[Magnesium deficiency and therapy in cardiac arrhythmias: recommendations of the German Society for Magnesium Research]. / Magnesiummangel und Magnesiumtherapie bei Herzrhythmusstörungen. Empfehlungen der Gesellschaft für Magnesium-Forschung e. V.

Aim of the recommendations of the German Society for Magnesium Research: Recognition and compensation of magnesium deficiency in patients with risk factors for cardiac arrhythmias or manifest rhythm disturbances. Prevention of arrhythmias by administration of magnesium. Therapeutic administration of magnesium in patients with arrhythmias with and without magnesium deficiency. The current state of knowledge claims for considering the status of magnesium and the possibility of a therapeutic intervention with magnesium within the concept of the treatment of cardiovascular diseases. The use of magnesium as single agent or as an adjunct to other therapeutic actions in the prevention and therapy of cardiac arrhythmias can be effective and, in case of oral administration, very safe. In case of parenteral administration, it is important to use adequate doses, monitor cardiovascular and neuromuscular parameters and to consider contraindications.

Antimalarial and vasorelaxant constituents of the leaves of Allanblackia monticola (Guttiferae).

Phytochemical investigation of the leaves of Allanblackia monticola led to the isolation and characterisation of five prenylated xanthones [1,6-dihydroxy-3,7-dimethoxy-2-(3-methylbut-2-enyl)xanthone 1, alpha-mangostin 2, tovophyllin A 3, allanxanthone C 4 and 1,7-dihydroxy-3-methoxy-2-(3-methylbut-2-enyl)xanthone 5], two biflavonoid derivatives (amentoflavone 6 and podocarpusflavone A 7) and one pentacyclic triterpene (friedelan-3-one 8). The structures of these compounds were established on the basis of homo- and hetero-nuclear, one- and two-dimensional, nuclear magnetic resonance. Compounds 2-8 and a crude methanolic extract of A. monticola leaves were each tested for antimalarial activity in vitro, using the chloroquine-sensitive F32 and chloroquine-resistant FcM29 strains of Plasmodium falciparum; the median inhibitory concentrations (IC(50)) recorded varied from 0.7 to 83.5 mug/ml. The cytotoxicities of the compounds and crude extract, against cultures of human melanoma cells (A375), were then investigated, and cytotoxicity/antimalarial IC(50) ratios of 0.6-16.75 were recorded. In tests involving aortic rings from guinea pigs, a crude extract of the leaves of A. monticola was found to induce concentration-dependent vasorelaxation, causing up to 82% and 42% inhibition of noradrenaline- and KCl-induced contractions, respectively. The corresponding values for compounds 2 and 6 when tested against noradrenaline-induced contractions were approximately 18% and 35%, respectively.

Vasodilator effect of the extracts and some coumarins from the stem bark of Mammea africana (Guttiferae).

CH(2)Cl(2) fraction obtained from the stem bark of Mammea africana inhibited noradrenaline (NA) or KCl-induced contraction in isolated guinea pig and rat aorta. The vasorelaxant potency of the CH(2)Cl(2) fraction of Mammea africana was diminished by a pre-treatment with Nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, which was however not affected by indomethacin pre-treatment. These findings indicated that the vasorelaxant effect of Mammea africana may be partially endothelium dependent, mediated by nitric oxide and that vasoactive prostanoids might not be contributing to the vasorelaxation effect. Three bioactive compounds were isolated from this CH(2)Cl(2) fraction and identified as 4-n-propylcoumarins (1) (mammea B/BB), 4-phenylcoumarins (2) (mammea A/AA or mammeisin) and (B/BA) (3) and might involved in the vasorelaxant effect of the extract. The mechanisms of the vasorelaxant effect might therefore be multiple, including endothelium dependence and the mechanisms, which interfere with the liberation of Ca(2+) into the muscle cell.

Vasodilating properties of the stem bark extract of Mitragyna ciliata in rats and guinea pigs.

