bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for inhibition of sympathetic neurotransmission by endogenously released acetylcholine in the guinea‐pig trachea
Authors: Pendry Yvonne D. , Maclagan Jennifer 
Published: July 2012

Interactions between pulmonary cholinergic and noradrenergic nerves were studied in the innervated tracheal tube preparation isolated from guinea‐pigs anaesthetized with urethane. Relaxations of the trachealis smooth muscle in response to postganglionic stimulation of the sympathetic nerve were recorded as decreases in the intraluminal pressure of the tracheal tube after the pressure had been raised with the stable thromboxane‐mimetic, U46619. In contrast, contractions following preganglionic stimulation of the vagal nerve trunk were recorded as increases in intraluminal pressure.
In approximately half of the preparations studied, concurrent stimulation of the vagal nerve trunk inhibited relaxation responses elicited by stimulation of the sympathetic nerves. The vagi were stimulated at parameters which caused no change in intraluminal pressure, excluding the involvement of postjunctional mechanisms.
The effect of simultaneous stimulation of the sympathetic nerve trunk was studied on contractile responses evoked by preganglionic stimulation of the vagus nerve. In 80% of the preparations tested the vagal responses were inhibited. This inhibitory effect of sympathetic nerve stimulation was antagonized by propranolol.
The potassium channel agonist, cromakalim, endothelins 1 and 3 and the neuropeptides, vasoactive intestinal peptide, neurokinin A and substance P, did not significantly modulate sympathetic nerve‐induced relaxations.
The anticholinesterase drug, physostigmine, induced a concentration‐dependent increase in the intraluminal pressure of the tracheal tube and potentiated the postjunctional action of exogenously applied acetylcholine to contract the guinea‐pig trachealis muscle. In the presence of higher concentrations of physostigmine both vagally‐induced contractions and sympathetic nerve‐induced relaxations were reduced. Atropine blocked both the inhibitory effect of physostigmine on sympathetic relaxations and its postjunctional contractile action on the trachealis smooth muscle.
It is concluded that, in the guinea‐pig trachea, acetylcholine released endogenously from pulmonary parasympathetic nerves, either by anticholinesterase drugs or in response to nerve stimulation, can inhibit transmission in the adjacent sympathetic nerves via activation of prejunctional muscarinic heteroreceptors, probably of the M3 subtype.
The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers
Authors: Riva E. , Mennini T. , Latini R. 
Published: July 2012

We compared the α1, α2‐ and β1‐adrenoceptor blocking potencies of labetalol with those of its two stereoisomers (RR and SR) in pithed rats and in homogenized rat cerebral cortex and heart.
In pithed rats, labetalol and the RR‐SR combination were given orally either at doses of 25 and 50 mg kg−1 body wt. or intravenously at doses of 1 and 5 mg kg−1 body wt. Prazosin 4 and 20 μg kg−1 body wt. and propranolol 1 and 5 mg kg−1 body wt., were given intravenously for comparison studies of potency at α1‐ and β1‐adrenoceptors, respectively. Effects were studied before and after i.v. administration of either phenylephrine (at doses which increased the mean arterial pressure by approximately 80 mmHg) or isoprenaline (at doses that increased heart rate by approximately 100 beats min−1).
In pithed rats, labetalol and the RR‐SR combination antagonized, in a dose‐dependent manner, the pressor effect of phenylephrine (P < 0.05) and the chronotropic effect of isoprenaline (P < 0.05). Following both oral and intravenous dosing, the RR‐SR combination was twice potent as labetalol in terms of α1‐and β1‐adrenoceptor antagonism at equivalent doses.
Labetalol and the enantiomers lacked affinity at α2‐adrenoceptors while at α1‐adrenoceptors the order of potency was prazosin ≫ RR‐SR > labetalol. At β1‐adrenoceptors, the affinity of the compound RR‐SR was about 3 times that of labetalol.
