bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evidence for prejunctional inhibitory muscarinic receptors on sympathetic nerves innervating guinea‐pig trachealis muscle
Authors: Pendry Yvonne D. , Maclagan Jennifer 
Published: July 2012

Relaxation responses induced by stimulation of the postganglionic sympathetic nerve trunk were studied in the isolated, fluid‐filled, innervated tracheal tube preparation of the guinea‐pig.
The thromboxane‐mimetic U46619, prostaglandin F2α and histamine each caused concentration‐dependent increases in the intraluminal pressure (ILP) of the fluid‐filled tracheal tube, reflecting contraction of the trachealis muscle. Sympathetic nerve stimulation in the presence of the spasmogens caused relaxations which increased with increasing ILP. Relaxant responses evoked in the presence of these three spasmogens were comparable at any given ILP.
Muscarinic agonists caused concentration‐dependent increases in ILP, pilocarpine being more potent than acetylcholine. Sympathetic nerve‐induced relaxations were reduced in the presence of pilocarpine and acetylcholine when compared to those obtained at the same ILP in the presence of U46619. This inhibitory effect of muscarinic agonists on sympathetic nerve‐induced responses was concentration‐dependent.
Exogenously applied noradrenaline opposed the contractile effect of U46619 and acetylcholine to a similar extent, indicating that a comparable degree of postjunctional functional antagonism exists between the sympathetic neurotransmitter noradrenaline and both spasmogens.
The selective M2 muscarinic antagonists, gallamine and methoctramine, altered neither the postjunctional contractile action of acetylcholine nor its inhibitory effect on sympathetic nerve‐induced relaxations. In addition, the inhibitory effect of acetylcholine was not modified by concentrations of pirenzepine known to block M1 muscarinic receptors.
The postjunctional contractile action of acetylcholine and its inhibitory effect on sympathetic neurotransmission were antagonized by atropine, by the M3 muscarinic antagonist hexahydrosiladiphenidol and by higher concentrations of pirenzepine.
These results suggest that in the guinea‐pig trachea, muscarinic cholinoreceptor agonists inhibit sympathetic neurotransmission via activation of muscarinic receptors located on the sympathetic nerve endings. These inhibitory prejunctional muscarinic heteroreceptors are of the M3 subtype.
Characterization of endogenous noradrenaline release from intact and epithelium‐denuded rat isolated trachea
Authors: Racké Kurt , Bähring Astrid , Brunn Gernot , Eisner Mathias , Wessler Ignaz 
Published: July 2012

Overflow of endogenous noradrenaline (NA) from the in vitro incubated rat trachea evoked by two periods of electrical field stimulation (S1, S2, at 3 or 15 Hz) or by high potassium (60 mm) was determined by high performance liquid chromatography (h.p.l.c.) with electrochemical detection.
In the presence of the neuronal uptake inhibitor desipramine, the α2‐adrenoceptor antagonist, yohimbine, enhanced the overflow of NA evoked by stimulation at 3 Hz by about 100% suggesting the presence of presynaptic inhibitory autoreceptors on the sympathetic nerves innervating the trachea.
When desipramine and yohimbine were present throughout the experiments, the overflow of NA evoked by the second period of electrical stimulation (S2) was significantly smaller than that evoked by the first (S1). This decline of overflow was prevented when the NA precursor, tyrosine, was additionally present throughout the experiments.
After removal of the epithelium, the tissue content of NA was reduced by about 30%, suggesting that part of the NA may be present and released within the epithelium. However, the overflow of NA evoked by stimulation at 3 Hz or 15 Hz was reduced by 70–80%, indicating that the epithelium may additionally exert a permissive role on the release of NA within the airways, possibly by suppressing inhibitory factors.
Stimulation by high potassium (60 mm for 10 min) caused a large overflow of NA (about 45% of the tissue NA), both from epithelium‐free and epithelium‐denuded tracheae. Thus the ‘endogenous inhibition’ of NA release after removal of the epithelium is surmountable when a high potassium stimulus is applied.