Mitragyna ciliata is commonly used in traditional medicine for the treatment of inflammation, hypertension, headache, rheumatism, gonorrhoea and broncho-pulmonary diseases. In the present study, the vascular relaxant effect in the rat and guinea-pig was investigated. The extract induced aortic relaxation in a concentration-dependent manner, with an EC(50) of 1.3 and 7 microg/mL for the noradrenaline- and KCl-induced contractions, respectively. The relaxant effect of the extract on KCl-induced contractions was fi ve times greater than on noradrenaline-induced contractions. Moreover, the relaxant effect of the extract was higher in rat aortic rings with endothelium (104.67%) than without endothelium (49.44%). Chemical analysis of the extract showed the presence of alkaloids and flavonoids which may be responsible for the antihypertensive properties.

Investigation of the pharmaceutical and pharmacological equivalence of different Hawthorn extracts.

Seven Hawthorn extracts were tested in isolated guinea pig aorta rings. The effect on noradrenaline- (10 microM) induced contraction was investigated. The extracts were prepared using ethanol (40 to 70% v/v), methanol (40 to 70% v/v), and water as the extraction solvents. The aqueous-alcoholic extracts displayed similar spectra of constituents. They were characterised by similar procyanidin, flavonoid, total vitexin and total phenols content and by similar TLC fingerprint chromatograms. The aqueous extract, however, showed a different fingerprint and a noticeably lower concentration of procyanidins, flavonoids and total phenols but a similar total vitexin content. All 7 extracts had a relaxant effect on the aorta precontracted by noradrenaline and led to relaxations to 44 until 29% of the initial values. The EC50 values of the aqueous-alcoholic extracts varied between 4.16 and 9.8 mg/l. The aqueous extract produced a similarly strong maximal relaxation as the other extracts, but the EC50, at 22.39 mg/l, was markedly higher. The results show that Hawthorn extracts with comparable quality profiles were obtained by using aqueous-alcoholic extraction solvents (40 to 70% ethanol or methanol). The extracts exerted comparable pharmacological effects. When using water as the extraction solvent, both, the spectrum of constituents and the pharmacological effect, deviated remarkably. It is thus possible to obtain bioequivalent extracts with comparable effect profiles by using 40 to 70% ethanol or methanol as the extraction solvent.

Inhibition of intestinal motility by methanol extracts of Hibiscus sabdariffa L. (Malvaceae) in rats.

The methanol extracts of Hibiscus sabdariffa (p < 0.01) showed a significant dose dependent relaxant effect (IC50) = 350 microM) on rat ileal strip comparable to the effect shown by nifedipin and papaverine as reference compounds. Similarly, the extract when administered intraperitoneally significantly (p < 0.05-0.01) reduced the intestinal transit (13%-35%) in rats (IC50, = 250 microM). The extracts (40% +/- 04%) and nifedipin (51% +/- 05%) also potentiated the diarrhoea inducing effect of castor oil (IC50 = 350 microM). It is postulated that these effects are possibly generated by constituents such as quercetin and eugenol via a Ca2+ channel modulated mode of action.

Estrogenic and cholinergic properties of the methanol extract of Ruellia praetermissa Sceinf. ex. Lindau (Acanthaceae) in female rats.

In search for alternative drugs with pharmacological profile to replace hormone replacement therapy, the effects of MeOH extract of Ruellia praetermissa on the uterus and gestation in rats was investigated. 350 mg/kg/day of extract from days 1-9, 1-17 and 9-17 respectively, resulted in increase of the number of implantation sites (56 to 64) and the percentage of implantation (68.6 +/- 2.7 to 90.5 +/- 0.5%). There was also an increase in body weight (1-9 and 1-17) followed by a slight decrease (154 +/- 15.5 to 125 +/- 10) in the body weight at term. The number and the mean value of corpora lutea per female decreased from 25.4 +/- 1.6 to 14.00 +/- 1.6. The extract produced dose-related contraction of the isolated uterine muscle in vitro comparable to ACh. Atropine in doses from 3.4 x 10(-6) to 3 x 10(-3) microM antagonized the response of the uterus to ACh at 2 microM. It induced an increase (0.03 +/- 0.002 to 0.34 +/- 0.001 g) of the uterine weight comparable to that produced by using 3 microM estradiol (0.03 +/- 0.001 to 0.35 +/- 0.005 g). It could therefore be postulated that this extract possesses estrogenic and possible cholinergic effects. The estrogenic effect could have been generated by plant sterols (beta-sitosterol and stigmasterol) and flavonoids (luteolin and apigenin) while cholinergic effect could be due to iridoid glycosides.