As labetalol is a mixture of active (RR and SR) and inactive (SS and SR) enantiomers (in terms of α‐ and β‐receptor actions), the combination of RR and SR may be a valuable substitute for labetalol in the treatment of systemic hypertension. Although the potential for non‐specific side effects (common to all four enantiomers) could be expected to be diminished, recent reports by postmarketing surveillance indicate that the RR isomer (dilevalol) can induce liver toxicity. Interestingly, labetalol is devoid of this effect; whether the combination of RR and SR enantiomers could be of clinical importance warrants further investigation.
An analysis of the nitrate‐like and K channel opening actions of KRN2391 in canine coronary arterial smooth muscle
Authors: Okada Yuji , Yanagisawa Teruyuki , Taira Norio 
Published: July 2012

To clarify the mechanism of action of KRN2391, a new vasodilator containing a nitroxy group, its effects on intracellular Ca2+ concentration ([Ca2+]i) and force of contraction in canine coronary artery were compared with those of two derivatives lacking the nitro group.
KRN2391, its hydroxy and acetoxy derivative (Compound 2 and Compound 3, respectively) partially reduced [Ca2+]i in 5 or 30 mm KCl physiological salt solution (PSS), effects which were antagonized by glibenclamide. No KRN2391‐induced change in [Ca2+]i was observed in 90 mm KCl‐PSS.
The order of potency in reducing [Ca2+]i and inhibiting the contracture in 30 mm KCl‐PSS was: KRN2391 > Compound 3 > Compound 2.
In 30 mm KCl‐PSS, KRN2391 shifted the [Ca2+]i‐force relationship so that a greater increase in [Ca2+]i was needed to produce force. Compounds 2 and 3 were ineffective. The [Ca2+]i‐force curve obtained in 90 mm KCl‐PSS was shifted to the right by KRN2391 (10−4 m).
The ability of KRN2391 to reduce the force of contraction in both 30 mm and 90 mm KCl‐PSS was inhibited by 10−5 m methylene blue.
KRN2391 inhibited U46619‐induced contractions; this effect was associated with a reduction of [Ca2+]i, which decreased below the basal level.
Thus, KRN2391 is a potent vasodilator in canine coronary artery. It possesses nitrate‐like and potassium channel opening actions and can be designated as a nitrate‐potassium channel opener (N‐K) hybrid. The denitrate derivatives of KRN2391 are specific K channel openers. The nitroxy moiety in KRN2391 is important for not only its action as a nitrate but also its potency as a K channel opener.
The mechanism of LTE4‐induced histamine hyperresponsiveness in guinea‐pig tracheal and human bronchial smooth muscle, in vitro
Authors: Jacques Crawford A.J. , Spur Bernd W. , Johnson Malcolm , Lee Tak H. 
Published: July 2012

Preincubation of guinea‐pig tracheal smooth muscle with leukotriene E4 (LTE4) in vitro increased its subsequent responsiveness to histamine.
LTE4 pretreatment of guinea‐pig tracheal strips did not affect the subsequent responsiveness to either the contractile agents, carbachol and KCl, or to the relaxant β‐adrenoceptor agonist, isoprenaline.
LTE4‐induced airway histamine hyperresponsiveness was blocked by indomethacin (5 μm), GR32191 (3 μm), atropine (1 μm) and tetrodotoxin (1 μm).
U46619, a stable thromboxane A2‐analogue, at a non‐contractile concentration of 4 nm, increased tracheal smooth muscle sensitivity to histamine.
Both LTE4 and U46619 pretreatment increased the contractile response of tracheal smooth muscle to electrical field stimulation.
Preincubation of human bronchial spirals with LTE4 in vitro increased its subsequent responsiveness to histamine.
LTE4‐induced histamine hyperresponsiveness of human bronchus was inhibited by GR32191 (3 μm) and atropine (1 μm).
