Biomedical subjects

C Advenier

Publications and source records attributed to C Advenier.

At least 91 records · Page 5Linked to original sources

PubMed1996

The effect of S-(+)-boldine on the alpha 1-adrenoceptor of the guinea-pig aorta.

1. The cardiovascular activity of S-(+)-boldine, an aporphine alkaloid structurally related to papaverine, was determined. The work includes functional studies on guinea-pig isolated aorta contracted with noradrenaline, caffeine, KCl or Ca2+, and on guinea-pig trachea contracted with acetylcholine or histamine. 2. S-(+)-boldine inhibited in a concentration-dependent manner the contractile response evoked by noradrenaline (10 microM) in guinea-pig aorta (IC50 = 1.4 +/- 0.2 microM) while the KCl depolarizing solution (60 mM)- or the Ca2+ (1 mM)-induced contractions were only partially affected by boldine up to 300 microM. In contrast, papaverine relaxed noradrenaline (NA), KCl or Ca2+ induced contractions showing similar IC50 values in all cases. S-(+)-boldine had a greater potency on the contraction elicited by NA whereas papaverine acted in a non-selective manner. 3. S-(+)-boldine was found to be an alpha 1-adrenoceptor blocking agent in guinea-pig aorta as revealed by its competitive antagonism of noradrenaline-induced vasoconstriction (pA2 = 5.64 +/- 0.08), and its potency was compared with that of prazosin (pA2 = 8.56 +/- 0.24), a known potent alpha 1-adrenoceptor antagonist. In contrast, papaverine caused rightward shifts of the NA concentration-response curves with depression of maximal response indicating that it acts as a non-competitive antagonist. 4. Contraction of guinea-pig aorta induced by caffeine (60 mM) in a Ca(2+)-containing Krebs solution was not affected by a 60 min incubation period with different doses of S-(+)-boldine (1-300 microM). Papaverine inhibited partially this caffeine-induced contraction at the maximal dose used (100 microM). 5. Inositol phosphates formation induced by noradrenaline (10 microM) in guinea-pig thoracic aorta was inhibited by S-(+)-boldine (30 microM) but not by papaverine (10 microM). 6. Contractions of guinea-pig trachea caused by acetylcholine (100 microM) or histamine (10 microM) were not modified by S-(+)-boldine (0.1-100 microM). 7. These results provide evidence that S-(+)-boldine, an aporphine alkaloid, has interesting properties as an alpha 1-adrenoceptor blocker in vascular smooth muscle, and acts as a competitive antagonist of the alpha 1-adrenoceptor present in the guinea pig aorta.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1996

Evidence for functional tachykinin NK1 receptors on human isolated small bronchi.

On human small isolated bronchi (diameter < 1 mm), but not on larger bronchi (diameter 3-5 mm), substance P (SP) and specific tachykinin SP-preferring neurokinin (NK1) receptor agonists {[beta Ala4, Sar9, Met(O2)11]SP-(4-11), [Sar9, Met(O2)11]SP, [Arg6,Sar9,Met(O2)11]SP-(6-11), and septide; 10(-10) to 10(-6) M} produced a concentration-dependent contraction that occurred at low concentrations (pD2 values of 7.79-8.33) and was characterized by a low intrinsic activity [maximal effect (Emax) of 38-45% of Emax induced by 3 mM acetylcholine, in a noncumulative manner]. Comparison of cumulative and noncumulative concentration-response curves to SP and NK1 receptor agonists suggest rapid receptor desensitization. The SP (10(-8) M)-induced contraction was inhibited by tachykinin NK1 receptor antagonists (rank order of potency: SR-140333 > CP-96,345 > RP-67580) but not by the tachykinin NK2 receptor antagonist SR-48968. Indomethacin (10(-6) M) abolished the SP-induced contraction. Our results suggest that tachykinin NK1 receptors are present on human small bronchi and that their stimulation induces a prostanoid-dependent contraction. The small isolated bronchus is an interesting model of human tissue to test NK1 receptor antagonists.

Benzamides↗

PubMed1996

The tachykinin NK2 receptor antagonist SR 48968 inhibits citric acid-induced airway hyperresponsiveness in guinea pigs.