An enhanced muscarinic inhibition of NA release in epithelium‐denuded tracheae may not be responsible for the reduction in NA overflow, since the muscarinic receptor antagonist, scopolamine, did not significantly affect the overflow of NA evoked by 3 or 15 Hz, either in the presence or the absence of the epithelium.
The muscarinic receptor agonist, oxotremorine, inhibited the overflow of NA evoked by stimulation at 3 Hz almost completely, an effect antagonized by scopolamine, demonstrating specific, inhibitory muscarinic receptors.
Since damage to the epithelium is known to occur in obstructive bronchial disease, the present experiments suggest that an impaired sympathetic (broncho‐relaxant) neurotransmission could be involved in the pathogenesis of bronchoconstriction.
Possible dependence of pressor and heart rate effects of NG‐nitro‐l‐arginine on autonomic nerve activity
Authors: Wang Yong‐Xiang , Pang Catherine C.Y. 
Published: July 2012

The effects of NG‐nitro‐l‐arginine (l‐NNA) on mean arterial pressure (MAP) and heart rate (HR) were investigated in conscious rats.
Intravenous bolus cumulative doses of l‐NNA (1–32 mg kg−1) dose‐dependently increased MAP. Both mecamylamine and phentolamine increased MAP responses to l‐NNA, angiotensin II and methoxamine. Propranolol, reserpine, atropine and captopril did not affect MAP response to l‐NNA.
A significant negative correlation of HR and MAP responses to l‐NNA was obtained in control rats but not in rats pretreated with reserpine or mecamylamine. Significant negative correlations also occurred in the presence of atropine, propranolol, phentolamine or captopril.
A single i.v. bolus dose of l‐NNA (32 mg kg−1) raised MAP to a peak value of 53 ± 3 mmHg and the effect lasted more than 2 h; the rise and recovery of MAP were accompanied by significant decrease and increase in HR, respectively. While both phentolamine and mecamylamine increased peak MAP response to l‐NNA, mecamylamine abolished the biphasic HR response and phentolamine potentiated the bradycardic component of HR.
Blockade of the autonomic nervous and renin‐angiotensin systems did not attenuate the pressor effects of l‐NNA. However, the biphasic HR response to l‐NNA is mediated via modulation of autonomic nerve activities.
Further evidence for the existence of NK2 tachykinin receptor subtypes
Authors: Patacchini Riccardo , Astolfi Mara , Quartara Laura , Rovero Paolo , Giachetti Antonio , Maggi Carlo Alberto 
Published: July 2012

We have evaluated the biological activity of a number of neurokinin A (4–10), (NKA (4–10)) analogues in the endothelium‐deprived rabbit isolated pulmonary artery (RPA) and hamster isolated trachea (HT), two tissues rich in different NK2 receptor subtypes.
MDL 28,564, a pseudopeptide selective for NK2 receptor sites, behaved as a full agonist in the RPA, while in the HT it competitively antagonized NKA or [βAla8]‐NKA (4–10) contractile effects.
The peculiar behaviour of MDL 28,564 in the RPA and HT may be explained neither by a difference in receptor reserve between the two organs (the reserve being three times greater in RPA than in the HT) nor by a different affinity for the two receptor subtypes (identical dissociation constants, pKA or pKB, calculated in the RPA and in the HT). On the other hand, MDL 28,564 displayed a very different intrinsic efficacy for the two receptor subtypes.
The novel peptides MEN 10,295 ([Trp7, βAla8]‐NKA‐(4–10)) and MEN 10,296 ([Tyr5, Trp7, βAla8]‐NKA‐(4–10)) behaved as weaker agonists than MDL 28,564 in the RPA, but retained appreciable agonist activity also in the HT.
The novel peptides: MEN 10,282 ([Tyr5, d‐Trp6,8, Trp9, Arg10]‐NKA‐(4–10)), MEN 10,449 ([diI‐Try5, d‐Trp6,8,9, Arg10]‐NKA‐(4–10)) and the cyclic hexapeptide L 659,877 (cyclo [Leu‐Met‐Gln‐Trp‐Phe‐Gly]) behaved as competitive antagonists against NKA contractile effects both in the RPA and HT. MEN 10,282 and MEN 10,449 were unable to distinguish between the NK2 receptor subtypes, having almost the same affinity in the two organs. On the other hand L 659,877 was about 15 times more potent in the HT than in the RPA.
