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J Zaagsma

Publications and source records attributed to J Zaagsma.

At least 73 records · Page 4Linked to original sources
PubMed1993

Cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors.

The muscarinic receptor subtype mediating contraction of the guinea pig lung strip preparation was investigated and compared with that in guinea pig tracheal and human peripheral airway (small bronchi) smooth muscle preparations, using a number of subtype selective muscarinic receptor antagonists. It was found that guinea pig lung strip contraction was not mediated by a homogeneous class of muscarinic M3 receptors, in contrast to guinea pig tracheal and human peripheral airway smooth muscle. The affinities of the M1- and M3/M2-selective muscarinic receptor antagonists on the guinea pig lung strip were between 0.35 and 1.94 log units lower than in the M3 receptor tissues (respective pA2 values on guinea pig lung strip and trachea: pirenzepine 6.36/6.71, AF-DX 474 6.39/7.11, AQ-RA 721 6.93/7.96, DAU 5884 6.78/8.72, UH-AH 371 7.04/8.20), whereas the affinities of the M2/M3-selective antagonists were between 0.63 and 1.97 log units higher (AF-DX 116 6.63/6.00, AQ-RA 741 7.48/6.63, gallamine 5.44/3.47, methoctramine 7.30/5.38). As a result, a good correlation was obtained when pA2 values from guinea pig lung strip were compared to pKi values towards bovine cardiac muscarinic M2 receptors, though it was noticed that pirenzepine and the M3/M2-selective antagonists showed a closer relationship than the M2-selective compounds. These results suggest that cholinergic contraction of the guinea pig lung strip is mediated by muscarinic M2-like receptors, possibly representing a novel subtype or a mixture of M2 (cardiac) and M3 (or M4) subtypes. It remains to be established, however, on what structure in the lung these contractile M2-like receptors are located and also by which transduction mechanism they produce contraction.

Adult↗
PubMed1993

Muscarinic M2 receptors do not participate in the functional antagonism between methacholine and isoprenaline in guinea pig tracheal smooth muscle.

We investigated whether muscarinic M2 receptors, known to inhibit adenylyl cyclase activity in airway smooth muscle, also inhibit isoprenaline-induced relaxation of guinea pig tracheal smooth muscle, as has recently been described for the dog (Fernandes et al., 1992, J. Pharmacol. Exp. Ther. 262, 119). Smooth muscle strips were contracted with various concentrations of methacholine or histamine (which served as a control) in the absence or presence of the M2-selective muscarinic receptor antagonist, gallamine (30 microM), and cumulative isoprenaline-relaxation curves were obtained. It was found that muscarinic M2 receptor blockade had no significant effect on isoprenaline pD2 and Emax values, neither with histamine nor with methacholine. The results show that, in guinea pig trachea, muscarinic M2 receptors do not significantly influence the functional antagonism of cholinergic smooth muscle contraction by isoprenaline.

Animals↗
PubMed1993

Strong activation of vascular prejunctional beta 2-adrenoceptors in freely moving rats by adrenaline released as a co-transmitter.

The effect of adrenaline on the electrically evoked noradrenaline overflow in the portal vein of adrenal demedullated freely moving rats was studied. Adrenaline (100 ng/min) was infused for 2 h into the portal vein. After a 1-h interval when plasma adrenaline had returned to pre-infusion undetectable levels, the portal vein nervus plexus was electrically stimulated. During stimulation (2 Hz, 3 ms, 5 mA) adrenaline and noradrenaline were released. The stimulus-evoked noradrenaline overflow was facilitated to 194% of the control-evoked overflow (infusion of saline). Total catecholamine overflow (noradrenaline plus adrenaline) was enhanced to 258%. The facilitation of the evoked overflow of both noradrenaline and adrenaline was blocked by the selective beta 2-adrenoceptor antagonist, ICI 118,551 (0.3 mg/kg). Cocaine (2.5 mg/kg plus 0.05 mg/kg per min) infused together with adrenaline prevented the evoked release of adrenaline and no facilitation of the stimulus-induced noradrenaline overflow occurred. Inhibition of prejunctional inhibitory alpha 2-adrenoceptors with yohimbine (0.5 mg/kg) further enhanced, to 577%, the electrically evoked catecholamine overflow after adrenaline infusion. The results demonstrate that adrenaline can be taken up by sympathetic nerve endings through cocaine-sensitive uptake carriers, and is released from these nerves during electrical stimulation of the portal vein nervus plexus. Neuronally released adrenaline can strongly facilitate electrically evoked neurotransmitter overflow through activation of prejunctional beta 2-adrenoceptors.

