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Biomedical subjects

A Fleckenstein

Publications and source records attributed to A Fleckenstein.

At least 55 records · Page 3Linked to original sources
PubMed1979

[Comparative studies on the basic Ca2+ antagonistic activities of niludipine (Bay a 7168) and nifedipine (Bay a 1040) on the myocardium, myometrium and vessels of smooth muscles (author's transl)].

Niludipine (bis(2-propoxyethyl)1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicarboxylate; Bay a 7168) with respect to its specific actions on mammalian myocardium, sino-auricular or atrio-ventricular pacemakers, myometrium, and vascular smooth muscle has to be considered one of the most potent representatives of the new group of calcium antagonists. The pharmacodynamic effects of niludipine strikingly resemble those of nifedipine both qualitatively and quantitatively. Interestingly enough, niludipine is also a powerful coronary vasodilator. This is made particularly evident by the present experiments on potassium- or glycoside-contractured smooth musculature originating from large extramural coronary stem arteries.

Action Potentials↗
PubMed1977

Inhibition of the slow inward current by nifedipine in mammalian ventricular myocardium.

In order to elucidate the mode of action of the Ca2+-antagonistic inhibitor nifedipine, its effect on Ca2+-mediated action potentials and transmembrane slow inward current in papillary muscles of guinea pigs and cats was studied. Nifedipine (0.5 mg/1 approximately 1.4 X 10(-6) M) depressed upstroke velocity and overshoot of the Ca2+-mediated action potential and reduced the transmembrane slow inward current by about 50%, but the kinetics of inactivation and recovery from inactivation were not affected. The decrease of upstroke velocity was accompanied by a proportional diminution of isometric contractile force. This indicates that nifedipine exerts its Ca2+-antagonistic effect on excitation-contraction coupling in mammalian ventricular myocardium by inhibition of the transmembrane Ca2+ inward current. The inhibitory action of nifedipine on contractile tension development could be neutralized by an augmentation of the extracellular Ca2+ concentration from 2 mM to 4 mM or by beta-receptor stimulation (isoproterenol) that promotes the transmembrane Ca2+ uptake during excitation. Simultaneously, in the Ca2+-rich medium or under the influence of isoproterenol the upstroke velocity of the Ca2+-mediated action potentials rose even above the initial values which were measured prior to the nifedipine administration.

Action Potentials↗
PubMed1977

[Mechanism of the cardioprotective effect of triamterene in the rat heart. Myocardial protection via elevation of extracellular K+ and Mg++ concentrations].

1. 2,4,7-Triamino-6-phenyl-pteridine (triamterene) protects the rat heart against isoproterenol-induced myocardial lesions: Whilst cardiotoxic doses of isoproterenol produce deleterious myocardial Ca overload, simultaneous admistration of triamterene diminishes myocardial Ca incorporation considerably. 2. As to the mechanism of action, triamterene increases the plasma contents of K and Mg by inhibiting renal excretion. Accordingly, oral administration of K and Mg salts, leading to a similar rise in the K and Mg concentrations of the plasma, also prevents abundant myocardial Ca incorporation. 3. Cardioprotection by triamterene can, in fact, be simply explained by its action on the plasma K and (particularly) Mg levels. This conclusion is drawn from a quantitative comparison of the inhibitory effects of triamterene (40 mg/kg s.c.) with those of KCl or MgCl2 (10 mMol/kg p.o.) on the isoproterenol-induced increase in myocardial 45Ca uptake and absolute Ca concentration. 4. Isoproterenol induced cardiomyopathy of the rat, an experimental model of non-coronarogenic myocardial lesions, has hitherto been successfully prevented with the use of Ca-antagonists (verapamil, D 600, prenylamine, fendiline). These compounds reduce Ca influx by restricting the Ca conductivity of the myocardial sarcolemma membrane ("slow channel"). The action of triamterene, on the other hand, is based on a totally different cardioprotective principle, namely competitive inhibition of intracellular myocardial Ca accumulation via an increase in K and Mg supply. In the future treatment of cardiomyopathy it seems rather promising to try a combination of both a Ca-antagonist and triamterene, thus applying two different therapeutic principles simultaneously.

Animals↗
PubMed1977

[Combined therapy with glycosides and Ca++-antagonistic agents (author's transl)].

Ca-antagonistic drugs increase cardiac oxygen supply by a coronary vasodilator action whilst they simultaneously lower myocardial oxygen demand. The latter drug effect is due to a decrease in cardiac contractile energy expenditure both directly (restriction of myocardial contractility) and indirectly (reduction of arterial blood pressure resulting from systemic vasodilation). In coronary disease all these factors can contribute to an improvement of the disturbed myocardial energy balance. As to the coronary vasodilator action of Ca-antagonistic drugs in particular, it is important to note that they readily relax the smooth musculature of the major extramural stem arteries where most of the occlusive atherosclerotic intima processes (about 95%) are located. In contrast, other coronary vasodilators such as adenosine, dipyridamole, chromonar, lidoflazine, theophylline, which lack Ca-antagonistic properties, are primarily acting on the small intramural resistance vessels of the heart whereas vascular smooth musculature originating from the major extramural arteries is less affected. Therefore, in elderly atherosclerotic patients the possible risk of glycoside-induced vasoconstriction in extramural coronary stem arteries (and also in arteries of systemic circulation) can be sufficiently eliminated only with the help of Ca-antagonists.

