane receptor‐sites in the systemic vasculature of this species.
BW A868C (10 μg kg−1 min−1 i.v.) caused a rightward shift (59 fold) of the dose‐response relationship for BW245C, the putative PGD2‐receptor agonist. This antagonism lasted for at least 1h after termination of the BW A868C infusion. Higher doses of BW A868C (20–100 μg kg−1 min−1) caused no further antagonism of the vasodepressor responses to BW245C, suggesting that this prostanoid also acts at vascular receptors other than of the DP‐type.
BW A868C (10 μg kg−1 min−1, i.v.) failed to alter the vasodepressor actions of prostacyclin.
These findings in the rat in vivo support the characterization of BW A868C as a potent and selective antagonist of the cardiovascular actions of PGD2 at the DP‐receptor.
Structure‐activity relationships of new analogues of arecaidine propargyl ester at muscarinic M1 and M2 receptor subtypes
Authors: Moser U. , Lambrecht G. , Wagner M. , Wess J. , Mutschler E. 
Published: July 2012

The potency of arecaidine propargyl ester (APE) and of several analogues containing a modified ester side chain has been assessed at M1 and M2 muscarinic receptor subtypes. APE was shown to act as a potent agonist at ganglionic M1 receptors in the pithed rat, at M2 receptors in guinea‐pig isolated atria (‐log EC50 = 8.22) and ileum (‐log EC50 = 7.77).
The arecaidine 2‐butynyl and 2‐pentynyl esters were approximately equipotent with APE at M1 and M2 receptors, whereas the 2‐hexynyl derivative was found to be less potent than APE in atria (‐log EC50 = 6.80) and ileum (‐log EC50 = 6.70) by about one order of magnitude. The 2‐heptynyl and 3‐phenyl propargyl esters exhibited no agonist actions in atria and ileum.
Shifting the triple bond from the 2 to the 3 position and introducing a bulky group at position 1 of the ester side chain of APE and analogues resulted in competitive antagonists (pA2 ranging from 4.9 to 7.3).
APE and its 2‐butynyl analogue showed some agonistic selectivity for cardiac M2 receptors (potency ratio, ileum/atria = 2.8 and 4.6 respectively). All antagonists in this series of compounds were not selective in terms of affinity since their pA2 values at cardiac and ileal M2 receptors were similar (potency ratios, ileum/atria = 0.4 to 1.2).