Vasodilating, spasmolytic, inotropic and chronotropic activities of curcuminoids from Curcuma longa in isolated organ preparations of guinea pigs.

Turmeric is a yellowish orange spice, widely used in Asian cuisine and obtained from the rhizome of Curcuma longa. It is a mixture of three curcuminoids namely, curcumin, demethoxycurcumin and bisdemethoxycurcumin. Turmeric has been used as a medicinal substance since ancient times for respiratory and gastrointestinal problems. The aim of the present study was to investigate which curcuminoid contributes to the observed pharmacological activities, all three curcuminoids, the major curcumin metabolite tetrahydrocurcumin, and the non-enzymatic curcumin hydrolysis products ferulic acid, feruloyl methane and vanillin were analyzed for spasmolytic, inotropic and chronotropic activity. Furthermore, their uptake in respective tissue samples was also investigated and correlated with activity. Spasmolytic activity was determined in guinea pig ileum, aorta and pulmonary artery. Inotropic and chronotropic activity was determined on guinea pig papillary muscles and right atrium respectively, while tissue uptake was quantified by using high-performance liquid chromatography (HPLC). All the curcuminoids exhibited significant spasmolytic activity with highest EC50 values for bisdemethoxycurcumin (5.8 ± 0.6 µM) followed by curcumin (12.9 ± 0.7 µM), demethoxycurcumin (16.8 ± 3 µM) and tetrahydrocurcumin (22.9 ± 1.5 µM). While only demethoxycurcumin was able to significantly relax the pulmonary artery with EC50 value of 15.78 ± 0.85 µM. All three curcuminoids showed mild negative chronotropic effects in the isolated right atrium; tetrahydrocurcumin demonstrated no activity. Curcumin and bisdemethoxycurcumin also showed mild positive inotropic effect whereas demethoxycurcumin and tetrahydrocurcumin exhibited weak negative inotropic one. Interestingly, ferulic acid, feruloyl methane and vanillin demonstrated no pharmacologicical activity at all in the various isolated organs. All three curcuminoids and tetrahydrocurcumin showed high uptake into the various tissues where concentrations correlated with pharmacological activity. The results indicate pronounced differences in the in vitro pharmacological activities of curcumin, demethoxycurcumin, bisdemethoxycurcumin and tetrahydrocurcumin which have to be considered in humans after per-oral intake of turmeric powder.

Effects of moniliformin in presence of cyclohexadepsipeptides on isolated mammalian tissue and cells.

Secondary metabolites produced by Fusarium spp. including beauvericin, enniatin and moniliformin are mycotoxins identified in cereal samples. The two cyclohexadepsipeptide mycotoxins beauvericin and enniatin have cytotoxic, antibiotic, insecticidal and ionophoric properties, while moniliformin primarily acts as a cardiotoxic mycotoxin. In this study, we examined the electromechanical and electrophysiological effects of moniliformin and moniliformin with ionophoric mycotoxins on cells (ventricular myocytes, Caco-2 cells) and in multicellular preparations (papillary muscles and terminal ilea of the guinea pig). Additionally, we investigated the influence of moniliformin on cell homeostasis in absence and presence of the cyclodepsipeptide mycotoxins (ventricular myocytes, Caco-2 cells). Experiments were performed using isometric measurements of contractility, intracellular microelectrode and patch-clamp techniques, and fluorescence imaging. While ionophoric cyclohexadepsipeptides affect action potential parameters and cell homeostasis, moniliformin did not change spontaneous rates of activity or cardiac action potentials. Furthermore, moniliformin had no effect on intracellular concentrations of ions and ATP, and did not affect pH. Moniliformin reduced contractility in papillary muscle, terminal ileum, the aorta and the pulmonary artery. However, moniliformin did not alter beauvericin and enniatin induced effects. From our studies, we conclude that moniliformin is not solely a cardiotoxic secondary metabolite, but also exerts its effects on smooth muscle. Moreover, there is no synergistic relationship between moniliformin and the concurrently produced cyclohexadepsipeptide mycotoxins beauvericin and enniatin.

Differences in action potential and early afterdepolarization properties in LQT2 and LQT3 models of long QT syndrome.