It is proposed that LTE4 induces guinea‐pig airway smooth muscle hyperresponsiveness to histamine via a facilitation of cholinergic neurotransmission, which is dependent upon the secondary generation of prostanoid mediator(s) acting on TP‐receptors situated on cholinergic nerve terminals. In addition, it is suggested that LTE4 may induce histamine hyperresponsiveness of human bronchus in vitro by a similar mechanism as to that seen in guinea‐pig central airway smooth muscle.
An analysis of the mechanism of the inotropic action of some milrinone analogues in guinea‐pig isolated atria
Authors: Dorigo P. , Gaion R.M. , Belluco P. , Mosti L. , Borea P.A. , Maragno I. 
Published: July 2012

It has been reported previously that the milrinone analogues, ethyl 5‐cyano‐1,6‐dihydro‐2‐methyl‐6‐oxo‐3 pyridine carboxylate (I) and ethyl 5‐cyano‐1,6‐dihydro‐2‐ethyl‐6‐oxo‐3 pyridine carboxilate (II) exert a positive inotropic effect (EC50 = 15.6 ± 0.2 μm and 40.3 ± 0.1 μm) both on spontaneously beating and on electrically driven atria from reserpine‐treated guinea‐pigs. In the present study the mechanism of the inotropic action of these two agents was investigated.
In electrically driven left atrium from resperpine‐treated guinea‐pigs the EC50 values for inotropic activity for compounds (I) and (II) corresponded to that of milrinone (EC50 = 25 ± 0.1 μm) but compound (I) induced a greater maximum effect. This corresponded to a percentage increase in developed tension over control of 63 ± 0.3 whereas the maximum inotropic effect of milrinone was 48 ± 0.3 and that of compound (II) was 47 ± 0.2.
The inotropic activity of compounds (I) and (II) (10–100 μm) was resistant to propranolol (0.1 μm), thus excluding the involvement of β‐adrenoceptors.
Since the inotropism induced by compounds (I) and (II) was not reduced by carbachol (1 nm‐0.5 μm), an action involving changes in adenosine 3′:5′‐cyclic monophosphate (cyclic AMP) can be excluded.
The inotropic action of compounds (I) and (II) was blocked selectively by 8‐phenyltheophyline (10 μm) or adenosine deaminase (2 u ml−1).
Both (I) and (II) inhibited, in an apparently competitive manner, the negative inotropic effect induced by N6‐(l‐phenylisopropyl) adenosine (l‐PIA), a stable adenosine agonist. The pA2 values for (I) and (II) were 4.79 and 4.36, respectively.
In rat brain compounds (I) and (II) inhibited the specific binding of N6‐cyclohexyl[3H]‐adenosine‐([3H]‐CHA) with an IC50 of 0.18 ± 0.01 mm and 0.25 ± 0.02 mm, respectively, which were similar to their IC50 values for blocking the PIA‐induced negative inotropic effect and which are also in the range of concentrations that are effective in inducing positive inotropism in guinea‐pig atria.
The results from the present study suggest that antagonism of endogenous purines causes positive inotropism without affecting intracellular cyclic AMP levels.
Analysis of the 5‐HT receptors mediating contractions in the rabbit isolated renal artery
Authors: Tadipatri Sreekanth , van Heuven‐Nolsen Dicky , Feniuk Wasyl , Saxena Pramod R. 
Published: July 2012

Using a number of agonist and antagonist compounds, we have attempted to characterize the responses and receptors involved in the effects of 5‐hydroxytryptamine (5‐HT) in the rabbit isolated renal artery.
In vessel segments precontracted with the thromboxane‐mimetic agent, U46619 (100 nm), neither 5‐HT (10−8 to 10−4 m) nor 5‐carboxamidotryptamine (5‐CT; 10−8 to 3 × 10−4 m) caused relaxations like those observed with methacholine. Both 5‐HT and 5‐CT further increased the tone of the vessels, with pD2 values of 7.1 and 7.9, respectively.
