In sheep cardiac Purkinje fibers concentration-dependent inhibition of transient outward current (ito) by 4-aminopyridine (4-AP, 3-1000 mumol/l) was recorded with the two-microelectrode voltage-clamp technique, and correlated effects on action potential duration measured at -70 mV (APD-70) were investigated. Half-maximal inhibition of ito-amplitude occurred at 15 mumol/l 4-AP. The drug exhibited no major effect on voltage-dependent control of inactivation but reduced the maximally available ito-current. At different activation frequencies (0.05 Hz, 0.25 Hz, 1 Hz) an equal amount of ito-current, measured as percentage of the respective control, was inhibited by 4-AP. The APD-70 was on the average increased by 4-AP (3-500 mumol/l) in a concentration-dependent manner up to 151% of control. The drug-induced prolongation, measured as percentage of the respective control, was independent of stimulation frequency (0.05 Hz, 0.25 Hz, 1 Hz). Prolongation of APD-70 was on the average more pronounced for short action potentials (APD-70 < 150 ms: 169% of reference) than for longer ones (APD-70 150-300 ms: prolongation to 117% of reference; 500 mumol/l 4-AP; 0.25 Hz stimulation rate). Few long control signals (APD-70 > 300 ms) were shortened by 4-AP. These results indicate that inhibition of ito-current by appropriate drugs will result in a reduction of inhomogeneity of action potential duration.

4-Aminopyridine↗

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[Quantitative evaluation of cardioactive drugs using computer analysis of the ventricular pressure curve during isovolumetric contraction (author's transl)].

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Animals↗

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Influence of vanadate on electrophysiological and contractile parameters of atrial myocardium.

Whereas vanadate increases isometric force of contraction in stimulated rat left atria (EC50: 36.6 mumol/1), it decreases force of contraction in guinea-pigs (EC50: 4.7 mumol/1). Action potential duration at 90 and 30% repolarisation is decreased in guinea-pig atria by 70 and 60%, but in rat atria by only 40 and 7% respectively. Whereas the time course of the negative inotropic action is rapid and correlates with that of the shortening of the action potential, there is no relationship between action potential changes and the slowly developing positive intropic effect. Negative and positive inotropic actions seem to be the result of two superimposed processes, whose kinetics suggest an extra- and intracellular site of action. Na+, K+-ATPase prepared from rat and guinea-pig atria and ventricle is inhibited by vanadate to a similar extent: IC50 (mumol/1) rat: atria 1.05, ventricle 0.49; guinea-pig: atria 0.75, ventricle 0.62. This indicates that the discrepancy in inotropy cannot be explained by the different sensitivity of the Na+, K+-ATPase to vanadate.

Action Potentials↗

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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.

Animals↗

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Effect of flecainide on action potentials and alternating current-induced arrhythmias in mammalian myocardium.

The new antiarrhythmic drug flecainide (2,5-bis-(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl) benzamide acetate) increases action potential duration at 30 and 90% repolarization, and functional refractory period in guinea pig papillary muscle up to 10 mumol/L, but shortens the action potential and decreases its amplitude at 30 mumol/L, without significant change in resting potential. 10 mumol/L flecainide decreases maximal upstroke velocity (Vmax) by about 40% at a stimulation rate of 1 Hz, whereas at 0.017 Hz Vmax remains nearly unchanged (use-dependence). Flecainide delays recovery from inactivation of the fast-sodium channels. Its potential-dependent action on Vmax is demonstrated by a shift to more negative potentials of the membrane responsiveness curve and of the curve that relates membrane potential to Vmax in K+ depolarized papillary muscles driven at 0.017 Hz (h infinity -curve). Flecainide increases threshold of alternating current-induced arrhythmia and asystole in left atria and papillary muscles to a similar extent, and in this respect resembles the local anesthetics. Force of contraction of atrial and ventricular myocardium is significantly decreased at greater than or equal to 10 mumol/L flecainide, and frequency of spontaneously beating right atria at greater than or equal to 0.3 mumol/L. The results indicate that the predominant action of flecainide consists of a potent inhibition of cardiac fast sodium channels.

Action Potentials↗

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Effects of vanadate on isolated vascular tissue: biochemical and functional investigations.

Vanadate is a potent inhibitor of Na+,K+-ATPase derived from bovine aorta. The Ca2+, Mg2+-ATPase of the same preparation was inhibited at 10 times higher concentrations. Compared with [3H]ouabain, 48V bound quickly to bovine aortic microsomes. Equilibrium binding experiments revealed one high-affinity, low-capacity and one low-affinity binding site for 48V, whereas [3H]ouabain possessed only one binding site of high affinity. A high NADH-vanadate reductase activity was measured in the same preparation, suggesting that, in this tissue, vanadate may be converted to vanadyl, a form to which the Na+,K+-ATPase is relatively insensitive. An increase in the contractile force of isolated rabbit aorta was measured with the following potency: phenylephrine greater than ouabain greater than vanadate. The order in intrinsic activity was as follows: phenylephrine congruent to ouabain greater than vanadate. The action of vanadate was rapid in onset and stable over several hours, while that of ouabain was slow and transitory. Vanadate increased tension in isolated rabbit veins to an extent similar to phenylephrine, but at concentrations two orders of magnitude higher. Vanadate action decreased with decreasing (Ca2+)0, but remained constant at a constant ratio of (Ca2+)0/(Na+)2(0). Vanadate-induced increases in tension were decreased by verapamil by about 43% and persisted in a solution in which Na+ was replaced by Li+. Vanadate increased electrically stimulated contractions. It is concluded that most of the effect of vanadate is due to an increase in calcium influx into the smooth muscle cell and that the effect of vanadate on Na+,Ca2+ exchange is of minor importance.

Animals↗