Airway hyperresponsiveness is a main feature of asthma, and several lines of evidence suggest that tachykinins might be involved in the pathogenesis of airway hyperresponsiveness in rodents. We conducted a study designed to describe an original model of airway hyperresponsiveness induced by citric acid administered as aerosol to guinea pigs, and to investigate the effects of the nonpeptide neurokinin1 (NK1) and neurokinin2 (NK2)-receptor antagonists, SR 140333 and SR 48968, respectively, on the development of this airway hyperresponsiveness. Animals received thiorphan 1 mg/kg intraperitoneally and 30 min later were exposed to an aerosol of citric acid 0.4 M for 1 h. After 24 h, the animals were anesthetized and ventilated. Airway hyperresponsiveness was evidenced by significant shifts to the left of dose-response curves for intravenous acetylcholine (ACh) without a change in maximum responses to ACh. Exposure to citric acid induced an airway hyperresponsive that was abolished by chronic pretreatment with capsaicin (120 mg/kg, 5 d before citric acid exposure). SR 48968 1 mg/kg intraperitoneally, given once at 30 min before the citric acid exposure, inhibited airway hyperresponsiveness, whereas SR 140333 1 mg/kg or codeine 30 mg/kg given under similar conditions did not. The inhibition of airway hyperresponsiveness by SR 48968 did not result from functional antagonism, since SR 48968 did not affect ACh-induced bronchoconstriction, nor did it result from inhibition of tachykinin, which could have been released under the influence of ACh in hyperresponsive animals, since SR 48968 given after the exposure to aerosolized citric acid failed to inhibit airway hyperresponsiveness. In conclusion, these results show that inhaled citric acid can induce the development of an airway hyperresponsiveness in the guinea pig through a release of tachykinins, and also demonstrate that NK2-receptor stimulation plays a predominant role in the development of airway hyperresponsiveness.

Acetylcholine↗

PubMed1996

Involvement of tachykinin NK1 and NK2 receptors in substance P-induced microvascular leakage hypersensitivity and airway hyperresponsiveness in guinea-pigs.

Tachykinins, such as substance P, might be involved in the development of airway hyperresponsiveness (AHR) and airway inflammation. However, it is unknown which tachykinin receptors mediate these biological activities. The effects of two antagonists of tachykinin neurokinin-1 (NK1) and tachykinin neurokinin-2 (NK2) receptors, SR 140333 and SR 48968, respectively, were investigated on substance P (SP)-induced airway hyperresponsiveness and potentiation of the histamine-induced increase in microvascular leakage, in phosphoramidon-pretreated guinea-pigs. Guinea-pigs were pretreated with phosphoramidon (0.1 mM aerosol for 15 min) and exposed 15 min later to saline solution alone or to saline solution containing SP (0.1 mg.mL-1 for 30 min). Twenty four hours later, the animals were anaesthetized and prepared for the recording of the pulmonary inflation pressure (PIP) to acetylcholine or for the investigation of microvascular leakage to histamine. Pretreatment of the guinea-pigs with a single dose of SR 48968 (1 mg.kg-1, i.p.) 30 min before SP exposure, significantly prevented the development of AHR, whereas SR 140333 (1 mg.kg-1, i.p.) did not. In a second set of experiments, phosphoramidon-pretreated guinea-pigs exposed to SP presented a significant potentiation of the histamine-induced increase in microvascular leakage in pulmonary airways. When the guinea-pigs were pretreated with SR 140333, an inhibition of the increased microvascular leakage to histamine was observed. In contrast, no significant inhibitory activity was noted when the guinea-pigs were pretreated with SR 48968. The present data demonstrate the importance of tachykinin NK2 receptor stimulation in the development of airway hyperresponsiveness and that of tachykinin NK1 receptor stimulation in microvascular leakage hypersensitivity in phosphoramidon-pretreated and substance P-exposed guinea-pigs. The results also suggest a dissociation between the presence of microvascular leakage and the occurrence of airway hyperresponsiveness.

Animals↗

PubMed1995

In vitro and in vivo evidence for a tachykinin NK1 receptor antagonist effect of vapreotide, an analgesic cyclic analog of somatostatin.