Animals↗
PubMed1993

The interaction of selective and non-selective antagonists with pre- and postjunctional muscarinic receptor subtypes in the guinea pig trachea.

Muscarinic receptor antagonists were used to study prejunctional M2 and postjunctional M3 receptors in the isolated guinea pig trachea. The effects of four M2-selective muscarinic receptor antagonists (gallamine, methoctramine, AQ-RA 741 and AF-DX 116) were studied on twitch contractions, elicited by electrical field stimulation, of tracheal ring preparations. M1-selective (pirenzepine, (+)- and (-)-telenzepine), M3-selective (4-DAMP-methobromide and UH-AH 371) and non-selective (atropine and ipratropium) muscarinic receptor antagonists were also used. The clear potentiation of the twitch contractions and the subsequent strong inhibition observed with M2-selective antagonists demonstrate antagonism at prejunctional M2 and postjunctional M3 muscarinic receptors, respectively. The maximal potentiation correlated well with the M2/M3-selectivity known from binding experiments: gallamine > methoctramine > AQ-RA 741 > AF-DX 116. Strong correlations were also found between the pEC20 values for potentiation of the twitch response and the pKi values for bovine cardiac M2 muscarinic receptors and between the pIC50 values for inhibition of the twitch response and the pA2 values for M3 muscarinic receptors as determined on non-stimulated methacholine-contracted tracheal smooth muscle preparations. Thus, study of the effects of a wide concentration range of putative M2-selective muscarinic receptor antagonists on the twitch contractions of single tracheal rings induced by low-intensity electrical field stimulation yields information about M2/M3 receptor selectivity and about prejunctional M2 and postjunctional M3 receptor affinity within the same experiment.

Animals↗
PubMed1993

The beta-adrenoceptors mediating relaxation of rat oesophageal muscularis mucosae are predominantly of the beta 3-, but also of the beta 2-subtype.

1. beta-Adrenoceptor-mediated relaxation of rat oesophageal smooth muscle was investigated by studying the effects of beta 1- and beta 2-selective antagonists on the relaxation induced by (-)-isoprenaline, the beta 2-selective agonists fenoterol and clenbuterol and the beta 3-agonist, BRL 37344. 2. The highly beta 1-selective antagonist CGP 20721A did not antagonize (-)-isoprenaline- or BRL 37344-induced relaxations in concentrations up to 10 microM. Only at 100 microM of CGP 20712A were clear rightward shifts of the agonist concentration-response curves (CRCs) observed, with pA2 values of 4.70 and 4.97 against (-)-isoprenaline and BRL 37344, respectively. 3. ICI 118,551, a potent and selective beta 2-antagonist, at 100 nM caused moderate rightward shifts of the CRCs of (-)-isoprenaline, fenoterol and clenbuterol; with fenoterol and clenbuterol, this was accompanied by a clear steepening of the curve. Only at the highest concentration (100 microM ICI 118,551) did the shifts to the right further increase substantially. Resulting Schild-plots were clearly biphasic. BRL 37344-induced relaxations were only antagonized at 100 microM ICI 118,551, yielding a pA2 value of 5.48. 4. These results clearly demonstrate that the BRL 37344-induced relaxation of rat oesophageal muscularis mucosae is mediated solely through beta 3-adrenoceptors, whereas (-)-isoprenaline-, fenoterol- and clenbuterol-induced relaxations were shown to involve both beta 2- and, predominantly, beta 3-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1993

Lack of coupling of muscarinic receptors to phosphoinositide metabolism and adenylyl cyclase in human lymphocytes and polymorphonuclear leukocytes: studies in healthy subjects and allergic asthmatic patients.