1. Long OT syndrome has many causes from both acquired and congenital disorders. For the congenital disorders, their presentation and disease course are not identical. We studied two pharmacological models of long QT syndrome (LQT) to identify differences in cellular electrophysiological properties that may account for this. LQT2 was simulated by suppression of the rapidly activating delayed rectifier potassium current (I(Kr)) with the drug E-4031, and LQT3 was simulated by slowing of the sodium current (I(Na)) decay with the toxin ATX II. 2. Single rabbit ventricular cell action potentials were studied using the amphotericin B perforated patch clamp technique. Action potential and early afterdepolarization (EAD) properties were rigorously defined by the frequency power spectra obtained with fast Fourier transforms. 3. The E-4031 (n=43 myocytes) and ATX II (n=50 myocytes) models produced different effects on action potential and EAD properties. The major differences are that ATX II, compared with E-4031, caused greater action potential prolongation, more positive plateau voltages, lower amplitude EADs with less negative take-off potentials, greater time to the EAD peak voltage, and longer duration EADs. Despite causing greater action potential prolongation, the incidence of EAD induction was much less with the ATX II model (28%) than with the E-4031 model (84%). Thus these two pharmacological models have strikingly different cellular electrophysiological properties. 4. Our findings provide cellular mechanisms that may account for some differences in the clinical presentation of LQT2 and LQT3.

Studies on the chemistry of thienoannelated O,N- and S,N-containing heterocycles. Part 19: thieno[2,3-b][1,4]thiazines with calcium antagonistic and potassium opening activities.

In this study novel substituted 6-benzyl-thieno[2,3-b][1,4]thiazines with an urea moiety were synthesized. Structural modifications of the amino side chain were carried out with the aim of finding tissue specific compounds. The effects on papillary muscles, right atria, aortic strips, and terminal ilea were investigated. Compounds 10c and 10d showed the most potent negative inotropic effect. The calcium antagonism of all derivatives occurred in a non-competitive manner, which may indicate that they also have potassium channel opening activities.

Cardiotoxic effects of fenfluramine hydrochloride on isolated cardiac preparations and ventricular myocytes of guinea-pigs.

The cardiotoxic effects of fenfluramine hydrochloride on mechanical and electrical activity were studied in papillary muscles, Purkinje fibres, left atria and ventricular myocytes of guinea-pigs. Force of contraction (f(c)) was measured isometrically, action potentials and maximum rate of rise of the action potential (V(max)) were recorded by means of the intracellular microelectrode technique and the sodium current (I(Na)) with patch-clamp technique in the cell-attached mode. For kinetic analysis (S)-DPI-201-106-modified Na(+) channels from isolated guinea-pig ventricular heart cells were used. Fenfluramine (1 - 300 microM) produced negative chronotropic and inotropic effects; additional extracellular Ca(2+) competitively antagonized the negative inotropic effect. Fenfluramine concentration-dependently reduced V(max) and showed tonic blockade of sodium channels, shortened the action potential duration in papillary muscles and Purkinje fibres. In cell-attached patches, fenfluramine decreased I(Na) concentration-dependently (10 - 100 microM), frequency-independently (0.1 - 3 Hz; 30 microM). The h(infinity) curve was shifted towards hyperpolarizing direction. At 30 microM, fenfluramine blocked the sodium channel at all test potentials to the same degree, and neither changed the threshold and reversal potentials nor the peak of the curve. No effect on single channel availability, but a significant decrease in mean open times and increase in mean closed times was observed. Mean duration of the bursts decreased and number of openings per record increased with increasing drug concentration. It is concluded that the effect on I(Na) plays an important role in the cardiotoxicity of fenfluramine in addition to primary pulmonary hypertension and valvular disorders.

Structure-activity relationships of new thienothiazine derivatives in isolated heart and smooth muscle preparations of guinea pigs.