Vapreotide, a long-acting somatostatin analog, possesses an analgesic effect. The purpose of this work was to determine a tachykinergic involvement. Vapreotide reduced substance P-induced biting and scratching in mice. This inhibitory effect of substance P action was confirmed by experiments performed on the bronchial apparatus of guinea-pigs known to possess tachykinin NK1 and NK2 receptors. (i) Vapreotide reduced the substance P-induced plasmatic exudation. (ii) It inhibited selectively the tachykinin-dependent second contractile phase induced by electrical field stimulation of isolated bronchi. (iii) It shifted to the right the concentration-effect curve of substance P-induced contraction of isolated main bronchi. The peptide displaced [3H]substance P (IC50 = 3.3 +/- 1.8 x 10(-7) M) from guinea-pig bronchial tachykinin NK1 sites. The displacement of [125I]neurokinin A, a specific tachykinin NK2 receptor ligand, needed higher concentrations (IC50 = 4.5 +/- 0.6 x 10(-6) M). It is concluded that vapreotide possesses an antagonist activity on guinea-pig tachykinin NK1 receptors; the involvement in its analgesic action is discussed.

Acetylcholine↗

PubMed1995

Furosemide inhibits bradykinin-induced contraction of human bronchi: role of thromboxane A2 receptor antagonism.

Bradykinin contracts human isolated small bronchi through prostanoid release and subsequent TP receptor stimulation. Furosemide 10(-4) to 10(-3) M concentration dependently inhibited bradykinin- and the stable TP receptor agonist U-46619-induced contraction of human isolated small airways. The inhibitory effect of furosemide on U-46619-induced contraction involves competitive antagonism at TP receptors. Such an inhibition of TP receptors could a least partly explain the inhibitory effect of furosemide on bradykinin-induced contraction, and could be one of the mechanisms of the protective effect of furosemide in asthma.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

Role of thromboxane A2 in bradykinin-induced human isolated small bronchi contraction.

We previously demonstrated that the bradykinin-induced contraction of human isolated small bronchi is inhibited by indomethacin, capsaicin (N-methyl-N-6-nonenamide) and ruthenium red but not by tachykinin receptor antagonists. The thromboxane A2 receptor (TP receptor) antagonist GR32191 ((1R-(1 alpha(Z),2 beta,3 beta,5 alpha))-(+)-7-(5-(((1,1'-biphenyl)-4-yl)- methoxy)-3-hydroxy-2-(1-piperidinyl)cyclopentyl)-4-heptenoic acid, hydrochloride) (10(-10) to 10(-8) M) dose dependently inhibited the effect of bradykinin, suggesting the mediation of the TP receptor in the action of bradykinin. With higher concentrations of GR32191 (10(-7) and 10(-6) M) bradykinin induced a relaxation which was inhibited by indomethacin and by the bradykinin B2 receptor antagonist Hoe 140 (D-Arg0[Hyp3,Thi-5,D-Tic7,Oic8]bradykinin). The thromboxane A2 synthase inhibitor dazoxiben (4-(-2-(1H-imidazol-1-yl)ethoxy) benzoic acid hydrochloride) 10(-6) M inhibited the bradykinin-induced contraction, suggesting that thromboxane A2 was involved in TP receptor stimulation. The thromboxane A2 mimetic U-46619 (9,11-dideoxy-11 alpha,9 alpha-epoxy-methano-prostaglandin F2 alpha)-induced contraction of human distal bronchi was not inhibited by capsaicin and ruthenium red. Our data suggest that bradykinin contracts human isolated small bronchi through thromboxane A2 release. The inhibitory effect of ruthenium red and capsaicin on the bradykinin response may be due to inhibition of thromboxane A2 release or arachidonic mobilisation.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1995

In vitro effects of HOE 140 in human bronchial and vascular tissue.

