Interaction of phosphodiesterase inhibitors triamterene, papaverine, theophylline, IBMX and amrinone with other positive inotropic acting substances on isolated guinea-pig atria.

On isolated electrically stimulated left and spontaneously beating right guinea-pig atria the interaction between PDE-inhibitors and the positive inotropic and chronotropic action of orciprenaline, forskolin and histamine in dose-response curve was examined. The experiments led to the following results: triamterene (20-120 mumol/l) and papaverine (10-100 mumol/l) inhibit the positive inotropic and chronotropic action of orciprenaline, whereas theophylline (10-100 mumol/l) and isobutyl-methyl-xanthine (0.1-10 mumol/l) only inhibit the inotropic action of orciprenaline. Amrinone (100-316 mumol/l) increases the positive inotropic and chronotropic action of orciprenaline; the positive inotropic and chronotropic action of forskolin is inhibited by triamterene but not by theophylline and IBMX. The positive chronotropic action of forskolin and histamine is inhibited by triamterene, whereas the positive inotropic action of histamine is not influenced; our experimental results suggest that triamterene and papaverine antagonize orciprenaline action by inhibition of adenylate cyclase. For this there is further evidence in the antagonism between triamterene and the inotropic action of forskolin and the tachycardic action of histamine. As theophylline and IBMX inhibit only the inotropic action of orciprenaline, there might be a different mechanism for their interaction regarding the chronotropic action of orciprenaline compared to triamterene and papaverine. The amrinone mechanism differs from that of the other PDE-inhibitors as it increases the positive inotropic and chronotropic action of orciprenaline.

Pharmacodynamic specification and membrane stabilising action of a homologous series of silasympathomimetics.

The pharmacodynamic effect of a homologous series of aminomethyldimethyl-(methoxyphenyl)-silane derivatives have been tested on isolated guinea-pig left atria. All molecules increase the force of contraction to different degrees by a partly direct and partly indirect mechanism (measured on atria isolated from reserpine treated guinea-pigs). The positive inotropic effect is reduced by bupranolol. Furthermore the compounds show an antagonistic effect to orciprenaline. The membrane stabilising action is lowest for those compounds showing the highest inotropic effects and vice versa.

Comparative studies of some semisynthetic K-strophanthins with natural cardiac glycosides.

In this study the pharmacological effects of seven semisynthetic cardenolides have been investigated and compared with those of 11 natural cardiac glycosides. These compounds are of different potency on electrically driven isolated guinea-pig atria. Their concentration response curves showed different slopes, which could be an indication of varying therapeutic range. The pharmacodynamics of these compounds on isolated guinea-pig atria are in good correlation with the data obtained from binding studies on guinea-pig ventricular homogenate as well as that obtained from comparative experiments on Na+,K+-ATPase activity inhibition.

Bepridil: a review of its pharmacology and clinical efficacy as an anti-anginal agent with anti-arrhythmic properties.

Bepridil is an anti-anginal agent with a novel chemical structure. Its main pharmacological effects are an increase in coronary blood flow, a reduction in myocardial oxygen demand, reduction in cardiac work, primarily by a decrease in after-load and a dose-dependent negative chronotropic effect, and anti-arrhythmic properties. These are mainly due to a calcium-antagonistic action. There is evidence that fast sodium channels in heart muscle are also inhibited. Trials have shown that bepridil is effective in the prophylactic treatment of various forms of angina pectoris and accompanying arrhythmias. Pharmacokinetic data justify once-daily administration. The evidence suggests that bepridil is generally well tolerated. This paper reviews already published studies and the results of recent investigations on the pharmacological and clinical efficacy of bepridil.

Investigations on the mechanism of positive inotropic action of (+)-tranylcypromine in isolated guinea-pig atria.

Investigations on the mechanism of the positive inotropic action of (+)-tranylcypromine (TCP) on left, electrically stimulated, isolated guinea-pig atria led to the following results: In contrast to (-)-TCP, the positive inotropic action of (+)-TCP on the guinea-pig atria is not abolished, but only weakened by pretreating animals with reserpine. The positive inotropic effect of indirectly acting sympathomimetics, such as tyramine or methamphetamine, on isolated atria of reserpine pretreated guinea pigs recovers within 15-30 min of incubation with (+)-TCP. The same applies to other inhibitors of MAO-A, such as clorgiline and pargyline as well as selegiline (deprenyl) in higher concentrations. Inhibitors of norepinephrine (noradrenaline) synthesis as alpha-methyl-p-tyrosine and FLA-63 (bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)-disulphide] prevent the positive inotropic action of (+)-TCP on atrial preparations of reserpine pretreated guinea pigs, and abolish the (+)-TCP induced restitution of the effects of tyramine and methamphetamine. A destruction of adrenergic nerves using 6-hydroxydopamine also prevents the positive inotropic action of (+)-TCP. These results suggest that (+)-TCP increases the net neuronal synthesis of catecholamines.