These results provide further evidence for NK2 receptors heterogeneity and are useful in outlining pharmacological features of the two subtypes present in the RPA and HT.
Effect of a 7‐day treatment with idazoxan and its 2‐methoxy derivative RX 821001 on α2‐adrenoceptors and non‐adrenoceptor idazoxan binding sites in rabbits
Authors: Portillo M. , Reverte M. , Langin D. , Senard J.M. , Tran M.A. , Berlan M. , Montastruc J.L. 
Published: July 2012

The present study investigates the influence of a 7‐day treatment with 2 mg kg−1, s.c., twice daily of RX 821002 (an α2‐adrenoceptor antagonist which binds only to α2‐adrenoceptors) or idazoxan (α2‐antagonist which binds to α2‐adrenoceptors and also to non‐adrenoceptor idazoxan binding sites: NAIBS) on α2‐adrenoceptor (labelled with [3H]‐RX 821002) and NAIBS (labelled with [3H]‐idazoxan) number in three tissues (adipocytes, colocytes and platelets) in the rabbit.
Acute administration of RX 821002 or idazoxan increased plasma non‐esterified fatty acids (NEFA) and catecholamine levels with no change in plasma glucose levels.
The 7‐day treatment with RX 821002 or idazoxan failed to influence food intake, total body weight or perirenal adipose tissue weight.
RX 821002 and idazoxan increased the number of [3H]‐RX 821002 binding sites in adipose tissue with no change in colocytes or platelets.
RX 821002 and idazoxan failed to modify [3H]‐idazoxan binding sites on adipocytes and colocytes. No significant [3H]‐idazoxan binding was detected on rabbit platelets.
The results show that a 7‐day treatment with α2‐antagonists induces an up‐regulation in adipocyte α2‐adrenoceptors. In contrast, this phenomenon does not involve all the tissues since colocytes and platelets escape the effects of α2‐antagonists. The data suggest a differential regulation of α2‐adrenoceptors according to their location.
The fact that NAIBS did not vary suggests that α2‐adrenoceptors and NAIBS are two different entities. Finally, since RX 821002 and idazoxan exert similar effects after either acute or chronic treatment, it is suggested that NAIBS are not involved in the control of catecholamine release or in NEFA or glucose metabolism.
Evidence against a role for dopamine D1 receptors in the myocardium of the pig
Authors: Van Woerkens L.J. , Duncker D.J. , Den Boer M.O. , McFalls E.O. , Sassen L.M.A. , Saxena P.R. , Verdouw P.D. 
Published: July 2012

We investigated the presence of dopamine D1 receptors in the myocardium of anaesthetized pigs using intravenous infusions of dopamine, alone and after α‐ and β‐adrenoceptor blockade and intracoronary infusions of the selective D1 receptor agonist, fenoldopam.
Intravenous infusion of dopamine (2.5, 5 and 10 μg kg−1 min−1 for 10 min, n = 6) caused dose‐dependent changes in heart rate (from 94 ± 6 to 132 ± 10 beats min−1, P < 0.05), the maximal rate of rise of left ventricular pressure (LVdP/dtmax; from 2280 ± 170 to 4800 ± 410 mmHgs−1, P < 0.05), mean arterial blood pressure (from 87 ± 5 to 62 ± 3 mmHg) and systemic vascular resistance (from 40 ± 4 to 28 ± 2 mmHg l−1 min, P < 0.05). The increases in heart rate and LVdP/dtmax were abolished when dopamine was infused after α‐ and β‐adrenoceptor blockade. The vasodilator response was, however, only minimally affected.
Intravenous infusions of dopamine decreased coronary vascular resistance from 0.90 ± 0.06 to 0.53 ± 0.07 mmHg ml−1 min 100 g (P < 0.05). This action of dopamine was not observed when dopamine was infused after blockade of the α‐ and β‐adrenoceptors.