New thienothiazine derivatives that differ in their side chains on the nitrogen atom of the thienothiazine ring were investigated regarding structure-activity relationships and calcium antagonistic and/or potassium channel opening properties. Isometric contraction force was measured in guinea pig papillary muscles, aortic strips, and terminal ilea. Chronotropic activity was studied in right atria of guinea pigs. The derivatives with a dimethylaminoethylcarboxamide side chain (HO4) and with a dimethoxyphenylethyl-N-methylaminoethylcarboxamide side chain (HO7) had the most potent negative inotropic effects on papillary muscles and spontaneously beating right atria. The negative inotropic and chronotropic effects of the compounds with a methylpiperazinylcarbonyl side chain (HO5) or a diethylaminopropylcarboxamide side chain (HO6) were less pronounced. The negative inotropic action was reversed by increasing the extracellular calcium concentration. It was also reversed by glibenclamide, for concentrations of the compounds up to the EC50, but not at higher compound concentrations. Among all the compounds studied, HO 7 had the strongest relaxing effect on aortic strips and terminal ilea. The effects of the derivatives on the smooth muscles could not be reversed by glibenclamide. The calcium antagonistic effect of the thienothiazine derivatives is more pronounced than the potassium channel opening activity, at least in high drug concentrations. Compounds with an aromatic or heterocyclic ring in the side chain have the weakest negative inotropic and negative chronotropic effects on papillary muscles and right atria. However, HO7 showed a tissue specificity with the most potent relaxing effect on aortic strips and terminal ilea.

Biological activities of novel thienothiazine derivatives on heart and smooth muscle preparations of guinea pigs.

New thienothiazine derivatives which differ in their side chains on the nitrogen atom of the thienothiazine ring were investigated regarding their biological activity and compared with calcium antagonistic drugs. Isometric contraction force was measured in guinea-pig papillary muscles, aortic strips and terminal ilea. Chronotropic activity was studied in right atria of guinea pigs. MS 69 with a ethylpyridylcarbonyl side chain had the most potent negative inotropic effect on isolated papillary muscles, followed by MS 74, which has an ethylmethylpiperazinylthiocarbonyl side chain. The negative inotropic effect could be antagonized by increasing the extracellular calcium concentration. MS 87 with an ethylpyridylcarboxamide side chain had the most potent relaxing effect on aortic strips and MS 48 with an ethylbenzylpiperazinylcarbonyl side chain was most potent on terminal ilea. Compounds with a more hydrophilic side chain had less activity. It is concluded that increasing the lipophilicity by substitution of an oxygen atom by a sulfur atom (MS 74) or addition of a pyridine ring (MS 69) results in a higher biological activity.

Effects of novel pyridothiazepines and pyridothiazines on contractility of isolated guinea-pig heart muscle and vascular smooth muscle preparations.

The effects of newly synthesized pyridothiazepines MM 4 (1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminoacetyl]-1,2,3,4 -tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate), MM 6 (1-[N-[2-(3,4-dimethoxyphenyl)-ethyl]-N-methylaminopropionyl]-1,2, 3,4-tetrahydro-pyrido[2,3-b][1,4]thiazepine fumarate) and the novel pyridothiazines MM 10 (2,3-dihydro-1-[N-[2-(3,4-dimethoxyphenyl)ethyl]-N-methylaminoacetyl+ ++]-1H-pyrido[2,3-b][1,4]thiazine fumarate) and MM 11 (2,3-dihydro-1-[N-[2-(3,4-dimethoxy-phenyl)ethyl]-N-methylaminopropio nyl]-1H-pyrido[2,3-b][1,4]thiazine fumarate) on the contractility of isolated papillary muscles and aortic preparations of guinea pigs were studied using isometric contraction force measurements. The EC50 values for the negative inotropic effect were 27 micromol/l (MM 4), 19 micromol/l (MM 6), 32 micromol/l (MM 10) and 24 micromol/l (MM 11). In K+-precontracted aortic rings ([K+]o 60 mmol/l), the compounds induced relaxation with EC50 values of 27 micromol/l (MM 4), 24 micromol/l (MM 6), 84 micromol/l (MM 10) and 68 micromol/l (MM 11). Pyridothiazepines as well as pyridothiazines (100 micromol/l) were able to depress norepinephrine bitartrate (NE 10 micromol/l)-induced contraction of aortic rings in a calcium-free solution. It was concluded that the investigated compounds exert calcium antagonistic properties in both cardiac and smooth muscle. This antagonistic effect might be due to the inhibition of transmembrane calcium influx and/or intracellular calcium release.