[Animal experimental studies on the pharmacology of a new anti-arrhythmic of the imino-cycloheptane series, stirocainide]. / Tierexperimentelle Untersuchungen zur Pharmakologie des neuen Antiarrhythmikums aus der Imino-cycloheptan-Reihe, Stirocainid.

The action of 2- benzal -1-(2'-diisopropyl-amino-ethoxy-imino)- cycloheptane hydrogenfumarate ( Stirocainide , Th 494) has been investigated on isolated guinea-pig atria and papillary muscles and on the circulation of the anaesthetized and conscious cat. Th 494 is characterized as a Na+-inhibitory antiarrhythmic agent in isolated atria and papillary muscles. 1-10 mumol/l Th 494 induces only a small increase in action potential duration in both preparations, whereas no change in resting potential or amplitude of the action potential is observed. The action on the maximal rate of rise of the action potential (Vmax) depends on the rate of stimulation ("use-dependence"), this effect being somewhat smaller in atria as compared to papillary muscles. The increase in threshold of alternating current induced arrhythmias and in functional refractory period is also smaller in atria. Isometric force of contraction is reduced by Th 494 in guinea-pig atria and papillary muscles to a greater extent than in rabbit and cat. In the anaesthetized cat 2 mg/kg Th 494 i.v. induces a transient decrease in heart rate and a decrease in the maximal rise of left ventricular pressure. In addition, 4 mg/kg i.v. induces a transient decrease in systolic and diastolic blood pressure as well as a broadening of the QRS complex in the ECG. High doses of 4 and 8 mg/kg, respectively, lead to arrhythmias and apnoea, 8 mg/kg to exitus. Atropine does not influence the action of Th 494. 2 and 4 mg/kg Th 494 do not alter the action of norepinephrine on heart and circulation.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiac glycosides and sodium/potassium-ATPase.

The sodium/potassium-ATPase complex is, according to modern research, the binding site for cardiac glycosides on the outer surface of the cell membrane and their receptor. Inhibition of this enzyme by cardiac glycosides leads for instance in the heart to a decrease or a delay in membrane sodium/potassium-ion transport, and indirectly to an increase in the intracellular ionized calcium-concentration and an increase in cardiac contractile force. According to recent observations the activity of the sodium/potassium-ATPase or its concentration, and therefore the concentration of binding sites can increase in some tissues after long term treatment with cardiac glycosides. This might explain the occasionally observed tolerance to digitalis glycosides.

The effect of triamterene on myocardial phosphodiesterase and adenylate cyclase.

The study concerned the effect of triamterene (TA) and its phase-II metabolite p-hydroxytriamterene-sulphuric acid ester (OH-TA ester) on myocardial phosphodiesterase (PDE) and adenylate cyclase (AC): (1) TA and OH-TA ester exerted a concentration-dependent inhibition of PDE. The estimated IC50 values of 127 and 72 mumol/l were 16 and 9 times higher than that of papaverine with 8 mumol/l. At comparable concentrations, TA produced its inotropic effect (EC50 96 mumol/l) in isolated guinea-pig atria so that PDE inhibition may well account for its pharmacodynamic action. (2) In isolated guinea-pig atria, the cyclic AMP content increased significantly with 15-30 s after the addition of TA and remained increased over a period of 15 min. This increase preceded the positive inotropic action, which reached its maximum after 5-10 min. (3) TA did not affect the basal activity of myocardial AC preparations. AC activation by isoprenaline (30 mumol/l) was, however, strongly inhibited.

Characterization of antiarrhythmic drugs by alternating current induced arrhythmias in isolated heart tissues.

