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At least 217 records · Page 12Linked to original sources
PubMed1982

Sympathetic Nerve Stimulation on the perfused rat heart. Affinities of N-methylatropine and pirenzepine at pre- and postsynaptic muscarine receptors.

Rat isolated hearts with the sympathetic nerves attached were perfused with (-)-3H-noradrenaline in order to label the storage vesicles of the adrenergic nerves. Release was induced either by electrical stimulation of the nerves (3 Hz, 1 min) or by perfusion with high K+ solution (54 mM). The overflow of 3H-noradrenaline and its metabolites was determined by liquid scintillation counting after separation of the compounds by column chromatography. The experimental conditions ensured a minor contribution of 3H-metabolites to the evoked total tritium overflow. The release of 3H-noradrenaline evoked by nerve stimulation or high K+ solution was decreased in the presence of the muscarinic agonist, methacholine, N-methylatropine reversed the inhibition completely. Thus, the rat heart contains inhibitory muscarine receptors modulating noradrenaline release from adrenergic nerve fibres. In order to compare the presynaptic muscarine receptors with postsynaptic muscarine receptors in one and the same organ, the pA2 values of N-methylatropine and pirenzepine at both of these sites were measured. The antagonism of methacholine-induced inhibition of 3H-noradrenaline overflow was determined as the presynaptic parameter. pA2 values of 9.61 for N-methylatropine and 6.63 for pirenzepine were found. The methacholine-induced inhibition of the atrial tension development of isolated left rat atria paced at 2Hz was measured as a postsynaptic parameter. pA2 values of 9.90 for N-methylatropine and 6.69 for pirenzepine were found. The postsynaptic pA2 values did not differ from the presynaptic affinity constants indicating that neither substance revealed differences in structure between neuronal and myocardial muscarine receptors in the rat heart.

Animals↗
PubMed1990

Selective inhibition of peripheral histamine responses by loratadine and terfenadine.

To determine the selectivity of the non-sedating antihistamines loratadine and terfenadine and the sedating antihistamine diphenhydramine for peripheral and central histamine H1-receptors, these compounds were examined against intravenous (i.v.) and intracerebroventricular (i.c.v.) histamine-induced bronchoconstriction in anesthetized, spontaneously breathing guinea pigs. Animals were prepared with i.c.v. or i.v. cannulas and instrumented for the measurement of airway resistance (RAW) and dynamic lung compliance (CDyN). Loratadine, terfenadine or diphenhydramine were administered orally 2 h before either i.v. or i.c.v. injection of histamine. Each antihistamine blocked the i.v. histamine bronchospasm with the order of potency loratadine (ED40 = 0.08 mg/kg) greater than terfenadine (ED40 = 0.44 mg/kg) greater than diphenhydramine (ED40 = 5 mg/kg). These drugs also blocked i.c.v. histamine-induced bronchoconstrictions, but loratadine and terfenadine were approximately 10 times less potent against i.c.v. histamine bronchoconstriction than they were against i.v. histamine. In contrast, diphenhydramine was equipotent against i.c.v. and i.v. histamine bronchoconstriction. These results demonstrate that the non-sedating antihistamines loratadine and terfenadine, unlike diphenhydramine, are more effective against peripheral than central H1-receptors, probably because of poor penetration of the blood-brain barrier.

Animals↗
PubMed1982

The affinity of pirenzepine and other antimuscarinic compounds for pre- and postsynaptic muscarine receptors of the isolated rabbit and rat heart.

To compare in one and the same organ the presynaptic muscarine receptors located at the postganglionic adrenergic nerves with postsynaptic receptors at the atrial myocardium, the affinities of pirenzepine were determined in the perfused rabbit heart and those of pirenzepine and N-methylatropine in the isolated rat heart. Methacholine was used as an agonist to decrease the stimulation-evoked overflow of either endogenous noradrenaline (rabbit heart) or previously incorporated 3H-noradrenaline (rat heart) by a presynaptic muscarine receptor mechanism, and to reduce the atrial tension development of either the spontaneously beating perfused rabbit heart or incubated rat left atria paced at 2 Hz (postsynaptic effect). The pA2 values of the antagonists calculated from the Schild plots were very similar and, thus, did not reveal differences in the receptor structure. It is concluded that pirenzepine does not differ from seven other antimuscarinic drugs which did not differentiate presynaptic receptors from postsynaptic ones in the rabbit or rat heart.

Animals↗
PubMed2000

[Pharmaceutical contribution to the non specific challenge in bronchial provocation tests].