In the absence of U46619, both 5‐HT (10−7 to 3 × 10−3 m) and 5‐CT (10−7 to 10−3 m) contracted the rabbit renal artery, but with reduced potencies. The contractions to 5‐HT were reproducible and the rank order of potency (pD2) of the agonists was: α‐methyl‐5‐HT (5.7), sumatriptan (5.3), 5‐HT (5.1), 8‐hydroxy‐2(di‐n‐propylamino)tetralin (5.0), 5‐CT (4.7) and 5‐methoxytryptamine (4.3). 1‐(2,5‐Dimethoxy‐4‐iodophenyl)‐2‐aminopropane, flesinoxan and RU 24969 elicited either only small contractions or none at all.
The contractile effect of 5‐HT was unaffected by MDL 72222 (10−6 m) and metergoline (10−8 and 10−7 m), was weakly antagonized by ketanserin and phentolamine (pKB: 6.6 and 6.8, respectively), but was effectively antagonized by methiothepin (pKB: 8.6). Responses to 5‐CT and sumatriptan were affected by ketanserin, phentolamine and methiothepin similarly to 5‐HT‐induced responses.
Ketanserin was ineffective against noradrenaline‐induced contractions, which were antagonized by phentolamine with a pKB of 7.3. The pKB values of phentolamine against 5‐HT, 5‐CT or sumatriptan were about half a log unit lower than against noradrenaline.
In vascular preparations treated with cocaine (3 × 10−5 m), the potency (pKB) of phentolamine as an antagonist of the responses to noradrenaline (7.6) and 5‐HT (6.7) did not differ significantly from the values in untreated preparations. However, the difference between the pKB values of phentolamine against the two agonists was now about one log unit.
Pretreatment of the vascular strips with 6‐hydroxydopamine (1.5 × 10−3 m) did not significantly affect responses to 5‐HT or 5‐CT, but almost eliminated those to tyramine. Cocaine (3 × 10−5 m) slightly potentiated noradrenaline‐induced contractions, but did not significantly affect those induced by 5‐HT.
These data suggest that: (i) 5‐HT receptors mediating vasodilatation are not present in the rabbit renal artery smooth muscle or endothelium; (ii) the contractile effect of 5‐HT does not involve the release of noradrenaline from sympathetic nerve stores; (iii) the 5‐HT receptor in the rabbit renal artery is not of the 5‐HT2, 5‐HT3 or 5‐HT4 type. The pharmacological properties of this receptor most closely resemble those described for the heterogeneous 5‐HT1‐like category.
Attenuated responses to endothelin‐1, KCl and CaCl2, but not noradrenaline, of aortae from rats with streptozotocin‐induced diabetes mellitus
Authors: Fulton DJ.R. , Hodgson W.C. , Sikorski B.W. , King R.G. 
Published: July 2012

This study investigated the responsiveness to vasoconstrictor agents (including endothelin‐1, ET‐1) of aortic rings from rats with two‐week streptozotocin (STZ, 60 mg kg−1, i.v.)‐induced diabetes and vehicle‐treated control rats. The basal tension was 10 g, which was estimated to be more physiological than the tension of 1–2 g that has been previously used for most studies of aortic rings from diabetic rats.
Maximum responses to ET‐1 (0.13–18 nm), KCl (2–20 mm) or CaCl2 (10 μm–10 mm) were reduced in aortae from STZ‐treated rats compared to those from control rats. Such reductions were still evident after removal of the endothelium.
Responses to noradrenaline (NA, 0.1 nm‐26 μm) of aortae from STZ‐treated rats were not significantly different from responses of aortae of control rats.
Removal of endothelium resulted in a significant reduction in the EC50 values for NA of rings from both STZ‐treated rats (6.90 ± 0.13 and 8.17 ± 0.35 (–log m) with and without endothelium, respectively, n = 5) and control rats (6.90 ± 0.15 and 8.37 ± 0.44 (–log m) with and without endothelium, respectively, n = 5).