Pretreatment with α‐ and β‐adrenoceptor blockade had no effect or only slightly attenuated the dopamine‐induced decrease in vascular resistance of the brain, kidneys, adrenals and small intestine.
In 7 animals, intracoronary doses of 0.04, 0.1, 0.2 and 0.4 μg kg−1 min−1 of fenoldopam had no effect on coronary venous oxygen content, local myocardial oxygen consumption, coronary blood flow or coronary vascular resistance. However, systemic effects were observed at the highest two doses, as manifested by a drop in mean arterial blood pressure from 82 ± 4 to 72 ± 4 mmHg (P < 0.05) due to peripheral vasodilatation (e.g. cerebral vascular bed). Heart rate, LVdP/dtmax, regional myocardial segment length shortening and left ventricular end‐diastolic pressure were not affected at these doses. In 2 animals the infusion rate was increased to 4 μg kg−1 min−1, but again there was no evidence for coronary vasodilatation.
We conclude that the intravenous infusion of dopamine after α‐ and β‐adrenoceptor blockade and the intracoronary infusion of fenoldopam provided no evidence for a major role of D1 receptors in the coronary circulation of pigs. The absence of any effect of the employed doses of fenoldopam on LVdP/dtmax and on regional myocardial segment length shortening also indicates that fenoldopam does not exhibit any inotropic action in this species.
Different mechanisms of action of agents acting on β‐adrenoceptors in barium‐stimulated and electrically‐stimulated rat vas deferens
Authors: Diaz‐Toledo Alejandro , Jurkiewicz Aron 
Published: July 2012

The relaxation induced by β‐adrenoceptor agonists in rat vas deferens was examined under two different experimental conditions: on electrically‐induced twitch responses (35 V, 3 ms, 0.07 Hz), and on contractions induced by single doses of barium chloride (300 μm). The experiments were performed in vasa of reserpine‐treated rats, after blockade of α‐adrenoceptors and extraneuronal uptake with dibenamine (10 μm, 30 min), and neuronal uptake with cocaine (10 μm).
When twitch responses were used, the values of pD2, interpolated from cumulative concentration‐response curves for isoprenaline (Iso), adrenaline (Ad), and noradrenaline (NA) showed a rank order of potency consistent with the presence of β2‐adrenoceptors (Iso > Ad ≫ NA).
When twitch responses were used, the non‐selective β‐antagonist, propranolol, caused a concentration‐dependent parallel shift to the right of Iso concentration‐response curves. Similar shifts were obtained by use of the β2‐antagonist, isopropylmethoxamine (IMA), and higher doses of the β1‐antagonist, practolol, according to the expectations from receptor occupation theory. Practolol presented the lowest value of pKB, 5.03, corroborating the presence of β2‐adrenoceptors.
When twitch responses were used, and Ad or NA employed instead of Iso, the antagonists produced shifts of concentration‐response curves which were smaller than expected from theory, precluding the determination of pKB values. This indicates that other mechanisms are involved besides an interaction with a single population of postsynaptic β2‐adrenoceptors.
When barium chloride was used instead of twitch responses, although the potencies of Iso and Ad were increased respectively by about 30 fold and 5 fold, the rank order of potency was still consistent with an interaction with β2‐adrenoceptors. In addition, the antagonists produced parallel and concentration‐dependent shifts of the curves of all the agonists, as expected from receptor theory. The values of pKB for a given antagonist were not modified by interchanging the agonists used, indicating a typical interaction with a single population of β2‐adrenoceptors. When compared to the field‐stimulated vas, the values of pKB for propranolol and IMA against isoprenaline were respectively 1.3 and 0.6 log units larger. These results suggest the β‐adrenoceptor agents act by different mechanisms of action in barium‐stimulated and electrically‐stimulated vas.
It is suggested that when barium is used, the effects of agents acting on β‐adrenoceptors are mediated only by postsynaptic β2‐receptors, while other complicating factors, probably nerve‐dependent presynaptic mechanisms, may be involved with electrical stimulation.
Ruthenium‐red inhibits CGRP release by capsaicin and resiniferatoxin but not by ouabain, bradykinin or nicotine in guinea‐pig heart: correlation with effects on cardiac contractility
Authors: Franco‐Cereceda Anders , Lou Ya‐Ping , Lundberg Jan M. 