Aerosols of methacholine chloride are used in inhalation tests to measure non-specific bronchial responsiveness. Inhalation challenge solutions are not commercially available neither by pharmaceutical industry nor in France by the PCH-APHP. To reply to doctor's request, dilute concentrations of methacholine must be prepared properly in order to protect the patient and to assure doctor of test reproductibility. Osmolarity, pH and degradation of different dilute concentration of methacholine chloride have been compared with two diluents. This study allowed us to validate our preparation of solutions.

Administration, Inhalation↗
PubMed1969

Studies on the mode of action of vasopressin on the isolated proximal colon of the guinea-pig.

1. Contractions of guinea-pig isolated proximal colon produced by vasopressin are not affected by methyloxytocin (a compound that blocks pressor effects of vasopressin).2. Vasopressin contractions are inhibited by replacement of sodium with mannitol or sucrose, elevation of potassium or magnesium concentrations, the presence of the metabolic inhibitors sodium azide and triethyl tin or tetrodotoxin in the bathing fluid. Contractions produced by histamine or choline esters are comparatively insensitive to these procedures.3. Contractions of rat isolated uterus following vasopressin, oxytocin and methacholine are equally affected by replacement of sodium, increase of potassium or magnesium or addition of sodium azide.4. Neither vasopressin contractions nor contractions caused by transmural stimulation were consistently affected by morphine (10(-6) g/ml.) or hyoscine (10(-7) g/ml.) although both were reduced by anoxia or cooling the tissue. Morphine did not reduce the output of acetylcholine from stimulated colon.5. It is concluded that the action of vasopressin on proximal colon is unlike its action on other smooth muscle and is mediated by nervous tissue.

Acetylcholine↗
PubMed1993

Comparison of the airways relaxant and hypotensive potencies of the potassium channel activators BRL 55834 and levcromakalim (BRL 38227) in vivo in guinea-pigs and rats.

1. BRL 55834, a novel potassium channel activator, has been compared with levcromakalim (BRL 38227) for its relaxant effects in vivo on the airways and vasculature of the guinea-pig and rat. 2. When administered intravenously 2 min prior to challenge, BRL 55834 and levcromakalim each inhibited histamine-induced increases in airways resistance (Raw) in the anaesthetized guinea-pig, with BRL 55834 showing a 4.5 fold greater potency than levcromakalim (ED25 = 2.5 micrograms kg-1 and 11.3 micrograms kg-1 respectively). By contrast, both compounds had similar hypotensive potencies (ED18 = 8.5 micrograms kg-1 and 6.5 micrograms kg-1 respectively). 3. In the same guinea-pig model, intraduodenally administered BRL 55834 (100 and 250 micrograms kg-1) and levcromakalim (500 micrograms kg-1) each protected against histamine-induced changes in Raw and dynamic lung compliance (Cdyn), both compounds showing a rapid onset of action that persisted for more than 50 min. The lower dose of BRL 55834 had a similar bronchodilator effect to that of levcromakalim, yet both doses of BRL 55834 elicited substantially smaller effects than levcromakalim on mean arterial blood pressure. 4. In the anaesthetized rat, BRL 55834 and levcromakalim each evoked a dose-related inhibition of inhaled methacholine-induced changes in Raw and Cdyn when given i.v., with BRL 55834 showing some four fold greater potency than levcromakalim (BRL 55834: Raw ED35 = 3.7 micrograms kg-1, Cdyn ED35 = 5.9 micrograms kg-1; levcromakalim: Raw ED35 = 16 micrograms kg-1, Cdyn ED35 = 23.5 micrograms kg-1). As in the guinea-pig,BRL 55834 had a reduced propensity to lower mean arterial blood pressure (ED11 = 8 microg kg-1 for BRL55834, 11 +/- 3% being its maximum effect; ED11= 16 microg kg-1, maximum effect= 34 +/- 6% for levcromakalim.5. When administered intraduodenally to anaesthetized rats, BRL 55834 (10, 20 and 100 microg kg-1)evoked rapid and dose-related inhibitions of methacholine-induced Raw and Cdyn changes which persisted for over 30 min. At the lower and middle dose there was little effect on mean arterial blood pressure(<10% fall). Levcromakalim (500 microg kg-1) by contrast elicited transient airways responses that diminished rapidly after 5 min, while the effects on blood pressure were well maintained (>20% at 65 min). Levcromakalim (100 microg kg-1) did not affect airways responses but also evoked a marked and sustained fall in blood pressure.6. BRL 55834, administered per os, prolonged the time to histamine-induced dyspnoea in conscious guinea-pigs. The greatest effect of BRL 55834 was observed when it was administered 60 min prior to challenge, a dose of 0.20 mg kg-1 doubling the mean time to collapse. A similar level of protection was afforded by levcromakalim (1.25 mg kg-1), with maximal activity occurring between 30 and 60 min.7. The present studies in guinea-pigs and rats indicate that BRL 55834 is the first potassium channel activator to exhibit greater bronchodilator potency than levcromakalim but reduced tendency to lower arterial blood pressure. It is suggested that BRL 55834 may have greater potential than levcromakalim as a bronchodilator for therapeutic use in man.