In calcium‐free medium (with 1 mm EGTA), responses to NA and ET‐1 were reduced compared with those in normal Krebs solution and maximum responses were less in rings from STZ‐treated compared with control rats.
Indomethacin (5 μm) did not prevent the reduced maximum responsiveness to ET‐1 in rings from STZ‐treated rats compared with those from controls.
This study indicates that changes in vascular responsiveness to ET‐1, KCl and CaCl2 (but not NA) occur in aortae of two‐week STZ‐treated rats. The endothelium does not appear to play a major role in mediating changes in responsiveness to ET‐1.
Potentiation by endothelin‐1 of 5‐hydroxytryptamine‐induced contraction in coronary artery of the pig
Authors: Nakayama Koichi , Ishigai Yutaka , Uchida Hirohisa , Tanaka Yoshio 
Published: July 2012

In order to elucidate the physiological and potential pathological roles of endothelin‐1 (ET‐1) in coronary artery contraction and relaxation, we undertook the present study to examine the action of ET‐1 itself, and the combined effects of ET‐1 with vasoconstrictor agonists such as acetylcholine (ACh), histamine, and 5‐hydroxytryptamine (5‐HT), all of which have been implicated in the genesis of coronary spasm.
Isometric tension and cytosolic Ca2+ concentration ([Ca2+]i) in a ring segment of porcine coronary artery loaded with fura‐2 were measured simultaneously.
ET‐1 contracted the artery in a concentration‐dependent manner; and nisoldipine, a Ca2+ channel blocking drug of the 1,4‐dihydropyridine type, antagonized the ET‐1 action non‐competitively. A radioreceptor binding assay also indicated the mutually exclusive binding of ET‐1 and (+)‐[3H]‐PN200–110, a Ca2+ channel ligand, to the membrane fraction of porcine coronary artery.
ET‐1 (10–100 pm) increased tension and [Ca2+]i in a parallel manner, while at higher concentrations (1–10 nm) it produced further contraction with a small increase in [Ca2+]i.
ET‐1 (30–100 pm) selectively potentiated the 5‐HT‐induced contraction 1.5 to 2 times over the control without causing a significant increase in [Ca2+]i, which seems to be qualitatively similar to a tumour promoting phorbol ester, 12‐deoxyphorbol 13‐isobutylate (DPB). Bay K 8644 (10 nm), on the other hand, potentiated the contraction in response to practically all agonists used and affected a concomitant increase in [Ca2+]i.
A Ca2+ channel blocking drug such as diltiazem abolished the increase in [Ca2+]i and partially attenuated the mechanical potentiation produced by a small amount of ET‐1 in combination with 5‐HT.
The results suggest that ET‐1 and 5‐HT interact functionally at the cellular or subcellular level and modulate the Ca2+ sensitivity of the contractile elements through the possible activation of protein kinase C.
Activation of the 5‐HT1c receptor expressed in Xenopus oocytes by the benzazepines SCH 23390 and SKF 38393
Authors: Briggs Clark A. , Pollock Nancy J. , Frail Donald E. , Paxson Cheryl L. , Rakowski Robert F. , Kang Chae Hee , Kebabian John W. 
Published: July 2012

A cloned 5‐HT1C receptor expressed in Xenopus laevis oocytes was used to characterize the action of four dopamine D1‐selective benzazepines at the 5‐HT1C receptor. Additionally, the apparent binding of the D1‐selective benzazepines to 5‐HT1C receptors was measured in the choroid plexus of the pig.
In voltage‐clamped oocytes expressing the cloned 5‐HT1C receptor, 5‐hydroxytryptamine (5‐HT) elicited a characteristic inward current response with an EC50 of 13 nm. SCH 23390 acted as a stereoselective agonist (or partial agonist) with an EC50 of about 550 nm. SKF 38393 (1 μm–1 mm), SKF 77434 (100 μm), and SKF 82958 (100 μm) also acted as agonists (or partial agonists) at the cloned 5‐HT1C receptor. SKF 38393 was not stereoselective at the 5‐HT1C receptor.
