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Mechanism of neuromuscular blockade induced by phenthonium, a quaternary derivative of (-)-hyoscyamine, in skeletal muscles.

Souccar C, Lima-Landman MT, Ballejo G, Lapa AJ.

Universidade Federal de Sao Paulo, Escola Paulista de Medicina, Department of Pharmacology, SP, Brazil.

1. The mechanisms underlying the postjunctional blockade induced by phenthonium [N-(4-phenyl) phenacyl 1-hyoscyamine] were investigated in mammalian and amphibian muscles. This muscarinic antagonist was previously shown to enhance specifically the spontaneous acetylcholine (ACh) release at concentrations that blocked neuromuscular transmission. 2. In both rat diaphragm and frog sartorius muscles, phenthonium (Phen, 1-100 microM) depressed the muscle twitches elicited by nerve stimulation (IC50: 23 microM and 5 microM, respectively), and blocked the nerve-evoked muscle action potential. The neuromuscular blockade was not reversed after incubation with neostigmine. 3. Equal concentrations of Phen decreased the rate of rise and prolonged the falling phase of the directly elicited action potential in frog sartorius muscle fibres, indicating that the drug also affects the sodium and potassium conductance. 4. Phen (50 and 100 microM) protected the ACh receptor against alpha-bungarotoxin (BUTX) blockade in the mouse diaphragm allowing recording of endplate potentials and action potentials after 5 h wash with physiological salt solution. 5. Phen (10-100 microM) produced a concentration- and voltage-dependent decrease of the endplate current (e.p.c.), and induced nonlinearity of the current-voltage relationship. At high concentrations Phen also shortened the decay time constant of e.p.c (tau(e.p.c.)) and reduced its voltage sensitivity. 6. At the same range of concentrations, Phen also reduced the initial rate of [125I]-BUTX binding to junctional ACh receptors of the rat diaphragm (apparent dissociation constant = 24 microM), the relationship between the degree of inhibition and antagonist concentration being that expected for a competitive mechanism. 7. It is concluded that Phen affects the electrical excitability of the muscle fibre membrane, and blocks neuromuscular transmission through a mechanism that affects the agonist binding to its recognition site and ionic channel conductance of the nicotinic ACh receptor.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9720800&dopt=Abstract hyoscyamine Levbid SL



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1-Methylpyrrolidine-2-acetic Acid is not a Precursor of Tropane Alkaloids.

Huang MN, Abraham TW, Kim SH, Leete E.

AgroEvo USA Company, Pikeville, NC 27863, USA.

1-Methylpyrrolidine-2-acetic acid and related compounds were studied as precursors in the biosynthesis of the tropane alkaloids in Erythroxylum coca and Datura innoxia. (R,S)-[1',2-(13)C2,2-(14)C,(15)N]-1-methylpyrrolidine-2- acid, (R,S)-[1',2'-(13)C2,1'-(14)C]-1-methylpyrrolidine-2-acetic acid, (R,S) [1',2'-(13)C2,1-(14)C]-1-methylpyrrolidine-2-acetate, and (R,S)-+2'-(14)C] methylpyrrolidine-2-acetic acid N-acetylcysteamine thioester were synthesized an intact plants by leaf-planting or hydroponic-feeding. Specific incorporation of compounds into ( - )-hyoscyamine, ( - )-scopolamine, ( - )-cocaine and the biosynthetically related cuscohygrine were very low. These results indicate that 1-methylpyrrolidine acid is not an efficient precursor of tropane alkaloids.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8835455&dopt=Abstract hyoscyamine Levbid SL



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Genotypes and alkaloid contents of Datura metel varieties.

Hiraoka N, Tashimo K, Kinoshita C, Hiro'oka M.

Niigata College of Pharmacy, Japan.

Datura metel L. var. muricata (BERNH.) DANERT was found to be double recessive with respect to the genes concerning the color and form of the corolla by breeding experiments involving four varieties, i.e. var. metel (white, simple corolla), var. rubra (purple, simple), var. fastuosa (purple, double or triple) and var. muricata (white, purple). The results support the proposal by Danert and others that these variants should be considered as varieties or forms of a single species, Datura metel. The analysis of tropane alkaloids in the seeds, flowers, and leaves of these four varieties showed that scopolamine was always dominant over hyoscyamine. The range of the scopolamine content (% of dry weight) of seeds, flowers, and leaves was 0.294 (var. rubra)-0.631 (var. fastuosa), 0.190 (var. metel)-0.698 (var. rubra), and 0.042 (var. rubra)-0.255 (var.metel), respectively. These findings proved that all the varieties, including var. muricata, which exhibited medium scopolamine content among the varieties, can be utilized as sources of scopolamine.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=8874823&dopt=Abstract hyoscyamine Levbid SL



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Stereoselective increase in cholinergic transmission by R-(+)-hyoscyamine.