Administration, Oral↗
PubMed1986

Ambroxol decreases bronchial hyperreactivity.

Ambroxol is a new compound which increases secretion of phosphatidylcholine by type II pneumocytes. The secretion of phosphatidylcholine could affect bronchial hyperreactivity in two ways: by increasing lysophosphatidylcholine turnover and/or by modifying the layer of bronchial secretion that covers airway receptors. To see whether ambroxol affects bronchial hyperreactivity, we carried out a double-blind cross-over study, evaluating the efficacy of this drug vs placebo in modifying methacholine PD20 in 11 asthmatic patients, 4 atopics and 7 non-atopics. 90 mg of ambroxol or placebo were randomly administered orally for one of two 14-day periods. Methacholine PD20 was evaluated before and after each treatment. A highly significant difference was demonstrated in the direct comparison between ambroxol and placebo as to their ability to modify mean metacholine PD20, which with ambroxol was more than double that with placebo. It was also seen that ambroxol induced a significant increase in baseline values of PD20, i.e. a significant decrease in bronchial hyperreactivity. Placebo did not do this.

Adult↗
PubMed1988

Bis-arenoxypropanolamines as potential beta-adrenolytics: a reinvestigation.

A number of symmetrical as well as asymmetrical bis-arenoxypropanolamines have been synthesized and evaluated for their beta-adrenolytic properties. The pharmacological characterization of these compounds was performed in vitro by direct studies (3H-dihydroalprenolol was used as the specific ligand for beta-receptors), and by determining the beta-blocking capacity on isoproterenol (ISO)-induced increased heart rate (isolated guinea-pig atrium); and in vivo by evaluating the antagonism on ISO-induced hypotension and tachycardia, as well as the intrinsic sympathomimetic activity (ISA) on reserpinized and vagotomized rats. The best result was observed with the simplest derivative, i.e. the bis-phenoxypropanolamine compound, which shows in vitro and in vivo potencies almost comparable to propranolol and, moreover, significant bronchodilating activity.

Adrenergic beta-Antagonists↗
PubMed1970

Beta-adrenoceptor stimulating properties of para-dimethylaminobenzaldehyde.

1. Studies on the various isolated tissues indicate that para-dimethylaminobenzaldehyde (DMAB) is a beta-adrenoceptor stimulant. DMAB is antagonized by the beta-adrenoceptor blocking agent, MJ 1999, but not by the alpha-adrenoceptor blocking agent, phentolamine.2. A study of dose-response relationships suggests a competitive interaction between MJ 1999 and DMAB.3. DMAB was about 122 times less potent than isoprenaline on the isolated guinea-pig tracheal preparation. The effects of DMAB on isolated rabbit atria were not only very weak, but were also very brief. On this tissue, DMAB was respectively 72,000 and 55,400 times less active than isoprenaline in producing positive chronotropic and inotropic effects. DMAB caused the relaxation of the guinea-pig taenia coli and the rabbit ileum. These actions were very weak in comparison with those of isoprenaline.4. These results suggest that a compound (DMAB) structurally different from isoprenaline may mimic isoprenaline responses by stimulating beta-adrenoceptors through different mechanisms.

Adrenergic alpha-Antagonists↗
PubMed1981

A comparative study of two parasympatholytic bronchodilator agents: ipratropium bromide and diphemanil methylsulfate.

Ipratropium and diphemanil are synthetic quaternary ammonium compounds with antimuscarinic properties. By using in vitro measurements of tension changes in isolated guinea-pig trachealis muscle strips and in vivo measurements of lung mechanics changes in anesthetized, vagotomized cats, the two drugs were compared in terms of their relative bronchodilator potency, mode of action and apparent site of activity in the bronchial tree. Ipratropium and diphemanil were about equipotent in antagonizing airway smooth muscle contraction induced by the cholinergic agonists, methacholine (in vitro) and carbachol (in vivo). When noncholinergic stimulation was used to augment smooth muscle tone, i.e., hypertonic potassium in the isolated preparations and serotonin in the vagotomized animals, only diphemanil exhibited significant bronchodilator activity. Simultaneous measurements of pulmonary resistance and dynamic compliance were used to partition in vivo bronchodilator effects between large and small airways. The parasympatholytic bronchodilator effects of both drugs were distributed uniformly along the bronchial tree, whereas the direct spasmolytic action of diphemanil appeared to manifest itself preferentially on large airways.