Bradykinin is a potent inflammatory mediator which may be involved in various airway diseases. A selective and potent antagonist of the bradykinin B2 receptor has recently been discovered (HOE 140: D-Arg-[Hyp3,Thi5,D-Tic7,Oic8]bradykinin). The purpose of this study was to evaluate the potency of this compound in isolated human tissue (bronchus, pulmonary artery endothelium, umbilical artery and vein smooth muscle). Bradykinin induced contractions of the isolated human bronchus and umbilical artery and vein (the umbilical vessels were pretreated with indomethacin and L-nitro-arginine to inhibit prostaglandin and nitric oxide synthesis). It provoked an endothelium-dependent relaxation in the human pulmonary artery. HOE 140 was a non-competitive antagonist in human bronchial tissue (pKB: 8.19 +/- 0.30) and a competitive one in vascular tissue (pA2: 7.97 +/- 0.12, 8.16 +/- 0.16 and 8.00 +/- 0.11 in human pulmonary artery, umbilical artery and vein respectively). The effect of HOE 140 was selective as it did not influence the umbilical vein contractile response to serotonin and histamine. HOE 140 up to 3 x 10(-6) M was devoid of residual agonistic activity in the various human preparations studied. Furthermore, although the effects of HOE 140 were fully reversible, in isolated bronchial airways and umbilical veins, HOE 140 (10(-6) M) still possessed activity 1 h after being washed out in both tissues. Our results indicate that HOE 140 is a potent and potentially long-acting antagonist of the human bradykinin B2 receptor.

Binding Sites↗

PubMed1995

Effects of three alpha 2-adrenoceptor agonists, rilmenidine, UK 14304 and clonidine on bradykinin- and substance P-induced airway microvascular leakage in guinea-pigs.

The effects of three alpha 2-adrenoceptor agonists, clonidine, rilmenidine and UK 14304 on the increase of microvascular permeability induced by bradykinin or substance P in guinea-pigs airways have been studied in vivo. Extravasation of intravenously (i.v.) injected Evans blue dye was used as index of permeability. The effects of the three alpha 2-adrenoceptor agonists on the contraction induced by bradykinin (0.3 micrograms.kg-1, i.v.) and substance P (0.3 micrograms.kg-1, i.v.) were also studied on the isolated guinea-pig trachea. The increase of plasma exudation induced by bradykinin (0.3 micrograms.kg-1, i.v.) was inhibited partially by rilmenidine and UK 14304 (20 micrograms and 100 micrograms, intratracheally) respectively. These two substances had no action on the effects of substance P. The effects of rilmenidine and UK 14304 were abolished by alpha 2-blockers (idazoxan 1mg.kg-1 i.v. and RX 821001 100 micrograms.kg-1, i.v.), but they were not altered by the alpha 1-blocker prazosin (30 micrograms.kg-1, i.v.). Under similar conditions, clonidine or the alpha 1-adrenoceptor agonist methoxamine were without significant effects. In vitro, rilmenidine and UK 14304 inhibited partially the contractile effects of bradykinin but not those of substance P. To conclude, both rilmenidine and UK 14304 inhibit the bradykinin-induced increase of vascular permeability in the airways, and they probably do so on peptidergic nerve endings at the prejunctional level since these substances are without effect on substance P. The absence of activity of clonidine in our study might be due to a difference in spectrum of action on the several types of alpha 2-adrenergic or imidazole receptors.

Acetylcholine↗

PubMed1995

Isoenzyme-selective cyclic nucleotide phosphodiesterase inhibitors: effects on airways smooth muscle.