A change in muscarinic receptor-induced phosphoinositide (PI) metabolism or inhibition of adenylyl cyclase activity could play a role in cholinergic hyperresponsiveness in patients with asthma. In the present study, we considered the possibility of using peripheral blood lymphocytes or polymorphonuclear leukocytes (PMN) as easily accessible models to investigate this hypothesis. Previous studies have indicated the presence of muscarinic binding sites on these cells; however, their transduction mechanisms are still unclear. We found that neither lymphocytes nor PMN from healthy donors, nor lymphocytes from allergic asthmatic patients accumulated inositol phosphates after stimulation with methacholine, whereas positive responses were found for phytohemagglutinin (PHA) in the lymphocytes and for formyl-methionyl-leucyl-phenyl-alanine in the PMN. Normal basal and PHA-stimulated inositol phosphates levels were found in the lymphocytes of the patients. Both levels were significantly enhanced after allergen challenge, indicating that activation of PI metabolism could play a role in the immune response of these cells. Since methacholine was also unable to inhibit adenylyl cyclase activity in both lymphocytes and PMN, we reevaluated the presence of muscarinic binding sites on these cells. Radioligand binding studies with the hydrophilic ligand [3H]-N-methyl-scopolamine surprisingly showed only a very small population of high affinity binding sites on lymphocytes (Bmax 57-127 sites/cell; Kd 45-133 pM), while no high affinity sites could be detected on PMN. The results indicate that leukocytes are not a suitable model to investigate the muscarinic receptor function in relation to bronchial asthma.

Adenylyl Cyclases↗
PubMed1992

Dysfunctional presynaptic alpha 2-adrenoceptors expose facilitatory beta 2-adrenoceptors in the vasculature of spontaneously hypertensive rats.

Previous studies on spontaneously hypertensive rats (SHR) have yielded inconsistent information about functional aberrations of the presynaptic alpha 2- and beta 2-adrenoceptor-mediated modulation of sympathetic neurotransmitter release. In the present investigation we studied the capacity of presynaptic beta 2-adrenoceptors that enhance noradrenaline (NA) release in the portal vein of freely moving, unanesthetized SHR and normotensive Wistar rats (WR) using the beta 2-selective agonist fenoterol. The results show that the presynaptic beta 2-adrenoceptor population in SHR responds to significantly lower dosages of fenoterol than that in WR. The reason for this enhanced action, however, could not be attributed to the beta 2-adrenoceptor itself, nor to a diminished neuronal uptake of NA, but to a diminished responsiveness of the presynaptic alpha 2-adrenoceptor. Stimulation of presynaptic alpha 2-adrenoceptors with oxymetazoline (45 micrograms/min) decreased basal NA levels by 46% in WR and by 3% in SHR. Blockade of alpha 2-adrenoceptors, using 0.5 mg/kg yohimbine, induced a 4.86-fold rise in the basal NA level in WR but only a 1.89-fold rise in SHR. A subsequent dose of fenoterol, however, resulted in a further 2.5- and 2.6-fold rise in WR and SHR, respectively, indicating that there is a normal presynaptic beta 2-adrenoceptor population in the vasculature of SHR.

Animals↗
PubMed1992

The effect of intrastriatal application of directly and indirectly acting dopamine agonists and antagonists on the in vivo release of acetylcholine measured by brain microdialysis. The importance of the post-surgery interval.