The response to SCH 23390 activated slowly and, although the response contained many oscillations characteristic of the activation of the phosphatidylinositol signal transduction system, SCH 23390 rarely elicited the rapid spike‐like response seen routinely in response to 5‐HT. However, the responses to SKF 38393, SKF 77434, and SKF 82958 were identical in appearance to the response to 5‐HT, except that the responses to the benzazepines were smaller. These comparisons were made by applying both a benzazepine and 5‐HT to each individual oocyte expressing the cloned 5‐HT1C receptor.
Consistent with the responses measured in oocytes, SCH 23390 bound stereoselectively to 5‐HT1C receptors in the choroid plexus of the pig (Ki = 6.3 nm), and SKF 38393 bound non‐stereoselectively with lower affinity (Ki = 2.0–2.2 μm).
It is concluded that while these benzazepines demonstrate selectivity for the dopamine D1 receptor, they also can act as agonists or partial agonists at the 5‐HT1C receptor in situ and as expressed in Xenopus oocytes. The oocyte expression system is useful for studies of the functional pharmacology of these 5‐HT1C receptors. Information about the pharmacological actions and variations in stereoselectivity among dopamine and 5‐HT receptors should be of interest in modelling the interactions of ligands with these G‐protein coupled receptors, and in the testing of such models through receptor mutagenesis.;
Role of nitric oxide in non‐adrenergic, non‐cholinergic inhibitory junction potentials in canine ileocolonic sphincter
Authors: Ward Sean M. , McKeen Emma S. , Sanders Kenton M. 
Published: July 2012

Electrical field stimulation causes neurally‐mediated relaxation of the ileocolonic sphincter that is due to activation of non‐adrenergic and non‐cholinergic (NANC) nerves. Recent studies have suggested that nitric oxide (NO) is the neurotransmitter that mediates relaxation.
Using intracellular recording techniques, we have tested whether NANC inhibitory junction potentials (i.j.ps) in the canine ileocolonic sphincter are also mediated by NO.
Electrical field stimulation elicited excitatory and inhibitory junction potentials: e.j.ps were blocked by atropine (10−6 m) and tetrodotoxin (TTX; 10−6 m); i.j.ps were also blocked by TTX and partially blocked by apamin (10−6 m). I.j.ps were unaffected by atropine, phentolamine and propranolol (all at 10−6 m).
The arginine analogues, l‐NG‐nitroarginine methyl ester (l‐NAME) and NG‐monomethyl‐l‐arginine (l‐NMMA), decreased the amplitude of i.j.ps and l‐arginine, but not d‐arginine, partially restored the i.j.ps.
I.j.ps were also inhibited by oxyhaemoglobin (1%), but not by methaemoglobin.
Exogenous NO (10−7 m to 3 × 10−5 m) caused concentration‐dependent hyperpolarizations that were similar in amplitude to the NANC nerve‐evoked i.j.ps. Hyperpolarizations to NO were unaffected by l‐NAME, but were blocked by oxyhaemoglobin.
Tetrodotoxin, l‐NAME and oxyhaemoglobin all caused depolarization of resting membrane potential.
The specific guanosine 3′:5′‐cyclic monophosphate phosphodiesterase inhibitor, M&B 22948, caused hyperpolarization, increased the maximum level of hyperpolarization reached during i.j.ps, and increased the duration of i.j.ps.
These data further support the hypothesis that NANC neurotransmission in the ileocolonic sphincter is mediated by NO or an NO‐releasing compound. The data also suggest that tonic release of NO, possibly from spontaneous firing of NANC nerves, may regulate resting membrane potential and tone in this sphincter.