Comparative studies of new thienothiazine derivatives on heart and smooth muscle preparations of guinea pigs.

New thienothiazine derivatives which differ in their side chain on the nitrogen atom of the thienothiazine molecule were studied in guinea pig papillary muscles and terminal ilea using isometric contraction force measurements. Compounds with a heterocyclic ring in their side chain like MS 57 (pyrrolidinylethylcarboxamide side chain), MS 58 (piperidinoethylcarboxamide side chain) and MS 55 (morpholinoethylcarboxamide side chain) had the most potent negative inotropic effect on isolated papillary muscles. The relaxing effect on smooth muscle was more pronounced with compounds carrying an aromatic ring in their side chain like MS 25 (dimethoxyphenylethyl-N-aminopropionyl side chain), MS 24 (dimethoxyphenylethyl-N-methylaminoacetyl side chain) and MS 27 (dimethoxyphenyl-N-methylethylaminoethylcarboxamide side chain). Our results show a tissue selectivity of the thienothiazine compounds.

New benzoxazine and benzothiazine derivatives--structure-activity relations in guinea-pig heart and smooth muscle preparations.

New benzoxazine and benzothiazine derivatives which differ in their side chains on the nitrogen atom of the benzoxazine or benzothiazine ring were investigated regarding structure-activity relations and compared with calcium antagonistic drugs. The isometric contraction force was measured in guinea-pig papillary muscles, aortic strips and terminal ilea. Chronotropic activity was studied in right atria of guinea pigs. The benzoxazine derivative with a dimethoxyphenylethyl-N-methylaminoethylcarboxamide side chain (MS 84) had the most potent negative inotropic effect on papillary muscles and the most potent relaxing effect on terminal ilea. The benzothiazine derivative with a methylpiperazinylcarbonyl side chain (MS 63) was less effective. Benzoxazine derivatives with a methylpiperazinylcarbonyl (MS 64) or a N-dimethylaminoethylcarboxamide side chain (MS 66) and the benzothiazine derivative (MS 65) with an analog side chain like MS 66 only had a weak effect. We conclude that the oxygen atom in the heterocyclic ring and the lipophilic side chain on the nitrogen atom, which is almost identical with the calcium antagonistic drug KT-362 is responsible for the most potent action.

Proarrhythmic effects of antidepressants and neuroleptic drugs on isolated, spontaneously beating guinea-pig Purkinje fibers.

Antidepressants and neuroleptic drugs are sometimes the reason for the occurrence of the polymorphic ventricular arrhythmia torsades de pointes in patients. Therefore, it was of interest to study the actions of some of these drugs such as imipramine, amitriptyline, doxepin, chlorpromazine, trifluoperazine and thioridazine in isolated, spontaneously beating Purkinje fibers of guinea-pig hearts using the intracellular microelectrode technique because experimentally induced early afterdepolarizations (EADs) may be associated with this special type of arrhythmia. If the extracellular K+ concentration was 2.7mM none of these drugs could elicit EADs. For that reason the K+ concentration was lowered to 1. 35mM and EADs were evoked by imipramine (2 and 5 microM). Amitriptyline (2 and 5 microM) and doxepin (2 microM) did not induce EADs. Only a concentration of 5 microM doxepin elicited EADs. Among the neuroleptic drugs, chlorpromazine at a concentration of 2 and 5 microM was responsible for the occurrence of EADs as well as thioridazine in the same concentrations. When trifluoperazine (2 and 5 microM) was applied no EADs could be observed. Tetrodotoxin (0. 2 microMl-1) abolished thioridazine-induced EADs. Several membrane depolarizing currents may participate in the initiation of these EADs. Our results demonstrate that in guinea-pig Purkinje fibers some tricyclic antidepressants and some neuroleptic drugs are responsible for the rare occurrence of EADs under hypokalemic conditions.

Effects of the new imidazopyridine CL 86-02-01 on isolated papillary muscle of guinea-pig hearts.