Cyclic nucleotide phosphodiesterase (PDE) isoenzymes (I-V) have been demonstrated in airways smooth muscle of several species including man. Theophylline is a non-selective inhibitor of PDE and is a potent relaxant of airways smooth muscle but its use is limited by its toxicity. Consequently, research into new, isoenzyme-selective PDE inhibitors is seen as important. The potential airways smooth muscle relaxant effects of these drugs is discussed in this review. Cyclic AMP PDE (types III and IV) inhibition produces greater relaxation than cyclic GMP PDE (types I and V) inhibition. No PDE II-selective inhibitors have been described. Airways smooth muscle relaxation in vitro, is greater with PDE IV than PDE III inhibitors in guinea-pig and bovine airways whereas PDE III is more important in porcine airways. Both cyclic AMP PDEs are important in human airways. PDE III or IV inhibition can produce additive effects and can augment isoprenaline actions. PDE V inhibition augments sodium nitroprusside-induced effects. There are no reported interactions between cyclic AMP and cyclic GMP PDE inhibitors. In vivo, cyclic AMP PDE inhibitors are more potent bronchodilators than cyclic GMP PDE inhibitors. PDE IV inhibitors have less cardiovascular side-effects. Topical administration may further increase efficacy and selectivity. Clinically PDE III inhibition improves lung function but also affects cardiovascular parameters. Inhaled PDE III/IV inhibitors produce bronchodilation without marked side effects. Potent, selective PDE IV inhibitors are currently being evaluated. In conclusion, isoenzyme-selective PDE inhibitors, especially PDE IV, may be useful airways smooth muscle relaxants in the treatment of lung disorders such as asthma.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-AMP Phosphodiesterases↗

PubMed1995

Calcium dependence of the mechanical response evoked by okadaic acid in smooth muscle.

The effects of okadaic acid (OA), obtained from a culture of the marine dinoflagellate Prorocentrum lima were studied on isolated strips of rat myometrium. The contractile response evoked by OA at 5, 10, and 20 microM in normal physiological solution was unaffected in the presence of tetrodotoxin (10 microM), indomethacin (3 microM), or a cocktail of antagonists which blocked muscarinic, adrenergic, histaminergic, serotonergic, and opioid receptors. Similarly, the response to OA was unaffected in the presence of nifedipine at a concentration (1 microM) which completely or highly blocked the response to KCl (60 mM), oxytocin (1 microM), or acetylcholine (100 microM). In a Ca(2+)-free 1 mM EGTA-containing solution, the response to 10 and 20 microM OA was slightly but significantly reduced whereas the response to 5 microM OA was abolished. However, a response similar to that evoked in Ca(2+)-containing solution was observed when 5 microM OA was added to the bath in the presence of 1 microM oxytocin or 160 microM vanadate in a Ca(2+)-depleted solution with 1 mM EGTA. These data suggest that the response of rat myometrium to OA (> or = 5 microM) is not mediated through activation of membrane receptors or neurotransmitter release nor by cyclo-oxygenase products. The response to OA (10 and 20 microM) is highly resistant to the absence of calcium in the medium and does not seem to involve calcium entry through dihydropyridine-sensitive Ca2+ channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Beta 3-adrenoceptors and airways.

beta 3-adrenoceptors have been identified in a variety of tissues from humans and animals: adipose tissue, gastrointestinal smooth muscle, rat skeletal muscle, bovine skeletal muscle, and human and canine heart. In the airways, the investigation of the beta 3-adrenoceptors came from studies with a series of novel selective agonists. Stimulation of the "atypical" beta-adrenoceptor increases the active transport of albumin across the ferret tracheal epithelium and the ciliary beat frequency of canine bronchial epithelium. Furthermore, it has been demonstrated that beta 3-adrenoceptors agonists selectively inhibited nonadrenergic noncholinergic contractions of guinea-pig bronchi induced by electrical field stimulation or capsaicin. The presence of functional beta 3-adrenoceptors in the bronchial smooth muscle is disputed and seems to be species-related. In isolated canine bronchi, selective agonists induced a relaxation whereas they had no or slight effect in isolated human, guinea-pig and sheep bronchi. Likewise in man, a fall in airway resistance measured by plethysmography, was mediated by beta 2-adrenoceptors, but not beta 3-adrenoceptors. To conclude, an "atypical" or beta 3-adrenoceptor-mediated modulation of bronchomotricity exists, nevertheless strong species specific differences have been reported.

Animals↗

PubMed1995

Prevention by the tachykinin NK2 receptor antagonist, SR 48968, of antigen-induced airway hyperresponsiveness in sensitized guinea-pigs.