Animals↗
PubMed1975

[The calcium-antagonistic fundamental effects of Verapamil on myocardial fibers and smooth muscle cells of the blood vessels].

Ca ions regulate the amount of ATP which is metabolized in the contractile system to produce mechanical energy. Since the consumption of ATP quantitatively determines the myocardial respiration rate, oxygen consumption is also Ca-dependent. Therefore, Ca-antagonistic compounds such as verapamil, D600 or nifedipine, by reducing the Ca supply to the beating heart, not only restrict ATP breakdown and mechanical activity but also myocardial oxygen demand. Moreover, Ca-antagonistic drugs lower the tone of vascular smooth muscle. This action leads to coronary vasodilation and a reduction in heart load because the peripheral vascular resistance is also diminished. All these factors contribute to an improvement of the cardiac energy balance in patients with coronary disease.

Adenosine Triphosphate↗
PubMed1975

[Key-role of intracellular calcium overload in acute necrosis of the myocardium. Cardioprotection with verapamil].

Ca ions are highly cardiotoxic if their influx into the myocardial fibres becomes abundant. The intracellular Ca overload initiates a deleterious high-energy phosphate deficiency by excessive activation of Ca-dependent intracellular ATPases and by impairing the phosphorylating capacity of mitochondria. This Ca-induced high-energy phosphate exhaustion is a crucial point in the etiology of the myocardial fibre necroses produced in rats by large doses of beta-adrenergic catecholamines, particularly isoproterenol, or by a number of other cardiotoxic agents. Accordinly, the myocardium is sensitized to necrotization by factors which favour Ca overload (dihydrotachysterol, 9alpha-flourocortisol acetate, NaH2PO4). Conversely, the structural integrity of the hearts can be protected by any substance or procedure which prevents an excessive intracellular Ca accumulation, particularly by inhibitors of the transmembrane Ca influx, such as verapamil, D 600 or prenylamine.

Adenosine Triphosphate↗
PubMed1975

[Calcium-antagonism, a new principle in coronary vasodilation].

As in all other vessels, coronary contractile tone depends on the availability of Ca ions. Thus, Ca-antagonistic drugs such as verapamil, prenylamine or nifedipine produce a loss of muscle tone in depolarized coronary strips. One molecule of these compounds successfully blocks the action of thousands of Ca ions in excitation-contraction coupling. Nitroglycerine and other nitrites exert a similar action, though in their case relaxation is more rapid, incomplete and spontaneously reversible. In analogy to their well-known Ca-synergistic action on heart muscle fibres, cardiac glycosides are also capable of increasing the coronary vascular tone even in very low concentrations. If, however, suitable doses of Ca-antagonistic compounds are simultaneously administered, the hearts are protected against this unpleasant coronary side effect without an appreciable loss of the inotropic glycoside action on the myocardium.

Animals↗
PubMed1975

Inhibition of calcium-dependent action potentials in mammalian myocardium by specific inhibitors of the transmembrane calcium conductivity (verapamil, D 600).

Cat papillary muscles were depolarized from about -80 mV to -50 mV by addition of KCl to Tyrode's solution. This causes an inactivation of the Na-carrying system so that the remaining transmembrane inward current is due, in practice, to Ca. Such action potentials show a reduced rate of rise, a greater overshoot, and a shorter duration. These parameters vary somewhat with the strength of stimulation and, particularly, with frequency. Excitability as well as contractility of the K-depolarized fibers are completely abolished by Ca withdrawal or by addition of verapamil or D 600, which block the transmembrane Ca inward current specifically. Conversely, extra Ca or epinephrine overcomes the verapamil and C 600 effects by increasing the transmembrane Ca influx. As soon as the papillary muscles are returned to Tyrode's solution with normal K0 the Na-carrying system is reactivated. Then Ca withdrawal or Ca-antagonistic compounds lose their inhibitory influence on excitation, whereas excitation-contraction uncoupling persists.

Action Potentials↗
PubMed1975

Restriction of isoproterenol-induced myocardial Ca uptake and necrotization in rats by a new Ca-antagonistic compound (ethyl-4-(3,4,5-trimethoxycinnamoyl) piperazinyl acetate (Vascordil)).

As shown in previous investigations overdoses of isoproterenol produce an abundant myocardial Ca uptake, followed by high energy phosphate breakdown, mitochondrial damage and, eventually, cardiac fibre necrotization. Conversely Ca antagonistic compounds such as verapamil, D 600 or prenylamine which reduce the transmembrane Ca influx into the heart muscle cells, can prevent high energy phosphate deficiency and cardiac lesions. Ethyl-4-(3,4,5-trimethoxycinnamoyl) poperazinyl acetate (Vascoril) is another compound which, according to our tracer studies, interferes with transmembrane Ca uptake into the myocardium. As expected the rat hearts were also protected by Vascoril against isoproterenol-induced metabolic disorders and structural alterations. Equiprotective subcutaneous doses, as studied on the right ventricular myocardium of rats, were 600 mg/kg Vascoril, 250 mg/kg prenylamine, 17 mg/kg verapamil or 10 mg/kg D 600.

Animals↗