Published: July 2012

The possible influence of ruthenium‐red (RR) on contractility and outflow of calcitonin gene‐related peptide (CGRP)‐like and neuropeptide Y (NPY)‐like immunoreactivity (LI) from the heart of the guinea‐pig induced by capsaicin, resiniferatoxin, nicotine, ouabain or bradykinin was studied in vitro.
In the isolated right atrium, exposure to capsaicin evoked an increase in contractile rate and tension simultaneously with an enhanced outflow of CGRP‐LI, indicating release from the atria. Repeated administration of capsaicin induced tachyphylaxis. Incubation with RR markedly attenuated the capsaicin‐evoked release of CGRP‐LI while no clear‐cut effects were seen on contractile tension or rate.
In the isolated whole heart, perfusion with capsaicin induced an increased outflow of CGRP‐LI and stimulated heart rate, while a negative inotropic effect was observed. A second administration of capsaicin to the same preparations failed to influence the CGRP‐LI outflow and in these experiments the positive chronotropic effect was absent while the negative inotropic action remained unchanged. Capsaicin‐perfusion in the presence of RR failed to induce any increased outflow of CGRP‐LI from the hearts or changes in contractile activity. However, after 1 h of rinsing with Tyrode solution repeated capsaicin perfusion in the absence of RR caused a clear‐cut (60% of control) release of CGRP‐LI and contractile responses were restored.
Perfusion with resiniferatoxin evoked a RR‐sensitive, clear‐cut increased CGRP‐LI output without any effects on contractile force or heart rate. Repeated administration of resiniferatoxin induced tachyphylaxis with respect to outflow. Capsaicin perfusion after resiniferatoxin did not influence cardiac rate, force or CGRP‐LI outflow suggesting development of cross‐tachyphylaxis.
Perfusion with RR did not influence the outflow of CGRP‐LI or contractility changes evoked by perfusion with nicotine, ouabain or bradykinin. In addition, the release of NPY‐LI by nicotine remained unchanged in the presence of RR. Furthermore, the positive chronotropic effect of human CGRP alpha remained intact in the presence of RR.
It is concluded that RR selectively inhibits capsaicin‐ and resiniferatoxin‐induced excitation of cardiac sensory nerves as revealed by inhibition of both CGRP‐LI release and the cardiostimulatory action of capsaicin. RR also seems to protect the cardiac capsaicin‐sensitive fibres from the development of tachyphylaxis to capsaicin. Finally, RR prevents the capsaicin‐evoked negative inotropic effect which is not related to activation of sensory nerves.
Endothelium‐dependent and independent relaxation of the rat aorta by cyclic nucleotide phosphodiesterase inhibitors
Authors: Komas Narcisse , Lugnier Claire , Stoclet Jean‐Claude 
Published: July 2012

The effects of selective inhibitors of adenosine 3′: 5′‐cyclic monophosphate (cyclic AMP) and guanosine 3′: 5′‐cyclic monophosphate (cyclic GMP) phosphodiesterases (PDEs) were investigated on PDEs isolated from the rat aorta and on relaxation of noradrenaline (1 μm) precontracted rat aortic rings, with and without functional endothelium.
Four PDE forms were isolated by DEAE‐sephacel chromatography from endothelium‐denuded rat aorta: a calmodulin‐activated PDE (PDE I) which hydrolyzed preferentially cyclic GMP, two cyclic AMP PDEs (PDE III and PDE IV) and one cyclic GMP‐specific PDE (PDE V). The latter was selectively and potently inhibited by zaprinast. The two cyclic AMP PDEs were discriminated by specific inhibitors: one was inhibited by cyclic GMP (PDE III) and by new cardiotonic agents (milrinone, CI 930, LY 195115 and SK&F 94120); the other was inhibited by denbufylline and rolipram (PDE IV). None of these drugs significantly inhibited PDE I.