The involvement of tachykinins in antigen-induced airway hyperresponsiveness (AHR) was characterized pharmacologically in guinea-pigs sensitized to ovalbumin with antagonists of tachykinin NK1 and NK2 receptors, namely SR 140333 and SR 48968, respectively. AHR was illustrated by increased sensitivity to bronchoconstriction provoked by aerosolized acetylcholine in anaesthetized, ventilated animals, administrated 48 h after ovalbumin aerosol challenge. SR 48968 (1 mg kg-1, i.p.), when given once 30 min before the antigen challenge, prevented AHR, whereas SR 140333 did not. These findings suggest that the tachykinin NK2 receptor antagonist, SR 48968, may be useful for investigating mechanisms of tachykinins in the development of airway hyperresponsiveness.

Acetylcholine↗

PubMed1995

Functional, biochemical and morphological studies on human bronchi after cryopreservation.

1. Human isolated bronchi have been investigated as fresh tissue or after storage (7 and 30 days) at -196 degrees C in foetal calf serum containing 1.8 M dimethyl sulphoxide. 2. After cryopreservation, the maximal contractile response to acetylcholine (3 mM) was reduced (approximately 25%) but the difference did not reach significance statistically. Maximal responses to other spasmogens tested (histamine, [Nle10]NKA(4-10), bradykinin, leukotriene D4, U46619, and KCl) did not differ between unfrozen and frozen/thawed tissues. The sensitivity of cryopreserved tissues to the constrictor agents tested was similar to that of fresh tissues. 3. The accumulation of inositol phosphates produced by acetylcholine in human bronchus in vitro was similar in fresh and cryostored (30 days) tissues. 4. Relaxant responses of acetylcholine (0.3 microM)-precontracted preparations to theophylline, isoprenaline, rolipram and sodium nitroprusside were unchanged after storage with the exception of the sensitivity to rolipram which was diminished in the 30-days cryostorage group. 5. Light microscopic examination of sections taken from 30 days cryostored tissues indicates that the epithelium, submucosal tissue and smooth muscle were well preserved. 6. These experiments suggest that cryopreservation of human bronchi results in maintenance of several morphological, functional (contraction/relaxation) and biochemical properties.

Acetylcholine↗

PubMed1995

Tachykinin NK2 receptors further characterized in the lung with nonpeptide receptor antagonists.

Two nonpeptide tackykinin NK2 receptor antagonists have now been described, SR 48968 and GR 159897. These drugs are highly specific and very potent antagonists with affinity (binding and in vitro study) for NK2 receptors in the subnanomolar range (pKi = 9-10), without intrinsic activity. They act preferentially on the human NK2A receptor subtype. These drugs exert potent and long-acting antagonism by both i.v. and oral administration. Their use has first confirmed the preponderant role of NK2 receptors in airway smooth muscle contraction, especially in human bronchi. A role for NK2 receptor stimulation has also been clearly demonstrated in bronchoconstriction induced by various agents known to induce the release of tachykinins (capsaicin, resiniferatoxin, citric acid, sodium metabisulfite diethyl ether, serotonin, and bradykinin), in allergen-induced airway constriction in the guinea pig sensitized to ovalbumin, and in hyperpnea-induced bronchoconstriction. Inhibition of neurokinin A mediated or capsaicin-mediated dyspnea by SR 48968 has also been demonstrated in the guinea pig. SR 48968 also is very efficient in inhibiting cough induced by citric acid or capsaicin. Finally, SR 48968 is able to abolish in guinea pigs in vivo the bronchial hyperreactivity induced after 24 or 48 h by a citric acid challenge or an ovalbumin challenge, respectively. Thus, nonpeptide, long-acting NK2 receptor antagonists can be regarded as suitable tools for investigations in humans. They may shortly allow a precise determination of the role of tachykinins in asthmatic patients.

Animals↗

PubMed1995

Role of 1,2-sn diacylglycerol in airway smooth muscle stimulated by carbachol.