The effect of intrastriatal application of D-1, D-2 and indirect dopaminergic drugs on the release of striatal acetylcholine as a function of the post-implantation intervals was studied using in vivo microdialysis. The dopamine D-2 agonists LY 171555 and (-)N0437 inhibited the release of striatal acetylcholine to 40% of control values 16-24 h after implantation of the dialysis cannula. When LY 171555 was infused 40-48 h after implantation of the dialysis cannula, the response was attenuated to 20% of control values. Meanwhile, the effectiveness of infusions of the antagonists (-)sulpiride and haloperidol was augmented from a non significant effect at 16-24 h to a 150% increase 40-48 h after implantation of the cannula. Infusions of the dopamine releasing agent amphetamine or the dopamine uptake inhibitor nomifensine resulted in a dose-dependent increase in the overflow of dopamine. Not until a sevenfold increase in the level of dopamine was seen, the release of acetylcholine was significantly affected. This hyporesponsiveness of the striatal cholinergic interneurons to endogenous dopamine could not be attributed to dopamine D-1 receptor activation, since no effects on striatal acetylcholine release were found by intrastriatal infusions of the selective D-1 agonist CY 208-243 or the selective D-1 antagonist SCH 23390. The results indicate that dopamine D-2 receptors are involved in the regulation of striatal acetylcholine release and that these receptors are tonically occupied by endogenous dopamine under the present experimental conditions 40-48 h after probe implantation.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1992

A novel method to assess airway function parameters in chronically instrumented, unrestrained guinea-pigs.

A new method has been developed to measure airway functions in unanaesthetized, unrestrained guinea-pigs. The technique utilizes a specially designed pneumotachograph that is placed inside the trachea, and a saline-filled balloon, placed inside the pleural cavity. The pneumotachograph consists of a stainless steel cylinder with coaxial and perpendicular tubes attached to it, measuring the total pressure and the lateral pressure in the trachea, respectively. Via air-filled silicon conducting tubes, subcutaneously driven and permanently attached to the neck of the animal, the pressures are fed into a differential pressure transducer, yielding a pressure difference proportional to the airflow in the trachea. Via a saline-filled tubing, the pleural balloon is similarly attached to the neck of the animal, and pleural pressure (Ppl) is measured using a second pressure transducer. These data permit calculation of airway functions in conscious, unstressed animals. Control values for airway resistance (RAW), Ppl, tidal volume and respiratory frequency are all in the range of results reported previously for this species. A very significant correlation between RAW and Ppl (P < 0.001) was observed, indicating that sole Ppl-measurement can be used as a relatively simple and sensitive method to assess bronchial obstructive reactions in unrestrained guinea-pigs. Using a specially designed provocation cage, which allowed the animals to remain in a stress-free, unrestrained condition, the method has been successfully applied for the assessment of the dose-dependent bronchoconstrictor sensitivity to histamine as well as to allergen-induced early and late phase airway reactions.(ABSTRACT TRUNCATED AT 250 WORDS)

Airway Resistance↗
PubMed1992

Human bronchial cyclic nucleotide phosphodiesterase isoenzymes: biochemical and pharmacological analysis using selective inhibitors.

1 The aims of the present study were to characterize the cyclic nucleotide phosphodiesterase (PDE) isoenzyme activities present in human bronchi and to examine the ability of selective isoenzyme inhibitors to relax histamine and methacholine precontracted preparations of human bronchi. 2 Three separations of pooled human bronchial tissue samples were performed. Ion-exchange chromatography showed that the soluble fraction of human bronchial preparations contains PDE I, II, III, IV and V isoenzyme activities. Multiple forms of PDE I and PDE IV were observed and PDE IV was the main cyclic AMP hydrolytic activity. 3 3-Isobutyl-l-methylxanthine (IBMX) non-selectively inhibited all separated isoenzyme activities. Zaprinast selectively inhibited PDE V, but also effectively inhibited one of the two PDE I isoforms identified. The PDE IV selective inhibitors rolipram and RO-201724, inhibited the PDE IV activities as did the dual PDE III/IV inhibitor, Org 30029. Org 9935, a PDE III selective inhibitor, potently attenuated part of the PDE IV activity peak in one of three separations performed, indicating that some PDE III activity may co-elute with PDE IV under the experimental conditions employed. 4 PDE IV-selective (rolipram), PDE III-selective (Org 9935) and dual PDE III/IV (Org 30029) inhibitors were effective relaxants of human bronchial smooth muscle. The PDE V/PDE I inhibitor, zaprinast was relatively ineffective. 5 The present study demonstrates in human bronchi, as in animal airways smooth muscle, that inhibitors of PDE III, PDEIV and dual PDE III/IV have potentially useful bronchodilator activity and are worthy of further consideration as anti-asthma drugs.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1991