Inotropic activity and the effect of CL 86-02-01 (2-(3-methoxy-5-methylsulfinyl-2-thienyl)-1H-imidazo[4,5-c]pyridine hydrochloride, CAS 109 792-24-7) on membrane resting and action potentials were studied in isolated guinea-pig papillary muscles. Membrane resting potential and action potential parameters were not significantly changed, while CL 86-02-01 exerted a concentration-dependent inotropic effect by increasing the maximum rate of force development and maximum rate of force relaxation. Time to peak force, relaxation time and total contraction time were reduced. These effects are similar to those of beta-adrenergic drugs and phosphodiesterase inhibitors, but markedly differ from those described for other positive inotropic agents like cardiac glycosides, calcium agonists, alpha-adrenergic drugs or increased extracellular calcium concentration.

Abolition of drug-induced early afterdepolarizations by potassium channel activators in guinea-pig Purkinje fibres.

1. Drug-induced early afterdepolarizations (EAD) are considered to be the underlying mechanism of the polymorphic ventricular dysrhythmia torsades de pointes. Sotalol and disopyramide are well known to generate EAD. Therefore, it was of interest to study the effects of potassium channel activators, such as nicorandil, pinacidil and lemakalim, on those drug-induced EAD in spontaneously beating guinea-pig Purkinje fibres using the intracellular microelectrode technique. 2. Early afterdepolarizations induced by sotalol at concentrations of 80 and 160 micromol/L could be completely abolished by nicorandil at concentrations between 50 and 500 micromol/L. The extracellular K+ concentration was 2.7 mmol/L. 3. Disopyramide-induced EAD at concentrations of 10, 20 and 30 micromol/L in a Tyrode's solution containing 1.35 mmol/L K+ and these EAD were abolished by pinacidil (30 and 100 micromol/L) and lemakalim (10 and 30 micromol/L). 4. Early afterdepolarizations could be regenerated by superfusion of Purkinje fibres with K+ channel activator-free Tyrode's solution containing either sotalol or disopyramide. 5. Our results demonstrate that drug-induced EAD can be abolished by K+ channel activators and, therefore, may provide anti-arrhythmic effects in heart diseases.

Mechanism of sodium channel blockade in the cardiotoxic action of emetine dihydrochloride in isolated cardiac preparations and ventricular myocytes of guinea pigs.

Emetine is used in the therapy of special forms of amebiasis and is abused as syrup of ipecac by persons with bulimia. Severe cardiac side effects were reported. Thus the intracellular microelectrode technique and the patch-clamp technique in the cell-attached mode were used to study the effects of emetine on the action potential and upstroke velocity (Vmax) in papillary muscles and Purkinje fibers of guinea pigs as well as on macroscopic and (S)-DPI 201-106-modified and unmodified single-sodium-channel current (I(Na)) of guinea-pig ventricular myocytes. Emetine caused a tonic block of Vmax and reduced I(Na) independent of frequency. Hill plots were linear, with slopes ranging from 0.96 to 1.06, suggestive of a first-order reaction. The current-voltage relation was not influenced, indicating a voltage-independent blockade of the sodium channels. The most prominent effects were an increase of sweeps without activity, a decrease of the fast component of the open-time distribution, an increase of the slow component of the closed-time distribution, and a reduction in the number of bursts per record. The amplitude of the unitary current was not changed. From the results, we conclude that I(Na) blockade contributes to the cardiotoxicity of emetine.

Torsade de pointes with an antihistamine metabolite: potassium channel blockade with desmethylastemizole.