Activation of muscarinic receptors in airway smooth muscle leads to breakdown of membrane polyphosphoinositides. In agreement with others, we show here that muscarinic stimulation elicits inositol-1,4,5-triphosphate formation. In addition, we show that carbachol also elicits total diacylglycerol and 1,2-sn diacylglycerol accumulation in a specific and dose-dependent manner (EC50 values: 2.1 x 10(-8) M for 1,2-sn diacylglycerol). The time-course of inositol-1,4,5-triphosphate accumulation is compatible with that of the clonic phase of muscle contraction. Since this derivative can mobilize intracellular Ca2+ stores, it may play a second-messenger role in the initial phase of contraction. The time-course of diacylglycerol accumulation is compatible with the muscarinic-induced tonic phase of smooth-muscle contraction. Carbachol induces similar dose-dependent reductions in isoproterenol-induced muscle relaxation (EC50 values for relaxation concentration-response curves to isoproterenol: 3 x 10(-6) M and 2.1 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively), and increases in adenylate cyclase activity (EC50 values for the concentration-response to isoproterenol: 1.2 x 10(-6) M and 1.5 x 10(-5) M, with carbachol at 10(-7) M and 10(-4) M, respectively). Since it is known that carbachol-induced uncoupling of beta 2-adrenergic receptors is proportional to the breakdown of polyphosphoinositides, and that 1,2-sn diacylglycerol is a potent activator of protein kinase C, 1,2-sn diacylglycerol could be mediating the uncoupling of beta 2-adrenergic receptors, via activation of alpha-protein kinase C and subsequent phosphorylation of receptor, and/or cyclase, and/or G proteins.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclases↗

PubMed1995

Effect of the two tachykinin antagonists, SR 48968 and SR 140333, on cough induced by citric acid in the unanaesthetized guinea pig.

It is now well-established that sensory nerves stimulation in the airway induces bronchoconstriction and inflammation, but also protective reflexes, such as coughing. These effects are mediated through the release of tachykinins (substance P and neurokinin A) and we have recently shown that SR 48968, a tachykinin NK2-receptor antagonist, inhibited cough induced by citric acid. In this paper, we have studied the effects of SR 48968 administered by aerosol. We have also investigated the effects of SR 140333, a tachykinin NK1-receptor antagonist, and the combination of both SR 48968 and SR140333 to determine whether tachykinin NK1 receptors are involved in cough. Finally, we have studied the combined effects of SR 48968 and salbutamol to find out whether the antitussive effect of SR 48968 is a consequence of the inhibition of bronchoconstriction. Unanaesthetized guinea-pigs were placed in a transparent chamber and exposed to an aerosol of citric acid (0.4 M). The number of coughs was counted by visual inspection and by determination of sounds and pressure variations in the chamber. By the aerosol route, SR 48968 was an efficient antitussive and 16 times more potent than codeine. SR 140333 (0.1-1 mg.kg-1 i.p.) did not exert any antitussive effect but it potentiated the maximal effect induced by SR 48968. Finally, salbutamol, in a dose (0.3 mg.kg-1) which inhibits bronchoconstriction, but not cough induced by citric acid, did not modify the antitussive effect of SR 48968.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Inhalation↗

PubMed1994

Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction.

This study investigated the effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction induced in isolated rat lung perfused at constant flow. In order to evaluate the mechanism of the hypoxic vasoconstriction we also studied the effects of an inhibitor of the endothelium-derived relaxing factor (EDRF), NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of the guanylate cyclase, methylene blue (30 microM), two K+ channel blockers, glibenclamide (1 microM) and tetraethylammonium (20 mM). In normoxia, NG-nitro-L-arginine methyl ester, methylene blue, glibenclamide or tetraethylammonium did not enhance significantly the baseline perfusion pressure, suggesting that neither EDRF nor K+ channels are involved in the modulation of the low basal pulmonary vascular tone. In hypoxia, aprikalim and pinacidil (0.03-3 microM) induced a concentration-dependent decrease of pulmonary pressure, exhibiting their spasmolytic effects in acute hypoxia. The hypoxic pressure response was significantly increased by NG-nitro-L-arginine methyl ester, methylene blue and tetraethylammonium, but not by glibenclamide suggesting that EDRF and K+ channels other than ATP-sensitive K+ channels are involved in the modulation of the hypoxic pressure response. The spasmolytic effects of aprikalim and pinacidil (1 microM) were not modified by NG-nitro-L-arginine methyl ester, but were partially reduced by tetraethylammonium and completely abolished by glibenclamide, suggesting that these effects are mainly but not exclusively mediated through ATP-sensitive K+ channel opening.

Animals↗