A new method for inducing arrhythmias or asystolia by the application of a 50 HZ alternating current (ac) to electrically driven heart preparations has been developed and applied to isolated left atria and right ventricular papillary muscles of the guinea-pig. An increase in driving frequency from 1 to 3 HZ effects a significant reduction of the threshold of ac-arrhythmia in guinea-pig papillary muscles but no change in atria. A decrease in temperature from 31 degrees C to 25 degrees C and an increase in [Ca2+]0 from 1.25 to 5 mmol/l elevates threshold for ac-arrhythmia and -asystolia. The fast sodium channel inhibitors quinidine, carticaine and benzylamino-5,6-dihydro-8,9-dimethoxy-imidazo-5,1-a-isoquinoline hydrochloride (HE-36) increase threshold of ac-arrhythmia in left atria and papillary muscles, whereas the slow channel inhibitor verapamil is ineffective in concentrations up to 6 mumol/l. Threshold of ac-arrhythmia is elevated by quinidine predominantly in papillary muscles. Carticaine and HE-36 are effective in left atria and papillary muscles to almost the same extent. Threshold of ac-asystolia is increased mainly in papillary muscles by quinidine and HE-36; carticaine produces a similar increase in left atria and papillary muscles. Verapamil even leads to a decrease in threshold predominantly in papillary muscles. It is concluded that model arrhythmias induced by alternating current are brought about mainly by an increase in Na+-conductance of cardiac cell membranes. The negative chronotropic potency in right atria occurs in the sequence verapamil greater than quinidine greater than carticane approximately HE-36. The negative inotropic potency in papillary muscle occurs in the same sequence but HE-36 increases force of contraction.

[Cardiovascular effects of (+)- and (-)-tranylcypromine compared to other monoamine oxidase inhibitors in animal studies (author's transl)]. / Tierexperimentelle Untersuchungen zur Kreislaufwirkung von (+)- und (-)-Tranylcypromin im Vergleich mit anderen Hemmstoffen der Monoaminoxydase.

The effect of (+)- and (-)-tranylcypromine (TCP), (-)-deprenyl and pargyline was tested and the interaction of these MAO inhibitors with tyramine and noradrenaline was compared on the circulation of the cat and on the isolated guinea-pig atria. 1. Anesthetised cats: An i.v. injection of 1 mg/kg of (+)- as well as (-)-TCP leads to an increase in the blood pressure and dp/dtmax. This effect is getting weaker on repeated doses. (-)-Deprenyl and pargyline decrease blood pressure and dp/dtmax. After a preadministration of (+)-TCP or pargyline the effect of tyramine on the blood pressure and contractility is prolonged. (-)-TCP prolongs slightly the cardiac effect of tyramine and is less effective than (+)-TCP. (-)-Deprenyl does not influence the effect of tyramine. The noradrenaline effect is not affected by the MAO-inhibitors. 2. Conscious cats: An i.v. injection of (+)- as well as (-)-TCP increases the blood pressure and decreases the heart rate. Desipramine (DMI) blocks this effect. Preadministration of (+)- as well as (-)-TCP and pargyline, but not (-)-deprenyl, potentiates the effect of tyramine on the blood pressure. According to this activity one can arrange these MAO-inhibitors as follows: (+)-TCP greater than (-)-TCP greater than pargyline. 3. Atrial preparations of guinea pigs: (+)- and (-)-TCP have a positive inotropic effect at concentrations from 10(-6) to 10(-5) mol/l, which is blocked by bupranolol and DMI. A pretreatment with reserpine prevents the effect of (-)- and weakens that of (+)-TCP. (+)-TCP, pargyline and (-)-deprenyl potentiate the effect of tyramine, while that of noradrenaline is potentiated by (+)- as well as (-)-TCP and (-)-deprenyl.

[The effect of the benzimidazole derivative AR-L 115 BS on the activities of myocardial adenylate cyclase and phosphodiesterase preparations (author's transl)]. / Zur Wirkung des Benzimidazol-Derivates AR-L 115 BS auf die myokardiale Adenylatcyclase und Phosphodiesterase.

The effect of benzimidazole derivative 2-[(2-methoxy-4-methylsulfinyl)phenyl]-1H-imidazol[4,5-b]pyridine (AR-L115 BS) on phosphodiesterase (PDE) and adenylate cyclase (AC) preparations from myocardial tissue was investigated in vitro. The following results were obtained: 1. AR-L 115 BS inhibits the PDE activity comparable to papaverine in a concentration-dependent and non-competitive way. Its inhibitory potency is about 40 times less if compared to papaverine since the Ki-values found are 315 and 7.9 mumol/l, respectively. The concentration of AR-L 115 BS producing a maximal positive inotropic effect on the isolated guinea-pig atrial preparation was shown to be 316 mumol/l, i.e., in the same concentration range as the biochemical findings. 2. The basal activity of myocardial AC preparations from reserpine pretreated guinea-pigs was not significantly altered in the presence of AR-L 115 BS concentrations ranging from 10 to 200 mumol/l. In contrast, the isoprenaline (1-100 mumol/l) stimulated AC was concentration-dependently inhibited already by 1 to 10 mumol/l AR-L 115 BS.

