Comparison of Pharmacological Actions of Verapamil and Papaverine in Isolated Rat Papillary Muscle

On the Different Mechanism for their Calcium Ion Channel Inhibition

Abstract

Electrical stimulation with twice the threshold intensity and a duration of 10 msec was given to an isolated rat papillary muscle at a frequency of 1 Hz, and the influences of diltiazem, verapamil, papaverine, isoproterenol, adrenaline and noradrenaline were examined on contractile tension, contraction velocity and relaxation velocity of the muscle.
1) When the muscle was kept in a modified Locke's solution in which the CaCl2 was reduced from 1.6 to 0.8 mM, i. e., in a low Ca²⁺ medium, each of contractile tension, contraction velocity and relaxation velocity decreased: the degree of the decrease in contractile tension was greatest, that in contraction velocity was second and that in relaxation velocity was smallest. When the muscle was kept in a high Ca²⁺ medium in which the CaCl2 was contained in a concentration of 3.2 or 6.4 mM, each of the tension and velocities increased: the greatests were those of contraction and relaxation velocities and the smallest was that of contractile tension.
2) Each o f isoproterenol (0.01 to 0.1 mg/l), adrenaline (0.1 to 10 mg/l) or noradrenaline (0.1 to 6.0 mg/l) increased contractile tension, contraction velocity and relaxation velocity: the increase in contraction and relaxation velocity was remarked. The effect of the drugs on the muscle which was kept in the low Ca²⁺ medium was less than that on the muscle kept in a standard Locke's solution, and the effect was scarcely increased, also, even when the muscle was kept in the high Ca²⁺ medium.
3) Diltiazem (0.1 to 1.0 mg/l) or verapamil (0.001 to 0.1 mg/l) decreased each of contractile tension, contraction velocity and relaxation velocity of the muscle: the mode of the inhibitory action of the drugs resembled each change of them which was seen when the muscle was kept in the low Ca²⁺ medium without any drug. In the presence of calcium antagonists, the addition of CaCl₂ to the medium caused a more remarkable increase in contractile tension, contraction velocity and relaxation velocity than the addition of isoproterenol.
4 ) Papaverine (0.1 mg/l) decreased contractile tension of the muscle, while increased the contraction and relaxation velocities. However, the drug (10 mg/l) increased all of them: the increase in the contraction and relaxation velocities resembled the increase induced by the high Ca²⁺ medium without any drug.
5) The increase in contractile tension, contraction velocity and relaxation velocity induced by the high Ca²⁺ medium was suppressed by the presence of papaverine (10 mg/l), and the increase in contractile tension induced by isoproterenol (0.01 mg/l), also, was suppressed by the presence of papaverine (0.01 mg/l).
From the results, it is presumed that there are two kinds of Ca²⁺ channels in the plasma membrane of papillary muscle: one is a channel which is voltage dependent and the other is a channel which is activated by Ca²⁺-calmodulin dependent proteinkinase (in an evironment in which the concentration of Ca²⁺ is excess) or by cyclic AMP dependent proteinkinase (in the presence of isoproterenol or another adrenergic,β-stimulant). The former voltage dependent channel is thought to be a main Ca²⁺ channel through sarcoplasmic membrane and to be modified by the latter channel activated by these proteinkinases. The contractile tension, contraction velocity and relaxation velocity are influenced by calcium ion concentration in the medium, while the velocities are considered to be influenced by cyclic AMP level which controls calcium concentration in an intracellular fluid.