Differences in functional cyclic AMP compartments mediating lipolysis by isoprenaline and BRL 37344 in four adipocyte types.

Triglyceride mobilization and adenylyl cyclase activation in adipocytes from Wistar rats, lean Zucker (Fa/?) rats, obese Zucker (fa/fa) rats and humans were investigated in concentration-response studies with (-)-isoprenaline and the atypical beta 3-adrenoceptor selective agonist BRL 37344. Maximum FFA production by both agonists was identical in Wistar rat and lean Zucker rat adipocytes, while obese Zucker rat adipocytes and human adipocytes produced significantly less FFA, especially with BRL 37344. Maximum adenylyl cyclase activation by (-)-isoprenaline was similar for all types of adipocyte ghosts, whereas BRL 37344 was a partial agonist in all cases with the lowest intrinsic activity in human adipocytes. For (-)-isoprenaline the relationship between cAMP and lipolysis was steepest with Wistar rat adipocytes, followed by human and lean Zucker rat adipocytes, while obese Zucker rat cells showed a shallow relationship. For BRL 37344, the relationship was very steep and similar for all four adipocyte types, despite the marked differences in maximal lipolysis and cyclic AMP production. The results strongly argue in favour of cyclic AMP compartmentalization, the activity ratio between the functional and the non-functional compartment being least favourable in obese Zucker rat adipocytes. The atypical beta 3-adrenoceptor agonist BRL 37344 very efficiently directs the generated cyclic AMP into the functional compartment in all four adipocytes types investigated.

Adenylyl Cyclases↗
PubMed1991

Positive cooperative interaction of quaternary anticholinergics with functional muscarinic receptors in bovine tracheal smooth muscle.

The interaction of quaternary anticholinergics with muscarinic receptors in bovine tracheal smooth muscle strips was investigated because some of these compounds have shown anomalous (biphasic) behaviour in radioligand displacement studies, in contrast to their tertiary analogues. It was found that ipratropium, N-methylscopolamine, oxyphenonium and N-methyldeptropine give Schild plots with slopes significantly greater than unity (up to 2.0) in contrast to 4-DAMP methobromide and thiazinamium, and the tertiary analogues atropine and scopolamine. However, in guinea pig tracheal smooth muscle, ipratropium and N-methyldeptropine behaved as classic antagonists with Schild slopes of unity. The high Schild plot slopes in bovine tracheal smooth muscle could not be solely explained by inadequate equilibration of the antagonists, since increased incubation times (3 or 5 h instead of 30 min) still brought about slopes significantly greater than unity, or by the presence of an atropinesterase in the tissue. However, by using combinations of atropine with ipratropium or oxyphenonium it could be demonstrated that these quaternary antagonists interact with muscarinic M3 receptors in bovine but not in guinea pig tracheal smooth muscle in a positive cooperative fashion.

Animals↗
PubMed1991

Relationship between lipolysis and cyclic AMP generation mediated by atypical beta-adrenoceptors in rat adipocytes.