Minor constituents of Spigelia anthelmia and their cardiac activities.

A more detailed phytochemical analysis of extracts of the aerial parts of Spigelia anthelmia L. (Loganiaceae) yielded 20 structurally related new compounds besides spiganthine and ryanodine. Structure elucidation was achieved mainly by spectroscopic methods. The compounds were tested on their cardiac and on their insect antifeedant activities.

Effects of inhibition of calcium and potassium currents in guinea-pig cardiac contraction: comparison of beta-caryophyllene oxide, eugenol, and nifedipine.

1. To investigate the effects of the clove oil constituents beta-caryophyllene oxide and eugenol on the heart muscle, experiments were performed on isolated papillary muscles and on ventricular myocytes of the guinea-pig. The results were compared with those obtained with the dihydropyridine, nifedipine. 2. All three substances exerted negative inotropic effects in heart muscle although with different potencies and different influences on the time course of the contraction curve. 3. They all reduced rested-state contractions (RSCs) in the presence of isoprenaline which are thought to be due to the Ca(2+) current (I(Ca)). 4. beta-Caryophyllene oxide, eugenol and nifedipine inhibited the I(Ca) in single cells from the guinea-pig ventricle in a concentration-dependent, reversible way, but with different potencies. 5. In addition to the I(Ca)-inhibiting effect, beta-caryophyllene oxide strongly inhibited and eugenol slightly inhibited the potassium current. 6. The action potential of papillary muscles at a 1 Hz contraction frequency was greatly shortened by nifedipine, slightly shortened by eugenol, but not changed by beta-caryophyllene oxide. 7. The inhibition of the potassium current by beta-caryophyllene oxide obviously prevents a shortening of the action potential due to the diminution of the I(Ca). Accordingly, the negative inotropic effect of beta-caryophyllene oxide is closely related to the inhibition of I(Ca). In contrast, eugenol and nifedipine, which shorten the action potential, exert stronger negative inotropic effects than expected from their influence on I(Ca). 8. The results show that the negative inotropic effect of a calcium channel blocker can be attenuated by an additional inhibition of potassium channels.

In vitro purgative effect of Ruellia praetermissa. Sceinf.ex.Lindau (Acanthaceae).

Methanol, ethylacetate and aqueous extracts of Ruellia praetermissa initiated spontaneous contractions in the quiescent and increased contraction on the electrically stimulated ileal strip at a concentration of 30 microg/ml. The extracts produced concentration-related contractions both in amplitude and tone up till 750 microg/ml with IC(50) of 360 microg/ml (methanol extract), 425 microg/ml (ethylacetate extract) and 540 microg/ml (aqueous extract). Acetylcholine also produced a concentration-related (IC(50)=18 microg/ml) contractions of the isolated ileum. Atropine in concentrations of 3.4 x 10(-6)-3 x 10(-3) microg/ml antagonized progressively the response of the isolated ileum to acetylcholine (32 x 10(-2) microg/ml) and the methanol extract (650 microg/ml) induced contractions suggesting a mode of action via cholinergic system. Luteolin and apigenin and iridoid glucosides (taxiphilin and 8-epi-deoyganic acid) might be responsible at least in part for the observed effect.

