Summary
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1.
In trabecular muscles obtained from the right ventricle of untreated dogs 4-aminopyridine (4-AP) (0.1–10 mM) increased the force of contraction elicited by electrical driving at 0.5 Hz.
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2.
This effect was associated with increases in mean velocities of force development and relaxation. The time to peak force was not changed by 4-AP and the relaxation time was increased by 3 and 10 mM 4-AP.
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3.
In ventricular muscles treated with the β-adrenoceptor blocking agent, pindolol, or in those obtained from dogs pretreated with reserpine the positive inotropic effect was reduced.
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4.
In such muscles 4-AP scarcely increased the mean velocity of force development and slightly increased the time to peak force. Marked prolongation of the relaxation time and a decrease in mean velocity of relaxation were characteristic of isometric contractions of such muscles in the presence of 4-AP.
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5.
These results indicate that the positive inotropic effect of 4-AP is sum of two effects, one being due to the release of endogenous catecholamines and the other to a possible direct action on cardiac muscle.
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6.
In muscles treated with pindolol or those obtained from dogs pretreated with reserpine 10 mM 4-AP elevated the resting force.
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7.
These observations suggest that 4-AP causes a persisting elevation of cytosolic Ca2+ in cardiac muscle cells.
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8.
In pindolol-treated muscles 4-AP prolonged the action potential duration. However, the prolongation of the action potential duration produced by 4-AP was much smaller than that of the relaxation time. Even with 10 mM 4-AP the resting membrane potential remained unchanged.
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9.
The above results suggest that the effects of 4-AP on the contraction and resting force of ventricular muscle may not be secondary to the effect on the transmembrane potential.
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10.
All the results taken together suggest that the primary action of 4-AP on ventricular muscle may not be to allow increased or prolonged entry of extracellular Ca2+ but rather may be either to promote the release of Ca2+ from intracellular binding or storage sites or to slow the binding of Ca2+ to intracellular structures. The prolongation of the action potential duration may be a consequence of change in calcium binding to the plasma membrane.
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Yanagisawa, T., Taira, N. Positive inotropic effect of 4-aminopyridine on dog ventricular muscle. Naunyn-Schmiedeberg's Arch. Pharmacol. 307, 207–212 (1979). https://doi.org/10.1007/BF00505935
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DOI: https://doi.org/10.1007/BF00505935