Effect of intracellular sodium on calcium uptake in isolated guinea-pig diaphragm and atria.

(1) Effects of cellular sodium on the 45Ca uptake of isolated guinea-pig diaphragm and atria were studied. (2) Cellular sodium and calcium contents were higher in diaphragm compared to atria after incubating the tissues in normal Krebs-Henseleit solution. (3) Cellular sodium content in atria and diaphragm were reduced significantly by incubating the tissues in high potassium Krebs-Henseleit solution (K+ = 34.7 mM), while it was increased by incubating the tissues in the ice-cold low potassium and low calcium Krebs-Henseleit solution (K+ = 0.65 mM, Ca2+ = 0.2 mM). Cellular potassium content was changed inversely to the sodium content. (4) In atria, cellular content of calcium was not altered significantly by the above conditions. But in diaphragm, the cellular content of calcium was decreased slightly but significantly after incubation in the ice-cold low potassium and low calcium Krebs-Henseleit solution. (5) At normal cellular sodium levels, the 45Ca uptake of both tissues was similar. (6) The reduction of the cellular sodium content caused a significant decrease in the 45Ca uptake in both tissues. (7) When the cellular sodium content was increased in atrial preparations, a marked increase in the 45Ca uptake was observed. On the other hand, in diaphragm preparations, only a slight increase was observed, even when cellular sodium content was much higher than the normal level. (8) These results indicate that even when the intracellular sodium is increased by some physiological of pharmacological events, calcium influx through Na+/Ca2+ exchange mechanism is very slight and slow in diaphragm.

Inotropic effects and Na+,K+-ATPase inhibition of ouabain in isolated guinea-pig atria and diaphragm.

Effects of ouabain on force of contraction were compared in electrically driven isolated tissue preparations of guinea-pig left atria and diaphragm. A distinct and steady positive inotropic effect of ouabain was observed in atrial preparations, whereas in diaphragm preparations, ouabain produced only a slight and transient positive inotropic effect, followed by the negative inotropic phase. The transient positive inotropic effect of ouabain was observed even in the absence of extracellular calcium, but was markedly dependent on the extracellular sodium concentration. In vitro [3H]ouabain binding studies revealed that the affinity of Na+,K+-ATPase for ouabain was about eight times higher and tissue concentration of the enzyme was significantly lower in diaphragm than in cardiac tissue. The Ki value for ouabain inhibition of the cardiac Na+,K+-ATPase was also approximately ten times higher than for the diaphragm enzyme. Ouabain-sensitive 86Rb uptake, an estimate of sodium pump activity, was inhibited by ouabain at a time when it produced its transient positive inotropic effect in diaphragm preparations. These results indicate that the lack of a distinct and steady positive inotropic effect of ouabain in diaphragm was due neither to the difference in the ouabain-Na+,K+-ATPase interaction between diaphragm and cardiac tissues nor the failure of sodium pump inhibition by ouabain in diaphragm.

Effects of vanadate on heart and circulation.

In anesthetized cats vanadate (Na3VO4) up to 0.5 mg/kg increased blood pressure and left ventricular end-diastolic pressure (LVEDP) but decreased the force of contraction and heart rate. At 1 mg/kg, LVEDP increased markedly in parallel with an elevation of the ST segment of the electrocardiogram and a pronounced decrease in blood pressure; these effects were reversible within a few minutes. In isolated Langendorff heart preparations of guinea pigs perfused at constant pressure, vanadate decreased flow rate (EC50 = 5.3 mumoles/liter) and contractile force (EC50 = 6.9 mumoles/liter). Vanadate increased tension in isolated aortic strips of cats (EC50 = 115 mumoles/liter) and rabbits (EC50 = 435 mumoles/liter). Vanadate also increased the force of isometric contractions of papillary muscles of guinea pigs, cats, and rabbits, the EC50 values being 124, 110, or 66 mumoles/liter, respectively. We conclude that the negative ionotropic action of vanadate is brought about by marked coronary constriction occurring at concentrations which are too low to have a direct positive action on ventricular myocardium.