Animals↗
PubMed1984

Synthesis and antiarrhythmic and parasympatholytic properties of substituted phenols. 2. Amides.

Thirty amides patterned after the antiarrhythmic drug changrolin were synthesized and their antiarrhythmic and parasympatholytic activities were assessed. There was no correlation between antiarrhythmic and parasympatholytic activities. Several of the amides were found to be potent antiarrhythmic agents that possessed low parasympatholytic activity. All of the compounds appear to act by a class I mechanism.

Amides↗
PubMed1975

Pharmacological properties of n1-piperonyl-n4-3,7,11-trimethyl-2,6,10-dodecatrienyl-piperazine, a new non-anticholinergic gastric antisecretory agent.

The special and general pharmacology of N1-piperonyl-N4-3,7,11-trimethyl-2,6,10-dodecatrienylpiperazine (U-27) is reported. According to the results of the animal experiments the compound turned out to be a well tolerated gastric antisecretory drug devoid of anticholinergic activity. The compound was able to prevent hypersecretion induced by pylorus ligature in rat and guinea pig. Its duration of action was remarkable and no tolerance occurred after a repeated treatment. The compound displayed also an interesting activity on several experimental ulcers.

Animals↗
PubMed1985

Muscarinic depression of evoked surface-negative field potentials recorded from guinea-pig olfactory cortex in vitro.

The action of some cholinergic drugs has been studied on the field potentials evoked by orthodromic stimulation of the lateral olfactory tract (LOT) in guinea-pig olfactory cortex slices maintained in vitro. A reversible depression of the electrically evoked surface-negative field potential (N-wave) was seen following superfusion of muscarine (10-200 microM) or mixed-agonist choline esters but not nicotinic agonists. This depression was blocked by atropine and pirenzepine, but not d-tubocurarine or by antagonists active at gamma-aminobutyric acid or adenosine receptors. Little effect of muscarinic agonists was observed on the compound action potential recorded from the LOT, or on pial surface DC potential. A possible presynaptic site of action of muscarinic agonists in the olfactory cortex is discussed.

Acetylcholine↗
PubMedDate not supplied

Augmented vasoconstrictor responses to serotonin precede development of atherosclerosis in aorta of WHHL rabbit.

Watanabe heritable hyperlipidemic (WHHL) rabbits have elevated concentrations of plasma cholesterol and develop progressive atherosclerosis. The present investigation was undertaken to evaluate the vascular responses to vasoactive compounds of aorta from WHHL rabbits and normal New Zealand White (NZW) rabbits at 1 and 6 months of age. Rings of distal thoracic aorta were suspended under isometric tension in oxygenated Krebs buffer. Developed tension was measured in response to graded concentrations of agonists. Maximal responses to KCl (40 mM) were the same in aortas from the 1-month-old and 6-month-old WHHL and NZW rabbits. Aortas from 1-month-old animals were more sensitive to serotonin than aortas from 6-month-old animals. Aortas from WHHL rabbits exhibited an increased maximal response to serotonin when compared with NZW controls. In contrast, the constrictor responses to norepinephrine were reduced in WHHL rabbits compared with NZW rabbits at both age groups. Methacholine decreased tension development in serotonin-contracted vessels. This relaxation was greatest in aortas from NZW rabbits. In 1-month-old NZW rabbits fed a high cholesterol diet, the constrictor responses to serotonin and the relaxation responses to methacholine did not differ from NZW rabbits ingesting a normal diet. However, the responses to norepinephrine were markedly attenuated in the hypercholesterolemic NZW rabbits. Microscopic evaluation of the aortas revealed occasional adherent leukocytes and irregularities in the vascular endothelium in 1-month-old WHHL animals. These changes were greater in aortas from 6-month-old WHHL animals, with more adherent leukocytes, adherent platelets, and severe irregularities in the endothelial surface.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1978

Preliminary data on antiserotonin effects of oxatomide, a novel anti-allergic compound.

Oxatomide or R 35443, 1-(3-[4-(diphenylmethyl)-1-piperazinyl]propyl)-1,3-dihydro--2H-benzimidazol-2-one, a compound with potent antihistaminic and anti-anaphylactic activities, shows specific antiserotonin effects on isolated caudal arteries of the rat. In vivo it is a powerful antagonist of bronchospasm induced by serotonin and by histamine; it has no anticholinergic effects and does not affect blood pressure in spontaneously hypertensive rats. These antiserotonin properties of oxatomide may contribute significantly to its anti-allergic activity.

Animals↗
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↗