The PDE III inhibitors caused endothelium‐independent relaxations of rat aortic rings with the following EC50 values (μm concentration producing 50% relaxation): LY 195115: 3.4, milrinone: 5.7, CI 930; 7.8, SK&F 94120: 14.7. Neither NG‐monomethyl‐l‐arginine (l‐NMMA, 300 μm), an inhibitor of the l‐arginine‐NO pathway, nor l‐arginine (1 mm) modified the effect of PDE III inhibitors. However, methylene blue (10 μm) an inhibitor of soluble guanylate cyclase abolished relaxation induced by PDE III inhibitors except in the case of compound CI 930.
The specific PDE IV and PDE V inhibitors both produced endothelium‐dependent relaxations which were inhibited by l‐NMMA and by methylene blue (10 μm). In the presence of l‐NMMA, relaxation was restored by subsequent addition of l‐arginine.
The relaxant effects of denbufylline and rolipram were studied in the presence of drugs stimulating either adenylate cyclase (forskolin and isoprenaline) or soluble guanylate cyclase (sodium nitroprusside, SNP), or inhibiting PDE III (milrinone). In endothelium‐denuded rings, a relaxing effect of both denbufylline and rolipram was found in the presence of milrinone (EC50 values 1.7 and 12 μm, respectively) or SNP (EC50 values 12.3 and 124 μm, respectively), but not in the presence of forskolin or isoprenaline. However in the presence of functional endothelium, relaxations produced by PDE IV inhibitors were significantly potentiated by forskolin, isoprenaline, milrinone and SNP (respective EC50 values for denbufylline: 2, 2, 0.4 and 0.7 μm and for rolipram: 7, 13, 7 and 1.2 μm).
These results indicate that the relaxant effects of inhibitors of the cyclic AMP‐specific PDE IV are markedly enhanced by cyclic GMP elevating agents and by the PDE III inhibitor milrinone. They support the hypothesis that cyclic GMP enhances cyclic AMP‐mediated relaxation, possibly through the inhibition of the cyclic GMP‐inhibited PDE III.
BAY u3405 an antagonist of thromboxane A2‐ and prostaglandin D2‐induced bronchoconstriction in the guinea‐pig
Authors: Francis H.P. , Greenham S.J. , Patel U.P. , Thompson A.M. , Gardiner P.J. 
Published: July 2012

The novel thromboxane (TX) antagonist, BAY u3405, has been evaluated against bronchoconstriction induced by the TXA2 mimetic U‐46619, prostaglandin D2 (PGD2), 5‐hydroxytryptamine (5‐HT), leukotriene D4 (LTD4) and histamine in the guinea‐pig in vivo by use of a modification of the model described by Konzett & Rössler.
When given intravenously (i.v.) at 30 or 100 μg kg−1, U‐46619 caused 80% maximal bronchoconstriction in most animals. In contrast, PGD2 caused a smaller 40%‐50% maximal bronchoconstriction at the highest dose tested (300 μg kg−1, i.v.).
BAY u3405, given intravenously, orally (p.o.) or by aerosol antagonized U‐46619‐induced bronchoconstriction in a dose‐related manner. The approximate ID50 values were 600 μg kg−1, i.v., 1.7 mg kg−1 p.o. and 0.1% w/v 20 breaths by aerosol.
BAY u3405 had similar inhibitory activities against U‐46619‐induced bronchoconstriction and hypertension suggesting that it had no preferential activity on the airways.
When given intravenously BAY u3405 antagonized the bronchoconstrictor effect of intravenous PGD2 with ID50 values between 30–100 μg kg−1.
The action of BAY u3405 (10 mg kg−1, p.o.) was long lasting, causing significant inhibition of U‐46619‐induced bronchoconstriction 7 h after dosing.
At 1 mg kg−1, i.v., a dose that abolished the response to U‐46619 and PGD2, BAY u3405 had no effect on histamine‐, 5‐HT‐ or LTD4‐induced bronchoconstriction.
BAY u3405 potently and selectively antagonized U‐46619‐ or PGD2‐induced bronchoconstriction in the Konzett‐Rössler model of guinea‐pig lung function. It should therefore prove to be a useful tool for defining the role of TXA2 and PGD2 in airway diseases such as asthma.