1. The nature of the beta-adrenoceptor(s) mediating adenylyl cyclase activation in rat adipocyte ghosts by (-)-isoprenaline and the lipolytically selective beta-adrenoceptor agonist, BRL 37344, was investigated by use of the beta 1-selective antagonist, CGP 20712A. The results were compared with lipolysis in adipocytes. 2. While in lipolysis BRL 37344 was a full and 10 times more potent agonist than (-)-isoprenaline, in adenylyl cyclase activation similar pD2 values for both agonists were found. BRL 37344 was only a partial agonist on rat adipocyte adenylyl cyclase, with an intrinsic activity of 0.62. 3. With CGP 20712A small rightward shifts of the (-)-isoprenaline concentration-response curve (CRC) were observed at concentrations up to 10 microM, while at 100 microM and 1 mM clear rightward shifts occurred. The BRL 37344 CRC was not shifted with antagonist concentrations up to 10 microM. Only at 100 microM and 1 mM CGP 20712A were rightward shifts observed. 4. CGP 20712A concentrations of 10 microM and 100 microM depressed the maximum of the (-)-isoprenaline CRC to 89 and 60%, while the BRL 37344 CRCs retained the control maximum effect (62% of (-)-isoprenaline). Only at 1 mM CGP 20712A, was the CRC of BRL 37344 depressed, while the (-)-isoprenaline maximum was diminished further. 5. It was concluded that as with lipolysis, (-)-isoprenaline acts both through typical beta 1- and atypical beta 3-adrenoceptors for activation of adenylyl cyclase, while BRL 37344 acts solely through atypical beta 3-adrenoceptors. 6. The results also demonstrate that the relationship between adenosine 3':5'-cyclic monophosphate (cyclic AMP) and lipolysis is different for BRL 37344 and (-)-isoprenaline. Although the maximum activation of adenylyl cyclase by BRL 37344 is only 62% of that by (-)-isoprenaline, the distance between the lipolysis and adenylyl cyclase CRCs is much larger in the case of BRL 37344, indicating a larger transduction reserve for this agonist.

Adipocytes↗
PubMed1991

The presence of five cyclic nucleotide phosphodiesterase isoenzyme activities in bovine tracheal smooth muscle and the functional effects of selective inhibitors.

1. The profile of cyclic nucleotide phosphodiesterase (PDE) isoenzymes and the relaxant effects of isoenzyme selective inhibitors were examined in bovine tracheal smooth muscle. The compounds examined were the non-selective inhibitor 3-isobutyl-1-methylxanthine (IBMX), zaprinast (PDE V selective), milrinone and Org 9935 (4,5-dihydro-6-(5,6-dimethoxy-benzo[b]thien-2-yl)-5-methyl-1 (2H)-pyridazinone; both PDE III selective), rolipram (PDE IV selective) and Org 30029 (N-hydroxy-5,6-dimethoxy-benzo[b]-thiophene-2-carboximidamide HCl a dual PDE III/IV inhibitor). 2. Ion exchange chromatography showed three main peaks of PDE activity. The first peak was stimulated by Ca2+/calmodulin (PDE I), the adenosine 3':5'-cyclic monophosphate (cyclic AMP) hydrolytic activity of the second peak was stimulated by guanosine 3':5'-cyclic monophosphate (cyclic GMP) (PDE II) whilst that of the third peak was not significantly modified by any regulator (PDE IV). Calmodulin affinity chromatography revealed the additional presence of cyclic GMP-specific PDE (PDE V) in the first peak. A clearly distinct peak of cyclic GMP-inhibited PDE (PDE III) was not observed. However, Org 9935 inhibited the third activity peak more effectively in the presence, than in the absence, of rolipram (3 mumol l-1), indicating the presence of PDE III activity. 3. Rolipram was the most potent inhibitor of PDE IV. The mean -log50 IC50 values for rolipram, IBMX, milrinone, Org 30029, Org 9935 and zaprinast were 5.9 +/- 0.1, 4.9 +/- 0.1, 4.7 +/- 0.1, 4.6 +/- 0.1 and 4.6 +/- 0.1, respectively. 4. Rolipram was a potent relaxant of both histamine (1 pumol -') and methacholine (0.03 pmol -') precontracted preparations; (pD2 values; histamine 7.1 +/- 0.1, methacholine 6.8 /-+ 0.2 and 4.5 +/- 0.1, biphasic relaxation). IBMX also relaxed all preparations (pD2 values; histamine 5.6 +/- 0.1, methacholine 5.6 +/- 0.1) whilst zaprinast (pD2 values; histamine 5.2 +/- 0.1, methacholine 4.4 +/- 0.3), milrinone (pD2 values; histamine 5.2 + 0.1, methacholine 4.3 + 0.3) and Org 9935 (pD2 values; histamine 4.1 + 0.1, methacholine 4.1 +/- 0.2) did not completely relax preparations at concentrations up to 100 pImol I-. Org 30029 (pD2 values; histamine 6.2 +/- 0.1, methacholine 5.4 +/- 0.1) was a more effective relaxant than can be explained on the basis of PDE IV inhibition alone.5. We conclude that bovine tracheal smooth muscle contains five distinct PDE isoenzymes. PDE IV appears to be more important in the modulation of tissue function than PDE III and PDE V.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed1991