OBJECTIVES: Proarrhythmic effects have been observed with the selective histamine1 (H1) receptor antagonist drug astemizole, a widely prescribed antihistamine. The metabolites of astemizole and those of other antihistamine compounds have not been implicated as causative agents of cardiac arrhythmias. The purpose of this study was to examine whether desmethylastemizole, the principal metabolite of astemizole, blocks delayed rectifier potassium (K+) channels. BACKGROUND: QT interval prolongation and torsade de pointes are associated with astemizole intake and have been ascribed to block the repolarizing K+ currents, specifically the rapidly activating component of the delayed rectifier iKr. Astemizole undergoes extensive first-pass metabolism, and its dominant metabolite, desmethylastemizole, has a markedly prolonged elimination time. We report the clinical observation of QT prolongation and torsade de pointes in a patient with undetectable serum concentrations of astemizole (< 0.5 ng/ml) and "therapeutic" concentrations of desmethylastemizole (up to 7.7 ng/ml or 17.3 nmol/liter). METHODS: The perforated patch clamp recording technique was used to study the effects of desmethylastemizole (20 nmol/liter) on action potentials and iKr in isolated rabbit ventricular myocytes. RESULTS: Desmethylastemizole produced action potential prolongation and the induction of plateau early afterdepolarizations. Under voltage clamp conditions, desmethylastemizole suppressed iKr amplitude by approximately 65%. The drug E-4031 (100 nmol/liter), which selectively blocks iKr, had a similar effect on current amplitude. CONCLUSIONS: Desmethylastemizole, the major astemizole metabolite, blocks the repolarizing K+ current iKr with high affinity. The clinical observation of QT prolongation and torsade de pointes found with astemizole intake may principally be caused by the proarrhythmic effects of its metabolite desmethylastemizole.

Synthesis and calcium antagonistic activity of 8-[N-[2-(3,4-dimethoxy- phenyl)ethyl]-beta-alanyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4]thiazepi ne fumarate.

KT-362 is an antiarrhythmic and antihypertensive agent with vasodilating activity. Since it carries a homoveratryl group in the side chain, an obvious relation exists to the verapamil-type calcium antagonists. Replacement of the fused aromatic moiety in KT-362 with thiophene provided 8-[N-[2-(3,4-dimethoxyphenyl) ethyl]-beta-alanyl]-5,6,7,8-tetrahydrothieno[3,2-b][1,4] thiazepine (1). Compound 1 shows a negative chronotropic activity in spontaneously beating right atria (IC50 = 23 microM, n = 7), and a negative inotropic effect in papillary muscles (IC50 = 2.7 microM, n = 7) and left atria (IC50 = 4 microM, n = 6) of the guinea-pig heart. The decrease of contractility in papillary muscles could be antagonized by increasing the extracellular calcium concentration. Compound 1 was found to affect high (IC50: 70 +/- 5 microM) and low (IC50: 129 +/- 34 microM) voltage-activated calcium channel currents as well as voltage-activated sodium channel currents (IC50: 80 +/- 13 microM) in chick dorsal root ganglion neurons. In addition nicotine-induced currents were potently inhibited (IC50: 6 +/- 0.7 microM) in bovine chromaffin cells.

Electromechanical effects of newly synthetized propafenone derivatives on isolated guinea-pig heart muscle preparations.

Inotropic, chronotropic and beta-adrenoceptor blocking activities of the newly synthetized propafenone derivatives 1-(2-(3-diethylamino-2-hydroxypropoxy)phenyl-3-phenyl-1-propanone hydrochloride (AM 03), 1-(2-(2-hydroxy-3-(1-piperidyl)propoxy)phenyl)-3-phenyl-1-propanone hydrochloride (AM 05), N,N-dimethyl-N-(2-hydroxy-3-(2-(3- phenylpropionyl)phenoxy)propyl)-propylammonium iodide (TH 41), N,N- diethyl-N-(2-hydroxy-3-(2-(3-phenylpropionyl)phenoxy)propyl)-methylammon ium iodide (AM 07), and N,N-diiso-propyl-N-(2-hydroxy-3-(2-(3-phenylpropionyl)phenoxy)prop yl)- methylammonium iodide (AM 09) studied in isolated, electrically stimulated papillary muscles and spontaneously beating right atria of guinea pigs. In comparison with propafenone the tertiary amines AM 03 and AM 05 showed a higher negative inotropic potency, while the quarternary amines TH 41, AM 07 and AM 09 were less effective. With regard to their negative chronotropic action, AM 03 and AM 05 were more and TH 41, AM 07 and AM 09 less potent than the parent drug. In contrast to propafenone none of its derivatives exerted beta-adrenoceptor blockade at the concentrations studied.