Ghelardini C, Gualtieri F, Novella Romanelli M, Angeli P, Pepeu G, Grazia Giovannini M, Casamenti F, Malmberg-Aiello P, Giotti A, Bartolini A.

Department of Preclinical and Clinical Pharmacology, University of Florence, Italy.

R-(+)-hyoscyamine, the dextro enantiomer of atropine, has been shown to amplify cholinergic transmission. R-(+)-hyoscyamine, unlike S-(-)-hyoscyamine, was able to increase acetylcholine release both in vitro and in vivo at a range of concentrations (10(-14) to 10(-12) M) and doses (5 microg/kg i.p.) which were inadequate for blocking muscarinic receptors. The increase over control values in ACh release was 15.9 +/- 2.1% in in vitro experiments performed in rat phrenic nerve-hemidiaphragm preparations (n = 6), and 63.3 + 16.3% in cortical microdialysis performed in free-moving rats (n = 5). The maximum ACh release was reached 60 min after R-(+)-hyoscyamine administration in in vivo experiments. At the same doses and concentrations, R-(+)-hyoscyamine was also able to elicit: antinociception of a cholinergic type (55.6-112.7% depending on the test used); complete prevention of scopolamine- and dicyclomine-induced amnesia; potentiation of muscular contractions electrically evoked in isolated guinea-pig ileum (16.7 +/- 3.6%) and in rat phrenic nerve-hemidiaphragm (19.9 +/- 3.2%) preparations. Antinociception was performed using the hot-plate and acetic acid abdominal constriction tests in mice, and the paw pressure test in rats, while prevention of induced amnesia was evaluated in mice using the passive-avoidance test. The respective affinities (pA2) for R-(+)- and S-(-)-hyoscyamine vs M1 (rabbit vas deferens), M2 (rat atrium) and M3 (rat ileum) receptor subtypes were as follows: 7.05 +/- 0.05/9.33 +/- 0.03 for M1; 7.25 +/- 0.04/8.95 +/- 0.01 for M2; 6.88 +/- 0.05/9.04 +/- 0.03 for M3. The respective pKi values for R-(+)- and S-(-)-hyoscyamine vs the five human muscarinic receptor subtypes expressed in Chinese hamster oocytes (CHO-K1) were as follows: 8.21 +/- 0.07/9.48 +/- 0.18 for m1; 7.89 +/- 0.06/9.45 +/- 0.31 for m2; 8.06 +/- 0.18/9.30 +/- 0.19 for m3; 8.35 +/- 0.11/9.55 +/- 0.13 for m4; 8.17 +/- 0.08/9.24 +/- 0.30 for m5.

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Spectral analysis of intercycle heart fluctuations in the diethyl-ether-anaesthetized or pithed rat treated with l-hyoscyamine.

Bernardi M, Deslauriers R, Docherty J, Galeazzi G, Rossini L, Rossini P.

I.M.O.-Institute of Experimental and Clinical Medicine, University of Ancona Medical School, Italy.

1. Within the context of neural regulation of the activity of sinus node pacemaker cells, the study of heart rate variability, as explored in the frequency domain by spectral analysis, was proposed about 15 years ago as a quantitative tool for the evaluation of short-term autonomic cardiovascular control. It has since been postulated that the two main oscillations observed, one at low and the other at high frequency, may respectively be markers of sympathetic vs. vagal efferent cardiac activity, and that the low- and high-frequency signals may reflect a reciprocal or 'push-pull' relationship between sympathetic and parasympathetic control. 2. In our power spectra assessment, ECG R-R intervals were submitted to fast Fourier transformation analysis in order to study the mechanisms underlying the control of heart beats in rats. Data were acquired in conditions of steady arterial blood pressure and cardiac and respiratory activity (spontaneous or artificially stimulated) in diethyl-ether-anaesthetized and pithed rats, as well as in a group of control rats, all in the presence and absence of l-hyoscyamine. 3. With increasing doses of the parasympathetic antagonist, the fractal dimension of the time-series structure remained stable in most cases. The low-frequency spectral component narrowed with increasing drug doses and the high-frequency band underwent either no, or only very slight, changes. 4. In these rodent assays, the low- and high-frequency signals cannot be interpreted as a push-pull relationship between sympathetic and parasympathetic control.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9201557&dopt=Abstract hyoscyamine Levbid SL