IgG- and IgE-mediated histamine release from superfused guinea-pig airway tissues.

Anaphylactic histamine release and the inhibition by the beta-adrenoceptor agonist fenoterol has been investigated using lung and tracheal tissues from two groups of guinea-pigs, differently sensitized to respond with IgG or IgE antibodies, respectively. A superfusion method was introduced and compared with classical batch incubation. The difference between IgG- and IgE-mediated histamine release during superfusion of both tissues was much greater than the difference obtained during batch-incubations. Fenoterol inhibited IgG-mediated histamine release during superfusion at lower concentrations and to a larger extent than the release from IgE-sensitized tissues. The inhibition by fenoterol was less pronounced after batch-wise incubations, preincubation at 0 degrees C abolished the quantitative difference of IgG- and IgE-mediated histamine release from lung slices as well as the difference in beta-adrenergic inhibition. It is concluded that the new superfusion procedure for airway tissues enhances the sensitivity of antigen-induced histamine release for pharmacological modulation, compared with batch-wise incubation. In addition, the effects of 0 degrees C pretreatment show that cooled transport and storage of airway tissue should be considered with care.

Animals↗
PubMed1990

An M3-like muscarinic autoreceptor regulates the in vivo release of acetylcholine in rat striatum.

Selective muscarinic antagonists were used in an attempt to characterize the muscarinic autoreceptor modulating the release of acetylcholine in the striatum of the rat. In vivo microdialysis was applied to infuse atropine, 4-DAMP (4-diphenylacetoxy-N-methylpiperidine), pirenzepine or AF-DX 116 (11-[[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro[2,3-b][1,4]benzodiazepine-6-one), leading to a dose-dependent increase in the overflow of acetylcholine, the order of potency being: atropine greater than 4-DAMP greater than pirenzepine greater than AF-DX 116. We conclude from these data that the muscarinic receptor modulating release in the striatum is of the M3 type.

Acetylcholine↗
PubMed1990

Muscarinic M3 receptors mediate contraction of human central and peripheral airway smooth muscle.

The muscarinic receptor subtype involved in human airway smooth muscle contraction was characterised for the first time, using subtype-selective muscarinic antagonists. It was demonstrated that methacholine-induced contraction of central (trachea) and peripheral (small bronchi) airway smooth muscle preparations was antagonised by pirenzepine, AF-DX 116, 4-DAMP methobromide, hexahydrosiladifenidol, and methoctramine with pA2-values characteristic of M3 (smooth muscle/glandular) muscarinic receptors. Since these pA2-values demonstrate significant correlations with those found in bovine and guinea-pig tracheal smooth muscle contraction, it is concluded that these animal tissues provide a good model for the study of M3 subtype-selective muscarinic antagonists to be used as bronchodilators.

Bronchi↗