Cardiotoxicity of emetine dihydrochloride by calcium channel blockade in isolated preparations and ventricular myocytes of guinea-pig hearts.

1. The cardiotoxic effects of emetine dihydrochloride on mechanical and electrical activity were studied in isolated preparations (papillary muscles, sinoatrial and atrioventricular nodes, ventricular myocytes) of the guinea-pig heart. 2. Force of contraction was measured isometrically, action potentials and maximum rate of rise of the action potential were recorded by means of the intracellular microelectrode technique. Single channel L-type calcium current (Ba2+ ions as charge carrier) was studied with the patch-clamp technique in the cell-attached mode. 3. Emetine dihydrochloride (8-256 microM) reduced force of contraction in papillary muscles and spontaneous activity of sinoatrial and atrioventricular nodes concentration-dependently; the negative inotropic effect was abolished when the extracellular Ca2+ concentration was increased. 4. Maximum diastolic potential, action potential amplitude, maximum rate of rise of the action potential and the slope of the slow diastolic depolarization were decreased by emetine in sinoatrial as well as atrioventricular noes, while action potential duration was prolonged in both preparations (1-64 microM). 5. The amplitude of the L-type calcium single channel current was not altered by emetine dihydrochloride, while average open state probability was decreased concentration-dependently (10, 30 and 60 microM). 6. The most prominent effect of emetine dihydrochloride on single channel current was an increase of sweeps without activity. 7. At 60 microM, emetine dihydrochloride caused a decrease of the mean open time an increase of the mean closed time. The number of openings per record and number of bursts per record were reduced. 8. It is concluded that emetine dihydrochloride produces an L-type calcium channel block which might contribute to its cardiac side effects.

Drug profile of new benzofurane derivatives in guinea-pig isolated heart muscle preparations.

The recently synthesized benzofuranylethanolamines GE 68, GE 70, GE 76, RG 16 and RG 25, were studied in guinea-pig isolated papillary muscles and right atria. With regard to their inotropic, chronotropic and beta-adrenoceptor-blocking activity, these compounds were compared with the reference drug propafenone. GE 68, GE 70 and GE 76 were almost equally potent as propafenone in reducing the isometric force of contraction of papillary muscles, while RG 16 and RG 25 were less effective than the parent drug. GE 70 decreased the spontaneous rate of activity of right atria in a similar concentration range as propafenone, whereas GE 68 showed a more, and GE 76, RG 16 and RG 25 a less pronounced negative chronotropy. In contrast to the reference compound propafenone, the derivatives GE 70, GE 76 and RG 16 lacked any beta-adrenoceptor-blocking activity, while GE 68 and RG 25 exerted only a weak and nonsignificant effect. It is concluded that the formation of a benzofurane ring in the propafenone molecule did not cause a prominent change in negative inotropic and negative chronotropic effects, but resulted in a decrease or loss of beta-adrenoceptor-blocking activity. Additionally, an exchange of the phenylethyl group (GE 68, GE 70, GE 76) on the benzofurane ring by a methyl (RG 25) or ethyl group (RG 16), attenuated the negative inotropic and chronotropic potency.

[Synthesis and pharmacodynamic activity of 2-(3-(2-phenylethyl)benzofuran-2-yl)-N-propyl-ethanamine]. / Synthese und Pharmakodynamische Aktivität von 2-(3-(2-Phenylethyl)benzofuran-2-yl)-N-propyl-ethanamin.

The benzofuranethanamines 3a and 3b were synthesized and pharmacologically tested to investigate structure-activity relationships with antiarrhythmic compounds. The key-step in the synthesis was the chemoselective reduction of the chloroacetyl-dihydrobenzofurane 5 to chloroethylbenzofurane 9 using triethylsilane/BF3.Et2O. Results of a series of further attempts to reduce 5 are also described. Pharmacological investigations on isolated guinea pig heart muscle preparations showed that 3a exhibits similar negative inotropic and negative chronotropic action in comparison to propafenone and the conformationally restricted benzofurane 1a. In contrast to these substances, however, 3a shows no beta 1-adrenoreceptor blocking activity.