[Diagnosing magnesium deficiency. Current recommendations of the Society for Magnesium Research]. / Diagnostikdes Magnesiummangels. Aktuelle Empfehlungen der Gesellschaft für Magnesium-forschung e. V.

The cardiovascular risk increases with decreasing serum levels of magnesium, and this already at concentrations within the previous reference range (0.70-1.10 mmol/L). For this reason, the Society for Magnesium Research has updated its 1986 recommendations for the diagnosis of magnesium deficiency. The diagnosis is based on the patient's history, his clinical symptoms, and the results of clinical-chemical investigations of plasma/serum and urine. Further diagnostic methods used include the determination of ionized serum magnesium and the magnesium retention test. The optimal serum magnesium concentration is > 0.80 mmol/L.

[Comments on the kinetics and extracellular effects of potassium and magnesium]. / Bemerkungen zur Kinetic und zu extrazellulären Wirkungen von Kalium und Magnesium.

Potassium and magnesium are important electrolytes which have to be ingested in sufficient amounts. They differ in the necessary daily intake (about 100 mmol potassium, about 12 mmol magnesium), the degree of intestinal absorption (potassium almost 100%, magnesium about 30%) and the distribution between the extracellular and intracellular space. If there is a deficiency in potassium or magnesium, it is necessary to substitute these materials. Deficiency of potassium is not rarely combined with deficiency of magnesium. The concentration gradient between intra- and extracellular potassium mainly determines the resting membrane potential of the cell. Lower extracellular potassium may lead to an instable membrane potential because of a decrease in potassium conductance. An increase in extracellular potassium concentration leads to the depolarization of the cell. Extracellular potassium activates the sodium potassium pump and thereby prevents an increased intracellular accumulation of sodium and calcium. Important effects of extracellular magnesium are: calcium antagonism, increase of excitation threshold and inhibition of transmitter release. By increasing the plasma concentration of magnesium, it is possible to exert pharmacodynamic effects. An increase above the normal range usually is only possible by parenteral application. However, a slight elevation can already be achieved by oral application. This increase may lead to limited pharmacodynamic effects. By elevation of the extracellular magnesium concentration, adverse, depolarisation-dependent effects of an increase in extracellular potassium concentration (for example slowing of conduction of excitation) can be compensated. This effect can be explained by a magnesium-dependent decrease of the membrane surface potential.

Screening of plant extracts and plant constituents for calcium-channel blocking activity.

Various constituents isolated from plants with described or suggested antihypertensive, spasmolytic or diuretic activity were tested in an in in vitro-guinea pig papillary muscle model for possible calcium-channel blocking activity. Among the isolated compounds some phenylpropanoids of essential oil (e.g. apiol), mono- and sesquiterpene derivatives (e.g. bisabolol-oxide A), naphthoquinones (e.g. juglone, 7-methyljuglone, plumbagin, garlic constituents), some phenolics and alkaloids showed good to moderate activity (IC(50):15-100 µM). Some of the tested compounds caused a prolonged duration of the contraction, suggesting an additional K(+)-channel blocking effect.

Increase in magnesium plasma level after orally administered trimagnesium dicitrate.

Magnesium plasma concentrations were measured in healthy probands before and after administration of trimagnesium dicitrate by the oral and intravenous routes. There was a notable circadian fluctuation of the plasma concentration with a peak in the evening hours. After oral administration of 12 and 24 mmol magnesium, a long-lasting, statistically significant increase in plasma magnesium concentration measured as the increase in area under the curve (AUC) between 0 and 12 h, of 3.1% and 4.6%, respectively, was found. After intravenous administration of 4 and 8 mmol magnesium, AUCs increased by 9.5% and 16.1%, respectively. The decline in the plasma magnesium concentration after i.v. administration was compatible with a three-compartment model with a terminal half-time of about 8 h. Although no absolute value of the oral bioavailability of trimagnesium dicitrate could be determined from the data, our results may be important in helping to elucidate the influence of magnesium preparations on the plasma magnesium concentration. By comparing the effects of different preparations, it should be possible to estimate the relative oral bioavailability and the bioequivalence of these preparations.

Spiganthine, the cardioactive principle of Spigelia anthelmia.

Spiganthine [1] was isolated as the main cardioactive principle from medicinally used extracts of Spigelia anthelmia. Its structure was established by spectroscopic methods. The biological effect of spiganthine is characterized by a delay in contraction development of the heart muscle.

Magnesium-dependent calcium efflux in mammalian heart muscle.

Extra and intracellular magnesium is involved in the control of myocardial calcium movements. Here we report on an increase in cytosolic calcium concentration in resting ventricular myocytes due to the withdrawal of extracellular magnesium under the condition of a blocked sodium-dependent calcium elimination. Evidence for an activation of cellular calcium efflux by extracellular magnesium showed experiments in perfused hearts. It is concluded that extracellular magnesium can modulate the intracellular free calcium concentration of the myocardial cells by its influence on calcium elimination.

Inhibition by magnesium of calcium inward current in heart ventricular muscle.

It was investigated whether the negative inotropic effect of magnesium in mammalian heart ventricular muscle is due to inhibition of the calcium inward current. Whole-cell voltage-clamp experiments were carried out with isolated guinea-pig heart cells. The sodium inward current was inactivated by a conditioning pre-pulse or by addition of tetrodotoxin. Magnesium concentration dependently and reversibly diminished the calcium inward current (by about 45% after an increase in magnesium concentration, from 1.2 to 9.6 mM). The decrease was mainly due to diminution of the maximally available calcium inward current but was additionally due to a shift of the current-voltage relationship to more positive potentials. The crucial dependence of the inhibition of the inward current on the pre-pulse potential was demonstrated. Conditioning depolarization to potentials more negative than -40 mV led to an increase of an inward current by magnesium. This was probably the consequence of incomplete inactivation of the sodium current and the shift of its current-voltage relationship by the divalent cation.

[High-dosage oral magnesium therapy in arrhythmias. Results of an observational study in 1.160 patients with arrhythmia]. / Hochdosierte orale Magnesiumtherapie bei Herzrhythmusstörungen. Ergebnisse einer Anwendungsbeobachtung bei 1,160 Patienten mit Arrhythmie.

In the treatment of cardiac arrhythmias of varying genesis, an "observational study" in 1,160 patients showed that a high-dose oral magnesium preparation (Magnesium-Diasporal N 300 Granulat) was effective. In 82% of the patients observed, a dose of at least 300 mg magnesium/day produced good to very good results. Adverse effects of the drug were observed in only 1.6% of the patients. For all groups, the "success parameters" improved significantly. High-rate arrhythmias showed a better response to magnesium treatment than did low-rate arrhythmias, with a close correlation being found with the heart rate at the start of treatment. High-dose oral magnesium had a positive effect on concomitant hypertension. At a dosage of 300 mg treatment should be continued for at least 6 weeks.

The action of organic mercury compounds on the function of isolated mammalian heart muscle.

The effects of four organic mercury compounds (methylmercuric chloride; bromomercurihydroypropane, BMHP; chlormerodrin; p-chloromercuribenzoic acid, PCMB) on mechanical and electrical functions of guinea-pig papillary muscles were investigated. An initial decline in contraction force was followed by a transient positive inotropic response. The first was accompanied by a shortening of the action-potential duration and by a reduction of the depolarization velocity and the duration of the Ca2+-dependent slow response. The latter was characterized by an indirect component (release of noradrenaline) and by a direct component, which was dependent on the stimulation rate and on the extracellular concentration of Na+ and K+. The direct positive effect, therefore, was likely to have resulted from inhibition of the sarcolemmal Na+ + K+-ATPase. This notion was confirmed by experiments with isolated membrane particles. The prevalence of the negative or positive inotropic action of these compounds could be ascribed to their lipophilic or hydrophilic properties, respectively.